This report contains the collective views of an international group of
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    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    First draft prepared by Dr. R.F. Hertel,
    Dr. T. Maass and Ms V.R. Muller,
    Fraunhofer Institute of Toxicology and Aerosol Research, Germany

    World Health Orgnization
    Geneva, 1991

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    WHO Library Cataloguing in Publication Data


        (Environmental health criteria ; 108)

        1.Nickel-adverse effects 2.Nickel-toxicity 3.Environmental exposure 

        ISBN 92 4 157108 X        (NLM Classification: QV 290)
        ISSN 0250-863X

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    1.1.  Identity, physical and chemical properties, and 
          analytical methods   
    1.2. Sources of human and environmental exposure   
    1.3. Environmental transport, distribution, and transformation      
    1.4. Environmental levels and human exposure   
    1.5. Kinetics and metabolism in human beings and animals      
    1.6. Effects on organisms in the environment   
    1.7. Effects on experimental animals and  in vitro test systems
    1.8. Effects on human beings   

    2.1. Identity, physical and chemical properties of nickel and 
          nickel compounds   
          2.1.1. Nickel carbonate hydroxide 
          2.1.2. Nickel carbonyl
          2.1.3. Nickel chloride and nickel chloride hexahydrate
          2.1.4. Nickel hydroxide
          2.1.5. Nickel nitrate
          2.1.6. Nickel oxide 
          2.1.7. Nickel sulfate 
          2.1.8. Nickel sulfide 
          2.1.9. Nickel subsulfide 
    2.2. Analytical methods   
          2.2.1. Determination of trace amounts   
          2.2.2. Sample collection   
          2.2.3. Sample pretreatment   
          2.2.4. Analytical methods   

    3.1. Natural occurrence   
          3.1.1. Rocks      
          3.1.2. Soils   
          3.1.3. Water      
          3.1.4. Fossil fuels   
          3.1.5. Air      
    3.2. Man-made sources   
          3.2.1. Production, use, and disposal   
           Primary production   
           Intermediate products and end-use   
           World production levels and trends   
           Emissions from the primary nickel 
           Emissions from the intermediate nickel 
           Emissions from the combustion of fossil
           Emissions from sewage sludge and waste 
           Miscellaneous emission sources   
           Waste disposal   

    4.1. Transport and distribution between media   
          4.1.1. Air      
          4.1.2. Water      
          4.1.3. Rocks and soil   
          4.1.4. Vegetation and wildlife   
    4.2. Uptake and bioaccumulation   
          4.2.1. Terrestrial organisms   
          4.2.2. Aquatic organisms   
    4.3. Biomagnification   

    5.1. Environmental levels   
          5.1.1. Air      
          5.1.2. Drinking-water   
          5.1.3. Food      
          5.1.4. Terrestrial and aquatic organisms
    5.2. General population exposure   
          5.2.1. Oral      
          5.2.2. Inhalation   
          5.2.3. Dermal      
    5.3. Iatrogenic exposure
    5.4. Occupational exposure   

    6.1. Absorption      
          6.1.1. Absorption via the respiratory tract   
           Particulate nickel   
           Nickel carbonyl   
          6.1.2. Absorption via the gastrointestinal tract   
           Experimental animals   
           Human beings   
           Factors influencing gastrointestinal 
          6.1.3. Absorption through the skin   
           Experimental animals   
           Human beings   
          6.1.4. Other routes of absorption   
           Experimental animals   
           Human beings   
          6.1.5. Transplacental transfer   
           Experimental animals   
           Human beings   
          6.1.6. Nickel carbonyl   
    6.2. Distribution, retention, and elimination   
          6.2.1. Transport
          6.2.2. Tissue distribution
           Experimental animals
           Kinetics of metabolism
           Nickel carbonyl
           Nickel levels in human beings
           Pathological states influencing nickel 
    6.3. Elimination and excretion
          6.3.1. Experimental animals
          6.3.2. Human beings

    7.1. Microorganisms
    7.2. Aquatic algae and plants
    7.3. Aquatic invertebrates
    7.4. Fish
    7.5. Terrestrial organisms
          7.5.1. Plants
          7.5.2. Animals
          7.5.3. Essentiality of nickel for bacteria and plants
    7.6. Population and ecosystem effects

    8.1. Animals 
          8.1.1. Essentiality      
           Nickel deficiency symptoms      
          8.1.2. Acute exposures
           Nickel carbonyl
           Other nickel compounds
           Possible mechanisms of acute nickel 
          8.1.3. Short- and long-term exposures      
           Effects on the respiratory tract
          8.1.4. Relationship of nickel toxicity and mixed metal 
          8.1.5. Endocrine effects
          8.1.6. Cardiovascular effects
          8.1.7. Effects on the immune system
          8.1.8. Skin and eye irritation and contact hypersensitivity
           Skin and eye irritation
           Contact hypersensitivity
          8.1.9. Reproduction, embryotoxicity, and teratogenicity
           Effects on the male reproductive system
           Effects on the female reproductive system
          8.1.10. Embryotoxicity and teratogenicity
    8.2. Mutagenicity and related end-points
          8.2.1. Mutagenesis in bacteria and mammalian cells
          8.2.2. Chromosomal aberration and sister chromatid 
                  exchange (SCE)      
          8.2.3. Mammalian cell transformation
    8.3. Other test systems
    8.4. Carcinogenicity
          8.4.1. Inhalation
          8.4.2. Oral 
          8.4.3. Other routes
          8.4.4. Interactions with known carcinogens
          8.4.5. Possible mechanisms of nickel carcinogenesis
          8.4.6. Factors influencing nickel carcinogenesis

    9.1. Systemic effects
          9.1.1. Acute toxicity - poisoning incidents
           Nickel carbonyl
           Other nickel compounds

          9.1.2. Short- and long-term exposure
           Respiratory effects
           Renal effects
           Cardiovascular effects
           Other effects
    9.2. Skin and eye irritation and contact hypersensitivity
          9.2.1. Skin and eye irritancy
          9.2.2. Contact hypersensitivity
    9.3. Reproduction, embryotoxicity and teratogenicity
    9.4. Genetic effects in exposed workers
    9.5. Carcinogenicity   
          9.5.1. Epidemiological studies
           Nickel refining industry
           Nickel alloy manufacturing
           Nickel plating industry
           Nickel powder
           Nickel-cadmium battery manufacturing      
           Case-control studies
          9.5.2. Carcinogenicity of metal alloys in orthopaedic 

     10.1. Exposure         
     10.2. Human health effects      
     10.3. Environmental effects      








Professor D.A. Calamari, Institute of Agricultural Entomology, 
University of Milan, Milan, Italy 

Dr R.F. Hertel, Fraunhofer Institute of Toxicology and Aerosol 
Research (ITA), Hanover, Germany  (Rapporteur) 

Professor S.M. Hopfer, University of Connecticut School of 
Medicine, Farmington, Connecticut, USA 

Professor B.A. Katsnelson, Occupational Health Research 
Institute, Sverdlovsk, USSR 

Professor Yasushi Kodama, Department of Environmental Health, 
School of Medicine, University of Occupational and Environmental 
Health, Kitakyushu City, Japan 

Professor V. Yu. Kogan, Occupational Health Research Institute, 
Erevan, USSR  (Vice-Chairman) 

Ms V.R. Müller, Fraunhofer Institute of Toxicology and Aerosol 
Research (ITA), Hanover, Germany 

Dr G.D. Nielsen, Department of Environmental Medicine, Odense 
University, Odense, Denmark 

Professor T. Norseth, National Institute of Occupational Health, 
Oslo, Norway  (Chairman) 

Dr J. Pastuszka, Institute of Environmental Protection, Katowice, 

Professor J. Peto, Section of Epidemiology, Institute of Cancer 
Research, Belmont, Surrey, United Kingdom 

Dr E.A. Soyombo, Environmental and Occupational Health Division, 
Federal Ministry of Health, Lagos, Nigeria 

Dr S.H.H. Swierenga, Genetic Toxicology Section, Bureau of Drug 
Research, Health Protection Branch, Health and Welfare Canada, 
Tunney's Pasture, Ottawa, Ontario, Canada 

Dr A.P. Tossavainen, Institute of Occupational Health, Helsinki, 

 Representatives of nongovernmental organizations

Professor N. Izmerov, Institute of Industrial Hygiene and 
Occupational Diseases, Moscow, USSR, representing the International 
Commission on Occupational Health (ICOH) 


Professor A. Horie, Department of Environmental Health, School of 
Medicine, University of Occupational and Environmental Health, 
Kitakyushu City, Japan 

Dr J. Ishmael, Central Toxicology Laboratory, ICI plc, 
Macclesfield, Cheshire, United Kingdom 

Professor M.I. Mikheev, Institute for Advanced Medical Studies, 
Leningrad, USSR 

Dr L.G. Morgan, INCO Europe Limited, Swansea, United Kingdom 

Dr M. Richold, Unilever Research, Colworth Laboratory, Bedford, 
United Kingdom 

Professor A.V. Roscin, Central Institute for Advanced Medical 
Studies, Moscow, USSR 


Dr A. Aitio, International Agency for Research on Cancer, Lyon, 

Dr E. Smith, International Programme on Chemical Safety, Division 
of Environmental Health, World Health Organization, Geneva, 


    Every effort has been made to present information in the 
criteria documents as accurately as possible without unduly 
delaying their publication.  In the interest of all users of the 
environmental health criteria documents, readers are kindly 
requested to communicate any errors that may have occurred to the 
Manager of the International Programme on Chemical Safety, World 
Health Organization, Geneva, Switzerland, in order that they may be 
included in corrigenda, which will appear in subsequent volumes. 

                         *    *    *

    A detailed data profile and a legal file can be obtained from  
the International Register of Potentially Toxic Chemicals, Palais 
des Nations, 1211 Geneva 10, Switzerland (Telephone no. 


    A WHO Task Group on Environmental Health Criteria for Nickel 
met at the Leningradskaya Hotel, Moscow, USSR, from 17 to 21 April 
1989, under the auspices of the USSR State Committee for 
Environmental Protection, Centre for International Projects.  Dr 
S.N. Morozov welcomed the participants on behalf of the host 
institution and Dr E. Smith opened the meeting on behalf of the 
three cooperating organizations of the IPCS (ILO/UNEP/WHO).  The 
Task Group reviewed and revised the draft criteria document and 
made an evaluation of the health risks of exposure to nickel. 

    The first draft of this document was prepared by Dr R.F. 
Hertel, Dr J. Maass, and Ms V. Müller, Fraunhofer Institute of 
Toxicology and Aerosol Research, Hanover, Germany.  This draft was 
reviewed in the light of international comments by a Working Group 
comprising Dr V. Bencko, Prague, Czechoslovakia, Dr M. Piscator, 
Stockholm, Sweden, and Dr F.W. Sunderman, Farmington, Connecticut, 
USA, with the assistance of Dr R.F. Hertel, Ms V. Müller and Dr G. 
Rosner.  The revised draft resulting from this Working Group was 
submitted for the Task Group review.  Dr E. Smith, IPCS Central 
Unit, was responsible for the overall scientific content of the 
document and for the organization of the meetings, and Mrs M.O. 
Head of Oxford, England, was responsible for the editing. 

    The efforts of all who helped in the preparation and 
finalization of the document are gratefully acknowledged. 

                       *  *  *

    Financial support for the Task Group was provided by the United 
Nations Environment Programme, through the USSR Commission for 
UNEP.  Partial financial support for the publication of this 
criteria document was kindly provided by the United States 
Department of Health and Human Services, through a contract from 
the National Institute of Environmental Health Sciences, Research 
Triangle Park, North Carolina, USA, a WHO Collaborating Centre for 
Environmental Health Effects. 


1.1.  Identity, physical and chemical properties, and analytical

    Nickel is a metallic element belonging to group VIIIb of the 
periodic table.  It is resistant to alkalis, but generally 
dissolves in dilute oxidizing acids.  Nickel carbonate, nickel 
sulfide, and nickel oxide are insoluble in water, whereas nickel 
chloride, nickel sulfate, and nickel nitrate are water soluble.  
Nickel carbonyl is a volatile colourless liquid that decomposes at 
temperatures above 50 °C.  The prevalent ionic form is nickel (II).  
In biological systems, dissolved nickel may form complex components 
with various ligands and bind to organic material. 

    The most commonly used methods for the analysis of biological 
and environmental materials are atomic absorption spectroscopy and 
voltammetry.  In order to obtain reliable results, especially in 
the ultratrace range, specific procedures have to be followed to 
minimize the risk of contamination during sample collection, 
storage, processing, and analysis.  Depending on sample 
pretreatment, extraction and enrichment procedures, detection 
limits of 1-100 ng/litre can be achieved in biological materials 
and water. 

1.2.  Sources of human and environmental exposure

    Nickel is a ubiquitous trace metal and occurs in soil, water, 
air, and in the biosphere.  The average content in the earth's 
crust is about 0.008%.  Farm soils contain between 3 and 1000 mg 
nickel/kg.  Levels in natural waters have been found to range from 
2 to 10 µg/litre (fresh water) and from 0.2 to 0.7 µg/litre
(marine).  Atmospheric nickel concentrations in remote areas range 
from <0.1 to 3 ng/m3. 

    Nickel ore deposits are accumulations of nickel sulfide 
minerals (mostly pentlandite) and laterites.  Nickel is extracted 
from the mined ore by pyro- and hydro-metallurgical refining 
processes.  Most of the nickel is used for the production of 
stainless steel and other nickel alloys with high corrosion and 
temperature resistance.  Nickel alloys and nickel platings are used 
in vehicles, processing machinery, armaments, tools, electrical 
equipment, household appliances, and coinage.  Nickel compounds are 
also used as catalysts, pigments, and in batteries.  Global mining 
production of nickel was approximately 67 million kg in 1985.  The 
primary sources of nickel emissions into the ambient air are the 
combustion of coal and oil for heat or power generation, the 
incineration of waste and sewage sludge, nickel mining and primary 
production, steel manufacture, electroplating, and miscellaneous 
sources, such as cement manufacturing.  In polluted air, the 
predominant nickel compounds appear to be nickel sulfate, oxides, 
and sulfides, and to a lesser extent, metallic nickel. 

    Nickel from various industrial processes and other sources 
finally reaches waste water.  Residues from waste-water treatment 

are disposed of by deep well injection, ocean dumping, land 
treatment, and incineration.  Effluents from waste-water treatment 
plants have been reported to contain up to 0.2 mg nickel/litre. 

1.3  Environmental transport, distribution, and transformation

    Nickel, which is emitted into the environment from both natural 
and man-made sources, is circulated throughout all environmental 
compartments by means of chemical and physical processes, and is 
biologically transported by living organisms. 

    Atmospheric nickel is considered to exist mainly in the form of 
particulate aerosols containing different concentrations of nickel, 
depending on the source.  The highest nickel concentrations in 
ambient air are usually found in the smallest particles.  Nickel 
carbonyl is unstable in air and decomposes to form nickel oxide. 

    The transport and distribution of nickel particles to, or 
between, different environmental compartments is strongly 
influenced by particle size and meteorological conditions.  
Particle size distribution is primarily a function of the emitting 
sources.  In general, particles from man-made sources are smaller 
than natural dust particles. 

    Nickel is introduced into the hydrosphere by removal from the 
atmosphere, by surface run-off, by discharge of industrial and 
municipal waste, and also following natural erosion of soils and 
rocks.  In rivers, nickel is mainly transported in the form of a 
precipitated coating on particles and in association with organic 
matter; in lakes, it is transported in the ionic form, also mainly 
in association with organic matter.  Nickel may also be absorbed on 
to clay particles and via uptake by biota.  Absorption processes 
may be reversed leading to release of nickel from the sediment.  
Part of the nickel is transported via rivers and streams to the 
ocean.  Riverine suspended particulate input is estimated to be 135 
x 107 kg/year. 

    Depending on the soil type, nickel may exhibit a high mobility 
within the soil profile finally reaching ground water and, thus, 
rivers and lakes.  Acid rain has a pronounced tendency to mobilize 
nickel from the soil.  Terrestrial plants take up nickel from soil 
primarily via the roots.  The amount of nickel uptake from soil 
depends on various geochemical and physical parameters including 
the type of soil, the soil pH and humidity, the organic matter 
content of the soil, and the concentration of extractable nickel.  
The best known example of nickel accumulation is the increased 
nickel levels, in excess of 1 mg/kg dry weight, found in a number 
of plant species ("hyperaccumulators") growing on relatively 
infertile serpentine soils.  Nickel levels above 50 mg/kg dry 
weight are toxic for most plants.  Accumulation and toxic effects 
have been observed in vegetables grown on sewage sludge-treated 
soils and in vegetation close to nickel-emitting sources.  High 
concentration factors have been found in aquatic plants.  
Laboratory studies showed that nickel had little capacity for 
accumulation in all the fish studied.  In uncontaminated waters, 

the range of concentrations reported in whole fish (on a wet-weight 
basis) ranged from 0.02 to 2 mg/kg.  These values could be up to 10 
times higher in fish from contaminated waters.  In wildlife, nickel 
is found in many organs and tissues, due to dietary uptake by 
herbivorous animals and their carnivorous predators.  However, 
there is no evidence for the biomagnification of nickel in the food 

1.4  Environmental levels and human exposure

    Nickel levels in terrestrial and aquatic organisms can vary 
over several orders of magnitude.  Typical atmospheric nickel 
levels for human exposure range from about 5 to 35 ng/m3 at rural 
and urban sites, leading to a nickel uptake via inhalation of 0.1-
0.7 µg/day.  Drinking-water generally contains less than 10 µg 
nickel/litre, but occasionally nickel may be released from the 
plumbing fittings, resulting in concentrations of up to 500 µg 

    Nickel concentrations in food are usually below 0.5 mg/kg fresh 
weight.  Cocoa, soybeans, some dried legumes, various nuts, and 
oatmeal contain high concentrations of nickel.  Daily intake of 
nickel from food will vary widely, because of different dietary 
habits, and can range from 100 to 800 µg/day; the mean dietary 
nickel intake in most countries is 100-300 µg/day.  Release of 
nickel from kitchen utensils may contribute significantly to oral 
intake.  Pulmonary intake of 2-23 µg nickel/day can result from 
smoking 40 cigarettes a day. 

    Dermal exposure in the general environment is important for the 
induction and maintenance of contact hypersensitivity caused by 
daily skin contact with nickel-plated objects or nickel-containing 
alloys (e.g., jewellery, coins, clips). 

    Iatrogenic exposure to nickel results from implants and 
prostheses made from nickel-containing alloys, from intravenous or 
dialysis fluids, and from radiographic contrast media.  An 
estimated average intravenous nickel uptake from dialysis fluids is 
100 µg per treatment. 

    In the working environment, airborne nickel concentrations can 
vary from a few µg/m3 to, occasionally, a few mg/m3, depending on 
the process involved and the nickel content of the material being 

    Throughout the world, millions of workers are exposed to 
nickel-containing dusts and fumes during welding, plating and 
grinding, mining, nickel refining, and in steel plants, foundries, 
and other metal industries. 

    Dermal exposure to nickel may occur in a wide range of jobs, 
either by direct exposure to dissolved nickel, e.g., in refining, 
electroplating, and electroforming industries or by handling 
nickel-containing tools.  Wet cleaning work may involve exposure to 
nickel, because of the amounts of nickel that become dissolved in 
the washing water. 

1.5  Kinetics and metabolism in human beings and animals

    Nickel can be absorbed in human beings and animals via 
inhalation or ingestion, or percutaneously.  Respiratory absorption 
with secondary gastrointestinal absorption of nickel (insoluble and 
soluble) is the major route of entry during occupational exposure.  
A significant quantity of inhaled material is swallowed following 
mucociliary clearance from the respiratory tract.  Poor personal 
hygiene and work practices can contribute to gastrointestinal 
exposure.  Percutaneous absorption is negligible, quantitatively, 
but is important in the pathogenesis of contact hypersensitivity.  
Absorption is related to the solubility of the compound, following 
the general relationships nickel carbonyl > soluble nickel 
compounds > insoluble nickel compounds.  Nickel carbonyl is the 
most rapidly and completely absorbed nickel compound in both 
animals and human beings.  Studies in which nickel was administered 
via inhalation are limited.  Studies on hamsters and rats with 
insoluble nickel oxide showed poor absorption, with retention of 
much of the material in the lung after several weeks.  In contrast, 
absorption of soluble nickel chloride or amorphous nickel sulfide 
was rapid.  Nickel is transported in the blood, principally bound 
to albumin. 

    Gastrointestinal absorption of nickel is variable and depends 
on the composition of the diet.  In a recent study on human 
volunteers, absorption of nickel was 27% from water compared with 
less than 1% from food.  All body secretions are potential routes 
of excretion including urine, bile, sweat, tears, milk, and 
mucociliary fluid.  Non-absorbed nickel is eliminated in the 
faeces.  Transplacental transfer has been demonstrated in rodents.  
Following parenteral administration of nickel salts, the highest 
nickel accumulation occurs in the kidney, endocrine glands, lung, 
and liver: high concentrations are also observed in the brain 
following administration of nickel carbonyl.  Data on nickel 
excretion suggest a two-compartment model.  Nickel concentrations 
in the serum and urine of healthy non-occupationally exposed adults 
are 0.2 µg/litre (range: 0.05-1.1 µg/litre) and l.5 µg/g creatinine 
(range: 0.5-4.0 mg/g creatinine), respectively.  Increased 
concentrations of nickel are seen in both of these fluids following 
occupational exposure.  The body burden of nickel in a non-exposed, 
70-kg adult is 0.5 µg. 

1.6  Effects on organisms in the environment

    In microorganisms, growth was generally inhibited at nickel 
concentrations in the medium of 1-5 mg/litre in the case of
actinomycetes, yeast, and marine and non-marine eubacteria and at
levels of 5-1000 mg/litre in filamentous fungi.  In algae, no growth
was observed at approximately 0.05-5 mg nickel/litre.  Abiotic
factors, such as the pH, hardness, temperature, and salinity of the
medium and the presence of organic and inorganic particles,
influence the toxicity of nickel. 

    Nickel toxicity in aquatic invertebrates varies considerably 
according to species and abiotic factors.  A 96-h LC50 of 0.5 mg 
nickel/litre has been found for  Daphnia spp., while, in molluscs, 
96-h LC50 values were around 0.2 mg/litre in two freshwater snail 
species and 1100 mg/litre in a bivalve. 

    In fish, 96-h LC50 values generally fall within the range of
4-20 mg nickel/litre, but can be higher in some species.  Long-term
studies on fish, and fish development, in soft water demonstrated
some effects on rainbow trout at levels as low as 0.05 mg
nickel/litre.  In terrestrial plants, nickel levels above 50 mg/kg
dry weight are usually toxic.  Copper was found to act
toxicologically in a synergistic way, whereas calcium reduced the
toxicity of nickel.  Data on the effects of nickel on terrestrial
animals are limited.  

    Earthworms seem to be relatively insensitive to nickel, if the 
medium is rich in microorganisms and organic matter, thus, making 
the nickel less available to the earthworms.  Nickel has not been 
considered as a broad scale global contaminant; however, ecological 
changes, such as decreases in the number and diversity of species, 
have been observed near nickel-emitting sources.  Microecosystem 
studies have shown that addition of nickel to soil disturbs the 
nitrogen cycle. 

1.7  Effects on experimental animals and  in vitro test systems

    Nickel is essential for the catalytic activity of some plant 
and bacterial enzymes.  Slow weight gain, anaemia, and decreased 
viability of offspring have been described in some animal species 
after dietary deprivation of nickel. 

    The most acutely toxic nickel compound is nickel carbonyl, the 
lung being the target organ; pulmonary oedema may occur within 4 h 
following exposure.  The acute toxicity of other nickel species is 

    Though contact allergy to nickel is very common in human 
beings, experimental sensitization in animals is only successful 
under special conditions.  Long-term inhalation exposure to 
metallic nickel, nickel oxide, or nickel subsulfide caused mucosal 
damage and inflammatory reaction in the respiratory tract in rats, 
mice, and guinea-pigs.  Epithelial hyperplasia was observed in rats 
after inhalation exposure to aerosols of nickel chloride or nickel 

    High-level, long-term exposure to nickel oxide led to gradually 
progressive pneumoconiosis in rats.  Inflammatory reaction, 
sometimes accompanied by slight fibrosis, was observed in rabbits 
after high-level exposure to nickel-graphite dust.  Pulmonary 
fibrosis was seen in rats exposed to nickel subsulfide. 

    Nickel salts, administered parenterally, induced a rapid 
transitory hyperglycaemia in rats, rabbits, and chickens.  These 
changes may be associated with effects on alpha and beta cells in 
the islets of Langerhans.  Nickel also decreased the release of 
prolactin.  Nickel chloride, given orally or by inhalation, has 
been reported to decrease iodine uptake by the thyroid. 

    Nickel salts, given intravenously, decreased blood flow in the 
coronary arteries in the dog; high concentrations of nickel 
decreased the contractility of dog myocardium  in vitro. 

    Nickel chloride affects the T-cell system and suppresses the 
activity of natural killer cells.  Parenteral administration of 
nickel chloride and nickel subsulfide have been reported to cause 
intrauterine mortality and decreased weight gain in rats and mice.  
Inhalation exposure to nickel carbonyl caused fetal death and 
decreased weight gain, and was teratogenic in rats and hamsters.  
Information on maternal toxicity was not given in any of these 
studies.  Nickel carbonyl has been reported to cause dominant 
lethal mutations in rats. 

    Several inorganic nickel compounds were tested for mutagenicity 
in various test systems.  Nickel compounds were generally inactive 
in bacterial mutagenesis assays, except where fluctuation tests 
were used.  Mutations were observed in several cultured mammalian 
cell types.  Nickel compounds inhibited DNA synthesis in a wide 
variety of organisms.  In addition, nickel compounds induced 
chromosomal aberrations and sister chromatid exchange (SCE) in both 
mammalian and human cultured cells.  Chromosomal aberrations, but 
not sister chromatid exchange (except in one study on electrolysis 
workers), were observed in human beings, occupationally exposed to 
either insoluble or soluble nickel compounds.  Nickel induced cell 
transformation  in vitro. 

    In an inhalation study, nickel subsulfide induced benign and 
malignant pulmonary tumours in rats.  A few pulmonary tumours were 
seen in rats in a series of inhalation studies with nickel 
carbonyl.  There was no significant increase in lung tumours in 
rats in an adequate inhalation study with metallic nickel.  
Inhalation exposure to black nickel oxide did not induce lung 
tumours in Syrian golden hamsters (a species resistant to lung 
carcinogenesis).  Adequate carcinogenicity studies on inhalation 
exposure to other nickel compounds were not available.  However, 
nickel subsulfide, metallic nickel powder, and an unspecified 
nickel oxide induced benign and malignant lung tumours in rats 
after repeated intratracheal instillations. 

    Nickel carbonyl, nickelocene, and a large number of slightly 
soluble or insoluble nickel compounds, including nickel subsulfide, 
carbonate, chromate, hydroxide, sulfides, selenides, arsenides, 
telluride, antimonide, various unidentified oxide preparations, two 
nickel-copper oxides, metallic nickel, and various nickel alloys, 
induced local mesenchymal tumours in a variety of experimental 
animals after intramuscular, subcutaneous, intraperitoneal,
intrapleural, intraocular, intraosseous, intrarenal, intra-articular,
intratesticular or intra-adipose administration.  No local 
carcinogenic response was seen in single-dose studies with some 
nickel alloys, colloidal nickel hydroxide, or with two specimens of 
nickel oxide, especially prepared for carcinogenicity testing by 
calcining at 735 °C or 1045 °C. 

    Nickel sulfate and nickel acetate, but not nickel chloride, 
induced tumours of the peritoneal cavity in rats after repeated 
intraperitoneal administration. 

    Metallic nickel and a very large number of nickel compounds 
have been tested for carcinogenicity by parenteral routes of 
administration; with few exceptions, they caused local tumours. 

    Only nickel subsulfide has been shown convincingly to cause 
cancer after inhalation exposure.  However, the number of adequate 
inhalation studies is very small. 

    In studies using repeated intratracheal instillation, nickel 
powder, nickel oxide, and nickel subsulfide caused pulmonary 

    When nickel sulfate and nickel chloride, which had not induced 
local tumours in intramuscular studies, were tested using repeated 
intraperitoneal administration, they elicited a carcinogenic 

1.8 Effects on human beings

    In terms of human health, nickel carbonyl is the most acutely 
toxic nickel compound.  The effects of acute nickel carbonyl 
poisoning include frontal headache, vertigo, nausea, vomiting, 
insomnia, and irritability, followed by pulmonary symptoms similar 
to those of a viral pneumonia.  Pathological pulmonary lesions 
include haemorrhage, oedema, and cellular derangement.  The liver, 
kidneys, adrenal glands, spleen, and brain are also affected.  
Cases of nickel poisoning have also been reported in patients 
dialysed with nickel-contaminated dialysate and in electroplaters 
who accidentally ingested water contaminated with nickel sulfate 
and nickel chloride. 

    Chronic effects such as rhinitis, sinusitis, nasal septal 
perforations, and asthma have been reported in nickel refinery and 
nickel plating workers.  Some authors reported pulmonary changes 
with fibrosis in workers inhaling nickel dust. In addition, nasal 
dysplasia has been reported in nickel refinery workers.  Nickel 
contact hypersensitivity has been documented extensively in both 
the general population and in a number of occupations in which 
workers were exposed to soluble nickel compounds.  In several 
countries, it has been reported that 10% of the female population 
and 1% of the male population are sensitive to nickel.  Of these, 
40-50% have vesicular hand eczema, which, in some cases, can be 
very severe and lead to loss of working ability.  Oral nickel 
intake may aggravate vesicular hand eczema and, possibly, also 
eczema arising on other parts of the body where there has not been 
any skin contact with nickel. 

    Prostheses, or other surgical implants, made from nickel-
containing alloys have been reported to cause nickel sensitization 
or to aggravate existing dermatitis. 

    Nephrotoxic effects, such as renal oedema with hyperaemia and 
parenchymatous degeneration, have been reported in cases of 
accidental industrial exposure to nickel carbonyl.  Transient 
nephrotoxic effects have been recorded after accidental ingestion 
of nickel salts. 

    Very high risks of lung and nasal cancer have been reported in 
nickel refinery workers employed in the high-temperature roasting 
of sulfide ores, involving substantial exposure to nickel 
subsulfide, oxide, and, perhaps, sulfate.  Similar risks have been 
reported in processes involving exposure to soluble nickel 
(electrolysis, copper sulfate extraction, hydrometallurgy), often 
combined with some nickel oxide exposure, but with low nickel 
subsulfide exposure.  The risk to miners and other refinery workers 
has been reported to be much lower.  Cancer rates have generally 
been close to normal in stainless steel welding and nickel-using 
industries, with the exception of those involving exposure to 
chromium, particularly electroplating.  However, nickel/cadmium 
battery workers exposed to high levels of both nickel and cadmium 
may have suffered a slightly increased risk of lung cancer. 

    Excesses of various cancers other than lung and nasal cancers, 
such as renal, gastric, or prostatic cancer, have occasionally been 
reported in nickel workers, but none has been found consistently. 

    The epidemiological data can be used to address two important 
questions: (i) whether specific nickel compounds have been shown to 
be carcinogenic; and (ii) whether low-exposure cohorts provide 
upper limits of risk at specified exposure levels. 

 (a) Soluble nickel 

    There was evidence of a cancer hazard in workers exposed to 
soluble nickel concentrations of the order of 1-2 mg/m3, both in 
electrolysis and in the preparation of soluble salts.  These 
workers were also exposed to other nickel compounds, but often at 
lower levels than in other high-risk processes.  In the absence of 
historical exposure measurements it is impossible to draw 
unequivocal conclusions, but the evidence that soluble nickel is 
carcinogenic is certainly strong.  Refinery dust sometimes contains 
a substantial proportion of nickel sulfate in addition to nickel 
subsulfide.  This raises the possibility that the very high cancer 
risk observed in workers employed in the high-temperature oxidation 
of nickel subsulfide may be partly due to soluble nickel. 

 (b) Nickel subsulfide 

    In refinery areas where cancer risks were high, exposure to 
nickel subsulfide almost always occurred together with exposure to 
the oxide and, perhaps, sulfate (see above).  Thus, it is difficult 
to demonstrate from epidemiological data alone, that nickel 
subsulfide is carcinogenic, though this seems likely. 

 (c) Nickel oxide 

    Nickel oxide was present in almost all circumstances in which 
cancer risks were elevated, together with one or more other forms 
of nickel (nickel subsulfide, soluble nickel, metallic nickel).  As 
for nickel subsulfide, it is difficult to either demonstrate or 
disprove its suspected carcinogenicity on the basis of 
epidemiological data alone. 

 (d) Metallic nickel 

    No increased cancer risk has been demonstrated in workers 
exposed exclusively to metallic nickel.  The combined data on 
nickel alloy workers and gaseous diffusion workers, all of whom 
were exposed to average concentrations of the order of 0.5 mg 
nickel/m3, show no excess risk, though the total number of lung 
cancers in these cohorts was too small to exclude a small increase 
in risk at this level. 

 (e) Conclusion 

    Although some, and perhaps all, forms of nickel may be 
carcinogenic, there is little or no detectable risk in most sectors 
of the nickel industry at current exposure levels; this includes 
some processes that were associated, in the past, with very high 
lung and nasal cancer risks.  Long-term exposure to soluble nickel 
at concentrations of the order of 1 mg/m3 may cause a marked 
increase in the relative risk of lung cancer, but the relative risk 
among workers exposed to average metallic nickel levels of about 
0.5 mg/m3 is approximately 1.  The cancer risk at a given exposure 
level may be higher for soluble nickel compounds than for metallic 
nickel and, possibly, than for other forms as well.  The absence of 
any marked lung cancer risk among nickel platers is not surprising, 
as the average exposures to soluble nickel are very much lower than 
those in electrolytic refining or nickel salt processing. 

2.1.  Identity, and physical and chemical properties of nickel and
nickel compounds

    Nickel is a silvery white metal belonging to Group VIIIb of the 
periodic table.  Nickel is slightly more resistant to oxidation than
iron and cobalt, with a standard potential of -0.236 V relative to
the hydrogen electrode (Stoeppler, 1980).  Several hundreds of
nickel compounds have been identified and characterized.  Nickel has
a specific density of 8.90 g/cm3, a melting point of 1555 °C, and
a boiling point of 2837 °C (Table 1).  It is insoluble in water,
soluble in dilute nitric acid and aqua regia, and slightly soluble
in hydrochloric and sulfuric acid.  Nickel usually has an oxidation
state of two, but also occurs as relatively stable tri- and
tetravalent ions (Stoeppler, 1980).  Several binary nickel compounds
are commercially and environmentally significant.  A brief
description of the chemistry of some of these compounds is given
below.  Physical and chemical properties of nickel and its compounds
are summarized in Table 1. 

    Nickel forms complexes (chelates) that are insoluble in water, 
but soluble in organic solvents.  These compounds are often very 
stable and play an important role in trace analysis.  For example, 
nickel dimethylglyoxime is the compound that makes possible the 
separation of nickel from cobalt, which is similar in its chemical 
and analytical behaviour (Stoeppler, 1980).  Divided nickel (Raney 
nickel) absorbs up to seventeen times its volume of hydrogen and 
can act as an catalyst (Lewis & Ott, 1970). 

2.1.1.  Nickel carbonate hydroxide

    Nickel carbonate hydroxide (2NiCO3 x 3Ni(OH)2 x 4H2O) is 
insoluble in water, but soluble in ammonia and in dilute acids.  
The composition of basic nickel carbonate can vary.  The most 
common forms range from 2NiCO3 x 3Ni(OH)2 x XH2O to NiCO3 x Ni(OH)3 
x XH2O.  The tetrahydrate occurs in nature as zaratite.  It is used 
in nickel plating, as a catalyst for the hardening of fats, and in 
colours and glazes for ceramics (Windholz et al., 1983).  High 
purity nickel carbonate is used in electronic components (IARC, 1976). 

2.1.2.  Nickel carbonyl

    Nickel carbonyl (Ni(CO)4) is a colourless volatile liquid and 
is formed when nickel powder is treated with carbon monoxide at 
about 50 °C.  It is used for the production of pure nickel by 
thermal deposition at atmospheric pressure and at 200-250 °C 
(Stoeppler, 1980).  The carbonyl is insoluble in water, but soluble 
in most organic solvents (Windholz et al., 1983). 

Table 1.  Physical properties of nickel and nickel compoundsa
Name        Chemical     Relative   Appearance            Density  Melting    Boiling  Solubility
            formula      molecular                        (g/cm3)  point      point    (water; other
                         mass                                      (°C)       (°C)     solvents)
Nickel      Ni           58.70      lustrous, white,      8.90     1555       2837     insoluble
                                    face-centered cubic            1455b
Nickel      Ni(CH3CO2)2  176.80     green crystalline     1.744    -c         -        soluble; 
acetate                             mass or powder                                     soluble
                                                                                       in alcohol
Nickel      Ni3(AsO4)2   453.97     yellow-green powder   4.982    -          -        insoluble;
arsenate                                                                               soluble 
                                                                                       in acids
Nickel      NiBr2        218.53     yellow-green,         -        loses      -        soluble; 
bromide                             deliquescent crystals          H2O        -        soluble 
                                                                   at 200              in alcohol
Nickel      2NiCO3       118.70     light-green crystals  -        decomposes -        insoluble;
carbonate                                                                              soluble
                                                                                       in acids
Nickel      Ni(CO)4      170.73     colourless, volatile  1.318    -19.3      43       insoluble;
carbonyl                            liquid                (17 °C)                      soluble in

Nickel      NiCl2        129.61     yellow, deliquescent  3.55d               987d     soluble
chloride                            crystals
Nickel      NiCl2 x      237.70d    green, monoclinic,    -        -          -        soluble; 
chloride    6H2O                    deliquescent crystals                              soluble
hexahydrate                                                                            in alcohol
Table 1 (contd.)
Name        Chemical     Relative   Appearance            Density  Melting    Boiling  Solubility
            formula      molecular                        (g/cm3)  point      point    (water; other
                         mass                                      (°C)       (°C)     solvents)
Nickel      NiF2         96.69      yellow-green,         4.72     -          -        slightly 
fluoride                            tetragonal crystals                                soluble
Nickel      Ni(OH)2      92.72      green powder          -        decomposes -        insoluble;
hydroxide                                                          above 200           soluble in 
                                                                                       acids and 

Nickel      2NiCO3 x     587.67b    green powder          -        -          -        insoluble;
hydroxy-    3Ni(OH)2 x                                                                 soluble in 
carbonate   4H2O                                                                       acids
Nickel      Ni(NO3)2     182.72     green, deliquescent   2.05     56.7       137      soluble; 
nitrate                             crystals                                           soluble
                                                                                       in alcohol
Nickel      NiO          74.69      green or black        6.67d    1990d      -        insoluble;
oxide                               powder                                             soluble in 

Table 1 (contd.)
Name        Chemical     Relative   Appearance            Density  Melting    Boiling  Solubility
            formula      molecular                        (g/cm3)  point      point    (water; other
                         mass                                      (°C)       (°C)     solvents)
Nickel      Ni3(PO4)3    366.07     light-green powder    -        -          -        insoluble;
phosphate                                                                              soluble in 
Nickel      NiSO4        154.77     alpha blue-green,     -        53.3(a-b)  -        soluble
sulfate                             tetragonal crystals            loses             
                                    beta green,                    water               soluble
                                    monoclinic crystals            at 280
beta-Nickel NiS          90.77d     trigonal crystalse    5.3d     797d       -        insoluble
Nickel      Ni3S2        240.26b    pale, yellowish       5.82b    790b       -        insoluble;
subsulfide                          bronze metallicb                                   soluble in
                                                                                       nitric acidb
a  From: Windholz et al. (1983).
b  From: Weast (1981).
c  Data not available.
d  From: Blankenstein & Starck (1979).
e  From: Neumüller (1985).
2.1.3.  Nickel chloride and nickel chloride hexahydrate

    Nickel chloride (NiCl2) and nickel chloride hexahydrate 
(NiCl2 x 6H2O) are both soluble in water.  The anhydrate salt is used 
as an absorbent for ammonia in gas masks and in nickel plating 
(Windholz et al., 1983). 

2.1.4.  Nickel hydroxide

    Nickel hydroxide (Ni(OH)2) is insoluble in water but soluble in 
acids (Windholz et al., 1983).  When dissolved in ammonia it forms 
complexes.  It is used as electrode material for secondary cells 
(Blankenstein, 1979). 

2.1.5.  Nickel nitrate

    Nickel nitrate (Ni(NO3)2) dissolves easily in water and 
alcohol.  It is used in nickel plating and nickel-cadmium batteries 
(Neumüller, 1985). 

2.1.6.  Nickel oxide

    Nickel oxide (NiO) includes several nickel-oxygen compounds, 
which differ in stoichiometry, and chemical and physical properties 
(see Table 32 in section 8.4.3).  The different nickel oxides, and 
also the nickel-copper oxides present in the nickel refining 
industry, have different biological properties (Sunderman et al., 

    Nickel oxide is insoluble in water.  The solubility in acids 
and other properties depend on the method of preparation.  Nickel 
oxide is an important raw material for smelting and alloy-producing 
processes.  It is also used as a catalyst and in glass colours 
(Blankenstein & Starck, 1979).  Nickel oxide exists in two forms.  
Black nickel oxide is chemically reactive and forms simple salts in 
the presence of acids.  Green nickel oxide is an inert and 
refractory material.  It is used primarily in metallurgical 

2.1.7.  Nickel sulfate

    Nickel sulfate (NiSO4), which exists as a hexahydrate in the 
alpha-form, changes into the beta-form at 53.3 °C (Windholz et al., 
1983).  It is produced by dissolving nickel oxide or hydroxide in 
sulfuric acid (Neumüller, 1985).  It is the main component of the 
electrolyte solution in electrolytic refining and is a raw material 
for the production of catalysts.  It is also used in fabrication of 

2.1.8.  Nickel sulfide

    Nickel sulfide (NiS) occurs naturally as millerite.  It is 
insoluble in water and is of importance in catalyst production and 
in the hydrogenation of sulfur compounds in the oil industry 
(Blankenstein, 1979). 

2.1.9.  Nickel subsulfide

    Nickel subsulfide (Ni3S2) exists at high-temperatures in a 
bronze-yellow form (beta-Ni3S2).  At lower temperatures, it 
transforms to the green beta-form, which is stable at normal 
temperature, and may be formed electrolytically.  The grey mineral 
heazlewoodite is the same modification, but has been named alpha-
nickel subsulfide.  Nickel subsulfide may be formed during the 
production of nickel from sulfide ores. 

2.2.  Analytical methods

    A variety of methods has been used to determine nickel 
concentrations in different media.  Methods are summarized in 
Table 2. 

2.2.1.  Determination of trace amounts

    The use of very sensitive instrumental methods has shown that 
detection limits are not so much set by the capabilities of the 
instrument as by contamination from different sources.  Sources of 
contamination include laboratory air, laboratory equipment and 
construction material, reagents and the analyst.  In order to 
obtain reliable results, especially when determining trace (mg/kg) 
and ultratrace (µg/kg) amounts, specific procedures concerning 
contamination control during sample collection, storage, processing, 
and analysis must be adhered to. 

    Besides contamination control during sample processing, the 
establishment of the level of accuracy of the analytical procedure 
is of great importance.  Thus, analysis of certified reference 
materials is recommended.  Recovery experiments to check the 
analytical procedure include the spiking of samples with known 
amounts of nickel. 

2.2.2.  Sample collection

    Great care must be taken to minimize the risk of contamination 
during sample collection by the use of suitable procedures (Nieboer 
& Jusys, 1983; Boyer & Howitz, 1986).  Persons who handle samples 
should wear talc-free gloves to avoid nickel contamination from 
sweat.  When collecting liquid samples, e.g., sea water, fresh 
water, or urine, acid-washed polyethylene containers should be 
used.  As stainless steel is a source of nickel contamination, 
Teflon(R), intravenous catheters are recommended for blood 
collection.  Tissues should be dissected with plastic forceps and 
obsidian scalpels (Sunderman et al., 1985). 

    Collection of airborne particulate nickel involves pumping a 
known volume of air through a membrane filter, which usually 
consists of cellulose, PVC, or glass fibre (Mackenzie Peers, 1986).  
Equipment of the air sampling system with a cyclone, cascade, or 
cascade impactor allows sampling of respirable particulate nickel 
(Roy, 1985). 

Table 2.  Analytical methods for nickel determinationa
Medium   Sample treatment    Analytical method       Detection  Comment                     Reference
Biological materials                                           
Serum,   urine sampling in   analysis of extract     0.4 µg/    suitable for monitoring     Mikac-Devic
urine    PE-bottles; blood   by EAAS, with           litre      occupational exposure;      et al. (1977)
         collection with     graphite atomizer,                 interference from high
         PE-catheter and     using a deuterium                  iron contents possible       
         PE-syringe; wet     background corrector               
         extraction as                                           
         furildioxime into                                      

Liver,   wet digestion;      analysis of extract by  ns         removal of iron and copper  Dornemann
kidney   evaporation to      EAAS, with graphite                as  N-nitrosophenylhydr-     & Kleist
(animal) dryness;            atomizer                           oxylamine-chelates          (1980)
         extraction as
         chelate into
         and xylene

Food     filtration; wet     analysis of extract by  1 ng/      rapid and inexpensive       Pilhar et
         digestion           DPV, with HMDE          litre      method; higher sensitivity  al. (1981)
         extraction as                                          than AAS

Tissues, wet digestion;      analysis of extract     ns         good agreement between      Szathmary
body     evaporation to      and of digested sample             results from EAAS           & Daldrup
fluids   dryness;            by EAAS, with graphite             determination and results   (1982)
         extraction as       atomizer; analysis of              from GC-determination
         DDTC-chelate into   extract by GC with FID             

Table 2 (contd.)
Medium   Sample treatment    Analytical method       Detection  Comment                     Reference
Whole    wet digestion;      analysis of extract by  0.1 ng/    suitable for routine        Ostapczuk
blood,   evaporation to      DPV, with HMDE          litre      determination in a variety  et al. 
urine,   dryness and                                            of biological materials     (1983)
saliva,  dissolution;
liver,   extraction as
nails    DMG-chelate

Hair     washing in          analysis by AAS         ns         more convenient for         Bencko et
         redistilled                                            sampling and storage than   al. (1986)
         acetone, then in                                       other biological materials
         deionized water
         and again in
         redistilled acetone;
         repeat twice

Serum,   blood collection    analysis by EAAS, with  0.05 µg/   suitable for routine        Sunderman 
whole    with PE-cannula     Zeeman background       litre      determination               et al. 
blood    and PP-syringe;     corrector                                                      (1984a)
         wet digestion

Body     wet digestion;      analysis by SWV at      ns         more sensitive method       Ostapczuk et
fluids,  extraction as DMG-  HMDE                               compared with DPV           al. (1985a)
tissues  chelate

Tissue   sampling with       analysis of sample by   10 ng/g    minimal nickel              Sunderman 
         plastic forceps     EAAS, with Zeeman       dry weight contamination               et al.
         and obsidian        background corrector                                           (1985)
         scalpel; wet

Urine    sampling in PE-     analysis of extract     ns         suitable for monitoring     Long-zhu
         bottles; wet        by EAAS, with graphite             occupational exposure       & Zhe-ming
         digestion using     atomizer                                                       (1985)
         nitric acid,
         perchloric acid,
         and ascorbic acid;
         extraction as APDC-
         chelate into MIBK

Table 2 (contd.)
Medium   Sample treatment    Analytical method       Detection  Comment                     Reference
Urine    filtration;         automated               0.1 ng/    convenient for              Bond et al.
         acidification;      determination by        10 µlitre  determination of            (1986)
         complexation with   electrochemical         sample     multimetals (normal
         HPDC within         determination,                     to occupational 
         automated           following separation               exposure levels)
         analytical system   by HPLC (reversed                  after direct injection
                             phase)                             of sample

Urine    sampling in PE-     analysis by EAAS,       0.45 µg/   direct analysis of          Sunderman
         bottles;            with Zeeman background  litre      sample                      et al. 
         acidification;      corrector                                                      (1986a)

Plasma   dilution of sample  analysis by EAAS, with  0.09 µg/   no sample pretreatment      Andersen et
         with nitric acid    Zeeman background       litre      necessary                   al. (1986)
         and Triton X-100    corrector

Lung     freeze drying       analysis by EAAS, with  lower      suitable method for the     Baumgardt et
tissue   following           graphite atomizer       ng/g       routine determination       al (1986)
         collection; wet                             amounts    of trace elements
         evaporation to
         dryness; dilution

Blood,   enzymatic           analysis by EAAS, with  0.1 µg/    lower risk of               Christensen 
serum,   digestion of blood  Zeeman background       litre      contamination with          & Pedersen
sweat,   and serum;          corrector                          pretreatment method used    (1986)
urine    ultrasonic 
         treatment of urine
         and sweat

Table 2 (contd.)
Medium   Sample treatment    Analytical method       Detection  Comment                     Reference

Food-    wet digestion;      analysis of extract     0.048-     interference by high        Evans et al.
stuffs   dilution;           by FAAS                 0.061      copper content              (1978)
         extraction as APDC-                         mg/kg
         DDDC-chelate into

Fish     freeze-drying;      analysis of dissolved   ns                                     Ikebe &
shell-   low temperature     sample by FAAS                                                 Tanaka (1979)
fish     ashing

Food-    wet digestion;      analysis of extract     ns         accurate and inexpensive    Valenta et 
stuffs   evaporation to      by DPASV, with HMDE                method                      al. (1981)
         extraction as

Dried    dry ashing;         analysis of diluted     5 ng/      sensitive and accurate      Meyer &
milk     extraction as       extract by DPV, with    sample     method, less interference   Neeb (1985)
powder   DMG-chelate;        HMDE                               compared with FID-GC

Dried    dry ashing;         analysis of solution    100 ng/    interference by higher      Meyer &
milk     extraction as Na-   by GC, with FID         µlitre     iron content in presence    Neeb (1985)
powder   FDEDTC-chelate in                           sample     of low copper content is
         chloroform;                                            possible
         evaporation and
         dissolution in

Table 2 (contd.)
Medium   Sample treatment    Analytical method       Detection  Comment                     Reference
Citrus   wet digestion;      analysis of extract     µg/g       simultaneous determination  Ichinoki &
leaves,  extraction as HMDE  by HPLC                            of nickel, molybdenum,      Yamazaki
rice     chelates into                                          zinc, and copper            (1985)
flour    chloroform


Sea      extraction with     analysis of extract     ns         probably only ionic form    Danielsson
water    APDC and DDTC into  by EAAS with graphite              of total nickel is          et al. (1978)
         Freon TF and back-  atomizer using a                   measured; stability of
         extraction into     deuterium background               extract is good
         nitric acid         corrector

Sea      PE bottles or       analysis of extract                concentration factor 200    Bruland &
water    Teflon-coated PVC   by EAAS with graphite                                          Franks (1979)
         ball-valve          furnace

         a) double extraction                        10 ng/
         with APDC and DDTC                          litre
         into chloroform;                            (instrumental
         back extraction                             detection
         into nitric acid;                           limit)
         evaporation of                              
         back-extract and
         redissolution into
         nitric acid

Table 2 (contd.)
Medium   Sample treatment    Analytical method       Detection  Comment                     Reference
Sea      b) concentration on                         15 ng/     inefficient concentration   Bruland &
water    Chelex-100 resin                            litre      factor by Chelex-100        Franks (1979)
(contd.)                                             (instru-

Sea      PVC samplers;       analysis of             ns         probably only ionic form    Frache et al.
water    storage in PE       extract by FAAS                    of total nickel is measured (1980)
         extraction with
         ADPC into MIBK

Sea      adsorption on       analysis of resin       0.077 µg/  rapid and inexpensive       Yoshimura et
water    PAN-resin           phase by ion-exchange   litre      method                      al. (1980)

Fresh                                                0.34 µg/
water                                                litre

Fresh    buffered            analysis of extract     2 µg/      suitable for routine water  Flora &
water,   extraction as       by DPP, with HMDE       litre      analysis                    Nieboer
drink-   DMG-chelate                                                                        (1980)

Sea      UV-irradiation;     analysis of extract     1 µg/      rapid and inexpensive       Pilhar et
water,   extraction as       by DPV, with HMDE       litre      method; high sensitivity    al. (1981)
fresh    DMG-chelate

Table 2 (contd.)
Medium   Sample treatment    Analytical method       Detection  Comment                     Reference
Fresh    UV-irradiation;     analysis of             ns         enrichment factor           Wilson &
water    enrichment by       electrolyte by FAAS                decreases at higher         DiNunzio
(river)  Donnan dialysis                                        calcium concentration       (1981)

Aqueous  extraction as       analysis of extract     1-2 µg/    in case of high copper and  Gemmer-Colos
solution heptoxime-chelate;  by DPP with HMDE        litre      iron concentrations,        et al. (1981)
         evaporation and                                        extraction with NH4OH is
         redissolution in                                       necessary to prevent 
         toluene/methanol/                                      interference

Sea      preconcentration    analysis of diluted     0.05 mg/   concentration factor 200    Watanabe et
water    by complexation     extract by ICP-AES      litre                                  al. (1981)
         with 8-hydroxy-
         adsorption on 
         C18-bonded silica
         gel; evaporation of 
         eluate to dryness, 
         dissolution in 
         nitric acid 

Sea      preconcentration    analysis by EAAS with   ns         concentration factor 50     Sturgeon et
water    by complexation     graphite furnace                                               al. (1982)
         with 8-hydroxy-
         adsorption on 
         C18-bonded silica
         gel; evaporation of 
         eluate to dryness, 
         dissolution in 
         nitric acid 

Table 2 (contd.)
Medium   Sample treatment    Analytical method       Detection  Comment                     Reference
Indus-   complexation with   separation of chelate   0.5 ng     suitable for automated      Bond &
trial    APDC and DDTC with  by HPCC (reversed       (electro-  monitoring of nickel and    Wallace
plant    automated           phase) followed by      chemical)  copper                      (1983)
solu-    analytical system   electrochemical and     0.1 ng
tions                        spectrophotometric      (spectro-
                             detection within        photo-
                             automated system        metric)

Sea      preconcentration    analysis of eluate      1 µg/      50-fold preconcentration    McLaren et
water    by adsorption on    by ICP-MS               litre                                  al. (1985)

Sea      coprecipitation     analysis of dissolved   60 ng/     200-fold preconcentration,  Akagi et al.
water    with gallium        precipitate by ICP-AES  litre      appropriate for multi-      (1985b)
                                                                element analysis

Fresh    filtration;         analysis by DPCSV,      0.4 µg/    elimination of              Weidenauer
water    oxidative UV-       with HMDE               litre      interference caused by      & Lieser
river    photolysis                                             dissolved organic matter    (1985)
                                                                by UV-photolysis

Drink-   evaporation onto    analysis by PIXE        1.2 µg/    suitable for multi-element  Ali et al.
ing      cellulose matrix,                           litre      analysis                    (1985)
water    grinding and 
         pelletizing of

Waste    dilution;           ion-chromatographic     ns                                     Tanaka (1985)
water,   separation of       analysis, with anion
plating  metal ions as       separator
solution EDTA-complexes

Table 2 (contd.)
Medium   Sample treatment    Analytical method       Detection  Comment                     Reference
Sea      extraction with     analysis of diluted     17 µg/     inexpensive method;         Carvajal &
water    DDTC into           extracts by GC, with    litre to   appropriate for multimetal  Zienius 
(synth.) chloroform          FID by GC with ECD      0.2 µg/    analyses                    (1986)
                                                     on type of

Rain     filtration;         analysis by DPSV,       0.24 mg/   rapid, inexpensive and      Vos et al.
water    acidification;      with HMDE               litre      sensitive method for        (1986)
         extraction as DMG-                                     multielement analysis


Rock     wet digestion with  analysis of extract     5-200 mg/  appropriate for iron,       Sanzolone
material HF and HNO3;        by FAAS                 kg         molybdenum, and calcium-    et al. (1979)
(stand-  extraction as                                          rich geological materials
ard      DDTC-chelate into
refer-   MIBK

River    wet digestion;      analysis of diluted     0.1 mg/    elimination of              Abo-Rady
sedi-    filtration and      sample by FAAS using    kg         interference of matrix      (1979a)
ments,   dilution            a deuterium background             effects by use of 
rock                         corrector                          deuterium background 
material,                                                       detector

Soil     wet digestion;      analysis of             4 mg/kg    concentration factor 5;     Schmidt &
         extraction as       re-extracts by EAAS     re-        reduction of interference   Dietl (1981)
         APDC-chelate into   with zirconium coated   extract    by re-extraction
         MIBK; re-           graphite atomizer
         extraction with 
         nitric acid

Table 2 (contd.)
Medium   Sample treatment    Analytical method       Detection  Comment                     Reference
Soil     acid digestion      analysis by ICP-AES     0.010-     suitable for multielement   Church
                                                     0.015 mg/  analysis                    (1981)
                                                     on spectral

Soil     wet digestion;      analysis by ASWV        0.08 µg/   more sensitive and rapid    Ostapczuk
         extraction as                               ml analyte method for determination    et al. 
         DMG-chelate                                 solution   of heavy metals than DPV    (1985b)


Air      adsorption on       analysis by FAAS        1 µg/      suitable for determining    US NIOSH
         cellulose ester                             sample     occupational exposure       (1977b)
         membrane filter;
         wet digestion

Air      adsorption on       analysis by ICP-AES     1 µg/      suitable for simultaneous   Mackenzie
         cellulose ester                             sample     multielement analysis       Peers (1986)
         membrane filter;
         wet digestion; 
         evaporation to
         dryness; dilution

Air      adsorption in       analysis by             1 µg/m3    nickel carbonyl is          Stedman
         alcoholic iodine    colorimetry                        measured, interference by   (1986a)
         solution;                                              gaseous nickel compounds
         extraction as
         chelate into

Air      direct sampling     analysis by             0.2 µg/m3  allows continuous           Stedman
         into chemilumin-    chemiluminescence                  measuring of nickel         (1986b)
         escence detector;                                      carbonyl
         mixing of sampling
         with carbon

Table 2 (contd.)
Medium   Sample treatment    Analytical method       Detection  Comment                     Reference
Various materials

Steel    extraction as       analysis by DPP,        1 µg/kg    Copper can be determined    Weinzierl
         DMG-chelate;        with HMDE                          simultaneously              Umland (1982)
         complexation of
         Fe3+ and Mn2+ with

City     wet digestion;      analysis by ICP-AES     25 µg/     multistep digestion         Taylor et al.
waste    evaporation to                              litre      procedure necessary         (1985)
incin-   near dryness;                               analyte    because of difficult
erator   dilution                                    solution   matrix
ash      filtration
a Abbreviations:

APDC     ammonium pyrolidinedithiocarbamate          GC         gas-chromatography
ASWV     adsorption square wave voltammetry          HMDE       hanging mercury drop electrode
DDDC     diethylammonium diethyldithiocarbamate      HPLC       high-performance liquid chromatography
DDTC     diethyldithiocarbamate                      ICP-AES    inductively coupled plasma atomic
DMG      dimethylgyoxime                                          emission spectroscopy
DPASV    differential pulse aniodic stripping        ICP-MS     inductively coupled plasma mass
           voltammetry                                            spectroscopy
DPCSV    differential pulse cathodic stripping       MIBK       methyl isobutyl ketone
           voltammetry                               NaFDEDTC   natrium (ditrifluorethylene)dithio-
DPP      differential pulse polarography                          carbamate
DPV      differential pulse voltammetry              ns         not specified
EAAS     electrothermal atomic absorption            PAN        [1-(2-pyridylazo)-2-naphthol]
           spectrometry                              PE         polyethylene
ECD      electron-capture detector                   PIXE       particle-induced X-ray emission
FAAS     flame atomic absorption spectroscopy        PP         polypropylene
FID      flame ionization detector                   PVC        polyvinyl chloride
                                                     TPP        tetraphenylporphine
    Volatile nickel compounds, such as nickel carbonyl, can be 
absorbed in an alcoholic iodine solution through which the air 
being sampled is passed (NIOSH, 1977a; Stedman, 1986a). 

2.2.3.  Sample pretreatment

    Prior to the determination of nickel in biological and 
environmental materials, the organic constituents must be oxidized 
or removed to avoid interference during analysis.  The most common 
methods include wet digestion, i.e., oxidation of organic matter by 
reagents, such as nitric acid, sulfuric acid, perchloric acid, or 
hydrogen peroxide, or combinations of these compounds, and dry 
ashing, which ensures oxidation of organic matter by the action of 
oxygen and high temperatures.  Puchyr & Shapiro (1986) developed an 
extraction method for food samples that involved low-temperature 
HCl/HNO3-leaching followed by filtration.  This method proved to be 
very efficient and less hazardous and less time-consuming than 
common wet or dry digestion techniques.  Organic substances, 
dissolved in natural waters, and certain liquid foods are 
successfully decomposed by oxidative ultraviolet (UV) photolysis 
(Pilhar et al., 1981; Weidenauer & Lieser, 1985). 

    As nickel concentrations are often low in relation to 
analytical detection limits, preconcentration steps are introduced, 
which may also separate nickel from substances interfering with 
analysis.  Techniques very frequently employed include chelate 
extraction with dithiocarbamates, dimethylglyoxime, furildioxime, 
or 8-hydroxyquinoline into organic non-polar solvents.  Tanaka 
(1985) used EDTA as a complexing agent prior to determination of 
nickel in waste water and plating solution: Gemmer-Colos et al. 
(1981) reported complete extraction of nickel-heptoxime from an 
aqueous nickel solution at low pH values.  Interfering cobalt and 
iron ions were eliminated by treatment of the extract with ammonia.  
Another preconcentration technique, prior to analysis of nickel in 
fresh and sea water, is the use of chelating ion-exchanged resins, 
e.g., Chelex 100(R), (Bruland et al., 1979) or 1-(2-pyridylazo)-2-
naphthol (PAN) (Yoshimura et al., 1980).  Brajter & Slonawska 
(1986) considered Chelex-P(R), a dibasic phosphate ester of 
cellulose, as very efficient for the preconcentration of nickel in 
water samples. A less time-consuming method for the 
preconcentration of nickel in sea water was developed by Watanabe 
et al. (1981), Sturgeon et al. (1982), and McLaren et al. (1985).  
It involved complexation of the trace metals by 8-hydroxyquinoline 
followed by adsorption on C18 chemically bonded silica gel.  Wan et 
al. (1985) achieved a greater enrichment factor, smaller sample 
volume, and removal of interfering humic substances when 
preconcentrating nickel and other trace metals in natural waters on 
XAD-7 regions (cross-linked polymer of methylmethacrylate) in a 
two-step procedure at two different pH values.  A very efficient 
preconcentration method was developed by Burba & Willmer (1985) in 
which trace metals in natural waters were enriched on metal 
hydroxide coated cellulose, using iron hydroxide and indium 
hydroxide.  The use of gallium hydroxide as a coprecipitation agent 
for multi-element determination in sea water, and zirconium 
hydroxide as a coprecipitation agent for multi-element 

determination in sea and fresh water has been described (Akagi et 
al., 1985a,b).  Zirconium caused spectral interferences in the 
inductively coupled plasma atomic emission spectrometry, whereas 
coprecipitation with gallium proved to be more efficient with lower 
limits of detection in subsequent analysis. 

2.2.4.  Analytical methods

    The two most commonly used analytical methods for nickel are 
atomic absorption spectroscopy and voltammetry. 

    In biological samples, such as tissues and body fluids, nickel 
concentrations are routinely determined by electrothermal atomic 
absorption spectroscopy (EAAS).  Acid digestion is required before 
analysis of biological samples, which is commonly followed by an 
enrichment step.  The IUPAC Subcommittee on the Environmental and 
Occupational Toxicology of Nickel (Sunderman, 1980) developed a 
reference method for the determination of nickel in serum or urine 
by EAAS, after acid digestion and the subsequent extraction of 
nickel with ammonium pyrrolidine dithiocarbamate (APDC) into methyl 
isobutyl ketone (MIBK). 

    The introduction of a Zeeman-compensated system improved 
background compensation and permitted a more rapid and direct 
determination of nickel levels with considerably lower detection 
limits, which was suitable for routine use.  Sunderman et al. 
(1984a, 1985) applied EAAS with Zeeman background correction for the 
direct determination of nickel in acid-digested serum (detection 
limit, 0.05 µg/litre), in whole blood, and in acid-digested tissue 
homogenates (detection limit, 10 ng/g dry weight).  The suitability 
of this method for the direct determination of nickel in acidified 
urine with a detection limit of 0.5 µg/litre has been demonstrated 
(Sunderman et al., 1986a).  Andersen et al. (1986a) presented an 
even more direct method, which only required dilution of the human 
plasma prior to quantification by Zeeman-corrected EAAS.  The limit 
of detection was 0.09 µg/litre.  Recent progress in voltammetry has 
made this method the most sensitive.  Ostapczuk et al. (1983) used 
a new voltammetric method for the determination of nickel in a 
variety of biological materials following acid digestion of the 
sample.  The method was based on the application of differential 
pulse voltammetry (DPV) after prior interfacial accumulation by an 
adsorption layer of nickel-dimethylglyoxime chelate at the hanging 
mercury drop electrode (HMDE).  The measurement of nickel 
concentrations as low as 1 ng/litre was possible using this method, 
which was also suitable for analysing food samples (Meyer & Neeb, 
1985).  Though it requires time-consuming sample digestion 
procedures, voltammetry is more sensitive, more rapid, and less 
costly than EAAS (Ostapczuk et al., 1983).  An isotope dilution gas 
chromatography-mass spectrometric method for the detection of 
nickel in biological materials at the ng/litre level was recently 
introduced by Aggarwal et al. (1988).  The method depends on the 
preparation of a thermally stable and volatile chelate (chelating 
agents: sodium diethyldithiocarbonate or lithium 
bis(trifluoroethyl) dithiocarbamate) followed by on-column 
injection into a gas chromatographic column and electron 
ionization of the eluted chelate in the mass spectrometer. 

    Analysis for nickel in natural water is frequently performed by 
EAAS following preconcentration.  Large concentration factors 
(200:1) provide detection limits as low as 10 ng/litre in sea-water 
analysis (Bruland et al., 1979).  Inductively-coupled plasma atomic 
emission spectroscopy (ICP-AES) is gaining importance in 
simultaneous multi-element determination.  Provided that there is 
sufficient enrichment, nickel concentrations as low as 60 ng/litre 
can be determined in natural waters (Akagi et al., 1985a). 

    Pilhar et al. (1981) presented DPV-HMDE with prior chelate 
adsorption at the electrode as a simple, rapid, and inexpensive 
procedure for determining nickel levels in natural waters and waste 
water, with a detection limit of 1 ng/litre.  This method is also 
suitable for determining the nickel contents of various kinds of 
food (Valenta et al., 1981; Meyer & Neeb, 1985).  Particle-induced 
X-ray emission makes possible the detection of various trace metals 
in water at the ng/litre level (Ali et al., 1985). 

    Atomic absorption spectroscopy is the most widely used method 
of analysis for nickel in soil.  The sample must undergo acid 
digestion and may be submitted to enrichment procedures.  Detection 
limits are in the mg/kg range (Abo-Rady, 1979a; Sanzolone et al., 
1979; Schmidt & Dietl, 1981) .  Voltammetry, which has been 
successfully used for the determination of nickel in a variety of 
biological samples, has also been applied in the analysis of acid-
digested soil samples, using square wave voltammetry as the more 
efficient method (Ostapczuk et al., 1985b). 

    Determination of nickel in air samples has been performed using 
different methods (NIOSH, 1977b).  However, flame atomic absorption 
spectroscopy (FAAS) is the most commonly used analytical technique 
for measuring the nickel concentration in air samples.  Following 
an acid digestion procedure, 1 µg of nickel in 1 ml sample can be 
detected by this method.  Interference by a 100-fold excess of 
iron, manganese, chromium, copper, cobalt or zinc can be minimized 
by proper burner elevation and the use of an oxidizing flame. 

    A technique suitable for the simultaneous determination of 
several metals in air has been reported (Mackenzie Peers, 1986).  
Following acid digestion of the absorbing cellulose ester membrane 
filter the extracted sample was analysed by ICP-AES with a 
detection limit of 1 µg/sample. 

    Volatile nickel carbonyl in air can be determined by 
colorimetry, as a coloured furildioxime-chelate (Stedman, 1986a), 
or directly, by photometric detection of chemiluminescence 
(Stedman, 1986b).  Detection limits are 1 µg/m3 and 0.2 µg/m3, 

    Electron microscopy and X-ray microanalysis can be used for the 
determination of nickel in single dust particles, such as welding 
fumes and grinding dusts. 


3.1.  Natural occurrence

    Nickel is a ubiquitous element and has been detected in 
different media in all parts of the biosphere.  It is the fifth 
most abundant element by weight after iron, oxygen, magnesium, and 
silicon, and the 24th most abundant element in the earth's crust.  
However, the average concentration of nickel in the earth's crust 
is only about 0.008% (Mason, 1952).  Meteorites have been found to 
contain 5-50% nickel.  Nickel-enriched nodules have been discovered 
on the ocean floor (NAS, 1975). 

3.1.1.  Rocks

    Most nickel occurs in the ferromagnesium minerals of igneous 
and metamorphic rocks, e.g., olivine [(MgFe)2 x SiO4].  Normal nickel 
concentrations in igneous rocks range from 2 to 60 mg/kg (acidic 
rocks), 50-200 mg/kg (basic rocks), and 10-2000 mg/kg (ultramafic 
rocks) (Boyle, 1981).  Among the major sedimentary rocks, shale and 
carbonate rocks contain an average of 50 mg nickel/kg; sandstone 
contains only 1 mg nickel/kg (NAS, 1975). 

    The most commercially important nickel ore deposits are 
accumulations of nickel sulfide minerals in ultramafic igneous 
rocks.  Such deposits are found in Australia, Canada, and the USSR.  
The ores are composed almost entirely of pentlandite [(Fe,Ni)9S8], 
chalcopyrite (CuFeS2), and pyrrhotite (FexSx+1), and usually 
contain 1-4% nickel (Duke, 1980).  Other nickel ore deposits are 
formed by the weathering of ultramafic ferromagnesium silicate 
rocks in humid tropical areas.  The residual soil (laterite) 
developing during the weathering process may contain up to 10 times 
the amount of nickel in the original rock (Duke, 1980).  The 
nickeliferous lateritic weathering profile is characterized by two 
deposits, an upper oxide zone and a silicate zone, both varying in 
proportion.  The oxide zone is composed of iron oxides containing 
nickel in solid solution.  In the silicate zone, also called the 
garnierite zone, nickel is found in the mineral serpentine 
Mg3Si2O5(OH)5 substituting for magnesium. The nickel content of 
lateritic ores is approximately 1-3% (Duke, 1980).  Important 
deposits are located in Brazil, Cuba, Dominican Republic, 
Guatemala, Indonesia, New Caledonia, and the Philippines. 

3.1.2.  Soils

    In glacial areas, nickel-containing components may have been 
dispersed over wide areas; thus, the nickel contents of the soil 
can differ considerably from the nickel content of the underlying 
    In unweathered glacial sediments, nickel occurs in the same 
mineral phases as those in which it is found in the rocks, i.e., 
sulfides and silicates.  Weathering of rocks and soils leads to 
nickel release from nickeliferous minerals.  The nickel released is 

largely retained in the weathered material in association with clay 
particles and therefore not considered to be very mobile in the 
superficial environment (Duke, 1980). 

    Nickel can exist in soils in several forms (Hutchinson et al., 
1981) including: 

(a) inorganic crystalline minerals or precipitates (e.g., in the 
    lattice of aluminium silicates); 

(b) complexed or adsorbed on organic cation surfaces (e.g., organic 
    matter) or on inorganic cation exchange surfaces (e.g., clay 
    minerals); and 

(c) water-soluble, free-ion, or chelated metal complexes in soil 

    In a soil-water system, nickel may form complexes with 
inorganic ligands (Cl-, OH-, SO42-, or NH3) (Richter & Theiss, 
1980) and organic ligands (e.g., humic or fulvic acids) (Nriagu, 
1980).  Agricultural soils of the world contain between 3 and 1000 
mg nickel/kg (NAS, 1975).  In forest floor samples collected from 
78 sites in 9 states in the northeastern USA, nickel was present at 
concentrations in the range of 8.5-15 mg/kg (Friedland et al., 1986). 

3.1.3.  Water

    Nickel occurs in aquatic systems as soluble salts adsorbed on 
clay particles or organic matter (detritus, algae, bacteria), or 
associated with organic particles, such as humic and fulvic acids 
and proteins. 

    Nickel may enter surface waters from three natural sources 
(Boyle, 1981), i.e., as particulate matter in rainwater, through 
the dissolution of primary bedrock minerals, and from secondary 
soil phases. 

    The fate of nickel in freshwater and sea water is affected by 
several factors including pH, pE, ionic strength, type and 
concentration of organic and inorganic ligands, and the presence of 
solid surfaces for adsorption (Snodgras, 1980). 

    In natural waters, at a pH range of 5-9, the divalent ion Ni2+ 
(Ni(H2O)62+) is the dominant form.  In this pH range, nickel may 
also be adsorbed on iron and manganese oxides, or form complexes 
with inorganic ligands (OH-, SO42-, Cl- or NH3) (Richter & Theiss, 

    If sulfate concentrations are sufficiently high, nickel sulfate 
may be the predominant soluble form; under anaerobic conditions, 
sulfide is the major factor controlling the solubility of nickel 
(Richter & Theiss, 1980).  Nickel concentrations of 0.228-0.693 
µg/litre, determined for a vertical open-ocean water profile, were 
considered to reflect the actual nickel concentration in this 

medium (Bruland et al., 1979).  Concentrations of nickel in 
freshwater systems are generally less than 2-10 µg/litre (Stokes, 
1981).  For nickel levels in drinking-water see section 5.1.2. 

3.1.4.  Fossil fuels

    Nickel occurs in both coal and crude oil in minor quantities, 
originating from vegetation and from percolating waters containing 
nickel leached from rocks.  The average value in some Canadian 
coals was found to be 15 mg nickel/kg (Hawley, 1955).  The nickel 
contents in some Western Canadian crude oils, analysed by Hodgson 
(1954), were in the range of 0.09-76.6 mg/kg. 

3.1.5.  Air

    Atmospheric nickel is considered to exist mainly in the form of 
aerosols with different nickel concentrations in particles 
depending on the type of source (Schmidt & Andren, 1980).  Major 
natural sources include the aerosols constantly produced by the 
oceanic surface, windblown soil dusts, and volcanic ash.  Nickel is 
released from plants during growth, at different levels, depending 
on soil composition.  Forest fires produce nickel-containing smoke 
particles.  A part of atmospheric nickel originates from meteoric 

    Atmospheric nickel concentrations for remote areas that are 
considered to be relatively free from man-made nickel emissions are 
in the range of <0.1-1 ng/m3 (marine) and 1-3 ng/m3 (continental) 
(Schmidt & Andren, 1980). The wide variation in ambient nickel 
concentrations reflects the influence of nickel emissions from 
distant sources being transported by means of meteorological 

    Nickel from natural sources, excluding volcanic dust and forest 
fires, is probably in the form of the oxide (Barrie, 1981). 

3.2.  Man-made sources

3.2.1.  Production, use, and disposal Primary production 

    The methods for the extraction and refining of nickel minerals 
depend on the mineralogical and geological characteristics of the 
ore.  To date, nickel has mainly been extracted from sulfide and 
laterite ores. 

    Nickel sulfide ores are mostly mined underground using 
drilling, blasting, and other techniques.  Milling procedures 
include liberation, flotation, and magnetic separation.  Liberation 
of the sulfides from the gangue includes grinding of the rock 
material.  Then the sulfides are concentrated by flotation 
processes.  Flotation involves streaming air bubbles through an 
aqueous slurry of the ore particles in a flotation cell.  The 
particles that are not wetted by the liquid adhere to the air 

bubbles, rise to the surface of the slurry, and can be removed.  
The addition of different chemicals to the flotation medium allows 
the selective flotation of nickel- and copper-rich fractions. 

    Most of the pyrrhotite (both lump ore and ground ore) can be 
separated magnetically, because of its magnetic properties. 

    Laterite nickel deposits are mined from surface pits using 
earth-moving equipment. 

    Both sulfide ore concentrates and laterite ores are subjected 
to pyro- and hydrometallurgical processes.  The pyrometallurgical 
processing basically involves three operations, i.e., roasting, 
smelting, and converting. 

    During roasting, the concentrate is oxidized by hot air.  Most 
of the iron is oxidized, while nickel, copper, and cobalt remain 
combined with sulfur.  Part of the sulfur is removed as gaseous 
sulfur dioxide. 

    The roasted product is smelted in a furnace together with a 
siliceous flux to obtain two immiscible phases, an iron-rich 
silicate slag and a nickel-rich sulfide matte, which also contains 
iron, copper, and cobalt. 

    The matte is treated in a "converter" where more sulfur is 
driven off and the remaining iron is oxidized and removed as slag.  
The matte is allowed to cool and treated in different ways.  It may 
be, for example, cast into anodes for electrolytic refining or 
cooled slowly to facilitate crystallization to nickel sulfide, 
copper sulfide and a nickel-copper alloy containing the desired 
metals.  These three phases can then be separated by flotation and 
magnetic separation.  The species of nickel likely to be present 
during roasting, smelting, and converting include the ore, nickel 
subsulfides, nickel copper sulfides, nickel oxides, nickel-copper 
oxides, arsenides, and anhydrous nickel sulfate.  The extraction of 
nickel from laterite ores is similar to the extraction of nickel 
from sulfide ores with the exception that sulfur (commonly gypsum) 
has to be added.  The molten matte is charged into a converter 
where the iron is oxidized and the sulfur combines with nickel to 
form Ni3S2. 

    Smelting to ferronickel is essentially the same as matte 
smelting, except that no sulfur is added.  It is often applied to 
laterite ores.  The resulting iron-nickel alloy contains 20-50% 
nickel (Duke, 1980). 

    Most of the nickel matte obtained from sulfide or laterite ore 
smelting undergoes further refining techniques, such as electro-, 
vapo-, or hydrometallurgical refining, but a part of the matte is 
roasted to marketable nickel oxide sinter. 

    Hydrometallurgical refining can be applied both to laterite ore 
and sulfide ore or sulfide ore concentrates.  Soluble nickel amines 
are formed during pressure leaching of the sulfide ore concentrate 
with strong ammoniacal solution at a moderately elevated 

temperature.  The saturated solution is boiled to drive off ammonia 
and precipitate copper as sulfide.  Sulfur is oxidized.  Nickel and 
cobalt are recovered as pure metal powders by reduction with 
hydrogen under pressure. 

    Laterite ores must first be reduced.  The reduced ore is 
leached with an ammonia-ammonium carbonate solution.  Nickel 
dissolves as nickel amine.  The saturated solution is heated by 
steam, ammonia is driven off, and nickel is precipitated as a basic 

    Pure nickel (99.9%) can be produced by electrolytic refining.  
Generally, an impure metal anode (produced by reducing nickel 
oxide) and a cathode starting sheet are placed in an acidic 
electrolytic solution.  When a current flows, nickel and other 
metals are dissolved from the anode.  The electrolyte is then 
removed, purified and returned to the cathode compartment, where 
nickel is deposited on the cathode. 

    During vapometallurgical refining, impure metal obtained by the 
reduction of nickel oxide is subjected to the action of carbon 
monoxide forming volatile nickel carbonyl [Ni(CO)4] (carbonyl or 
Mond process).  This reaction is reversed by heat and the nickel 
carbonyl decomposes to pure nickel metal and carbon monoxide.  The 
carbonyl process produces the purest nickel (99.97% or more). 

    The smelting and refining processes yield various marketable 
forms of nickel of different purities (Table 3). 
Table 3.  Commercial forms of primary nickela
Type                                   Composition (%)
               Nickel  Carbon   Copper  Iron    Sulfur   Cobalt   Oxygen  Silicon  Chromium   
Pure unwrought nickel

Cathode        >99.9   0.01     0.005   0.002   0.001    -        -       -        -

Pellets        >99.97  <0.1     0.001   0.0015  0.0003   5 x 10-5 -       -        -

Powder         99.74   <0.1     -       <0.1    <0.01    -        <0.15   -        -

Briquettes     99.9    0.01     0.001   0.002   0.0035   0.03     -       -        -

Rondelles      99.25   0.022    0.046   0.087   0.004    0.37     0.042   -        -

Ferronickelb   20-50c  1.5-1.8  -       Rest    <0.3     -c       -       1.8-4    1.2-1.8

Nickel oxide   76.0    -        0.75    0.3     0.006    1.0      Rest    -        -
a  Modified from: Corrick (1977).
b  Ranges used to denote variable grades produced.
c  Cobalt included with nickel (1-2%). Intermediate products and end-use 

    Most of the nickel produced is used in the production of alloys 
(Table 4).  In the production of nickel steel alloys, steel scrap, 
limestone, iron oxide ore, and nickel are charged into a furnace 
(open-hearth furnace, electric arc furnace and cupola) where the 
steel and iron alloys are melted.  After final adjustment of the 
carbon and alloy contents, the steel is cast into moulds.  Non-
ferrous melting is commonly performed in a reverberatory furnace.  

Table 4.  Consumption of nickel by 
intermediate product and end-use industry in 
1985 in the USA
Index                           Consumptiona
                                (% of total)
Intermediate product

Stainless and alloy steels      42
Nonferrous alloys               36
Electroplating                  18

End-use industry

Transportation                  23
Chemical industry               15
Electrical equipment            12
Construction                    10
Fabricating metal products      9
Petroleum                       8
Household appliances            8
Machinery                       8
Other                           7
a  Data from: US Bureau of Mines (1986).

    The forming and shaping of ingots, after the casting of the 
alloy, is performed by hot-working, grinding, and welding.  Hot-
working includes the reduction of the cross section, e.g., by 
forging or rolling.  The resulting product may be cut and then 
extruded to the desired form.  Grinding is necessary to condition 
the metal surface for further processing, e.g., welding.  Welding 
techniques, such as electric-arc, electric-spot oxyacetylene-torch, 
or furnace-brazing, are used to fabricate assembled shapes.  In 
special cases, forming of parts may also be performed by sintering, 
e.g., by sintering nickel powder from the Mond process. 

    The addition of nickel to steel and cast iron yields an alloy 
with increased strength and toughness and resistance to corrosion.  
Stainless steel is used in the chemical and food-processing 
industries.  Because of their ferromagnetic properties, iron-nickel 
alloys are important materials for the electrical industry. 

    Various medical devices, such as prostheses or orthopaedic 
implants, are made from stainless steel. 

    Nickel-copper alloys exhibit the highest mechanical strength 
and resistance to corrosion and are used in the chemical and 
machine industries (pipes, nozzles, machine parts for the food and 
textile industries).  Their high resistance to corrosion makes 
these alloys a valuable material for the shipbuilding industry.  
The nickel-copper alloy containing 77-63% nickel is known as Monel 

    Nickel alloys containing chromium, molybdenum, aluminium, 
cobalt, titanium, or combinations of these elements are of special 
industrial importance, because of their high-temperature 

    Nickel-chromium alloys are used for jet engine components, in 
nuclear reactors, and for turbine blades.  Superalloy is an 
extremely high-temperature resistant alloy containing 10-20% 
cobalt.  It is used in turbine blades and other engine components 
of jets, ships, and racing vehicles, where extreme mechanical and 
high-temperature resistance is required. 

    In plating, nickel gives a hard, tarnish resistant surface that 
can be polished, which makes the finished product suitable for 
consumer items, such as automobile components, household furniture, 
and plumbing fixtures.  Normally nickel-plated consumer items are 
covered with a thin layer of chromium plating. 

    Other important uses of nickel are in nickel-cadmium batteries, 
electronic equipment, and computers.  Nickel compounds are used as 
catalysts in the manufacture of organic chemicals, petroleum 
refining, and edible oil hardening.  They are also constituents of 
pigments and colours for ceramics and glassware, and of marine 
anti-fouling paint.  In the glass industry, nickel is used in 
moulds for bottles.  Nickel compounds are also used as a coating 
for pressure sensitive papers.  In the United Kingdom, "silver" 
coinage (5 p, 10 p, and 20 p) is based on cupro-nickel alloys 
containing approximately 20% nickel.  Coinage from other countries 
contains higher levels, e.g., Canadian 10 cents (99.8% nickel), and 
French 1 and 2 francs (99.8-99.9% nickel). 

    The production of secondary nickel in the form of scrap 
recovery is a major source of nickel.  Recycled scrap is generally 
melted and refined and subsequently used for the production of 
steels and alloys, similar in composition to those in which it 
entered the recycling process.  Thus, scrap recycling processes are 
analogous with those used in primary production. World production levels and trends 

    The development of global mine production during this decade is 
shown in Table 5. 

Table 5.  Global mine production of nickel, by countrya,b (short tonnes of nickel)
Country or territory                         1980      1981      1982      1983c     1984d     1985d
Albania (content of ore)d                    6 100     6 200     6 400     6 400     6 600     6 600
Australia (content of concentrate)           81 927    81 963e   96 510    84 465    82 900    81 000
Botswana (content of matte)                  17 022    18 200    19 573    20 079    19 300    19 000
Brazil (content of ore)                      2 504e    2 573e    5 306     11 840    12 100    12 000
Burma (content of speiss)                    15        22        22d       22d       22        -
Canadaf                                      203 709   176 642   97 824    134 300   192 000   195 000
Chinad                                       12 000    12 000    13 200e   14 300e   15 400    16 000
Colombia (content of ferroalloys)            -         -         1 100     15 000    15 400    10 000
Cuba (content of oxide, sinter, sulfide)     40 338    42 489    39 790    41 500d,e 35 050    40 000
Dominican Republic                           18 019    20 601    5 838     23 369    26 698g   27 000
Finland (content of concentrate)             7 199     7 566     6 852     5 418     5 500     6 000
German Democratic Republicd                  3 000     3 000     2 800     2 400     2 300
Greece (recoverable content of ore)h         16 796    17 200    5 500d,e  18 500d,e 18 400    16 000
Guatemala                                    7 650     -         -         -         -         -
Indonesia (content of ore)h                  58 738    53 848    50 578    54 430    68 900    70 000
Morocco (content of nickel ore and           148       144e      140       -         -
  cobalt ore)
New Caledonia (recoverable content or ore)   95 451    86 079    66 250    43 542    45 200    44 000
Norway (content of concentrate)d             2 200e    7 700e    3 900e    4 000e    3 900e
Philippines                                  51 934    32 239    22 183    17 522    18 300    25 000
Poland (content of ore)d                     2 300     2 300     2 300     2 300     2 300     -
South Africa, Republic of                    28 239    29 100    24 250d   22 600d   27 600    27 000
USSR (content of ore)d                       170 000   174 000   182 000   187 000   192 000   197 000
USA (content of ore shipped)                 14 653    12 099    3 203     -         14 540g   6 900
Yugoslavia (content of ore)d                 2 200     4 400     4 400e    3 300e    4 400     3 000
Zimbabwe (content of concentrate)            16 617    14 350    14 671    11 186    11 080    11 000
Total                                        858 850e  804 715e  674 590   723 473   819 890   821 000
a  From: US Bureau of Mines (1985; 1986).
b  As far as possible, this table represents recoverable mine production of nickel.  Where data relate 
   to some more highly processed form of nickel, the figure given has been used in place of an 
   unreported actual mine output, to provide some indication of the magnitude of mine output.  See notes 
   in parentheses and footnotes.
c  Preliminary.
d  Estimated.
e  Revised.
f  Refined nickel and nickel content.
g  Reported figure.
h  Includes a small amount of cobalt not reported and not recovered separately.
    The nickel market weakened considerably from 1981 to 1983, 
because of a reduction in demand arising from a recession in the 
economy.  In 1984, production and demand increased again.  From a 
1983 base, the US Bureau of Mines (1986) estimated that there would 
be an increase in the average annual demand of about 2.5%, up 
to 1990. 

    The identified world deposits with an average nickel content of 
approximately 1% or more, contain 143 million tonnes of nickel (US 
Bureau of Mines, 1986).  In addition, there are extensive deep-sea 
resources of nickel in manganese nodules, particularly in the 
Pacific Ocean (US Bureau of Mines, 1986). 

    At present, there are only a few actual and potential 
substitutes for nickel, e.g., aluminium, coated steel, titanium, 
and plastic for industrial purposes, and platinum, cobalt, and 
copper for catalytic uses.  However, the use of these substitutes 
results in increased costs and a lower quality end-product (US 
Bureau of Mines, 1986). Emissions from the primary nickel industry 

    Data on the loss of nickel into the environment during 
production are limited.  The smelting and roasting stages of ore 
refining and alloy production may be considered as the more 
important sources of nickel emission, because these processes 
generate flue dust, i.e., fine particulate matter that is swept 
from roasters and reverberatory furnaces by air and combustion 
gases that pass through these units. 

    During an environmental study initiated by the Ontario Ministry 
of Environment, trace metal emission rates from two nickel smelters 
were calculated on the basis of the results of chimney stack 
emission tests (Chan & Lusis, 1986). 

    The annual emissions of nickel during the study period are 
given in Table 6.  Annual emissions from a 381-m stack of one 
smelter that emits particulates and gases from pyrometallurgical 
smelting processes are listed in Table 7.  This was considered the 
most significant emission source. 

    Data on the chemical forms of nickel released into the 
atmosphere from production processes are practically non-existent.  
In most cases, statements are based on assumptions. 

    Species of nickel emitted into the air from mining garnierite 
and processing it to produce ferronickel at a facility in the USA, 
were assumed to be in the form of silicates, as in the ore, but 
were expected to be minimal (Radian Corporation, 1984).  Depending 
on the temperature reached during drying and calcining, some nickel 
on the surface of ore fragments may become oxidized and emitted as 
iron-nickel oxide (Radian Corporation, 1984).  Emissions during 
roasting and smelting would probably be in the form of nickel oxide 
combined with iron oxide as a ferrite (Radian Corporation, 1984; 
Warner, 1984). 

Table 6.  Yearly emission (in tonnes) 
of nickel (Sudbury Basin, Canada) for 
the period 1973-81a,b
Source            Variation    Nickel
INCO 381-m stack  Maximum      342
                  Average      228
                  Minimum      53

INCO 194-m stack  Maximum      226

INCO Smelter      Maximum      40
(low level)       Average      31
                  Minimum      15

Falconbridge      Maximum
93-m stack        Average      9.6
a  From: Chan & Lusis (1986).
b  Basis: 365 x 24 h/day production.

Table 7.  Average measured emissions
of nickel from a 381-m stack (Canada)
(in kg/h)a
Year              Emission
1973              48
1974              55
1975              15
1976              22
1977              33
1978              20
1979              12
1980              44
Average           31
a  From: Chan & Lusis (1986).

    When producing nickel from the sulfide ore, the process of 
roasting the concentrated ore may lead to the formation of small 
amounts of nickel sulfate and the emission of fine particles that 
are sulfated as they are carried through the flues (Warner, 1984). 

    According to the investigations of Radian Corporation (1984), 
emissions from matte refining processes at a US nickel refinery are 
expected to be predominantly in the form of subsulfide, as the 
processed matte is sulfide, and metallic nickel.  A refinery dust 
sample from a Canadian nickel refinery was calculated to contain 
20% nickel sulfate, 57% nickel sulfide, and 6.3% nickel oxide 

(Gilman & Ruckerbauer, 1962).  Warner (1984) reported a nickel 
content of 5-10% (10% of which was water-soluble) in flue dusts 
from a Canadian smelter; most of these dusts are captured and 
recycled. Emissions from the intermediate nickel industry 

    Fumes from stainless steel melting processes were found to 
contain 5% of total nickel in a water-soluble form.  Chemically, it 
occurs in fumes from stainless steel manufacturing mainly as the 
metallic alloyed element in the iron matrix or in small amounts as 
nickel oxide (Koponen et al., 1981).  Nickel emissions into the 
atmosphere can occur potentially from electroplating, and from 
grinding, polishing, and cutting operations performed on the 
finished product and scrap metal.  However, in the case of 
electroplating, they are considered to be very low or non-existent, 
or are retained in the workplace area (Radian Corporation, 1984). 

    Grinding, polishing, and cutting operations could release 
metallic nickel into the working environment with possible emission 
to the outside atmosphere as a result of work-area ventilation 
(Radian Corporation, 1984). Emissions from the combustion of fossil fuels 

    The major source of airborne nickel is the combustion of fossil 
fuels containing trace amounts of nickel (section 3.1.4).  
Combustion sources include facilities burning coal and oil for 
power generation or space heating. 

    Krishnan & Hellwig (1982) estimated emissions of trace metals 
in the USA from various coal and oil combustion sources (Table 8) 
and showed that nickel was a substantial trace pollutant.  Nickel 
was the only trace metal emitted at a significant rate from 
domestic oil-fired boilers.  The combustion of oil is a much more 
significant source of nickel emissions than the combustion of coal 
and is estimated to contribute 76-98% of the total nickel emissions 
from coal and oil combustion in the USA (Krishnan & Hellwig, 1982).  
A quantitative assessment of source contributions to inhalable 
particulate matter in metropolitan Boston revealed a high 
correlation between inhalable nickel particles (aerodynamic 
diameter, 2.5-15 µm) and residual oil combustion (Thurston & 
Spengler, 1985). 

    Cass & McRae (1983) evaluated routine air monitoring data from 
sites in the South Coast Air Basin of California, in order to 
relate sources to particular trace elements determined in the 
samples.  Eighty-one percent of fine nickel emissions (aerodynamic 
diameter <10 µm) were calculated to arise from fuel oil fly ash.  
However, a similar study by Kowalczyk et al. (1982) failed to 
assign nickel particulate to any specific type of source. 

Table 8.  Emissions of trace metals in the USA from coal and oil combustion (metric tonnes
per year)a
Trace       Utility boilersb  Industrial boilersc  Commercial boilersc  Residential boilersb
            (>264 GJ/h input) (>26 GJ/h input)     (>26 GJ/h input)     (>422 MJ/h input)
            Coal      Oil     Coal      Oil        Coal      Oil        Coal       Oil
Arsenic     149.1     144.7   214.8     54.7       99.3      84.6       60.3       3.2
Beryllium   19.2      7.0     6.2       2.2        3.7       0.1        0.8        4.1
Cadmium     7.7       219.7   4.9       83.9       2.7       128.4      1.6        23.1
Chromium    561.3     87.5    33.3      33.1       7.9       76.8       7.8        2.3
Lead        360.0     61.1    113.3     23.6       58.2      36.5       36.8       19.9
Manganese   407.2     33.7    31.5      7.5        22.8      11.6       163.9      1.2
Mercury     86.9      3.1     4.6       1.0        1.3       1.5        1.0        2.5
Nickel      281.1     877.3   34.0      363.1      14.1      818.0      7.8        216.4
Selenium    120.9     30.9    44.4      11.7       17.4      18.1       14.5       21.2
Vanadium    390.0     4637.0  29.4      1505.0     12.0      3293.0     7.8        6.1
a  From: Krishnan & Hellwig (1982).
b  1978.
c  1977.

    Fly ash emitted from combustion sources has been analysed, in 
order to gain information on the chemical species of nickel present 
in air.  Henry & Knapp (1980) analysed fly ash samples from the 
stacks of oil-fired and coal-fired power plants.  In fly ash 
samples from oil-fired plants, 60-100% of the nickel components 
were water soluble, whereas, with one exception, samples from coal-
fired plants contained 20-80% water-soluble material.  As the 
sulfate ion was the only major ion detected in the water-soluble 
phase, it was concluded that nickel sulfate is the predominant form 
of nickel in emissions from oil-fired and coal-fired power plants.  
This conclusion was confirmed by Fourier transform infrared 
analysis (Gendreau et al., 1980). 

    Analysis of filter-collected fly ash from five oil-fired units 
revealed the presence of metals, including nickel, as sulfates in 
the soluble phase (Dietz & Wieser, 1983).  As the sulfate amount 
measured by ion chromatography was, on average, 17% less than the 
sulfate amount expected from stoichiometric considerations, Dietz & 
Wieser (1983) suggested that some of the soluble nickel might have 
been present as partially soluble oxide or very finely dispersed 
particles of metal oxide. 

    Major components in the insoluble phase of fly ash samples from 
oil-fired utility boilers were determined by X-ray diffraction to 
be oxides of iron, aluminium, calcium, and silicon, and possibly 
nickel oxide (Henry & Knapp, 1980). 

    Hulett et al. (1980) studied the 100-200 µm fractions of fly 
ash specimens from 4 coal-fired power plants.  They separated the 
ash magnetically into 3 insoluble fractions, i.e., glass, mullite-

quartz, and magnetic spinel.  Chemical determination showed that 
90% of the nickel was present in the magnetic spinel phase.  The 
nickel was assumed to be in the form of a substituted spinel, 

    The results of studies by Hansen & Fisher (1980) and Hansen et 
al. (1984) indicated that most of the nickel, present in coal 
combustion fly ash particles, was soluble and associated primarily 
with sulfate. 

    Thus, nickel emissions into the atmosphere from coal and oil 
combustion are considered to be composed predominantly of nickel 
sulfate, with smaller amounts of nickel oxide and nickel combined 
with other metals in complex oxides. 

    Another potentially important source of nickel in the 
environment is the combustion of diesel oil, which can contain 2 mg 
nickel/litre (2 ppm) (Fishbein, 1981).  The vapour phase of diesel 
engine exhaust may also contain nickel carbonyl.  In urban air near 
a busy intersection, Filkova & Jäger (1986), using EAAS, measured 
nickel carbonyl concentrations in the range of 0-14.1 ng/m3. Emissions from sewage sludge and waste incineration 

    Estimates made by Schmidt & Andren (1980) (section 4.1.1) 
indicated that, after fuel combustion, and nickel mining and 
refining, waste and sewage sludge incineration is the next major 
source of nickel emissions. 

    Evaluation of emission data from sewage sludge incinerators 
indicated that less than 1% of the nickel contained in the sludge 
feed was emitted as a fume, while the major part was emitted as fly 
ash (Gerstle & Albrinck, 1982).  Dewling et al. (1980) noted that 
80% of the nickel in the feed sludge of a fluidized bed, wastewater 
sludge incinerator in north-west Bergen was retained in the ash.  
Emission rates may vary widely, depending on combustion 
temperature, sludge composition, pollution control devices, and 
type of incinerator (Gerstle & Albrinck, 1982; Samela et al., 
1986).  Nickel species present in emissions from sewage sludge and 
waste incineration were analysed by Henry and co-workers (1982).  
The water-soluble phase of sewage sludge incinerator emissions 
contained mainly sulfate ions, indicating that the water-soluble 
nickel existed in the sulfate form.  The soluble phase of refuse 
incinerator emissions also contained chloride ions, suggesting that 
nickel can be present in this phase as the chloride or sulfate.  
The insoluble phases of emissions from the two sources were similar 
and it is highly probable that the nickel may exist as complex 
oxides and iron spinels. Miscellaneous emission sources 

    Nickel can be emitted during cement manufacturing and asbestos 
mining and milling, because nickel is a natural component of the 
minerals used in these operations. 

    During cement manufacturing, nickel is emitted, either as a 
component of the clays, limestones, and shales, used as raw 
materials, or as an oxide formed in the high temperature process 
kilns.  Swedish cement was found to contain 5-59 mg nickel/kg 
(Wahlberg et al., 1977). 

    Crude chrysotile asbestos fibres from different mines in Canada 
(Quebec) contained 63-389 mg nickel/kg.  In the host rock, the 
nickel content was 265-3075 mg/kg. Milled fibres are enriched by a 
factor of 4 (Barbeau et al., 1985).  Nickel emitted into the air is 
expected to be in the form of silicates. Waste disposal 

    Nickel from various industrial processes and other sources 
reaches waste water. 

    Klein et al. (1974) examined the major sources of nickel 
flowing into the New York City municipal wastewater collection 
system.  The electroplating industry was found to be the dominant 
source of nickel (62%) in wastewater treatment plants.  The total 
daily amount of nickel discharged into the sewers by electroplating 
firms was estimated to be 508 kg.  The effluent of an 
electroplating factory in India contained 578.12 mg nickel/litre 
(Ajmal & Khan, 1985).  Residential sources contribute 25% of the 
nickel in waste water, 3% comes from other industrial sources, and 
10% from run-off.  The total amount of nickel reaching the harbour 
of New York City, estimated to be 978 kg/day, originated as 43% 
from the treatment plant effluents, 30% from run-off, 20% from 
untreated waste water and 7% from sludge.  Nickel concentrations in 
the influents of 12 wastewater treatment plants ranged from 0.05 
to 0.31 mg/litre. 

    In the raw sewage of 25 full-scale municipal sewage-treatment 
plants, the nickel concentration varied between undetectable and 
0.69 mg/litre (Sung et al., 1986). 

    Conventional treatment of mixed waste water consists of 
hydroxide precipitation of the metals at an alkaline pH, followed 
by removal of the resulting solids by sedimentation and, sometimes, 
filtration.  Chen et al. (1974) reported a removal efficiency of 
the secondary treatment process (sludge activation and 
sedimentation) of 25-57%.  The final effluent contained 0.14-0.177 
mg nickel/litre.  Sung et al. (1986) measured nickel levels in the 
influents and effluents of 25 sewage-treatment plants in the USA.  
In treatment plants with 50% minimum removal efficiency, 50% or 
more of the nickel was removed in the primary effluent at 5% of the 
plants; 50% or more was removed in the secondary effluent in 11% of 
the plants, and 50% or more was removed in the discharge of 10% of 
the plants. 

    Finally, residues from wastewater treatment are disposed of by 
deep-well injection, ocean dumping, land treatment, landfill, or 
incineration.  Deep-well disposal is limited to residual liquids 
containing low levels of suspended solids and is most applicable to 
scrubber water blow-down.  Ocean dumping is a source of 
contamination for coastal areas.  Land treatment, such as sewage 
sludge treatment of agricultural soils, is a potential source of 
soil, and subsequent food plant, contamination. 

    Leachates from landfills may contaminate ground water and may 
contain 1.85-8.2 mg nickel/litre (Hrudey, 1985).  Incineration of 
sewage sludge gives rise to considerable air emissions. 


4.1.  Transport and distribution between media

    Nickel is introduced into the environment from both natural and 
man-made sources (section 3).  It is circulated throughout all 
environmental compartments (atmosphere, pedosphere, hydrosphere, 
and biosphere) by means of chemical and physical processes, such as 
wet and dry deposition, and, to a much lesser extent, by means of 
the biological transport mechanisms of living organisms. 

4.1.1.  Air

    Nickel is emitted into the atmosphere from various natural 
sources, as indicated in Table 9.  As only limited data are 
available concerning the relative quantities emitted, estimates 
have been made.  Estimated emission values vary depending on the 
impact that is attributed to individual sources.  Barrie (1981) 
considered sea spray to be a major contributor of atmospheric 
nickel.  Generally, soil and volcanoes appear to be major sources 
and may contribute 40-50% of airborne nickel from natural sources. 

Table 9.  Global emission of nickel from 
natural sources to the atmosphere.  
Emission rate (106 kg/year)
Source          Nriagu   Schmidt &      Barrie
                (1980)   Andren (1980)  (1981)
Soil dust       20       4.8            7.5-37.5
Volcanoes       3.8      2.5            10-60
Vegetation      1.6      0.82           1.5-20
Forest fires    -a       0.19           0.3-15
Meteoric dust   -        0.18           -
Sea salt        -        -              27
Sea aerosol     -        0.009          -

Total           26b      8.5            46-160
a  No data available.
b  Total includes 0.6 for "others".

    Estimated man-made inputs into the atmosphere exceed the 
natural inputs (Tables 9 and 10).  It has been estimated that the 
total amount of nickel that has been dispersed into the world 
ecosystems through the atmosphere is 1.0 x 109 kg (Nriagu, 1979).  
As indicated in Table 10, combustion of oil and incineration of 
waste contribute more than 70% of the nickel from man-made sources, 
followed by nickel mining and refining with 17%. 

Table 10.  Global emission of nickel from 
man-made sources to the atmospherea
Source                   Emission rate
                         (106 kg/year)
Residual oil combustion  17
Fuel oil combustion      9.7
Nickel mining and        7.2
Municipal incinerators   5.1
Steel production         1.2
Gasoline and diesel      0.9
  fuel combustion
Nickel alloy production  0.7
Coal burning             0.66
Cast iron production     0.3
Sewage sludge            0.048
Copper-Nickel alloy      0.04

Total                    42.85
a  Adapted from: Schmidt & Andren (1980).

    The transport and distribution of nickel particulates to, or 
between, different environmental compartments is strongly 
influenced by particle size and meteorological conditions.  
Particle size is primarily a function of the emitting source.  
Generally, particles from man-made sources are finer than dust 
particles of natural origin, e.g., soil (Beijer & Jernelöv, 1986).  
As the highest nickel concentrations are found in the smallest 
particles collected from ambient air (Lee & von Lehmden, 1973; 
Natusch et al., 1974), these particles are of special environmental 
and toxicological significance.  There is evidence that fine 
particulate matter, which has a longer residence time in the 
atmosphere, is carried a long distance, whereas larger particles 
are deposited near the emission source (Beijer & Jernelöv, 1986).  
Schmidt & Andren (1980) estimated an atmospheric residence time for 
nickel particulates of 5.4-7.9 days. 

    There are no data on the chemical forms of nickel from natural 
sources in the atmosphere.  When considering the composition of the 
source, a part of airborne nickel may exist as pentlandite 
((FeNi)9S8) and garnierite (a silicate mixture) (Schmidt & Andren, 
1980).  The chemical composition of nickel compounds released from 
man-made sources differs from that of compounds from natural 
sources because of the different processes involved.  Flue dust 
analysis revealed a predominance of oxides and sulfates (section 
3).  Alterations in the chemical forms, following distribution in 
the atmosphere, have not been investigated. 

    The fate of nickel carbonyl, the only gaseous nickel compound 
of environmental importance, may be deduced from its chemical 
properties.  Nickel carbonyl is unstable in air and decomposes to 
form nickel carbonate.  At 25 °C, the lifetime of ng/m3 
concentrations of nickel carbonyl is about one minute, increasing 
by one minute for each mg/m3 of carbon monoxide present (Stedman & 
Hikade, 1980). 

4.1.2.  Water

    Nickel is introduced into the hydrosphere by removal from the 
atmosphere (wet and dry deposition of naturally and 
anthropogenically released nickel), by surface run-off, by 
discharge of industrial and municipal waste, and following the 
natural erosion of soils and rocks. 

    In surface or ground waters not polluted by human beings, the 
nickel content often reflects the weathering process of the parent 
soil or rock.  However, data are insufficient to separate natural 
geochemical effects from man-made influences.  Keller & Pitblado 
(1986) demonstrated a relationship between elevated nickel levels 
in Sudbury area lakes and nickel-emitting sources. 

    In rivers, nickel is transported mainly as a precipitated 
coating on particles and in association with organic matter; in 
lakes, the ionic form and the association with organic matter are 
predominant (Snodgras, 1980). 

    Nickel may be deposited in the sediment by such processes as 
precipitation, complexation, adsorption on clay particles, and via 
uptake by biota.  Because of microbial activity or changes in 
physical and chemical parameters, including pH, ionic strength, and 
particle concentration, sorption processes may be reversed (Di Toro 
et al., 1986) leading to release of nickel from the sediment. 

    Part of the nickel is transported via rivers and streams to the 
ocean.  Riverine suspended particulate input is estimated to be 135 
x 107 kg/year (Nriagu, 1980).  Industrial and municipal waste and 
atmospheric fallout contribute 0.38 x 107 kg/year and 2.5 x 107 
kg/year, respectively (Nriagu, 1980). Possible routes of removal of 
nickel particulate are scavenging by ferromanganese phases on the 
ocean floor or algae.  The average residence time of nickel in the 
deep ocean is calculated to be 2.3 x 104 years (Nriagu, 1980). 

4.1.3.  Rocks and soil

    Nickel occurs naturally in several types of rocks (section 3.1) 
and it may enter the surface environment by the chemical and 
mechanical degradation of the rock to soil.  Nickel is fractionated 
within the different components of the soil profile, depending on 
the type of soil and soil chemical conditions.  In residual soils 
nickel is preferentially adsorbed on alkali and alkaline earth 
cations in the clay minerals (Boyle, 1981). 

    Depending on soil type, nickel may exhibit a high mobility 
within the soil profile as demonstrated by Heinrichs & Mayer (1980) 
for a brown forest soil in the Solling ecosystem, a relatively 
unpolluted area.  The soil profile in the study area revealed an 
accumulation of nickel in the top organic layer, and a 
concentration increasing with depth in the subsequent mineral 
layer, indicating a high mobility of nickel.  Similar results were 
obtained for peat muck soil profiles (Sapek & Sapek, 1980).  In the 
Solling forest ecosystem study, comparison of flux data and 
ecosystem output (seepage) and input (precipitation) showed that 
nickel was balanced within the ecosystem and that the forest 
ecosystem was neither a source nor a sink in the geochemical cycle 
of nickel.  However, this balance may be disturbed in case of heavy 

    Water solubility, and thus bioavailability to plants, is 
affected by soil pH; decreases in pH generally mobilize nickel.  
Most nickel compounds are relatively soluble at pH values <6.5, 
whereas nickel exists predominantly as insoluble nickel hydroxides 
at pH values >6.7.  Therefore, acid rain has a pronounced tendency 
to mobilize nickel from soil and increase nickel concentrations in 
ground water, leading eventually to increased uptake and potential 
toxicity for microorganisms, plants, and animals (Sunderman & 
Oskarsson, 1988).  Other factors are the numbers of organic and 
inorganic cation exchange sites, the adsorption strength, and the 
relative numbers of other cations competing with nickel for cation 
exchange sites (Hutchinson et al., 1981).  Depending on the 
geochemical characteristics of soils, nickel may become distributed 
among the different soil compartments finally reaching ground water 
and, thus, rivers and lakes.  Transport of nickel to river systems 
and oceans is also mediated by erosion and run-off processes. 

    The main man-made sources of nickel contamination in soils are 
emissions from nickel smelting and refining and disposal of 
contaminated sewage sludge.  Atmospheric input of nickel into the 
soil and inputs by waste disposal and through the application of 
fertilizers are estimated to be 5.5 x 104 kg/year and 1.4 x 104 
kg/year, respectively (Nriagu, 1980).  On the basis of the nickel 
pool in soils and the denudation of nickel from continents, the 
residence time of nickel in soils is calculated to be approximately 
3500 years (Nriagu, 1980). 

4.1.4.  Vegetation and wildlife

    Terrestrial plants take up nickel from soil primarily via the 
roots.  The nickel concentrations in most natural vegetation range 
from 0.05 to 5 mg/kg dry weight (NAS, 1975).  The amount of nickel 
uptake from the soil depends on various geochemical and physical 
parameters including the type of soil, soil pH, humidity, the 
organic matter content of the soil, and the concentration of 
extractable nickel. 

    Although nickel concentrations exceeding 50 mg/kg (on a dry 
weight basis) are usually toxic for plants (NAS, 1975), nickel-
tolerant species growing on serpentine soils can accumulate nickel 
levels that are orders of magnitude higher. 

    Aquatic plants are also known to take up and accumulate nickel 
(Jenkins, 1980a).  As algae are at the lower end of many 
foodchains, this fact needs special consideration.  The highest 
nickel levels found in aquatic algae and spermatophytes in 
contaminated areas were 150.9 mg/kg dry weight or 690 mg/kg wet 
weight, respectively, exceeding normal levels by more than 10 times 
(Jenkins, 1980a). 

    Investigations of nickel distribution and cycling in the 
Solling ecosystem indicated a steady state, i.e., a balance between 
atmospheric input and binding in the soil and phytomass (Heinrichs 
& Mayer, 1980).  This steady state may be disturbed by human 
impact, e.g., increase of atmospheric nickel input or acidity of 
rainfall.  Nickel is released into the atmosphere from plant 
exudates and forest fires.  It migrates into soil and surface 
waters following the decay and mineralization of plants. 

    Since nickel occurs in virtually all plants at different 
levels, it may be taken up by herbivorous terrestrial and aquatic 
animals and their predators.  Increased nickel levels in vegetation 
can give rise to increased nickel contents in grazing animals and 
their predators.  For example, nickel levels were found to be 
higher in the organs of wild ruminants than in those of domestic 
animals, because of the higher nickel content in their grazing 
areas (Groppel et al., 1980). 

4.2.  Uptake and bioaccumulation

4.2.1.  Terrestrial organisms

    The best known phenomenon of nickel accumulation in plants is 
the considerably increased nickel levels found in certain species 
growing on infertile serpentine soils.  Approximately 70 nickel 
hyperaccumulators, i.e., species with nickel concentrations 
exceeding 1000 mg/kg, are known, most of them belonging to the 
genus  Allyssum.  Investigations of nickel-accumulating 
Flacourtiaceae in New Caledonia revealed nickel levels in the range 
of 1000-50 000 mg/kg dry weight (Jaffre et al., 1979).  Yang et al. 
(1985) found a significant inverse correlation between the contents 
of nickel and the nutrients manganese, boron, and sodium in plant 
material, thus indicating the role of high nickel concentrations in 
serpentine substrates as controlling factors in nutrient uptake.  
Nickel hyperaccumulators are of scientific interest, because of the 
possible use of vegetation, regrowing on mine dumps, for nickel 
exploitation (Brooks, 1980). 

    The major source of nickel accumulation in terrestrial plants 
is the increased occurrence of nickel in soils.  High levels of 
nickel in soils result from nickel-emitting industrial sources 
(Rutherford & Bray, 1979; Polemio et al., 1982; Alloway & Morgan, 
1986; Gignac & Beckett, 1986) and sewage sludge treatment (Berrow & 
Burridge, 1981; Chang et al., 1984).  Nickel was found to be more 
available to plants from soils treated with sewage sludge than from 
inorganically polluted soils (Alloway & Morgan, 1986).  The total 

nickel content in sludge samples collected from different municipal 
sewage treatment plants in the USA was in the range of 21-1990 
mg/kg dry weight (Sung et al., 1986).  Coker & Matthews (1983) 
reported a nickel content of 10-2000 mg/kg dry weight in sewage 
sludge applied to land in the United Kingdom in 1977.  The 
persistence of nickel in acetic acid-extractable form in soil was 
found to be 10 years (Berrow & Burridge, 1981).  Nickel in polluted 
soils was found to be highly concentrated in the upper organic soil 
horizon (Chang et al., 1982; Brown et al., 1983a; Chang et al., 
1984), probably because of the high cation exchange capacity of the 
surface organic layer (Hutchinson et al., 1981). 

    In a research project initiated by the Federal Environmental 
Protection Agency of Germany, vegetables and plant crops were grown 
on soils that were polluted with nickel (average 558 mg/kg soil) 
through sewage sludge application (Grössman, 1988).  Levels in 
green vegetables, different types of cabbage, and onions ranged 
from 10.8 to 65 mg nickel/kg dry weight.  In beans and peas, nickel 
levels ranged from 42 to 65.1 mg/kg and 16.5 to 23.4 mg/kg dry 
weight, respectively.  In root vegetables, nickel was accumulated 
to a lesser extent; concentrations of 7.95-26.9 mg nickel/kg dry 
weight were measured.  Increasing nickel concentrations in the soil 
resulted in increasing nickel accumulation in the plants.  This 
also held true for maize used as fodder for animals.  However, in 
maize, nickel levels were generally lower ranging from 2.32 to 4.27 
mg/kg dry weight in kernels, 6.69 to 10.7 mg/kg in leaves, and 4.33 
to 5.53 mg/kg in stems.  The nickel concentration in the soil was 
745 mg/kg. 

    Reddy & Dunn (1984) grew soya beans on sewage sludge-treated 
soil in glass houses and found increasing nickel levels in plant 
tissues with increasing rates of sludge application.  Concentrations 
were greater in leaves than in stems and ranged from 2.1 to 8.5 
mg/kg dry weight in leaves and from 1.2 to 6.2 mg/kg dry weight in 
stems, following application of 0-8.4 kg nickel/ha.

    Keefer et al. (1986) found accumulation of nickel in both the 
edible and inedible parts of vegetables grown on soils treated with 
different types of sewage sludge.  Nickel loading of the soil was 
in the range of 2-2540 kg/ha.  Nickel concentrations detected in 
cabbage heads were 2.04-22.1 mg/kg dry weight (control, 3.78 
mg/kg).  Radish roots and tops contained 1.28-12.3 mg nickel/kg 
(control, 1.64 mg/kg) and 3.12-18.3 mg/kg (control, 3.16 mg/kg), 
respectively.  In green bean leaves and pods, nickel levels were 
4.68-14.0 mg/kg (control, 4.00 mg/kg) and 5.0-11.0 mg/kg (control 
5.04 mg/kg).  The water-soluble nickel concentration in sewage 
sludges was related to nickel uptake in the species tested.  Soil 
characteristics, such as texture, drainage status, and sorptive 
capacity, play a dominant role in nickel availability to plants.  
When vegetables were grown in greenhouse pots on sewage sludge-
treated soils of a calcareous loam, a clay, and a sandy loam type, 
the highest nickel accumulation occurred in cabbage grown on clay 
and lettuce grown on sandy loam (Alloway & Morgan, 1986).  Gignac & 
Beckett (1986) found a negative correlation between the nickel 
content of peat and the percentage organic content. 

    Increased acidity of soils resulting, e.g., from SO2- emission, 
enhanced nickel solubility and uptake by plants (Hutchinson & 
Whitby, 1977; Brown et al., 1983b; Sanders et al., 1986).  Liming 
of soil can reduce nickel uptake by plants (Machelett & Podlesak, 
1980; Francis et al., 1985). 

    Nickel accumulation in plants growing in the vicinity of a 
nickel smelter was investigated by Hutchinson & Whitby (1977).  The 
nickel contents of foliage from  Comptonia peregrina, Deschampsia 
 flexuosa, Acer rubrum, and  Betula papyrifera, growing at a distance 
of 1.6 km from the Coniston nickel smelter near Sudbury, Ontario, 
were 113 mg/kg, 902 mg/kg, 109 mg/kg, and 148 mg/kg dry weight, 
respectively.  The corresponding nickel concentration in the upper 
soil surface was 2.679 mg/kg dry weight.  The nickel contents of 
the soil and the plant leaves declined with increasing distance 
from the smelter.  Similar observations were reported by Gignac & 
Beckett (1986) for vascular plant species, sphagnum species, and 
bryophytes growing near Sudbury. 

    Determination of nickel concentrations in plant species growing 
on a copper mine spoil heap demonstrated relative bioconcentration 
values (mg nickel per kg in plants/mg nickel per kg in EDTA soil 
fraction) of 2.7 (leaves) and 1.4 (branches) in  Thlaspi montanum, 
and 2.0 (leaves) and 0.9 (branches) in  Phlox austromontana (Hobbs & 
Streit, 1986). 

    Animals grazing on nickel-contaminated vegetation accumulated 
nickel in various organs.  Wild ruminants grazing near nickel-
emitting industrial sources accumulated nickel in the ribs and 
kidneys at levels of from 1.13-1.50 mg/kg dry weight and 0.47-0.86 
mg/kg dry weight, respectively.  The nickel contents of their 
winter grazing were determined to be in the range of 3.12-14.49 
mg/kg dry weight (Groppel et al., 1980).  Highly elevated nickel 
levels (27 times the control value) were detected in primary flight 
feathers of mallard and black duck in the Sudbury district (20-140 
km from a nickel smelter) (Ranta et al., 1978). 

4.2.2.  Aquatic organisms

    In general, aquatic organisms resorb metals over their entire 
surface.  They also incorporate metals from their food.  In rooted 
aquatic plants, metals can be absorbed not only by the roots but 
also by submerged stems and leaves (Mortimer, 1985).  Most groups 
of aquatic organisms include some species capable of accumulating 
nickel (Jenkins, 1980a).  The highest levels have been found in 
aquatic organisms near sources of pollution, especially nickel 

    Clark et al. (1981) studied the accumulation and depuration of 
nickel by the duckweed  Lemna perpusilla.  Plants collected from a 
fly-ash pond were allowed to depurate in dechlorinated tap water at 
20 °C for 14 days.  Accumulation was then examined over a 10-day 
period and depuration over the following 8 days.  During the 14-day 
depuration period, nickel concentrations fell from 160 mg/kg dry 
weight to less than 40 mg/kg dry weight and, in clean water, 
remained at this level.  When exposed to 0.1 mg nickel/litre in the 

water, duckweed accumulated nickel to levels of about 800 mg/kg dry 
weight at the end of a 10-day exposure period.  The peak 
bioaccumulation concentration of nickel occurred 2 days after the 
depuration period began, with most nickel elimination occurring in 
the 2 succeeding days.  After 8 days, the nickel level was down to 
the original value of <160 mg/kg.  Because the concentration of 
nickel in the water of the fly-ash pond was also about 0.1 
mg/litre, greater accumulation occurred in the laboratory than in 
the field. 

    Cowgill (1976) found that  Euglena gracilis accumulated nickel 
to a concentration of 1.8 mg/kg dry weight when exposed to 8.9 x 
104 mg nickel/litre in spring water.  A biological concentration 
factor of about 2000 was calculated. 

    In a study by Hutchinson & Czyrska (1975),  Lemna minor was 
collected from 23 ponds and lakes in Southern Ontario in which the 
mean content of nickel in the water was 0.027 mg/litre.  The plants 
contained 5.4-35.1 mg nickel/kg dry weight, equivalent to 
concentration factors of 200-1300.  The authors also cultured  Lemna 
 minor in a growth medium containing 0.01-1.00 mg nickel/litre at a 
temperature of 24±52 °C and a pH of 6.8, for 3 weeks.  Nickel 
accumulation ranged from 4000 (0.01 mg nickel/litre in the growth 
medium) to 6134 (0.5 mg nickel/litre in the growth medium).  There 
was a correlation between levels of nickel in the plant and levels 
in water.  Nickel accumulation was greater in the presence of 

     Elodea densa, cultivated at 21-25 °C in a flowing water system 
with a constant nickel concentration in the medium of 0.01 
mg/litre, showed an accumulation factor of 200 after 12 days 
(Mortimer, 1985). 

    The highest concentration factor reported, approximately 20 000, 
was found in an aquatic ecosystem study, conducted by Hutchinson et 
al. (1975), in periphyton algae sampled from a section of the 
metal-contaminated Wanapitei river in the Sudbury area.  Analysis 
of aquatic macrophytes, which were collected from metal-
contaminated rivers in this area, indicated a species specificity 
for uptake and a significant correlation between total nickel 
content in the sediment and water and in rooted macrophytes. 

    Watras et al. (1985) studied the accumulation of nickel in two 
levels of a simple aquatic food chain using  Scenedesmus obliquus 
and  Daphnia magna.  The algae accumulated nickel to concentrations 
30-300 times the ambient concentration.  In  Daphnia, concentration 
factors were only 2-12.  There was little difference in 
accumulation from incubation in 63Ni-labelled medium without algae 
or from incubation in labelled medium with labelled algae.  The 
data indicated that direct uptake from the medium rather than 
uptake from ingested algae was the primary accumulation mechanism.  
These results confirmed earlier studies by Hall (1982), who 
described nickel accumulation in  Daphnia magna as the sum of five 
processes occurring in the various body components, namely, 
adsorption to, and desorption from, body and tissue surfaces, 
absorption, retention or storage, and excretion. 

    In the course of the aquatic ecosystem study performed by 
Hutchinson et al. (1975), nickel levels were determined in aquatic 
animals.  Accumulation factors in animals were lower than in 
aquatic vegetation and were found to be 643 in zooplankton, 929 in 
crayfish, and 262 in clams.  In fish species caught in the 
Wanapitei river (42 mg nickel/litre), nickel levels in muscle 
tissue were lower than those in the liver, kidneys, and gills.  The 
predatory yellow pickerel exhibited the highest nickel levels with 
51.6 mg/kg wet weight in kidney tissue, giving a concentration 
value of 229. 

    Calamari et al. (1982) reported nickel levels of 2.9 mg/kg wet 
weight in liver, 4.0 mg/kg in kidneys, and 0.8 mg/kg in muscle in 
 Salmo gairdneri, after 180 days exposure to 1 mg nickel/litre in 
the water.  Nickel levels at the start of the study were 1.5, 1.5, 
and 0.5 mg/kg, in liver, kidneys, and muscle, respectively.  The 
authors also found, by means of a toxicokinetic model, that 
theoretical asymptotic values for liver, kidney, and muscle should 
be reached in 397, 313, and 460 days, respectively, yielding 
bioconcentration values of 3.1, 4.2, and 1.0, respectively.  
Laboratory studies showed that nickel had little capacity for 
accumulation in all the fish species studied.  However, it was also 
demonstrated that this relatively low concentration of nickel in 
tissues could cause biochemical damage.  The range of 
concentrations reported in whole fish in uncontaminated waters, on 
a wet-weight basis, is 0.2-2 mg/kg.  This value could be increased 
by a factor of ten in contaminated areas (Calamari et al., 1984). 

    White et al. (1986) investigated nickel levels in coots  (Fulica 
 americana) resting and feeding by a pond that was used for the 
disposal of fly ash from a nearby coal-fired power plant.  Though 
the nickel concentration in the pond sediment was much higher than 
the concentration in the water (which was below detection limit, 
except at one collection period), accumulation of nickel in coot 
livers was not observed in 2 years of plant operation. 

4.3.  Biomagnification

    Accumulation factors in different trophic levels of aquatic 
food chains suggest that biomagnification of nickel along the food 
chain, at least in aquatic ecosystems, does not occur. 

    Hutchinson et al. (1975), in their investigations on nickel 
compartmentation in an aquatic ecosystem, found large concentration 
factors in the vegetation and decreasing factors in the higher 
trophic levels.  In a small food chain consisting of an alga 
 (Scenedesmus obliquus) and a zooplankton species  (Daphnia magna), 
there was no biomagnification (Watras et al., 1985).  Because 
nickel in aquatic ecosystems decreases in concentration with 
increasing levels of the food chain, biomagnification does not 


5.1.  Environmental levels

5.1.1.  Air

    Owing to the large number of sources releasing nickel into the 
atmosphere and their uneven distribution over the globe, ambient 
nickel concentrations may vary over several orders of magnitude. 

    Urban and rural areas usually exhibit air nickel levels ranging 
from 5 to 35 ng/m3 (Bennett, 1984).  Higher values were recorded in 
heavily industrialized areas and larger cities.  Nickel 
concentrations, monitored continuously over one year in 4 American 
cities, were found to be in the range of 18-42 ng/m3 (Saltzman et 
al., 1985).  In the vicinity of a nickel smelter in the Sudbury 
area, Ontario, levels of 124 ng/m3 were measured (Chan & Lusis, 
1986).  Atmospheric concentrations at Spitsbergen, measured during 
two months, ranged between approximately 1 and 2 ng nickel/m3 
(Pacyna et al., 1985).  In the Canadian Arctic, the annual mean 
concentration was 0.38 ng/m3.  The winter mean was 0.62 ng/m3, 
indicating a seasonal cycle (Hoff & Barrie, 1986).  Assuming a 
ventilation rate of 20 m3 and air concentrations of 5-35 ng/m3, the 
amount of nickel entering the human respiratory tract is in the 
range of 0.1-0.7 µg/day. 

    The distribution of nickel among suspended particulates in the 
air will determine the fraction that is inhalable.  Data on the 
size distribution of nickel particulates are limited.  Lee & von 
Lehmden (1973) summarized data on the size of nickel particulates 
in urban air and found mass median diameters of 0.83-1.67 µm, 28-
55% of the particles being <1 µm.  A more recent summary of size 
distribution of trace elements in different areas yielded a mass 
median diameter for nickel particulates of 0.98 µm (Milford & 
Davidson, 1985).  Particles of less than about 1 µm are deposited 
predominantly in the alveolar regions of the lung (Stern et al., 
1984).  Nickel was found to be most concentrated in the smallest 
particles emitted from coal-fired power plants (Natusch et al., 
1974).  Particles of a mass median diameter of 0.65-1.1 µm 
contained 1600 mg nickel/kg while 4.7-11 µm particles contained 
about 400 mg nickel/kg. 

    Another important route of nickel exposure is tobacco smoking.  
Cigarette tobacco may contain approximately 1.3-4.0 mg nickel/kg.  
About 0.04-0.58 µg nickel is released with the main stream smoke 
(gas phase and particle phase) of one cigarette (Szadowski et al., 
1969a; Menden et al., 1972; Gutenmann et al., 1982).  Smoking 40 
cigarettes per day may result in the inhalation of 2-23 µg nickel 
per day.  The formation of nickel carbonyl in the main stream smoke 
is suspected (Sunderman & Sunderman, 1961a; Stahley, 1973), but it 
could not be detected using Fourier-transform infrared spectrometry 
(detection limit 0.1 µg/litre) (Alexander et al., 1983). 

5.1.2.  Drinking-water

    On the basis of determinations of nickel concentrations in 969 
water supplies in the USA during 1965-70, the average concentration 
of nickel in water samples taken at the consumer's tap was 4.8 
µg/litre (NAS, 1975). 

    In Italy, nickel levels in drinking-water were mostly below 10 
µg/litre (Clemente et al., 1980).  Schumann (1980) measured levels 
of 6.8-10.9 µg/litre in the German Democratic Republic.  Leaching 
processes from water taps and fixtures contribute to nickel levels 
already present in drinking-water.  Between 18 and 900 mg of nickel 
were leached from 10 used water taps, which had been filled, in an 
inverted position, with 15 ml deionized water, and left overnight 
for 16 h (Strain et al., 1980).  In Denmark, levels of up to 490 
µg/litre were observed, when water was left standing overnight in 
nickel-containing plumbing fittings (Andersen et al., 1983). 

    In areas where nickel is mined, as much as 200 µg nickel/litre 
has been recorded in drinking-water (McNeely et al., 1972). 

    Assuming a daily intake of 1.5 litres water and a level of 5-10 
µg nickel/litre, the mean daily intake of nickel from water for 
adults would be between 7.5 and 15 µg. 

5.1.3.  Food

    Nickel is ingested by human beings through the consumption of 
plants and animals that contain nickel.  Nickel levels were 
determined, using EAAS, in foods in the Netherlands by Ellen et al. 
(1978).  They were found to be less than 0.5 mg/kg fresh weight in 
most products, except for cacao products and nuts, which contained 
nickel levels of up to 9.8 and 5.1 mg/kg, respectively.  Smart & 
Sherlock (1987) reported that nickel levels, determined using FAAS, 
in English meat, fruit, and vegetables were of the order of > 0.2 
mg/kg fresh weight.  Aquatic organisms, e.g., molluscs and fish, 
may contain relatively large amounts of nickel, if the nickel 
concentration in the water is high (Table 11). 

Table 11.  Nickel concentrations in aquatic organisms
Species                   Tissue  Locality                  Concentrationa  Reference
                          or                                (mg/kg)

 Lemna minor               whole   Southern Ontario; ponds   5.4-35.1    D   Hutchinson & 
(duckweed)                        and lakes                                 Czyrska (1975)

 Eichhornia crassipes      whole   Yamuna river, India;      4.4-83.0    D   Ajmal et al.
                                  near big cities                           (1985)

Table 11 (contd.)
Species                   Tissue  Locality                  Concentrationa  Reference
                          or                                (mg/kg)
 Fontiralis antipyretrica          Augraben river, Italy;    5.5-10.6    D   Dallinger & 
                                  near motorway                             Kautzky (1985)
                                  Leiferer Graben river,    17.7-29.2   D
                                  Italy; metal industry

 Ranunculus fluitans               Augraben river, Italy;    69          D   Dallinger &
                                  near motorway                             Kautzky (1985)


 Penaeus semisulcatusb     body    AD-Damman, Saudi Arabia;  0.54        W   Sadiq et al.
(shrimp)                  tissue  sewage outfall area                       (1982)

 Paphia undulatab  \               Gulf of Thailand          1.30-2.00   W   Phillips &
(clam)             |                                                        Muttarasin
                   |      whole                                             (1985)
                   |      soft
 Anadara granosab   |      parts                             0.65-2.31   W
(cockle)           |          

 Perna viridisb     \              Gulf of Thailand          0.26-4.74   W   Phillips &
(green mussel)     |                                                        Muttarasin
                   |      whole                                             (1985)
                   |      soft
 Crassostrea        |      parts                             0.60-2.52   W
 commercialisb      |          
(rock oyster)      /

 Crassostrea virginicab    body    Estuary of Mississippi;   2.1         D   Byrne &
(oyster)                  tissue  pollutants from rivers,                   Deleon (1986)
 Rangia cuneatab                   bayous, municipal and
(clam)                            agricultural run-off

Table 11 (contd.)
Species                   Tissue  Locality                  Concentrationa  Reference
                          or                                (mg/kg)

 Elliptio complanata       shell   Great Lakes, Ontario      6.56-7.6    D   Dermott &
(bivalve)                 tissue                            6.79-10.7   D   Lum (1986)

 Mytilus edulisb           tissue  Eastern Scheldt,          0.24-1.0    W   Vos et al.
(mussel)                          Netherlands, 1977-1980                    (1986)

 Crangon crangonb                                            0.13-0.70   W

 Salmo truttab             muscle  Leine river, Germany      0.220-0.220 W   Abo-Rady 
(brook trout)             liver   municipal discharge area  0.327-0.469 W   (1979b)
                          body                              0.359-0.477 W

 Leuciscus cephalusa       muscle  River Danube, Federal     0.5-1.2     W   Wachs (1982)
(chub)                            Republic of Germany
 Vimba vimba (vimba bream)
 Abramis brama (bream)
 Esox lucius (pike)

 Psetta maximaa (turbot)   muscle  Southern Baltic, Poland   0.24        W   Falandysz (1985)

 Pleuronectes platessab                                      0.19        W

 Platichthys flesusb                                         0.14        W

 Heteropnuestes fossilisb  muscle  Yamura river, India;      1.9-32.7    D   Ajmal et al.
                                  near big cities                           (1985)

 Basilichthys bonariensisb whole   Lago Poopo, Bolivia; tin  1.37        D   Beveridge et 
(pejerry)                 carcass mining and refining area                  al. (1985)

Table 11 (contd.)
Species                   Tissue  Locality                  Concentration   Reference
                          or                                (mg/kg)

 Orestias luteusb                                            2.85        D

 Salmo gairdnerib          gills   Augraben river, Italy;    14.5        D   Dallinger &
(rainbow trout)                   near motorway                             Kautzky (1985)
                          liver                             5.8         D
                          kidney                            7.9         D
                          muscle                            5.9         D
                          gonads                            3.6         D
                          gills   Leifer Graben river,      21.8        D
                                  Italy; metal industry 
                          liver                             8.4         D
                          kidney                            11.5        D
                          muscle                            7.8         D
                          gonads                            9.9         D

 Salvelinus namaycushb     kidney  Lakes near Sudbury,       2.0-5.1     D   Bradley &
(lake trout)                      Ontario                                   Morris (1986)

 Perca flavescensb         muscle                            2.8;3.4     D
(yellow perch)            liver                             2.2;2.9     D

white suckerb             liver                             16.4        D

 Gadus morhua              muscle  Southern Baltic Sea       0.081       W   Falandysz
(cod)                                                                       (1986a)

 Clupea harengus           muscle  Southern Baltic Sea       0.10        W   Falandysz
(herring)                                                                   (1986b)

 Solea solea               edible  Coast of Netherlands,     0.01-0.05   W   Vos et al.
(sole)                    parts   1977-80                                   (1986)

Table 11 (contd.)
Species                   Tissue  Locality                  Concentrationa  Reference
                          or                                (mg/kg)
 Gadus morhua                                                0.03-0.22   W

 Clupea harengus                                             0.02-0.12   W

 Anguilla anguilla                                           0.02-0.31   W

 Stenella coeruleoalba     cart-   Kii peninsula, Japan      0.029-0.009 D   Honda et al.
(stripped dolphin)        ilage                                             (1984)
                          skull                             0.025-0.083 D
                          verte-                            0.024-0.057 D
                          ribs                              0.036-0.44  D
a  D = dry weight.
   W = wet weight.
b  Intended for human consumption.

    Nickel levels were determined in 234 foods from a 1984 US FDA 
Total Diet Study, using ICP-AES (Pennington & Jones, 1987); 91% of 
the foods contained nickel levels of less than 0.4 mg/kg and 66.2% 
contained levels of less than 0.1 mg/kg.  Only seven foods had 
values exceeding 1 mg/kg.  Foods highest in nickel included nuts, 
legumes, items containing chocolate, canned foods, and grain 

    Food processing and storage methods apparently add to the 
nickel levels already present in foodstuffs through: leaching from 
nickel-containing alloys in food-processing equipment made from 
stainless steel; the milling of flour; and the catalytic 
hydrogenation of fats and oils using nickel catalysts (NAS, 1975).  
Grandjean (1984) estimated that leaching from cooking ware, kitchen 
utensils, and water piping could occasionally add 1 mg to the daily 
intake of nickel, i.e., much more than the intake resulting from 
nickel in food and beverages. 

    Schroeder et al. (1962) calculated the average oral intake of 
nickel by American adults to be about 300-600 µg/day, but more 
recent estimates are lower.  Myron et al. (1978) determined the 
nickel content of 9 typical diets in the USA and calculated an 
average intake of 165 µg/day.  Clemente et al. (1980) evaluated the 
available data and derived a mean intake value of 200-300 µg/day 
for the normal adult in the Western countries.  However, because of 
the wide variation in the nickel contents of single food items, the 
daily intake may vary considerably (100-800 µg/day) as a function 
of dietary habits.  Levels of 250-270 µg/day, determined by Smart & 

Sherlock (1987) for United Kingdom diets, are within this range.  
This includes an estimated 100 µg/day for nickel migrating from 
metal cookware.  An actual measured value using glass cookware for 
food preparation was only 140-150 µg/day.  The maximum daily nickel 
intake from an average Danish diet was calculated to be 900 µg/day 
(Nielsen & Flyvholm, 1984). 

5.1.4.  Terrestrial and aquatic organisms

    Levels in terrestrial and aquatic organisms may vary over 
several orders of magnitude, according to the species and 
environmental factors (Jenkins, 1980a,b).  Tables 11 and 12, 
include data on nickel levels in tissue samples of different 
organisms, including plants and animals relevant to human 

5.2.  General population exposure

    The general population is exposed to nickel species through the 
oral, inhalation, and dermal routes. 

5.2.1.  Oral

    Nickel is ingested through the consumption of foodstuffs and 
beverages that contain nickel and through the ingestion of inhaled 
material returned to the pharynx by mucociliary clearance.  Nickel 
levels in European and USA foodstuffs generally ranged from less 
than 0.1 mg/kg to 0.5 mg/kg, though a few foodstuffs, e.g., nuts 
and legumes, contained levels of more than 1 mg/kg (section 5.1.3).  
The results of dietary studies in the United Kingdom and the USA 
showed average intakes from food of 200-300 µg nickel/day.  In the 
United Kingdom, it has been estimated that 100 µg nickel/day is 
contributed by nickel-containing cooking utensils and that the 
level in food ranges from 100 to 200 µg/day.  Drinking-water may 
contain nickel derived from its source, from environmental 
contamination, and from nickel-containing plumbing fittings.  
Concentrations in uncontaminated water may range from 5 to 11 
µg/litre (section 5.1.2).  Assuming a nickel level of 5-10 µg/litre 
and a daily intake of 1.5 litres water, a mean daily intake of 
nickel from water would be 7.5-15 µg. 

5.2.2.  Inhalation

    Measured atmospheric nickel concentrations have been in the 
ranges of 18-42 ng/m3 in industrial areas and 5-35 ng/m3 in non-
industrial urban and rural areas.  Taking a concentration range of 
5-35 ng/m3 and a daily ventilation rate of 20 m3, 0.1-0.7 µg 
nickel/day will enter the respiratory tract; absorption will then 
be a function of the nickel species and the physical state.  
Cigarette smoking also contributes to the inhalation of nickel; for 
example, smoking 40 cigarettes daily may result in the inhalation 
of 2-23 µg nickel (section 5.1.1). 

Table 12.  Nickel concentration in terrestrial organisms
Species                  Tissue or       Locality                    Concentrationa  Reference
                         organ                                       (mg/kg)
 Aster tripoliumb         shoots          Salt marsh in Netherlands;  0.3-4.9     D   Beeftink &
 Halimione portulacoides                  discharge from urban and    0.1-3.3     D   Nieuwenhuize
 Limonium vulgare                         industrial areas            0.8-5.4     D   (1982)
 Plantago maritima                                                    0.9-4.5     D
 Puccinellia maritima                                                 0.5-5.0     D
 Salicornia europaeab                                                 0.4-4.2     D
 Spartina anglica                                                     0.2-1.8     D
 Suaeda maritima                                                      0.3-4.6     D
 Triglochin martim                                                    0.5-6.2     D
Peanuts                  kernels                                     <0.14-14    W   Wolnik et
Soybeans                 beans (without                              0.35-29     W   al. (1983)
Sweet corn               kernels                                     <0.026-0.35 W
Field corn               kernels                                     <0.2-1.1    W   Wolnik et
Spinach                  leaves                                      <0.02-0.3   W   al. (1985)
Onions                   peeled bulb                                 <0.02-0.16  W
Tomatoes                 fruit                                       <0.002-     W
Rice                     kernels                                     <0.2-1.2    W
Carrots                  root                                        <0.02-0.46  W

 Thlaspi montanum         leaves          Grand Canyon, Arizona;      54          D   Hobbs &
                         shoots          copper mine spoil           27          D   Streit (1986)
 Phlox austromontana      leaves                                      39          D
                         shoots                                      <17         D
 Juniperus osteosperma    leaves                                      8           D
                         shoots                                      17          D

Table 12 (contd.)
Species                  Tissue or       Locality                    Concentrationa  Reference
                         organ                                       (mg/kg)
 Lagopus lagopus          plumage         remote areas in Ontario     0.91        D   Parker (1985)
(willow ptarmigan)
 Bonasa umbellus                                                      0.74        D
(ruffed grouse)
 Canachites canadensis                                                1.09        D
(spruce grouse)

 Egretta alba             muscle          Central Korea               0.03-0.04   W   Honda et
(great white egret)      bone                                        0.03-0.19   W   al. (1985)
                         feather                                     0.14-1.59   W

 Sterna kirundo           liver           Providence, Rhode Island;   ND-1.0      D   Custer et
(common tern)                            former electroplating                       al. (1986)
                                         industry centre

 Fulica americana         liver           Texas; fly ash pond         0.06-0.24   Wc  White et
(coot)                                   control site                0.07-0.22   W   al. (1986)

 Microtus pensylvannicus  liver           Sudbury, Ontario;           ND-9.9      Dd  Cloutier et
                         kidney          nickel and copper mine      ND-18.4     D   al. (1986)
                         muscle          tailings control site       5.9         D

                         liver                                       ND-8.7      D
                         kidney                                      ND-25.3     D
                         muscle                                      5.5         D
a  D = dry weight.
   W = wet weight.
   ND = not detected.
b  Intended for human consumption.
c  No statistically significant difference between sites.
d  Nickel levels in most samples were below detection limit; site effects were not observed.

5.2.3.  Dermal

    This route of exposure is of particular significance for nickel 
contact hypersensitivity.  Because of the ubiquity of nickel-
containing commodities in an industrial society, dermal exposure to 
nickel is almost continuous in the general population.  This is 
reflected by the constantly increasing number of patients with 
nickel contact dermatitis (Dooms-Goossens et al., 1980).  Sources 
of environmental exposure include jewellery, coinage, clothing, 
fasteners, tools, cooking utensils, and stainless steel kitchen 
utensils (NAS, 1975).  Even jewellery made of white gold containing 
2-15% of nickel may cause eczema (Fischer, 1984). 

    A number of common sources of nickel dermatitis are listed in 
Table 13.  The amount of nickel released from these items depends 
on the corrosion resistance of the object and the presence of sweat 
and other fluids in the environment; because of its chloride 
content and relative low pH, sweat can dissolve nickel. The 
solution of nickel in synthetic sweat was examined for 15 different 
nickel alloys and surfaces; a high release of nickel ions was 
documented for nickel-plated items (both electrolytically and 
chemically plated), nickel-iron alloy (65% nickel), German silver 
(10-20% nickel), Monel 400(R) alloy (66% nickel), Nicrobraze LM(R) 
alloy (83% nickel), and coin alloy (25% nickel).  These nickel 
objects were also tested for their ability to provoke nickel 
allergy in sensitized persons.  Nine of the materials tested caused 
a medium to severe degree of allergic skin reactions, and the 
amount of nickel dissolved was related to the degree of the 
allergic reaction (Kato & Samitz, 1975). 

Table 13.  Non-occupational exposure to nickela
Source causing dermatitis            Location
Earrings                             Earlobes
Garter clasps, metal chairs          Thighs
Thimbles, crochet and knitting       Fingers
  needles, scissors, nickel coins,
  cover of fountain pen
Handles of car doors, baby           Palms
  carriage, umbrella, refrigerator,
  and handbags
Clasp of necklace, zipper            Neck
Watch band, bracelet                 Wrists
Wire support of brassiere cup        Breast
Handbags                             Antecubital area
Bobby pins                           Side of face
Spectacle frames                     Back of ears
Nickel coin (patient had rubbing     Side of nose
Eyelash curler                       Eyelids
Zipper                               Axilla
Safety pin                           Pubic area
Eyelets of shoe                      Dorsum of foot

Table 13 (contd.)
Source causing dermatitis            Location
Metal arch support                   Plantar aspect
                                       of foot
Bobby pins held in mouth, metal      Lips
  lipstick cases
Hair gripsb                          Scalp
Jeans buttonsc                       Belly
a  Adapted from: Fisher & Shapiro (1956).
b  From: Cronin (1980).
c  From: Fisher (1985).

    Fisher's dimethyglyoxime spot test can be used, in most cases, 
to identify nickel alloys and nickel-plated surfaces releasing 
nickel ions.  Important exceptions are Inconnel 600(R), which has a 
low nickel release to synthetic sweat, but was positive when tested 
on nickel sensitive patients, and Nicrobraze(R), which has a high 
nickel release and was positive when tested on patients (Menné et 
al. 1987b). 

    Stainless steel, which contains about 10% nickel, is very 
resistant because of the protective effect of chromium oxides on 
the surface.  It did not release noticeable amounts of nickel ions 
into synthetic sweat and did not produce skin reactions in nickel-
sensitive patients (Kato & Samitz, 1975; Menné et al., 1987b).  
However, nickel can be released from stainless steel in a very 
corrosive environment or by prolonged treatment in a sweat 

5.3.  Iatrogenic exposure

    Iatrogenic exposures to nickel arise from: (a) nickel-
containing implants (joint replacements, intraosseous pins, cardiac 
valve replacements, cardiac pacemaker wires, and dental 
prostheses); (b) intravenous fluids and medications that are 
contaminated with nickel; and (c) haemodialysis with nickel 
contamination of the dialysate fluid (Sunderman, 1986; Hopfer et 
al., 1989).  Marek & Treharne (1982) investigated nickel release 
from surgical implant alloys (14 and 36% nickel) into Ringer's 
solution.  Nickel release from the alloy shavings declined after a 
few days and reached a constant value of approximately 0.3 ng/cm2 
per day.  Thus, a prosthesis with a surface area of 200 cm2 would 
release about 60 ng nickel per day or 22 µg/year.  The significance 
of nickel release from implants has been questioned (Fisher, 1977; 
Burrows et al., 1981 ).  Hypernickelaemia (serum-nickel >1.1 
µg/litre) occurred in only one out of 13 patients with stainless 
steel hip prostheses.  This patient suffered from mild renal 
insufficiency, suggesting an impaired ability to excrete nickel 
absorbed from the prosthesis (Linden et al., 1985; Sunderman, 

    Brune (1986) compiled data on the amounts of different metals 
released from dental alloys in natural or artificial saliva in  in 
 vitro and  in vivo tests.  The quantities released were calculated 
on the basis of a standard man with a specified number or area of 
dental restorations.  Nickel was released  in vitro from a metal 
alloy with a high nickel content (ca 80%), at the same level as 
from food and drink.  Nickel release from cobalt-based alloys (0.1-
0.2% nickel) was less than 2 µg per day. 

    Contamination of dialysate fluids may produce parenteral 
exposure to nickel.  Hopfer et al. (1985) demonstrated that serum-
nickel concentrations in haemodialysis patients may, on average, be 
11-22 times the mean concentration in serum from healthy subjects.  
During normal dialysis, the average intravenous nickel uptake has 
been estimated to be 100 µg per treatment (Sunderman, 1983a). 
Hypernickelaemia has also been observed in patients following 
intravenous administration of meglumine diatrizoate (Renografin-
76(R), a radiographic contrast medium) for coronary arteriography.  
Nickel analysis revealed levels of 144±44 µg nickel/litre contrast 
medium.  Approximately half an hour after arteriography, the 
incremental serum-nickel concentration in patients averaged 
1.81±0.39 µg/litre.  The authors recommended that nickel 
concentrations in radiographic contrast media should not exceed 10 
µg/litre (Leach & Sunderman, 1987). 

5.4.  Occupational exposure

    Nickel concentrations may be significantly higher in the 
working environment than normal atmospheric air levels.  US NIOSH 
(1977b) estimated that about 250 000 individuals in the USA were 
occupationally exposed to inorganic nickel.  A list of occupations, 
identified as involving exposure to nickel, is presented in Table 
14 (US NIOSH, 1977b). 

Table 14.  Occupations with potential exposure to nickela
Battery makers, storage         Nickel-alloy makers
Cashiers                        Nickel miners
Catalyst workers                Nickel refiners
Cemented-carbide makers         Nickel smelters
Ceramic makers                  Oil hydrogenators
Disinfectant makers             Organic-chemical synthesizers
Dyers                           Paint makers
Electroplaters                  Penpoint makers
Enamellers                      Petroleum-refinery workers
Gas-mask makers                 Spark-plug makers
Glass makersb                   Stainless-steel makers
Ink makers                      Textile dyers
Jewellers                       Vacuum-tube makers
Magnet makers                   Varnish makers
Metallizers                     Welders
Mond-process workers
a  Adapted from: US NIOSH (1977b).
b  From: Raithel et al. (1981).

    Representative exposure data are difficult to obtain, and most 
published values of occupational exposure were gained during 
biological monitoring studies.  US NIOSH (1977b) compiled data on 
the concentrations of nickel in air, in smelting and refining 
operations, the alloy industry, welding operations, and other 
processes; the concentrations ranged from a few µg/m3 to several 
mg/m3.  Recent exposure data from the primary and secondary nickel 
industries are summarized in Table 15.  Levels may vary 
considerably, according to the individual operations, or areas of a 
manufacturing process.  For example, in alloy production an average 
concentration of airborne nickel during pickling and handling was 
determined to be 0.008 mg/m3, whereas, during grinding,the average 
airborne nickel level was 0.298 mg/m3 (Warner, 1984).  Generally, 
the concentration of nickel in the material being handled and the 
operation being performed affect the concentration of nickel in 
air.  Levels of airborne nickel are expected to be higher in dusty 
operations involving fine, dry particulates, e.g., metal powder or 
salts.  Welding operations can create airborne nickel levels of 
0.004-0.24 mg/m3.  A higher exposure, especially to metallic 
nickel, exists in the user industries.  Improvements in operational 
techniques and ventilation reduce nickel concentrations in the air 
of work-places (Boysen et al., 1982; Coenen et al., 1986). 

    In the occupational environment, nickel dust may also enter the 
body through oral exposure, because of poor personal hygiene or 
inadequate work practices.  This route of exposure was reported in 
a battery factory where high faecal levels of nickel were related 
to dusty working conditions (Adamsson et al., 1980). 

    The dermal route of exposure is of significance to workers 
sensitized to nickel.  Occupational dermal exposure to nickel may 
occur in battery makers, nickel-catalyst makers, ceramics makers, 
duplicating machine workers, dyers, electronics workers, 
electroplaters, ink-makers, jewellers, spark-plug makers, and 
rubber workers (NAS, 1975).  In some occupations, the skin may be 
directly exposed to dissolved nickel, e.g., in the electroplating 
and electroforming industry (Wall & Calnan, 1980).  Nickel contact 
dermatitis was observed in hairdressers and was attributed to the 
handling of nickel-bearing tools and contact with liquids 
throughout the day (Wahlberg, 1975).  Nickel contact dermatitis has 
been reported in hospital cleaning personnel (Gawkrodger, 1986a).  
The level of nickel in the water they used for washing surfaces 
increased during the cleaning process by transfer from cleaned 
areas on wash cloths.  In water from used cloths, a mean level of 
90 µg nickel/litre was found (Clemmensen et al., 1981). 

Table 15.  Occupational exposure to nickel
Process/Operations           Average nickel      Number     Chemical formb     Reference         
                             concentration in    of                                          
                             air (mg/m3)a        samplesb                                    
Nickel mining and refining                                                                   
Mining                       0.025          A    ns         mineral form       Warner (1984)     
Concentrating                0.03-0.13      P    ns         mineral form       Warner (1984)     
Roasting/smelting            <0.1           A    ns         nickel subsulfide  Boysen et         
                                                            nickel oxide       al. (1982)        
Roasting/smelting            0.048; 0.075   A    ns         mineral form,      Warner (1984)     
                                                            nickel subsulfide,                    
                                                            nickel oxide                         
                                                            combined with iron                   
                                                            oxide, nickel                        
Converting                   0.033; 0.037   A    ns         nickel subsulfide  Warner (1984)     
Smelting to ferronickel      0.0022-0.274   P    >79        nickel oxide       Warner (1984) 
                             0.0047-0.029   A               combined with iron                   
                             0.005-0.193    P               nickel subsulfide                    
Hydrometallurgical refining  0.029-0.336    A,P  577        nickel subsulfide, Warner (1984)     
                                                            nickel oxide,                        
                                                            metallic nickel,                     
                                                            nickel sulfate,                      
                                                            nickel chloride                      
Electrolytic refining        <0.1           A    ns         ns                 Boysen et         
                                                                               al. (1982)        
                             0.34; 0.19     A    ns         as under Hydro-    Warner (1984)     

Table 15 (contd.)
Process/Operations           Average nickel      Number     Chemical formb     Reference         
                             concentration in    of                                          
                             air (mg/m3)a        samplesb                                    
Use of primary nickel products                                                               
Stainless steel welding      0.004          A    35         ns                 Wilson et         
                             0.313          P    7          ns                 al. (1981)        
                             0.07-0.24c     P    182        ns                 Coenen et         
                             0.02-0.22c     A    280        ns                 al. (1986)        
Stainless steel production   0.014-0.134    P    40d        nickel oxide,      Warner (1984)     
                                                            metallic nickel                      
High nickel alloy            0.008-0.298    P    1530       nickel oxide,      Warner (1984)
  production                                                metallic nickel                      
Foundry operations           <0.3           P    ns         nickel oxide,      Bernacki et       
(melting, casting, grinding)                                nickel alloys      al. (1978b)       
                             0.013-0.310    P    217        nickel oxide,      Warner (1984)     
                                                            nickel alloys                        
Electroplating               0.03-0.16      P    25         nickel sulfate     Tola et al.       
                             0.005-0.016    P    15         ns                 Bernacki et       
                                                                               al. (1980)        
                             <0.003-<0.011  A,P  48         various nickel     Warner (1984)     
Metal sintering                                                                              
  Furnace maintenance        0.001-0.168    P    20         ns                 Lichty & Zey      
  Metal powder mixing        0.006-1.28     P    6          ns                 (1985)            

Table 15 (contd.)
Process/Operations           Average nickel      Number     Chemical formb     Reference         
                             concentration in    of                                          
                             air (mg/m3)a        samplesb                                    
Nickel-cadmium battery       0.012-0.033    P    213        ns                 Adamsson et       
  manufacturing                                                                al. (1980)        
                             0.02-1.91      P    36         ns                 Warner (1984)     
Glass production             0.03-3.8       A    ns         ns                 Raithel et        
                             0.07-2.622     P                                  al. (1981)        
a  A = area samples; P = personal samples.
b  ns = not specified.
c  90% value.
d  Number of companies reporting exposure.


    Health hazards associated with exposure to nickel in the 
occupational environment have resulted primarily from inhalation.  
For this reason, deposition, retention, and clearance of nickel 
from the human respiratory tract are of special importance.  
However, in addition to this main exposure through inhaled air 
(ambient and at the work-place), human beings are also exposed to 
nickel in drinking-water and food, and through skin contact, which 
is of special concern in view of resulting adverse effects, namely, 
nickel contact dermatitis. 

6.1.  Absorption

    Human exposure to nickel originates from a variety of sources 
and is highly variable.  Nickel and its inorganic compounds can be 
absorbed via the gastrointestinal tract as well as the respiratory 
passages.  Under certain circumstances, the skin is a qualitatively 
important route by which nickel enters the body.  However, 
percutaneous absorption is less important for the systemic effects 
of nickel than for the allergenic responses to it.  Placental 
transfer is of importance because of the effects on the fetus.  
Knowledge of this route of absorption makes it possible to estimate 
the contribution to the body burden at birth.  The diverse routes 
of parenteral administration of nickel compounds are mainly of 
interest in toxicity studies on animals and are particularly useful 
in assessing the kinetics of nickel transport, distribution, and 

    The relative amounts of nickel absorbed by an organism are 
determined, not only by the quantities inhaled, ingested, or 
administered, but also by the physical and chemical characteristics 
of the nickel compound.  Solubility is an important factor in all 
routes of absorption.  Soluble salts of nickel dissociate readily 
in the aqueous environment of biological membranes, thus 
facilitating their transport as metal ions.  Conversely, insoluble 
nickel compounds are relatively poorly absorbed. 

    Kuehn & Sunderman (1982) incubated 17 nickel compounds in 
water, rat serum, and renal cytosol for 72 h at 37 °C.  
Concentrations of dissolved nickel were determined by 
electrothermal atomic absorption and dissolution half-times were 
calculated.  Eleven of the nickel compounds (Ni, beta-NiS, 
amorphous NiS, alpha-Ni3S2, NiSe, Ni3Se2, NiTe, NiAs, Ni11As8, 
Ni5As2, and NiFeS4) dissolved more rapidly in serum or cytosol than 
in water.  Dissolution of 4 of the compounds (NiO, NiSb, NiFe 
alloy, and NiTiO3) was not detectable in any of the media (half-
time, >11 years).  One compound (NiAsS) had approximately equal 
dissolution half-times in the 3 media.  Because of precipitation, 
the half-time value for NiS2 could not be determined.  These 
findings were in close agreement with the elimination half-time (24 
days) obtained from elimination of 63Ni in the urine and faeces of 
rats, after intramuscular injection of alpha-63Ni3S2.  The authors 
suggested that the  in vitro dissolution half-times of nickel 
compounds might be used to predict their  in vivo elimination half-
times, since the dissolution process is rate limiting for the 
metabolism and elimination of the compounds. 

    It is possible that other factors, such as host, nutritional 
and physiological status, or stage of development, also play a 
role, but these have not been studied. 

    Several studies on the dissolution kinetics of nickel 
subsulfide have been performed.  Autoradiographic observations 
(Kasprzak, 1974) showed that extracellular particles of 63Ni 
subsulfide or Ni335S2 could persist at the site of injection for 
many months, without detectable alterations, and could eventually 
become surrounded by neoplastic tissue.  Intracellular localization 
of 63Ni or 35S was not detected within muscle or tumour cells.  
This finding was confirmed quantitatively by Sunderman et al. 
(1976b), who measured the elimination of 63Ni following 63Ni 
subsulfide administration to rats, and by Oskarsson (1979), who 
carried out whole-body autoradiography in mice.  After 20 weeks, as 
much as 19% of the 63Ni dose was found at the site of injection, 
while the retention of nickel in organs distant from the injection 
site was less than 0.1% (Sunderman et al., 1976b).  Addition of 
manganese to the administered nickel subsulfide, which 
significantly decreased the carcinogenicity of the latter, did not 
affect the gross elimination of 63Ni.  The role of manganese was to 
effect the subcellular partition of soluble 63Ni derived from 63Ni 
subsulfide.  Ultrafiltered homogenates of muscle tissue injected 
with 63Ni derived from 63Ni subsulfide + Mn contained less nickel 
than those injected with 63Ni subsulfide alone (Sunderman et al., 
1976b).  Nickel dissolution kinetics, similar to those  in vivo, 
were obtained when leaching of 63Ni was measured during two weeks 
of  in vitro incubation of 63Ni subsulfide with rat serum or aqueous 
triethylenetetramine, but not with water (Kasprzak & Sunderman, 
1977).  This finding suggested that the interaction of nickel 
subsulfide with body fluids could be of the same nature under both 
 in vivo and  in vitro conditions.  Evaluation of the kinetic curves 
and the X-ray diffractometry of the sediments following incubation 
of nickel subsulfide in the three media (Kasprzak & Sunderman, 
1977) revealed that solubilization of nickel required the presence 
of oxygen and involved two reactions: 

(a) 2 alpha-Ni3S2 + O2 + 2H2O <-> 4 beta-NiS + 2Ni(OH)2 

(b) beta-NiS + 202 <-> Ni2+ + SO2-

    When complexing agents, i.e., proteins, amino-acids, etc., are 
present, Ni2+ and Ni(OH)2 form water-soluble Ni(II)-complexes and 
undergo fast mobilization and elimination.  The remaining beta-Ni 
monosulfide constitutes a surface coating on the nickel subsulfide 
particles and requires more oxygen for the further dissolution of 

6.1.1.  Absorption via the respiratory tract

    Respiratory absorption of nickel is normally the principal 
route for its entry into the human body, under conditions of 
occupational exposure.  It usually involves the inhalation of one 
of the following substances: dust of relatively insoluble nickel 
compounds, aerosols derived from nickel solutions (soluble nickel), 

and gaseous forms containing nickel (usually nickel carbonyl).  The 
inhalation route is also of importance in exposure from the general 
environment, including tobacco smoke.  It has been reported that 
cigarette smoke may contain nickel carbonyl (section 5.1.1). 

    The relative amounts of inhaled nickel absorbed from various 
compartments of the pulmonary tract are a function of both the 
chemical and physical forms. Particulate nickel 

    The Task Group on Lung Dynamics (1966) considered that the 
respiratory absorption of nickel compounds in particulate form was 
influenced by three processes in the lung, namely deposition, 
mucociliary clearance, and alveolar clearance.  This Group 
developed deposition and clearance models for man for inhaled 
particulate matter of whatever chemical origin, as a function of 
particulate size, chemical category, and compartmentalization 
within the respiratory tract.  Nickel oxide and nickel halides are 
classified as compounds having moderate retention in the lungs and 
a clearance time of weeks.  Although this model approach has its 
limitations, it can be of some value in assessing deposition and 
clearance rates for nickel compounds of known particle size and 
chemical composition. 

    Removal of material deposited in the lung depends on its 
solubility characteristics and is slow for metallic nickel or 
nickel oxide dust, faster for soluble nickel salts, and most rapid 
for the volatile and lipid-soluble nickel carbonyl. 

    Nickel has a tendency to accumulate in lung tissue and in the 
regional lymph nodes.  Thus, only part of the nickel retained will 
be transferred to the blood, depending on the solubility of the 
nickel compound. 

    Absorption from the pulmonary tract of nickel in particulate 
matter is considerably less than that of nickel carbonyl.  Smaller 
particles penetrate deeper in the respiratory tract than larger 
particles and the relative absorption is greater.  Soluble nickel 
compounds are absorbed quickly, making them less available for 
mucociliary clearance.  A solubility model may be the most accurate 
means of evaluating the rate of absorption of the dust retained in 
the alveoli (Mercer, 1967; Morrow, 1970). 

 (a) Experimental animals 

    There are few animal studies dealing with respiratory 
absorption, and data on the pulmonary uptake of nickel in 
particulate form are limited. 

    Wehner & Craig (1972) exposed Syrian golden hamsters to nickel 
oxide (nickel oxide not specified) particles with a mass mean 
aerodynamic diameter (MMAD) of 1.0-2.5 µm, and observed that 
inhalation for 2 days (7 h/day) at a concentration of 10-190 mg/m3 
air resulted in a deposition of 20% of the inhaled amount.  On the 

10th day after exposure, more than 75% of the nickel oxide was 
still present in the lungs, and, even after 45 days, approximately 
50% of the total amount inhaled still remained.  As no significant 
quantities of nickel oxide were found in the liver and kidney at 
any time after exposure, absorption seemed to be negligible during 
this period.  In ancillary studies, Wehner et al. (1975) exposed 
hamsters for 61 days to nickel oxide aerosol (nickel oxide not 
specified) for 7 h/day and cigarette smoke (nose-only exposure of 
approximately 10 min duration, twice before, and once after, the 
daily 7-h dust exposure). It was found that the inhalation of 
cigarette smoke did not change either the deposition or the 
clearance pattern of the nickel oxide. 

    In a later study, Wehner et al. (1979) exposed Syrian golden 
hamsters to a highly respirable aerosol (MMAD = 2.8 µm) of nickel-
enriched fly ash (NEFA; nickel content 9%), at concentrations of 
220 mg/m3 (one 6-h exposure) and 190 mg/m3 (for 60 days, 6 h/day).  
In the acute exposure, approximately 95% (6.8 µg nickel = 75 µg 
NEFA) of the total deposited amount (7 µg nickel = 78 µg NEFA) was 
found in the deep lung, 1 month after exposure, indicating a very 
slow clearance.  The findings also show, that nickel in the NEFA is 
retained and does not leach appreciably from the NEFA into tissue 
fluids.  This assumption is supported by the observation that the 
average nickel content remained practically the same from 7 days 
after exposure (7 µg) to 30 days after exposure (6.8 µg), which 
would not be the case if the nickel were to leach from NEFA.  In 
the 2-month study, the deposition was 5.7 mg NEFA or 510 mg nickel 
on the third day after exposure. 

    In another study, Wehner et al. (1981) exposed Syrian golden 
hamsters to a high (70 mg/m3) and a low (17 mg/m3) respirable NEFA 
concentration, for up to 20 months.  The NEFA contained 
approximately 6% nickel.  Exposure resulted in heavy deposits of 
NEFA in the lungs of 731±507 µg and 91±65 µg nickel/lung in the 70 
mg/m3 and 17 mg/m3 exposure groups, respectively). 

    The short- and long-term NEFA studies showed that the time from 
the end of exposure to sacrifice (64 h-7 days) was not long enough 
to allow for mucociliary clearance of the nickel deposited in the 
ciliated part of the respiratory tract.  In addition, clearance 
mechanisms may be disturbed by the repeated 6-h exposures to high 
aerosol concentrations, making them decreasingly efficient and 
resulting in the retention of larger quantities of material. 

    However, trace elements are not homogeneously distributed, even 
in particles of similar size, and the mean content of a given trace 
element in fly ash is determined by relatively few particles with a 
very high content of that element. This means that cells in the 
respiratory tract or the lung would not come into contact with fly 
ash particles containing 0.03% nickel, but instead with particles 
containing many times that quantity.  It should be noted that 
respirable NEFA is emitted from coal-fired power plants (Natusch et 
al., 1974). 

    Leslie et al. (1976) exposed mice for 4 h to nickel-containing 
welding fume aerosols.  Particle size and nickel content were 
determined.  The nickel content was highest (8.4 µg/m3) with 
particles 0.5-1.0 µm in diameter.  It was reported that no 
clearance of lung-deposited nickel had occurred by 24 h, nor was 
there any elevation in blood-nickel levels, indicating that there 
had been no absorption into the bloodstream.  When rats were 
exposed through inhalation to nickel oxide aerosol (0.4-70 mg/m3) 
for 6-7 h, 5 days/week, for a maximum of 3 months, the fraction 
deposited in the lung significantly decreased with increasing mass 
median diameter and slightly decreased with increasing exposure 
concentration (Kodama et al., 1985). 

    The data obtained by Wehner et al., showing poor absorption and 
retention of the greatest portion of inhaled nickel oxide in the 
lungs, are supported by the study of Rittmann et al. (1981), who 
exposed Wistar rats via inhalation to nickel oxide, produced by the 
pyrolysis of nickel acetate at 500-600 °C (50 µg/m3 for 15 weeks).  
They found a half-life for the clearance of nickel from the deep 
tract of 36 days.  The half-life for clearance from the 
tracheobronchiolar compartment was less than one day. 

    Valentine & Fisher (1984) administered 63Ni3S2 intratracheally 
to mice (11.7 µg 63Ni3S2/animal).  During the initial phase of 
clearance, 38% of the instilled dose was cleared, with a 
biological half-time of 1.2 days in the final phase.  Four hours 
after instillation, the total lung burden was 85% of the 
administered dose.  Thirty-five days after exposure, 10% of the 
administered dose was still retained by the lung. 

    In a study by Graham et al. (1978), mice were exposed, through 
inhalation, to nickel chloride (particle diameter = 3 µm, 644 µg 
nickel/m3) for 2 h.  Clearance of 70% ( 5.77 mg nickel/kg dry 
weight) of the deposited fraction (8.06±0.506 mg nickel/kg dry 
weight) was found in the lung on the fourth day after exposure.  In 
rats that had received 1 mg nickel, administered intratracheally as 
a single dose of 63Ni chloride, most of the administered dose was 
found in the kidney (53%) and the lung (30%), the rest being 
distributed among the adrenals, liver, pancreas, spleen, heart, and 
testes (Clary, 1975).  As clearance by 3 days was faster in the 
kidney, the lungs became the organ with the highest 63Ni level (64% 
of the total amount deposited; kidney: 19%).  Lung clearance within 
6 h was 27%, which means that 70% of the material originally 
deposited had been absorbed. 

    Appreciable amounts of radioactive nickel, administered to male 
rats intratracheally as the chloride (1.27 µg nickel), were 
absorbed (Carvalho & Ziemer, 1982).  Twenty-one days after 
exposure, the only measurable activity was in the lungs and 
kidneys.  For example, 1 day after exposure, 29% of the initial 
burden was retained in the lungs, decreasing to 0.1% on day 21. 

    Following intratracheal instillation of nickel carbonate in 
mice (0.05 mg/animal), most of the nickel was eliminated after 12 
days (Furst & Al-Mahrouq, 1981). 

    Medinsky et al (1987) administered nickel sulfate solution 
intratracheally to rats at doses of 1 µg, 11.2 µg or 105.7 µg 
nickel/rat.  After 4 h, 49%, 21%, or 8%, respectively, of the 
instilled dose/g tissue was found in the lungs. 

    An important factor for retention in the lung is the solubility 
of the nickel compounds.  Insoluble forms, such as nickel oxide and 
metallic nickel, seem to be retained in the lung for a longer time, 
whereas the more soluble nickel salts are absorbed.  They are also 
solubilized in the fluids and mucus cleared from the lung by the 
mucociliary mechanisms into the alimentary tract. 

 (b) Human beings 

    Particulate nickel can be taken up from ambient air and from 
cigarette smoke.  Respiratory absorption of nickel in particulate 
form is the major route of entry, under conditions of occupational 

    The amount of nickel absorbed from the air is expected to vary 
according to ambient atmospheric levels.  Schroeder (1970) 
calculated that 75% of respiratory nickel intake is retained in the 
body and 25% is expired, depending on the particle size 
distribution.  About 50% of the inhaled nickel would be deposited 
on the bronchial mucosa (and swept upward by mucociliary transport 
to be swallowed), and 25% in the pulmonary parenchyma. Nickel carbonyl 

    In the toxicology of nickel, a special position is occupied by 
nickel carbonyl, a volatile, liquid compound.  After nickel 
carbonyl inhalation, removal of nickel deposited in the lung is the 
most rapid, compared with the clearance of all other compounds, 
indicating an extensive absorption and clearance.  Since the 
alveolar cells are covered by a phospolipid layer, the lipid 
solubility of nickel carbonyl vapours is of importance for their 
penetration of the alveolar membrane.  This explains why nickel 
carbonyl is the only one of the nickel compounds to cause acute 
symptoms of poisoning, when inhaled. 

 (a) Experimental animals 

    Because of its industrial importance, nickel carbonyl 
absorption through inhalation has been studied extensively in 
experimental animal species including the dog, cat, rabbit (Armit, 
1908; Tedeschi & Sunderman, 1957; Sunderman et al., 1961; Mikheyev, 
1971), rat (Barnes & Denz, 1951; Sunderman et al., 1957, 1961; 
Ghiringhelli & Agamennone, 1957; Sunderman & Selin, 1968; Sunderman 
et al., 1968) and mouse (Oskarsson & Tjälve, 1979a).  Animals 
received single doses ranging from 200 to 3050 mg nickel/m3 air for 
periods ranging from 5 to 240 min.  Sunderman et al. (1957) 
administered concentrations of 30 or 60 mg nickel/m3 air for 30-min 
periods, 3 times/weeks, for 3 or 52 weeks.  In all the studies, 
nickel was found in the respiratory tissues, brain, liver, kidneys, 
urinary bladder, adrenals, renal cortex, heart, diaphragm, and 

blood, from where it was rapidly mobilized after exposure (within 2 
days).  Sunderman & Selin (1968) reported that, 24 h after 
inhalation of 63Ni carbonyl, the partition of the body burden of 
63Ni was: viscera 50%, muscle and gut 30%; bone and connective 
tissue 16%, and nervous tissue 4%.  During 2-4 h following exposure 
of rats or rabbits to nickel carbonyl, the lung was the major 
excretory organ for the compound (Sunderman & Selin , 1968; 
Mikheyev, 1971).  Elimination of nickel has been reported to be 
mainly via the urine: 62% (after 3 days) in rabbit (Mikheyev, 
1971); 75% in dog, cat, rabbit (Armit, 1908); 90% in rat and dog 
(Tedeschi & Sunderman, 1957).  Sunderman & Selin (1968) indicated 
that 26% of the inhaled amount was excreted via the urine in 4 
days.  Since the same amount or more might have been exhaled during 
the same period, the authors speculated that at least 50% of the 
inhaled dose could have been absorbed. 

 (b) Human beings 

    The extensive absorption of nickel carbonyl by human beings 
after respiratory exposure has been demonstrated by the 
measurements of enhanced nickel concentrations in organs of workers 
who died from nickel carbonyl poisoning (Brandes, 1934; Bayer, 
1939; Sunderman & Kincaid, 1954; Ludewigs & Thiess, 1970; 
Sunderman, 1971; National Academy of Sciences, 1975) and of 
increased levels in the blood, serum, plasma, and urine in nickel-
refining workers (Kincaid et al., 1956; Sorinson et al., 1958; 
Hagedorn-Götz et al., 1977).  In general, the highest tissue 
concentrations after inhalation of nickel carbonyl have been found 
in the lungs; lower concentrations have been measured in the 
kidneys, liver, and brain.  However, there are no firm data on the 
dose levels of nickel carbonyl that are toxic for human beings.  
Experience suggests that, not only is there considerable 
interpersonal variation, but also that a certain degree of 
resistance can develop.  Exposure to concentrations estimated to 
have been of the order of 0.5 mg NiCO4/m3 for half an hour have 
caused severe illness (Morgan, 1989, personal communication). 

6.1.2.  Absorption via the gastrointestinal tract

    Absorption of nickel from the gastrointestinal tract occurs 
after ingestion of food, beverages, or drinking-water.  In the 
occupational environment, an appreciable amount of nickel dust may 
be swallowed via the mucociliary clearance mechanisms; insufficient 
personal hygiene, poor work practices, and inadequate work-place 
conditions may also increase this uptake.  Gastrointestinal intake 
of nickel leaching from nickel-containing dental alloys is of 
limited importance. 

    The rate of nickel absorption from the gastrointestinal tract 
is dependent on its chemical form.  While soluble nickel compounds 
(e.g., NiSO4) are better absorbed than relatively insoluble ones, 
the contribution of the poorly soluble compounds to the total 
nickel absorption may be more significant, since they are more 
soluble in the acidic gastric fluids. Experimental animals 

    Nickel is poorly absorbed from ordinary diets and is eliminated 
mainly in the faeces.  This has been shown in a nickel balance 
study on dogs (Tedeschi & Sunderman, 1957), in which the nickel 
intake in the food was equal to the output in the urine and faeces.  
The results also indicated that an average of 90% (1.01±0.44 mg) of 
the amount of nickel ingested (1.12±0.16 mg) was eliminated in the 
faeces.  In rats, even at very high intakes of nickel (approx. 14.5 
mg) from different sources, over periods of 4, 8, 12, and 16 days, 
nickel was absorbed poorly (0.15 mg, i.e., 1%) and was eliminated 
mainly in the faeces (13.9 mg = 96%).  Levels of retained nickel 
averaged 0.5 mg (range: 0.29-0.8 mg), i.e., 3.5% (Phatak & 
Patwardhan, 1950, 1952). 

    Schroeder et al. (1969, 1974) did not find any measurable 
absorption of nickel in mice that were given 5 mg nickel/litre in 
the drinking-water, throughout their lives. 

    It was reported by Elakhovskaya (1972) that nickel, given 
orally to rats as the chloride in the drinking-water (0.005, 0.5, 
or 5 mg/litre), was eliminated mainly in the faeces.  Ho & Furst 
(1973) reported that intubation in rats of 63Ni (as the chloride) 
in 0.1 NHCl led to 3-6% absorption of the labelled nickel, 
regardless of the administered dose (1.8 µg/animal, or 4, 16, and 
64 mg nickel/kg body weight).  From these two studies 
(Elakhovskaya, 1972; Ho & Furst, 1973), it can be concluded that 
very little nickel in water or beverages is bioavailable.  Phatak & 
Patwardhan (1950) showed that large doses are required to overcome 
the intestinal absorption-limiting mechanism. 

    The mechanism of nickel absorption in the perfused rat jejunum 
was studied by Foulkes & McMullen (1986).  In step 1, the 
absorption process (uptake from lumen of perfused jejunum) 
proceeded at a rate linearly dependent on the concentration up to 
about 20 µmol nickel/litre perfusate.  At higher levels, it 
approached apparent saturation.  In step 2 of nickel absorption 
(movement of nickel from mucosa into the body), nickel was not 
appreciably retained in the mucosa. Human beings 

    The intake of nickel via the gastrointestinal tract in human 
beings can be high, compared with that of other trace elements.  
Although the daily dietary intake may range up to 900 µg nickel, 
average values have been estimated to be around 200 µg (section 

    Nodiya (1972) performed nickel balance studies on 10 male 
volunteers, aged 17 years, who ingested a mean of 289±23 mg 
nickel/day (range 251-309 mg) and found that faecal elimination of 
nickel averaged around 89% (258±23 mg/day). 

    In human volunteers who ingested nickel sulfate in the 
drinking-water or food, at doses of between 12 and 50 µg/kg body 
weight (one treatment), the amount of nickel absorbed averaged 
27±17% of the dose ingested in water compared with 0.7±0.4% of the 
same dose ingested in food (Sunderman et al., 1989a). Factors influencing gastrointestinal absorption 

    In assessing toxicity from ingested nickel, it is important to 
keep in mind possible factors that might change the absorption rate. 

 (a) Bioavailability 

    The experimental data obtained by Ho & Furst (1973) and 
Elakhovskaya (1972) did not indicate any change in absorption 
efficiency in rats, whether the nickel was taken up from liquids or 
drinking-water (section  However, Cronin et al. (1980) 
reported that ingestion of a soluble nickel compound during fasting 
resulted in high urinary elimination rates of 4-20% of the dose.  
Fifteen female volunteers, who received single oral doses of 2.5, 
1.25, or 0.6 mg nickel (as the sulfate, in gelatine-lactose 
capsules, together with 100 ml water), excreted 95-206 µg, 62-253 
µg, and 48-89 µg nickel, respectively, (normal value 9 µg) in the 
urine.  Nickel naturally occurring in food items also increases 
urinary nickel elimination; a diet containing 850 µg nickel 
resulted in an increased nickel elimination corresponding to about 
1% of the amount in the diet (Nielsen et al., 1987a). 

    Solomons et al. (1982) estimated the bioavailability of nickel 
in human subjects by the serial determination of the changes in 
plasma-nickel concentrations following a standard dose of 22.4 mg 
of nickel sulfate hexahydrate (5 mg nickel), given in each of two 
standard meals, as well as in the drinking-water and 5 beverages 
(cow's milk, coffee, tea, orange juice, and Coca Cola(R)).  The 
plasma-nickel concentration was stable in the fasting state and 
after an unlabelled test meal, but was elevated after the standard 
dose of nickel in water.  It did not rise above fasting levels in 
the two labelled standard meals.  When 5 mg of nickel was added to 
each of the 5 beverages, the rise in the plasma concentration was 
significantly suppressed with all but Coca Cola(R).  These results 
indicate that nickel absorption may be suppressed by binding or 
chelating substances, competitive inhibitors, or redox reagents; on 
the other hand absorption is often enhanced by substances that 
increase pH, solubility, or oxidation, or by chelating agents that 
are actively absorbed.  Such compounds, which were constituents of 
the meals and beverages studied by Solomons et al. (1982), include: 
ascorbic acid, citric acid, pectins (from orange juice), which 
affect trace mineral absorption; tannins (in tea and coffee), which 
inhibit absorption of iron and zinc; ascorbic acid, which 
suppresses nickel absorption; and complexing agents, such as 
NaFeEDTA and EDTA, which depress plasma-nickel levels. 

    Sunderman et al. (1989a) studied the kinetics of nickel 
absorption, distribution, and elimination in healthy human 
volunteers who ingested NiSO4 in the drinking-water or added to 
food (section  Nickel levels were determined, using 

electrothermal atomic absorption spectrophotometry, in samples of 
serum, urine, and faeces collected 2 days before, and 4 days after, 
a specified NiSO4 dose (12 µg Ni/kg, N = 4; 18 µg Ni/kg, N = 4, or 
50 µg Ni/kg, N = 1).  Absorbed nickel averaged 27±17% (mean±SD) of 
the dose ingested in water versus 0.7±0.4% of the same dose 
ingested in food (40-fold difference).  The results of this study 
confirmed that dietary constituents profoundly reduce the 
bioavailability of the Ni2+ for gastrointestinal absorption.  
Approximately one-quarter of the nickel ingested in drinking-water 
after an overnight fast was absorbed from the human intestine and 
excreted in urine, compared to only 1% of nickel ingested in food.  
The kinetic parameters provided by this study reduce the 
uncertainty of toxicological risk assessments of human exposures to 
nickel in the drinking-water and food. 

    Nickel absorption and distribution can be influenced by other 
factors.  An example is disulfiram, which is used for alcohol 
aversion therapy, and which is immediately metabolized into two 
molecules of DDC (diethyldithiocarbamate).  Following oral exposure 
of mice to 57Ni (3 µg/kg), the residual body burdens of nickel 
after 22 h and 48 h were increased several fold in groups receiving 
clinically effective doses of DDC, either orally or intraperitoneally, 
compared with controls.  The organ distribution was considerably 
changed compared with the control values: at 48 h, the amount 
deposited in the brain was at least 100 times greater than the 
control value; deposition in the kidneys, liver, and lungs was also 
increased (Nielsen et al., 1987b). 

 (b) Nickel/iron interaction 

    Becker et al. (1980) suggested that iron might affect nickel 
absorption.  Using isolated intestinal segments of rats in an  in 
 vitro test system, they found that nickel ions had their own 
transport system located in the proximal part of the small 
intestine, thus making it likely that iron nutrition could affect 
nickel absorption.  Forth & Rummel (1971) found that the transfer 
of nickel from the mucosal to the serosal side was elevated in 
iron-deficient intestinal segments. 

6.1.3.  Absorption through the skin

    Percutaneous absorption is of negligible significance, 
quantitatively, but is clinically important in the pathogenesis of 
contact dermatitis.  Because of the ubiquity of nickel-containing 
objects in industrialized society, nickel-sensitive patients 
frequently face considerable problems in the work-place in a wide 
range of jobs, and also because of contact with nickel-containing 
material in household and everyday items. Experimental animals 

    The majority of studies on the dermal uptake of nickel do not 
permit the calculation of absorption data.  Norgaard (1957), using 
guinea-pigs and rabbits (two of each species), applied 10 µl of a 
5% solution of 57Ni (as the sulfate heptahydrate) to a shaved area 
of 5 x 5 cm on the animal's back and measured the radioactivity in 

the organs and body fluids, 24 h after the application.  The 
relative distribution levels in the urine, blood, kidney, and 
liver, measured as impulses/min using a Geiger-Müller counter, are 
shown in Table 16.  The findings demonstrate that nickel absorption 
took place through the skin of the two animal species examined. 

Table 16.  Radioactivity (impulses/min) in organs, blood,
and urine of rabbits and guinea-pigs, 24 h after
application of 57Ni to the skina
Organ or      Rabbit 1  Rabbit 2   Guinea-pig 1  Guinea-pig 2
body fluid
Urine, 5 ml   72        15

Blood, 10 ml  25        9          4             4

Kidney        26        22         2.6           2.6

Liver         5         4          2             1.4
a  From: Norgaard (1957)

    Mathur et al. (1977) found that nickel (as the sulfate) was 
absorbed systemically in male albino rats.  Nickel sulfate in 
saline solution was applied daily, for 15 or 30 days, at doses 
equivalent to 40, 60, or 100 mg nickel/kg body weight.  There were 
no clinical symptoms of toxicity in any of the animals and no gross 
changes were noted at autopsy.  However, in rats sacrificed at 15 
days, the livers of those that had received 60 or 100 mg nickel/kg 
body weight showed microscopic changes consisting of swollen 
hepatocytes and feathery degeneration; the testes were normal.  In 
rats sacrificed at 30 days, the liver changes were more marked, 
with focal necrosis in those that had received 60 or 100 mg 
nickel/kg body weight; the testes showed tubular damage and 

    In a study on dermal absorption, Lloyd (1980) applied 63Ni 
chloride (40 µCi) to the shaven flanks of guinea-pigs and reported 
that a small amount of the applied dose passed through the skin and 
appeared in the plasma.  After 4, 12, and 24 h exposure, 0.005, 
0.07, and 0.05%, respectively, of the total 63Ni dose were found in 
the plasma, and 0.009, 0.21, and 0.51%, respectively, of the 
absorbed nickel, were measured in urine.  In excised skin, levels 
of 1.94, 7.30, and 5.33%, respectively, were found.  Using micro-
autoradiography of 63Ni chloride exposed skin (2 µCi; periods of 
1/2-48 h, shaved flanks of guinea-pigs), Lloyd (1980) also found 
that the radioactive nickel accumulated within 1 h in the highly 
keratinized areas, the stratum corneum, and hair shafts, showing a 
route of entry via the hair follicles and sweat glands.  Increased 
radioactivity was also measured in the serum and urine.  Wells 
(1956) had also reported that nickel ions can penetrate via the 
sweat ducts and hair follicle ostia and that they have a special 
affinity for keratin.  Based on histochemical evidence, it was 
suggested that nickel is bound by the carboxyl groups of keratin 
(Samitz & Katz, 1976). 

    The greatest accumulation of nickel was found in the Malpighian 
layer, the sweat glands, and the walls of the blood vessels.  Wells 
(1956) reported that nickel sulfate did not penetrate the skin, 
because the stratum corneum was a barrier to its penetration.  
Samitz & Pomerantz (1958) found that the extent of penetration 
(nickel sulfate, 0.5% in aqueous solution) was enhanced by sweat 
and sodium lauryl sulfate (1% aqueous solution) in animals (species 
not indicated).  However, there was no evidence of the actual 
absorption of nickel sulfate. Human beings 

    Nickel/epidermal interactions were studied  in vitro in 
diffusion cells by Samitz & Katz (1976), who found that the 
diffusion of 63Ni (as the sulfate, specific activity 1 µCi/ml; 0.1, 
0.01, or 0.001 mol/litre in physiological salt solution) through 
the human epidermis was only slight after 17, 24, and 90 h, 
respectively.  Diffusion did not take place within the first 5 h.  
Sweat or surfactants (0.2% in physiological saline solution) 
slightly enhanced the diffusion of nickel (0.002 mol nickel 
sulfate/litre, containing 0.2 8 µCi 63Ni/ml). 

    Spruit et al. (1965) using human cadaver skin reported that 
nickel ions (from nickel chloride) penetrate, and are bound by, the 
dermis.  He suggested that nickel bound by the dermis can serve as 
a reservoir for the subsequent release of nickel ions.  In a study 
(using 57Ni as an indicator) on normal and nickel-hypersensitive 
persons, it was shown that when 10 µlitre of a 5, 2.5, 1.25, or 
0.68% solution of nickel sulfate was applied to the skin, about two 
thirds of the nickel was absorbed in 24 h (as measured with a 
Geiger-Müller counter) (Norgaard, 1955).  The absolute amount 
absorbed was highest during the first few hours following 
application.  Absorption was the same in normal and in 
hypersensitive patients.  In hypersensitive patients, the 
eczematous reaction appeared at the time when only about 10% of the 
quantity of nickel absorbed was left on the skin.  However, the 
findings have not been verified by examining nickel levels in the 
skin, other organs, and in body fluids.  Kolpakov (1963), using 
skin from persons who had died suddenly from accidental injury, 
found that the Malphigian layer of the epidermis, the dermis, and 
the hypodermis were readily permeable to nickel sulfate.  
Permeation of nickel from nickel chloride and nickel sulfate 
solution through the human skin was determined  in vitro in 
diffusion cells (Fullerton et al., 1986).  The permeation process 
was slow with a lag time of around 50 h.  Without occlusion, the 
amount of nickel permeation was negligible.  Permeation of nickel 
ions was faster from a nickel chloride solution than from a nickel 
sulfate solution.  After about 200 h, 13-43% of the nickel from a 
nickel chloride solution and about 4.7% from a nickel sulfate 
solution were present in the skin matrix. 

6.1.4.  Other routes of absorption

    Parenterally injected nickel is only of practical interest in 
toxicity studies, where it is particularly useful in assessing the 
kinetics of nickel transport, distribution, and elimination. Experimental animals 

    Bergman et al. (1980a) implanted specimens of non-precious 
dental casting alloys containing 70-75% nickel (by weight) 
subcutaneously in the neck region of mice.  After 5 months of 
exposure, most of the nickel, released from the implants through 
electrochemical corrosion, had accumulated in the soft tissue 
capsule at a concentration of 123 mg/kg (wet weight), whereas only 
0.31 mg/kg (wet weight) appeared in the kidney; other tissues 
contained amounts that were more than 10 times less. 

    Samitz & Katz (1975) found that nickel was leached from 
stainless steel spheres (nickel content not indicated) implanted in 
incisions in both hind legs of 3 rabbits.  Taking biopsies, from 
both legs, at the site of implant and at distances of 1, 2, 3, 4, 
and 5 cm around it, nickel was found only in the tissue near the 
implant (1 cm distance); levels ranged from 34.3 to 39.8 mg/kg (wet 
weight) after 3 weeks, and from 46.2 to 53.3 mg/kg (wet weight) 
after 6 weeks.  Whether nickel was translocated to organs and the 
blood was not examined. Human beings 

    In human beings, absorption may occur from a variety of 
implanted nickel-containing medications, metallic devices, and 
prostheses, which release nickel by leaching (section 5.3).  
However, leaching from implanted metals is difficult to assess in 
human beings, because of the few and conflicting experimental data.  
Leaching of nickel from nickel-coated containers may contaminate 
intravenous fluids (section 5.3). 

6.1.5.  Transplacental transfer

    Transplacental transfer provides an initial body burden that 
will be augmented by later environmental exposures.  For this 
reason, and, in view of the possible adverse effects associated 
with the exposure of pregnant women to nickel during early 
pregnancy, transplacental transfer is important.  Placental 
transfer is influenced by gestational age and the availability of 
nickel in the maternal blood.  Species differences in placental 
structure and implantation, which may possibly influence nickel 
transfer, must also be considered. Experimental animals 

    Several reports indicate that transplacental transfer of nickel 
occurs in animals.  In a study by Phatak & Padwardhan (1950), the 
newborn offspring of rats, fed nickel in various chemical forms 
(nickel carbonate, nickel catalyst, nickel soapa) at dietary 
concentrations of 250-1000 mg/kg, showed whole-body levels of 22-30 
mg/kg and 12-17 mg/kg body weight, when dams received 1000 mg 
nickel/kg diet, and 500 mg/kg, respectively. 
a  Nickel soap was prepared by neutralizing mixed fatty acids 
   (obtained by saponification of refined groundnut oil) with 
   nickel carbonate. 

    Lu et al. (1981) injected pregnant mice (ICR strain, 12-14 
weeks old) intraperitoneally, on day 16 of gestation, with a single 
0.1 ml dose of nickel chloride solution (equivalent to 4.6 mg 
nickel/kg).  The kinetics of nickel chloride in the fetal tissues 
showed a different pattern from that in maternal tissues.  The 
concentration of nickel in the maternal blood and the placenta were 
found to be at a maximum (19.8 and 3.9 mg/kg, respectively) 2 h 
after injection. The maximum concentration in fetal tissues (1.1 
mg/kg) was reached 8 h after injection, and only a slight and 
gradual decrease in concentration was observed up to 24 h.  The 
concentration began to decrease rapidly between 24 and 48 h.  The 
biological half-life was calculated to be 8.9 h in the rapid phase 
and 33 h in the slow phase.  In this study, the mean concentration 
of nickel in the placenta was less than those in the maternal 
kidneys and blood, but higher than those in the maternal liver and 
spleen after 24-48 h. 

    In a study by Lu et al. (1979), 10 pregnant ICR mice given an 
intraperitoneal injection of nickel chloride solution, equivalent 
to 4.6 mg nickel/kg body weight, on day 8 of gestation, were 
sacrificed after 4 h and the embryos removed.  The concentration of 
nickel retained in embryonic tissues was 800 times higher in the 
exposed animals than in the controls. 

    When pregnant mice were given a single intraperitoneal 
injection of 63Ni chloride (50 µCi; 0.14 mg/kg body weight) on day 
18 of gestation, passage of 63Ni from mother to fetus was rapid and 
concentrations in fetal tissues were generally higher than those in 
the dam (Jacobsen et al., 1978). 

    Olsen & Jonsen (1979a) investigated nickel uptake and retention 
after intraperitoneal injection of 0.5 ml 63Ni chloride in a 16-day 
pregnant mouse.  They observed that placental transfer of nickel 
occurred throughout gestation (in the visceral yolk sac during 
early gestation 10-11 days, and in the visceral yolk sac and 
chorioallantoic placenta during late gestation).  A significant 
uptake of nickel was seen on days 5-6 of gestation.  Fetal 
accumulation of nickel took place up to day 16 of gestation.  
Nickel was distributed throughout the tissues in the early embryo; 
distribution became more differentiated with increasing gestation 
and became similar to that in the dam. 

    Sunderman et al. (1978a) administered 63Ni intramuscularly to 
groups of pregnant Fischer 344 rats on days 8 or 18 of gestation 
and determined maternal and fetal tissue concentrations by 
autoradiography.  In the fetuses of dams injected on day 8 of 
gestation, the mean 63Ni concentration in the embryos and 
membranes, after 24 h, was equivalent to the 63Ni concentrations in 
the maternal lungs, adrenals, and ovaries. In dams injected on day 
18 of gestation, there was localization of 63Ni in the placentas 
and 63Ni was present in the yolk sacs and fetuses, after 24 h.  The 
fetal organ with the highest concentration of 63Ni was the urinary 
bladder, suggesting that there was renal elimination of the 63Ni 
that had entered the fetuses on day 18 of gestation. 

    Nadeenko et al. (1979) administered nickel to rats in the 
drinking-water for 7 months before, and during, pregnancy.  The 
nickel contents increased in the placentas, but not in the fetuses. 

    Dostal et al. (1989) studied the effects of nickel on lactating 
rats, their suckling pups, and the transfer of nickel via the milk.  
Dose-dependent increases were observed in the concentrations of 
nickel in the milk and plasma, 4 h after a single subcutaneous 
injection of nickel chloride at 10, 50, or 100 µmol/kg body weight 
to lactating dams giving a milk/plasma nickel ratio of 0.02.  Peak 
plasma nickel concentrations in the dams occurred 4 h after the 
injection, while the peak concentration in the milk was observed at 
12 h and remained elevated at 24 h.  Daily subcutaneous injections 
of dams with 50-100 µmol/kg body weight for 4 days increased the 
milk/plasma nickel ratio to 0.10.  Significant alterations in milk 
composition included increased solids and lipids (42% and 110%, 
respectively) and decreased milk protein and lactose (29% and 62%, 
respectively).  In multiple dose studies where 50 or 100 µmol 
nickel chloride/kg body weight were given subcutaneously, once 
daily, on days 12-15 of lactation, the plasma-nickel concentrations 
in suckling pups, sacrificed 4-6 h after the third daily injection 
of 50 or 100 µmol/kg body weight to the dams, were 24 and 48 
µg/litre, respectively.  Liver weights were decreased in the pups 
whose dams received 100 µmol/kg body weight, but no changes in 
hepatic lipid peroxidation or thymus weight were reported. Human beings 

    Nickel has been shown to cross the human placenta; it has been 
found in both the fetal tissue (Schroeder et al., 1962) and the 
umbilical cord serum, where the average concentration from 12 
newborn babies was 3±1.2 µg/litre (range 1.7-4.9 µg/litre) and was 
identical with that in the mother's serum, immediately after 
delivery (McNeely et al., 1971b).  Measurable concentrations have 
been found in various fetal tissues.  Stack et al. (1976) found a 
mean nickel concentration of 23 mg/kg (SD = 7.2) in developing 
teeth from 26 cases of stillbirth and neonatal death, while enamel 
and dentine of developing teeth from 4 fetuses showed levels 
ranging from 11 to 19 mg/kg for dentine and 12 to 20 mg/kg for 
enamel.  In tissues such as liver, kidney, brain, heart, lung, 
skeletal muscle, and bone, nickel was found in mean concentrations 
similar to those in adults ranging from 0.24 to 0.69 mg/kg dry 
matter (SD ranging from 0.16 to 0.6) (Casey & Robinson, 1978).  The 
passage of nickel across the human placental barrier is of 
relevance because of the presence of female workers in industry. 

    Appreciable amounts of nickel have been found in breast milk 
(Stovbun et al., 1962; Medvedeva, 1965). 

6.1.6.  Nickel carbonyl

    Nickel carbonyl absorption and toxicity is primarily of concern 
in occupational inhalation exposure (section  Other 
routes of absorption are not of practical significance.  Absorption 
by the gastrointestinal route could be of importance in case of 
accidental intake, but no data are available.  Because of its 

lipid-soluble properties, nickel carbonyl may be absorbed dermally, 
but this has not been demonstrated.  Parenteral absorption is only 
of experimental significance in studying nickel metabolism. 

6.2.  Distribution, retention, and elimination

    The distribution of nickel in the body and its mode of 
elimination are relevant in view of the occupational and non-
occupational exposures to nickel resulting from its wide industrial 
applications.  Studies on the distribution of nickel in the tissues 
of animals are useful for the understanding of the interaction 
between nickel and biological materials and, consequently, of its 
toxic and carcinogenic effects. 

    Nickel is concentrated in the kidneys, liver, and lungs; it is 
excreted primarily in the urine.  Nickel can also be found in the 
urine of non-occupationally exposed persons.  Since the 
bioavailability of nickel and the rate of elimination depend very 
much on the nature of the nickel compound, urinary excretion may 
not always be an appropriate measure of exposure. 

6.2.1.  Transport

    A few nickel-binding serum proteins have been identified in  in 
 vivo and  in vitro studies using labelled nickel chloride.  Nickel 
has been found in three major fractions of human and rabbit serum: 

(a) macroglobulin-bound nickel; 

(b) albumin-bound nickel; and 

(c) nickel bound to ultrafiltrable ligands (e.g., amino acids) 
    (Nomoto et al., 1971; Hendel & Sunderman, 1972; van Soestbergen 
    & Sunderman, 1972; Callan & Sunderman, 1973). 

    Albumin is the principal transport protein for nickel in human, 
bovine, rabbit, and rat sera (van Soestbergen & Sunderman, 1972; 
Callan & Sunderman, 1973). 

    A metalloprotein, designated nickeloplasmin, has been isolated 
from the sera of rabbits and man (Nomoto et al., 1971; Decsy & 
Sunderman, 1974).  It is a macroglobulin with an estimated relative 
molecular mass of 7 x 105 and contains approximately 0.8 g atomic 
nickel/mole.  Disc gel- and immunoelectrophoresis have shown that 
purified nickeloplasmin is an alpha-2-macroglobulin in rabbit serum 
and a 9.5 S alpha-glycoprotein in human serum.  These results have 
been confirmed, using more refined and sensitive techniques (Nomoto 
& Sunderman, 1988). 

    Ultrafiltrable, nickel-binding ligands play an important role 
in extracellular transport and in the elimination of nickel in 
urine (Hendel & Sunderman, 1972; van Soestbergen & Sunderman, 1972; 
Asato et al., 1975).  The low-relative-molecular-mass, nickel-
binding constituent of human serum has been identified as the amino 
acid, L-histidine (Lucassen & Sarkar, 1979; Glennon & Sarker, 1982).  
In an  in vitro system, L-histidine was found to have a 

greater affinity for nickel than serum-albumin.  Nickel-binding to 
human albumin became evident only when no more L-histidine was 
available.   In vivo, the concentration of albumin was much higher 
than the concentration of L-histidine and most of the nickel was 
associated with albumin.  The equilibrium between L-histidine-
nickel and serum-albumin-nickel may be biologically significant.  
The L-histidine nickel complex, which has a much smaller molecular 
size than the albumin-nickel complex, may mediate the transport 
through a biological membrane by virtue of the equilibrium between 
these two molecular species of nickel.  The equilibrium in favour 
of the L-histidine-nickel complex may be an explanation for the 
rapid urinary excretion of nickel observed by Onkelinx et al. 
(1973) and Sarkar (1980).  The exchange and transfer of nickel 
between L-histidine and albumin appear to be mediated by a ternary 
complex in the form of albumin-nickel-L-histidine.  The amount of 
nickel in each compartment varies from species to species and this 
may be due, in part, to species variation in the affinity of 
albumin for nickel (Hendel & Sunderman, 1972; Callan & Sunderman, 

6.2.2.  Tissue distribution

    Parameters, such as the nickel compound administered, the dose, 
the number of administrations, the length of time between exposure 
and sacrifice, the strain of animal, and the route of absorption, 
may strongly influence the organ distribution pattern.  Thus, the 
uptake of nickel by organs has differed in the reports of various 
investigators. Experimental animals 

    Levels of nickel in the tissues of experimental animals have 
been determined following exposure to various nickel compounds 
under different experimental conditions (Table 17).  The studies 
(in most cases with radioactive nickel, 63Ni) indicate that nickel 
is widely distributed and rapidly eliminated.  Administration of 
divalent nickel salts intravenously, intraperitoneally, or 
subcutaneously, as single or repeated injections, led to the 
highest accumulation in the kidney, endocrine glands, lung, and 
liver.  Concentrations in nerve tissue were low; this is consistent 
with the observed low neurotoxic potential of divalent nickel salts.  
There was also slight uptake by bone, consistent with the rapid and 
extensive elimination of nickel from the organism.  Low concentrations 
are retained in soft and mineral tissue. 

    A large amount of nickel was found in the guinea-pig kidney and 
pituitary gland, after daily subcutaneous injections of 1 mg nickel 
chloride/kg body weight for 5 days (Clary, 1975).  In a study by 
Parker & Sunderman (1974), substantial concentrations of 63Ni in 
the pituitary gland of the rabbit were found following single or 
repeated intravenous injections of 63Ni chloride.  The 63Ni level 
in the pituitary gland was second only to that in the kidneys.  The 
findng that nickel is particularly localized in the pituitary gland 
may have physiological significance.  LaBella et al. (1973a) suggested 
that nickel may exert a direct, specific inhibitory action on 
prolactin-secreting cells in the anterior pituitary gland. 

Table 17.  Relative tissue distribution of nickel in experimental animalsa           
Species (Number)  Dosage and stpb          Relative distributionc                    Reference
Rat (4)           617 µg/kg (single iv     kidney > lung > adrenal > ovary >         Smith & 
                  injection) 2 h           heart > gastrointestinal tract > skin >   Hackley
                                           eye > pancreas > spleen = liver > muscle  (1968)
                                           teeth > bone > brain = fat

Rabbit (3)        240 µg/kg (single iv     kidney > pituitary > serum > whole        Parker &
                  injection) 2 h           blood > skin > lung > heart >             Sunderman
                                           testis > pancreas > adrenal >             (1974)
                                           duodenum > bone > spleen > liver >
                                           muscle > spinal cord > cerebellum >
                                           medulla oblongata = hypothalamus

Rabbit (4)        4.5 µg/kg (34-38 daily   kidney > pituitary > spleen > lung >      Parker &
                  consecutive injections)  skin > testis > serum = pancreas =        Sunderman
                  24 h                     adrenal > sclearae > duodenum = liver >   (1974)
                                           whole blood > heart > bone > iris >
                                           muscle > cornea = cerebellum = 
                                           hypothalamus > medulla oblongata >
                                           spinal cord > retina > lens > 
                                           vitreous humor

Rat (4-11)        3.3 or 6.5 mg/kg         kidney > adrenal > lung > heart >         Chausmer
                  (single iv injection)    pancreas > small intestine > eye >        (1976)
                  2 h                      thymus > muscle > epididymis > ovary >
                                           liver > spleen > bone > brain > 
                                           incisor > fat

Mouse (12)        38.3 µg or 76.6 µg/kg    kidney > lung > sternal cartilage         Oskarsson &
                  (single iv injection)    liver > pancreas                          Tjälve 
                  1 h                                                                (1979a)

Mouse (3)         0.5 mg/kg (single iv     kidney > urinary 
bladder (urine) >        Bergman et
                  injection) 2 h           lung > skin > cartilage > eye (retina) >  al. (1980a)
                                           hair follicle > blood > oral epithelium >
                                           gastric epithelium > tooth enamel > tooth
                                           dentine > salivary glands > liver > 
                                           gastric mucosa > pancreas > spleen >
                                           brown fat > bone > muscle

Table 17 (contd.)
Species (Number)  Dosage and stpb          Relative distributionc                    Reference
Mouse (8)         6.2 mg/kg (one ip        kidney > lung > plasma > liver >          Wase et al.
                  injection) 2 h           erythrocytes > spleen > bladder >         (1954)
                                           heart > brain > carcass (muscle, bone,
                                           and fat)

Rat (18)          3 or 6 mg/kg (7 or 14     7 or 14 x 3 mg/kg: heart > spleen >       Mathur et
                  injections as NiSO4 x    kidney > testis > bone > liver            al. (1978)
                  6H2O) 48 h following
                  last injection            7 x 6 mg/kg: heart > spleen > kidney >
                                           testis > liver > bone

                                            14 x 6 mg/kg: heart > spleen > kidney >
                                           bone > testis > liver

Rat               82 µg/kg (ip) 6 h        kidney > spleen > lung > heart > liver >  Sarkar
                                           muscle                                    (1980)

Rat (5)           6 mg/kg (single ip       kidney > serum > heart > liver            Tandon
                  injection) 24 h                                                    (1982)

Mouse             50 mCi (single ip         6 days after injection: lung > kidney >   Herlant-
                  injection)               skin > small intestine > spleen >         Peers et
                                           liver > uterus > brain > stomach >        al. (1982)
                                           heart > whole blood > muscle > serum

Mouse             100 µCi (7 successive     24 h after injection: lung > kidney >     Herlant-
                  ip injections at 24 h    uterus > skin > stomach > spleen >        Peers et
                  intervals)               small intestine > liver > brain >         al. (1982)
                                           heart > serum > muscle > whole blood

Mouse (5)         1 or 24 (3 times/week)    1 injection: kidney > lung > pancreas >   Kasprzak &
                  ip injections of 42.5    spleen > liver > brain > heart > blood    Poirier
                  µmol 63Ni acetate/kg                                               (1983)
                  48 h                      24 injections: pancreas > lung > heart >
                                           kidney > spleen > liver > brain > blood

Table 17 (contd.)
Species (Number)  Dosage and stpb          Relative distributionc                    Reference
Mouse (10)        specimen of non-         soft tissue capsule around implants >     Bergman et
                  precious dental casting  kidney > lung > spleen > liver >          al. (1980b)
                  alloy implanted          pancreas > heart > blood
                  subcutaneously in the
                  neck region (10 x 5 x
                  1 mm) containing 71%
                  nickel, exposure time
                  5 months

Guinea-pig (6)    1 mg/kg (subcutaneously  kidney > pituitary > lung liver >         Clary 
                  for 5 days) 6 h          spleen > heart > adrenal > testis >       (1975)
                                           pancreas > medulla oblongata =
                                           cerebrum = cerebellum

Rat (5)           7.5 µg/kg (one           lung > kidney > blood > skin > bone =     Carvalho &
                  intratracheal            spleen = testes = liver > heart           Ziemer
                  injection ) 1 h                                                    (1982)

Rat (30)          1 mg/animal (one         kidney > lung > adrenal > liver >         Clary
                  intratracheal            pancreas = spleen = heart > testes        (1975)
                  injection) 6 h

Hamster (51)      53.2 % 11.1 mg nickel    lung > liver > kidney                     Wehner et
                  oxide/m3 (inhalation)                                              al. (1975)
                  life-span exposure

Rat (12)          25, 50, or 100 mg         100 mg: bones > heart > kidney > blood >  Phatak &
                  NiCO3/100 g diet         spleen > intestine > testes > skin >      Padwardhan
                  week 9                   liver                                     (1950)

                                            50 mg: bones > testes > spleen > intestine
                                           heart > liver > kidney > blood > skin

                                            25 mg: bones > intestine > testes > 
                                           kidney > heart > spleen > blood > skin >

Table 17 (contd.)
Species (Number)  Dosage and stpb          Relative distributionc                    Reference
Rat (72)          100 nmol NiCl2           lung > mediastinal lymph nodes >          English
                  (single intratracheal    kidney > ovaries > blood > femur >        et al.
                  injection) 0.5 h         heart = adrenals > skin = pancreas >      (1981)
                                           duodenum > pituitary > liver > spleen

                  100 nmol NiO             lung > mediastinal lymph nodes >
                  (single intratracheal    kidney > heart > femur > duodenum >
                  injection) 0.5 h         kidney > pancreas > ovaries > spleen >
                                           blood > adrenals > skin > pituitary >

Calf (12)         62.5, 250, 1000 mg        1000 mg/kg: serum > kidney > vitreous     O'Dell et
                  NiCO3/kg dietary         humor > lung > testis > bile > tongue >   al. (1971)
                  supplementation for      pancreas > rib > spleen > brain > 
                  8 weeks                  liver > heart

                                            250 mg/kg: lung > serum > kidney

                                            62.5 mg/kg: lung > kidney > liver > 

Rat (24)          100, 500, 1000 mg/kg     liver > heart > kidney > testis           Whanger
                  diet as nickel acetate                                             (1973)
                  for 6 weeks

Rat (64)          5.4 mg/kg in food and    spleen > heart > kidney > lung            Schroeder 
                  and water for life       liver                                     et al. 

Lamb (12)         65 µg/kg or 5 mg          65 mg/kg: kidney > lung > spleen >        Spears 
                  nickel/kg in diet for    heart > liver > brain > testis            et al. 
                  97 days; on day 94:                                                (1978)
                  single oral dose of       5 mg/g: kidney > spleen > lung >
                  40 µCi 63Ni/kg           liver > testis > heart > brain

Table 17 (contd.)
Species (Number)  Dosage and stpb          Relative distributionc                    Reference
Rat (45)          1, 11.2, or 105.7 µg     lung > trachea > larynx > kidney >        Medinsky
                  sulfate/rat (single      urinary bladder > adrenal glands >        et al.
                  intratracheal injection) blood > large intestine > thyroid         (1987)
                  4, 24, or 96 h

Rat (15)          2.5 µg/animal orally     trachea > nasopharynx > skull bone >      Huang et
                  for 30 days as nickel    oesophagus > spleen > kidneys >           al. (1986)
                  sulfate                  lungs > heart
a  Partially adapted from: NAS (1975).
b  Nickel given as 63Ni chloride unless other compound indicated; stp = sacrifice time 
   post exposure.
c  Distribution in decreasing nickel concentration.
    Studies by Herlant-Peers et al. (1982) and Kasprzak & Poirier 
(1983) showed that the number of administrations and the time 
interval between nickel injection and sacrifice of the animals 
influenced the distribution pattern of nickel chloride injected 
intraperitoneally (Table 17, Fig. 1). 


    The most striking findings of the study by Kasprzak et al. 
(1983) were the high accumulation of nickel in the pancreas and the 
decreasing nickel accumulation in the kidney and heart, following 
multiple intraperitoneal injections of nickel acetate.  The first 
finding would link nickel with zinc and insulin metabolism and 
relate the commonly observed nickel-induced elevation of serum 
glucose to this interaction (Clary, 1975; Sunderman et al., 1976a).  
The second finding suggests the development of some detoxifying 
mechanisms in the kidney and heart during prolonged exposure to 
nickel.  Huang et al. (1986) administered 2.5 µg nickel 
sulfate/animal to rats, orally, for 30 days.  The nickel contents 
in the trachea, nasopharynx, oesophagus, lungs, skull, bone, heart, 
spleen, and kidneys of rats fed with nickel were significantly 
higher than those in the control animals. 

    After exposing rats to nickel at a concentration of 5 mg/litre 
in the drinking-water for their lifetime, Schroeder et al. (1974) 
did not find any measurable accumulation of nickel in tissues.  

When rats were fed nickel carbonate, nickel soaps, or metallic 
nickel catalyst, tissue accumulation was significant only in the 
case of the carbonate (Phatak & Padwardhan, 1950).  O'Dell et al. 
(1971) fed calves supplemental dietary nickel at levels of 62.5, 
250, or 1000 mg/kg and found pronounced increases in nickel levels 
in the pancreas, testes, and bone at the highest dietary level.  
While comparison of data for monogastric and ruminant animals may 
not be valid, these data indicate that the skeleton is the main 
storage depot for nickel, even though the nickel concentration in 
bone differs greatly between the studies by Phatak & Padwardhan 
(1950) and O'Dell et al. (1971).  The data agree on the limited 
capacity of the liver to store nickel (which is in contrast to most 
of the trace elements).  A major difference between the data for 
rats and calves is in the nickel level in the heart muscle.  Nickel 
concentrations in this tissue were somewhat elevated in rats (250 
mg/kg), but not in calves. 

    Similar studies on weanling rats (Whanger, 1973) and lambs 
(Spears et al., 1978) given soluble nickel salts (acetate or 63Ni 
chloride) in the diet at various levels up to 1000 mg nickel/kg 
showed the highest accumulation in the kidney.  As the nickel dose 
increased, the nickel contents of the tissues (kidney, liver, 
heart, lung,and testes) also increased.  In rats, treated 
intratracheally, the distribution was virtually analogous (except 
for the pituitary gland), though, as expected, the lung (rather 
than the kidney) showed the highest accumulation (Clary, 1975; 
Carvalho & Ziemer, 1982). Kinetics of metabolism 

    Following inhalation of high concentrations of nickel oxide 
(10-190 mg/m3) by hamsters (7 h daily, repeated exposures for up to 
3 months), 20% of the inhaled amount of nickel oxide was still 
present in the lungs 3-4 days after exposure.  Complete clearance 
of this oxide was estimated to take weeks to months; 75% of the 
nickel oxide was still present in the lungs 10 days after exposure 
and 40% was still present 100 days after exposure (Wehner & Craig, 
1972; Wehner et al., 1975).  The lungs retained more than 99% of 
the nickel oxide deposited there.  The liver and kidney retained 
small amounts of 0.21 and 0.04%, respectively.  Kodama et al (1985) 
exposed rats to nickel oxide by inhalation at concentrations of 
0.4-70 mg/m3 for 6-7 h/day, 5 days/week, for a maximum of 3 months.  
Deposition of nickel oxide in the lungs ranged from 2.3±0.9 to 
23.4±1%.  The deposition fraction significantly decreased with 
increase in the mass median diameter of the particles, and slightly 
decreased with increasing exposure concentration.  The clearance 
rate was estimated to be approximately 100 µg/year. 

    In contrast to the prolonged retention of nickel oxide in the 
lung after inhalation, the more soluble nickel chloride was rapidly 
cleared after a single intratracheal injection (1 mg/kg body 
weight) in rats (Clary, 1975).  Six h after exposure, the kidneys 
showed the greatest amount of nickel followed, in order, by the 
lung and adrenals, with decreasing amounts in the pancreas, spleen, 
heart, and testes.  Other tissues, such as whole brain, thymus, 

eyes, and femur showed only trace amounts.  By 3 days, 90% of the 
injected nickel had been excreted, mainly in the urine (75%).  
Carvalho & Ziemer (1982) studied the deposition, clearance, and 
distribution of 63Ni after intratracheal instillation in rats of 
very low dose levels (1.27 µg 63Ni per animal); the highest 
concentrations of 63Ni were retained in the lungs and kidneys.  
These were the only organs containing measurable amounts of 63Ni, 
21 days after exposure.  Urinary excretion was the main route of 
elimination (78.5% of the initial deposition within 3 days).  On 
day 21, almost all the 63Ni (96.5% of the initial body burden) had 
been excreted in the urine.  The lungs retained 29% of their 
initial deposition (35 min after exposure), decreasing to less than 
1% on day 21.  Medinsky et al. (1987) gave 1, 11.2, or 105.7 µg 
nickel sulfate/animal, by intratracheal instillation, to Fischer 
344 rats.  Urinary excretion accounted for 50% of the dose, at 
doses of 1 and 11.2 µg/rat, and 80% at a dose of 105.7 µg/rat.  The 
half-time for urinary excretion of nickel increased from 4.6 h at 
the highest dose to 23 h at the lowest dose.  Faecal elimination of 
the initial dose was 30% (1 and 11.2 µg doses) or 13% (105.7 µg 
dose).  Over 50% of the nickel remaining in the body at the end of 
96 h was in the lungs.  The half-time for lung clearance of nickel 
sulfate ranged from 21 h (highest dose) to 36 h (lowest dose).  The 
results of this study indicate that the differences in the lung 
clearance of soluble nickel compounds reported by Carvalho & Ziemer 
(1982) and Clary (1975) can be explained by differences in 
instilled doses. 

    Tanaka et al. (1985, 1988) estimated the biological half-time 
of nickel monosulfide (amorphous) aerosol and of green nickel oxide 
in rats exposed through inhalation. The biological half-time of NiS 
(A) in the rat lung was 20-h, while that of the oxide was 21 months 
(particle size 4.0 µm) or 11.5 months (particle size 1.2 µm). 

    In several studies, 63Ni-labelled nickel salts have been used 
to study the distribution and elimination of nickel after 
parenteral injection (Wase et al., 1954; Smith & Hackley, 1968; 
Parker & Sunderman, 1974; Clary, 1975; Mathur et al., 1978; 
Oskarsson & Tjälve, 1979b; Bergman et al., 1980b; Tandon, 1982).  
Using this route of administration, most nickel was excreted in the 
urine, causing a high labelling of the kidneys, which may be 
related to the role of the kidneys in nickel clearance.  However, 
there have been different observations on its localization in other 
organs.  Smith & Hackley (1968) found a good correlation between 
the blood volume of each tissue and the amount of nickel retained 
by that tissue.  Mathur et al. (1978) investigated the effects of 
dose and duration of exposure on the relative distribution and 
found that, while a single exposure to nickel may not have a 
lasting effect on the body tissues, regular exposures could have a 
cumulative effect, particularly on the kidneys and the heart.  An 
autoradiographic distribution study by Bergman et al. (1980b) on 
the albino mouse showed that, between 30 min and 24 h, there were 
high concentrations of 63Ni in the urogenital, circulatory, and 
respiratory organs.  Accumulation was also found in cartilage, 
lacrimal glands, and the skin. After one day, the distribution 

pattern changed, so that the highest concentrations were in the 
lungs, kidneys, central nervous system, skin, and the epithelia of 
the oral cavity and the oesophageal part of the stomach, with the 
long residence time of 3 weeks; accumulation was highest in the 
lung, central nervous system, kidneys, hard tissues (teeth, 
cartilage, bone), and the skin.  A distribution study by Bergman et 
al. (1980a), who implanted specimens of non-precious dental casting 
alloys subcutaneously in the neck region of mice, did not yield any 
information about the dynamic pattern of the release of nickel, the 
uptake in various tissues and organs, or its elimination. 

    Metabolic data from nickel-balance studies carried out by 
Phatak & Padwardhan (1950) who fed rats, nickel carbonate, nickel 
soaps, or nickel catalyst (250, 500, or 1000 mg/kg in the diet for 
2 months) demonstrated that appreciable quantities of nickel from 
all the nickel-containing diets were retained.  Retention from the 
nickel carbonate diet was greater than that from the other two 
nickel preparations.  This can be attributed to the ready 
solubility of the compound in the stomach and the easier absorption 
from the intestine.  The proportion of the ingested nickel found in 
the faeces was lowest in the carbonate group.  The amount of nickel 
excreted in the urine was only slightly higher in this group than 
in the other two. 

    O'Dell et al. (1971) fed calves a basal diet supplemented with 
nickel (as the carbonate) at levels similar to those used by Phatak 
& Padwardhan (1950) and for the same period of time.  The results 
of this study showed that the absorption and tissue retention of 
dietary nickel can be increased and that the increase is related to 
the rate of nickel intake as well as to the total nickel intake. 

 (a) Kinetic modelling 

    The whole-body kinetics of nickel chloride (or other soluble 
metal salts) can be studied by injecting animals with suitable 
radiotracers, following the metal concentration in plasma as a 
function of time after injection and measuring the amounts 
eliminated in urinary and faecal collections.  In general, data 
obtained in this fashion can be analysed mathematically.  This 
allows the formulation of compartment models describing the 
metabolism of nickel in terms of distribution volumes, clearances 
by elimination and clearances by exchange.  Nickel metabolism is 
characterized by a typical distribution and elimination pattern 
(Fig. 2, Table 18). Onkelinx et al. (1973) injected 63NiCl2 
intravenously in male and female Wistar rats (17 µg/animal) and New 
Zealand albino rabbits (816 µg/animal) and measured the radioactive 
label in the urine and faeces, 3 days after injection, and, in the 
blood, at intervals ranging from 1 h to 7 or 9 days.  In the rats, 
during the first day, 68% 63Ni was excreted in the urine and, after 
3 days, 78%.  In the rabbit (2 animals), 9% of the administered 
dose was excreted in the urine, 5 h after injection, and 78% during 
the first day (Fig. 3).  Faecal elimination of 63Ni in the rat was 
15% of the administered dose during the first 3 days following 
injection; faecal elimination was not determined in the rabbits.  
Sunderman et al. (1976a) administered 2173 µg 63Ni chloride/animal 

to Fischer rats by intraperitoneal injection.  Blood samples were 
taken at intervals between 10 min and 24 h after injection.  Urine 
and faeces were collected at intervals between 6 h and 5 days after 
injection.  Both studies showed that absorption and elimination 
fitted a 2-compartment modela in both species, comprising a rapid 
clearance phase from plasma or serum during the first 2 days and a 
much slower phase between the third and seventh days. 

    Chausmer (1976) determined tissue exchangeable pools (in rats 
injected intravenously with 63Ni chloride) at a number of intervals 
following injection, and found (after performing a compartmental 
analysis of tissue exchangeable pools by computer evaluation of the 
percentage retained radioactive nickel) a rapid intracellular 
compartment having a half-life of several h in most tissues.  The 
slower compartment had a half-life of several days.  The kidney 
(followed by the lung, liver, and spleen) was found to have the 
largest rapidly exchangeable pool, 16 h after injection, with a 
two-compartment distribution, whereas bone had the best fit with a 
single compartment. 


a  Compartment I: central compartment including the plasma and from 
   which elimination takes place. 
   Compartment II: hypothetical volume that is connected to 
   compartment I by reversible exchange. 

Table 18.  Parameters of the two-compartment model of Ni(II)
Parameters            Symbol  Units  Wistar    Fischer     Rabbitb
                                     ratb      ratc
Compartment I         V1      ml     75.1      59.2        697

Compartment II        V2      ml     8.3       31.6        265

Exchange I-II         fe      ml/h   0.12      0.92        2.31

Total excretory       ft      ml/h   8.14      7.73        61.2

Urinary clearance     fu      ml/h   6.39      6.70        54.1

Faecal clearance      fd      ml/h   1.28      0.75        -d

Clearance into skin   fs      ml/h   0.47      0.28        -d

Average body weight   wt      g      208       165         3400

Injected dose                 µg     17 (iv)   2173 (ip)   816 (iv)
(µg Ni/animal)
a  From: Onkelinx & Sunderman (1980).
b  From: Onkelinx et al. (1973).
c  From: Sunderman et al. (1976a).
d  Measurements of faecal 63Ni(II) were not performed in rabbits;
   hence fd and fs could not be calculated.



    The distribution and elimination of nickel, given to animals as 
63Ni chloride, has been studied extensively.  Most of the 
introduced nickel is rapidly excreted in the urine (65-87% in 24 
h), the rest undergoing much slower elimination (76-90% in 5 days) 
(Sunderman & Selin, 1968; Sunderman et al., 1976a). 

    The 2-compartment model described by Onkelinx & Sunderman 
(1980) also provides a satisfactory fit for experimental data from 
human volunteers who ingested nickel sulfate in the drinking-water 
or food at doses of 12, 18, or 50 µg nickel/kg body weight 
(Sunderman et al., 1989a).  Faecal elimination of nickel during 4 
days following treatment averaged 76±19% of the dose ingested in 
water versus 102±20% of the dose ingested in food.  The elimination 
half-time for absorbed nickel averaged 28±9 h (range 17-48 h).  
Renal clearance was determined to be 8.3±2.0 ml/min per 1.73 m2 in 
human beings who had ingested nickel sulfate in water, and 5.8±4.3 
ml/min per 1.73 m2 in those who had received nickel sulfate in 
food.  The difference was not statistically significant. Nickel carbonyl 

    There are few studies on the fate of nickel carbonyl in 
experimental animals.  After the administration of nickel carbonyl, 
deposition occurs in the lung and in tissues, such as the brain, 
liver, and adrenals, and part of the administered dose of nickel is 
recovered in the urine (Armit, 1908; Barnes & Denz, 1951; Sunderman 
& Selin, 1968).  It was assumed earlier that nickel carbonyl was 
rapidly dissociated in the lung and that the nickel was then 
transported to other tissues.  However, the results of several 
studies (Sunderman & Selin, 1968; Sunderman et al., 1968; Kasprzak 
& Sunderman, 1969) have indicated that unchanged nickel carbonyl is 

present in the blood several hours after administration and can 
pass across the pulmonary alveoli in either direction without 
decomposition.  It was suggested by Kasprzak & Sunderman (1969) 
that the nickel carbonyl that was not exhaled underwent a slow 
intracellular decomposition to NiO and CO.  The released NiO was 
then oxidized to Ni2+, which might become bound to nucleic acids or 
proteins, or to albumin in the plasma and, ultimately, would be 
excreted in the urine; the released CO would become bound to 
haemoglobin and finally exhaled. 

    Oskarsson & Tjälve (1979a) studied the distribution of 
intravenously administered 63Ni and 14C-labelled nickel carbonyl 
(63Ni(CO4) and Ni(14CO4)) in mice by whole-body autoradiography and 
liquid scintillation counting.  Radioactivity in the animals given 
14C-labelled carbonyl was mainly confined to the blood, indicating 
the formation of 14CO-haemoglobin. This confirms the findings of 
Kasprzak & Sunderman (1969).  After the administration of 63Ni-
labelled carbonyl, the highest level of 63Ni was found in the lung, 
followed by the brain, spinal cord, heart, diaphragm, brown fat, 
adrenals, and corpora lutea.  Additional studies showed that nickel 
was present in the lung, brain, heart, and blood as the cation. Nickel levels in human beings 

    In human beings, wide variations have been reported in body 
nickel levels.  This makes it difficult to appraise and compare the 
results obtained by various investigators.  In addition to 
variations in the geographical origin of data and individual 
dietary and smoking habits, major differences can be attributed to 
the analytical methods employed.  Only limited comparisons can be 
made using variants of spectrography, atomic absorption 
spectrometry, photometric methods, and special analytical 
techniques.  Furthermore, no uniform reference samples have been 
used.  Nickel values from tissue analyses have been related to ash 
or dry weight as well as to wet weight.  The normal ranges of 
nickel concentrations in body fluids or tissues (serum, blood, 
lung, kidney) are not significantly influenced by age, sex, or 
pregnancy (McNeely et al., 1971; Turhan et al., 1983; Zober et al., 

 (a) Body fluids, hair, and nasal mucosa 

    The levels of nickel in biological fluids, hair, and some other 
materials increase remarkably in persons with increased 
occupational or environmental exposure and decline rapidly when 
exposure is reduced or stopped (Tables 19, 20, 21, and 22).  Thus, 
measurements of nickel, particularly in the urine, serum, or hair, 
may serve as indices of exposure. 

    Data for normal nickel values in urine, blood, plasma, and 
serum, published in the last three decades, vary widely.  Lower 
levels have been obtained by later investigators, because of the 
use of more sensitive analytical methods.  Reference values in 
specimens from healthy, non-exposed persons are listed in Table 19.  
Because of doubts about the reliability of older studies, only 
recent data have been included. 

Table 19.  Normal nickel concentrations in specimens from healthy non-exposed 
Specimen         No. of       Nickel concentrations     Units      References              
                 subjects     mean ± SD    range                                           
Whole blood      30 (15,15)   0.34 ± 0.28  < 0.05-1.05  µg/litre   Linden et al. 
Serum            10 (6, 4)    0.32 ± 0.17  0.1-0.6      µg/litre   Sunderman et            
                                                                   al. (1989a)             
Serum            43 (22, 21)  0.2 ± 0.2    < 0.05-1.0   µg/litre   Hopfer et al.

Serum            30 (15, 15)  0.28 ± 0.24  < 0.05-1.08  µg/litre   Linden et al. 
Lymphocytes      10 (4, 6)    0.72 ± 0.75  < 0.05-1.10  µg/1010    Wills et 
                                                        cells      al. (1985)              
Urine (spot      34 (18, 16)  2.0 ± 1.5    0.5-6.1      µg/litre   Sunderman               
collection)                   2.8 ± 1.9    0.5-8.8      µg/litre   et al.                  
                                                        (1.024     (1986a)                 
Urine (24-h      50 (24, 26)  2.2 ± 1.2    0.7-5.2      µg/litre   Sunderman               
collection)                   2.6 ± 1.4    0.5-6.4      µg/day     (1977)                  
Faeces (3-day    10 (6, 4)    14.2 ± 2.7   10.8-18.7    mg/kg      Horak &                 
collection)                                             (dry       Sunderman               
                                                        weight)    (1973)                  
                              258 ± 126    80-540       µg/day                             
Faeces           10 (6, 4)    1.5 ± 0.5    1.0-2.2      mg/kg      Sunderman               
                                                        (wet       et al.                  
                                                        weight)    (1989a)                 
Sweat            14 (6, 8)    51 ± 38      8-158        µg/litre   Christensen             
                                                                   et al. 
Bile             5(b)         2.3 ± 0.8    15-33        µg/litre   Rezuke et               
                                                                   al. (1987)              

Saliva           38 (32, 6)   1.9 ± 1.0    0.8-4.5      µg/litre   Catalanatto             
                                                                   et al.                  
Hair             102 (b)      0.29         0.0-13.0     mg/kg      Bencko et               
                                                        (net       al. (1986)              

Table 19 (contd.)
Specimen         No. of       Nickel concentrations     Units      References              
                 subjects     mean ± SD    range                                           
Hair             22 (15, 7)   0.22 ± 0.08  0.13-0.51    mg/kg      Nechay &                
                                                        (dry       Sunderman               
                                                        weight)    (1973)                  
Hair             905 (437,    -c           0.26-2.70    mg/kg      Tagaki et               
                 468)                                   (wet       al. (1986)              
Nasal mucosa     57 (57m)     0.13 ± 0.20  <0.53d       mg/kg      Torjussen &             
                                                        (wet       Andersen                
                                                        weight)    (1979)                  
a  Urine nickel concentrations, factored to specific gravity = 1.024.
b  Sex not indicated.
c  Range of means of samples from five countries.
d  Upper 95th percentile of nickel concentrations in nasal biopsies from
   non-exposed subjects.
    A large number of workers exposed to various nickel compounds 
have been found to have elevated levels of nickel in the urine. 
These include those working in: nickel refineries (Morgan, 1960; 
Kemka, 1971; Norseth, 1975; Hogetveit & Barton, 1976, 1977; 
Bernacki et al., 1978a; Hogetveit et al., 1978; Morgan & Rouge, 
1979; Torjussen & Andersen, 1979; Hogetveit et al., 1980; Boysen et 
al., 1982), the welding of nickel alloy steels (Norseth, 1975; 
Bernacki et al., 1978a; Grandjean et al., 1980; Polednak, 1981; 
Kalliomäki et al., 1981), nickel electroplating plants (Tandon et 
al., 1977; Tola et al., 1979; Bernacki et al., 1980; Tossavainen et 
al., 1980), nickel battery factories (Bernacki et al., 1978a; 
Adamsson et al., 1980), different occupations in shipyards 
(Grandjean et al., 1980), the pigment industry (Tandon et al., 
1977), the glass industry (Raithel et al., 1981), nickel carbonyl 
processing in nickel refining (Kincaid et al., 1956; Sorinson et 
al., 1958; Morgan, 1960; Nomoto & Sunderman, 1970; Hagedorn-Götz et 
al., 1977), aircraft mechanics and metal spraying (Bernacki et al., 
1978a).  The results of the investigations of Bernacki et al. 
(1978a), who analysed urine samples from nickel-exposed workers in 
10 occupational groups, are listed in Table 20. 

    Serum or plasma nickel levels have been determined in workers 
in the following occupations: nickel refining (Hogetveit & Barton, 
1976, 1977; Hogetveit et al., 1978, 1980; Torjussen & Andersen, 
1979; Boysen et al., 1982), welding (Grandjean et al., 1980), 
electroplating (Tola et al., 1979; Tossavainen et al., 1980), 
battery manufacture (Adamsson et al., 1980) and shipyards 
(Grandjean et al., 1980), and the Mond process in nickel refining 
(Sorinson et al., 1958; Nomoto & Sunderman, 1970). 

Table 20.  Nickel concentrations in urine of workers in various occupational groupsa
Occupation       No.  Description                     Concentration                  
                                             Atmospheric    Urineb      Creatinineb
                                             nickel (µg/m3) (µg/litre)  (µg/litre)
External         9    abrasive wheel         1.6±3.0        5.4±2.4     3.5±1.6
grinders              grinding of exteriors  (0.02-9.5)     (2.1-8.8)   (1.7-6.1)
                      of articles made of
                      nickel alloys

Arc welders      10   DC arc welding of      6.0±14.3       6.3±4.1c    5.6±6.2
                      aircraft made of       (0.2-46)       (1.6-14)    (1.1-17)
                      nickel alloys

Bench mechanics  8    assembling, fitting,   52±94          12.2±13.6c  7.2±6.8c
                      and finishing parts    (0.01-252)     (1.4-41)    (0.7-20)
                      made of nickel alloys

Nickel battery   6    fabricating nickel-    Not            11.7±7.75d  10.2±6.4d
workers               cadmium or nickel-     measured       (3.4-25)    (7.2-23)
                      zinc electrical 
                      storage batteries

Metal sprayers   5    flame-spraying         2.4±2.6        17.2±9.8d   16.0±21.9
                      nickel-containing      (0.04-2.1)     (1.4-26)    (1.4-54)
                      powders in phase on
                      to aircraft parts

Electroplaters   11   intermittent exposure  0.8±0.9        10.5±8.1d   5.9±5.0c
                      to nickel in combined  (0.04-2.1)     (1.3-30)    (1.0-20)
                      operations involving
                      silver, cadmium,
                      chromium plating, as
                      well as nickel

Nickel platers   21   full-time work in      Not            27.5±21.2e  19.0±14.7e
                      nickel plating         measured       (3.6-65)    (2.4-47)

Nickel refinery  15   workers in a nickel    489±560        222±226e    124±109e
                      refinery using         (20-2200)      (8.6-8.3)   (6.1-287)
                      electrolytic processes
a  From: Bernacki et al. (1978a).
b  Mean SD with range in parentheses.
c   P < 0.05 versus controls, calculated by t-test.
d   P < 0.01 versus controls.
e   P < 0.001 versus controls.
    The highest nickel concentrations were found in the body fluids 
of nickel refinery workers.  Concentrations in workers in 
electroplating shops, battery factories, and aircraft engineering 
works were lower (Table 10).  After occupational exposure to nickel 

in electroplating processes, biological half-times ranging from 13 
to 39 h for nickel in urine and from 20 to 34 h for nickel in 
plasma have been reported (Tossavainen et al., 1980). 

    Serum specimens of 22 residents of Sudbury, Ontario, who had 
been environmentally exposed to nickel (including air and tap 
water), contained nickel concentrations ranging from 0.2 to 1.3 
µg/litre (mean 0.6±0.3 µg/litre).  These were significantly higher 
than the serum levels of residents without environmental exposure 
(Hopfer et al., 1989). 

    Nickel determinations in blood and urine, are widely used and 
accepted methods for monitoring nickel exposure.  Although more 
data are available for urine, no clear-cut choice can be made 
between the use of blood or urine. 

    Grandjean et al. (1980, 1988) reported that analyses of nickel 
concentrations in both urine and plasma samples should be obtained 
to assess worker exposure.  There were significantly higher ratios 
of plasma/urine nickel levels in painters and lower ratios in 
welders, compared with other workers in the shipyard.  These 
differences probably reflected the different toxicokinetic 
characteristics of the nickel compounds to which the workers were 

    The correlation between exposure levels and nickel 
concentrations in body fluids is poor in most studies (Table 21).  
The closest positive relationships of nickel concentrations in body 
fluids with ambient air levels were found by Norseth (1975) and 
Rahkonen et al. (1983) in welders, and by Tola et al. (1979) and 
Bernacki et al. (1980) in electroplaters. 

Table 21.  Studies on the correlation between nickel concentrations 
in the air and in biological fluids in occupational exposure to 
nickel compoundsa
Exposure            Biological   Correlation     Reference
                    matrix       coefficient 
welding             urine        0.85            Norseth (1975)
roasting-smelting   urine        none

welding             urine        none            Bernacki et al.
bench mechanics     urine        none            (1978a)
electroplating      urine        none
metal spraying      urine        none
refinery            urine        none

roasting-smelting   plasma       -0.11           Hogetveit et al.
                    urine        0.14            (1978)
electrolysis        plasma       0.21
                    urine        0.31
refinery (other)    plasma       0.67
                    urine        0.47

Table 21 (contd.)
Exposure            Biological   Correlation     Reference
                    matrix       coefficient 
refinery (nickel    urine        0.49; 0.55      Morgan & Rouge
  salts)                                         (1979)
  Mond process      urine        0.01
  calciner          urine        0.22
  powder plant      urine        -0.05

electroplating      plasma       0.83            Tola et al.
                    urine        0.82b           (1979)
                    urine        0.96c

electroplating      urine        0.70d           Bernacki et al.

battery             urine        significante    Adamsson et al.
  manufacturing                                  (1980)

welding             blood        0.56            Rahkonen et al.
                    urine        0.95            (1983)
a  From: Aitio (1984).
b  Afternoon.
c  Next morning.
d  After shift.
e   P < 0.01.

    There seem to be at least three reasons for the inconsistencies 
in the correlation between exposure levels and biological 
measurements of nickel: 

(a) exposure is not to a single chemical species, but to a variety 
    of nickel compounds of very different solubility, absorption, 
    transportation, and elimination rates.  The same workers may be 
    simultaneously exposed to both insoluble and readily soluble 
    compounds, having half-lives ranging from days (Tola et al., 
    1979) to years (Torjussen & Andersen, 1979).  The influence of 
    the nickel species in ambient air on the concentration in body 
    fluids has been shown in a study by Bernacki et al. (1978a), 
    who found widely varying ratios of air/urine levels in 
    different occupational groups (Table 22); 

(b) differences in personal working habits and hygiene; 

(c) failure to standardize sampling methods. 

Table 22.  Nickel concentrations in serum, urine, nasal mucosa, and personal air samples 
from workers at the Falconbridge Nickel Refinery in Kristiansand, Norwaya
Category of        No. of     Plasma nickel   Urine nickel   Nasal mucosal   Air nickel
subjects/work      subjects   (µg/litre)      (µg/litre)     nickel          (mg/m3)
                              mean±SD         mean±SD        (µg/100g)       mean±SD
                                                             (wet weight)
 First studyb

Roasting/smelting  24         7.2±2.8         65±58                          0.86±1.20
Electrolysis       90         11.9±8.0        129±106                        0.23±0.40
Other process      13         6.4±1.9         45±27                          0.42±0.49

 Second studyc

Controls           57         1.9±1.4         4.9±4.2        13±20
Roasting/smelting  97         5.2±2.7         34±35          467±595
Electrolysis       144        8.1±6.0         73±85          178±235
Other process      77         4.3±2.2         22±18          211±301
a  From: Sunderman et al. (1986b).
b  From: Hogetveit et al. (1978).
c  From: Torjussen & Andersen (1979).
    The nickel contents of hair and nasal mucosa have been 
determined in occupationally-exposed persons.  Theoretically, the 
nasal mucosa is one of the target tissues for nickel 
carcinogenicity.  However, practical problems of sampling and 
standardization preclude the routine use of these measurements.  
Torjussen & Andersen (1979) analysed biopsy specimens of nasal 
mucosa from 318 nickel workers, 15 retired nickel workers, and 57 
unexposed controls.  The results showed that nickel exposure led to 
significantly raised nickel concentrations in the nasal mucosa in 
both active and retired nickel workers (2.74±4.12 mg/kg wet weight, 
and 1.14±1.78 mg/kg wet weight, respectively, versus 0.13±0.2 mg/kg 
wet weight in the controls).  The average nickel concentration in 
the nasal mucosa was highest in workers exposed to the highest 
atmospheric nickel concentration, inhaled as nickel subsulfide and 
nickel oxide dust.  Workers exposed to aerosols of soluble nickel 
components, such as the chloride and sulfate, at a lower 
atmospheric nickel concentration, had the highest mean nickel 
concentrations in the plasma and urine and the lowest in the nasal 
mucosa.  The mucosal concentration was significantly correlated 
with the duration of nickel exposure. 

    For hair, normal values ranged between 0.13 mg/kg (dry weight) 
and 2.7 mg/kg (wet weight).  In hair samples from 45 
occupationally-exposed adults, Bencko et al. (1986) found nickel 
concentrations ranging from 1.6 to 3.5 mg/kg (mean 2.39 mg/kg) in 
welders and from 42.7 to 2140 mg/kg (mean 222.5 mg/kg) in nickel 
smelter workers.  Control values ranged from 0 to 13 mg/kg (mean 
0.29 mg/kg).  In an accidental case of exposure to nickel carbonyl, 
nickel concentrations in hair samples from 5 workers ranged from 4 
to 48.1 mg/kg (Hagedorn-Götz et al., 1977). 

    Although hair has been studied as a rapid, non-invasive 
measurement of exposure/absorption relationships, conflicting 
values have been obtained.  Furthermore, the use of hair as an 
internal exposure index is controversial because of various 
factors, such as the external contamination of the hair surface, 
different sampling methods, and non-standardized cleaning methods. 

 (b) Tissues 

    There are few data on human tissue concentrations of nickel.  
Spectrographic analyses indicate that the retained nickel is widely 
distributed in very low concentrations in the body.  Information on 
normal nickel levels in organs and tissues is presented in Tables 
23 and 24. 
Table 23.  Reference values for nickel concentrations in human autopsy tissuesa
                             Nickel concentrations        
Tissue   No. of     Wet weight (µg/kg)   Dry weight (µg/kg)   Reference
         subjects   Mean±SD   Range      Mean±SD   Range
Lung     4          16±8      (8-24)     86±56     (33-146)   Sunderman et al. (1971)

         9                               132±99    (50-290)   Chen et al. (1977)

         41         7±10      (<1-70)                         Zober et al. (1984)

         15                              180±105   (43-361)   Seemann et al. (1985)

         9          18±12     (7-46)     173±94    (71-371)   Rezuke et al. (1987)

         15         44±56     (16-242)                        Raithel (1987)

Kidney   6                               125±54    (50-120)   Chen et al. (1977)

         36         14±27     (<1-165)                        Zober et al. (1984)

         18                              34±22     (<5-84)    Seemann et al. (1985)

         10         9±6       (3-25)     62±43     (19-171)   Rezuke et al. (1987)

Liver    4          9±3       (5-13)     32±12     (21-48)    Sunderman et al. (1971)

         23                              18±21     (<5-86)    Seemann et al. (1985)

         10         10±7      (8-21)     50±31     (11-102)   Rezuke et al. (1987)

Heart    4          6±2       (4-8)      23±6      (16-30)    Sunderman et al. (1971)

         9          8±5       (1-14)     54±40     (10-110)   Rezuke et al. (1987)

Spleen   22                              23±20     (<5-85)    Seemann et al. (1985)

         10         7±5       (1-15)     37±31     (9-95)     Rezuke et al. (1987)
a  Adapted from: Rezuke et al. (1987).
Table 24.  Normal nickel concentration in Japanese human 
tissues (mg/kg wet weight)a
Tissue       Sex/     Median   Average   Range       Mean±SD
Rib          M/6               0.19
                      0.230              0.13-0.35   0.23±0.07
             F/6               0.27

Lung         M/15              0.21
                      0.160              0.04-0.44   0.16±0.09
             F/15              <0.10

Small        M/5               0.11
intestine             0.120              0.05-0.29   0.13±0.07
             F/5               0.15

Large        M/5               0.14
intestine             0.111              0.04-0.30   0.14±0.10
             F/5               0.15

Trachea      M/3               0.09
                      0.098              0.06-0.11   0.09±0.02
             F/1               0.11

Kidney       M/14              0.10
                      0.081              0.01-0.30   0.10±0.07
             F/14              0.10

Skin         M/4               0.09
                      0.072              0.02-0.22   0.10±0.08
             F/2               0.14

Muscle       M/5               0.11
                      0.070              0.02-0.27   0.10±0.08
             F/5               0.09

Liver        M/14              0.10
                      0.068              0.03-0.22   0.08±0.05
             F/13              0.05

Cerebrum     M/2               0.06
                      0.025              0.02-0.11   0.05±0.11
             F/1               0.03

Cerebellum   M/1
                      NMb      <0.03     NIc         NM

Heart                 NM       NCd       NC          NM

Pancreas     M/6
                      NM       <0.10     NM          NM

Table 24 (contd.)
Tissue       Sex/     Median   Average   Range       Mean±SD
Spleen       M/1               <0.30
                      NM                 NM          NM

Adrenal      M/1               <0.10
glands                NM                 NM          NM

Testis       M/1               0.05
Ovary                 NM       -         NM          NM

Fat          F/3      NM       <0.01     NI          NM
a  From: Sumino et al. (1975).
b  NM = not measured.
c  NI = not indicated.
d  NC = not calculated because there were less than 5 samples
   available or there was no mean.

    Generally, there is no significant influence of sex or age on 
human organ levels of nickel (McNeely et al., 1971a; Turhan et al., 
1983; Zober et al., 1984).  The ribs, liver, and kidneys in babies 
up to the age of 3 months, were found to accumulate significantly 
more nickel than those in persons between 1 and 90 years of age 
(Schneider et al., 1980).  Few data exist on the organ levels of 
nickel in occupationally exposed persons.  In lung autopsy samples 
from 4 deceased persons living in the vicinity of a nickel-
processing industry in the German Democratic Republic, the mean 
nickel concentration was 2135±1867 mg/kg dry weight (Schneider et 
al., 1980). 

 (c) Body burden 

    One assessment of nickel metabolism in human beings indicated 
that the body burden of nickel in normal adults averaged 0.5 mg (7 
µg/kg for a 70-kg adult person) (Bennett, 1984).  However, in a 
study on 30 Japanese subjects, Sumino et al. (1975) calculated a 
total body burden of about 5.7 mg (for a body weight of 55 kg), and 
Schroeder et al. (1962) indicated a body burden of 10 mg nickel for 
an adult person.  Bennett (1984) concluded that the oral intake of 
nickel averaged 170 µg/day, of which approximately 5% would be 
absorbed (8.5 µg/day).  Inhalation of nickel averaged 0.4 µg/day 
for urban dwellers, of which 35% was retained (0.07-0.14 µg/day); 
this involves the assumption that 70% of the nickel absorbed into 
the blood is promptly excreted by the kidneys and that the 
remaining 30% is deposited in the tissues, with a mean retention 
time of 200 days (Bennett, 1984). Pathological states influencing nickel levels 

    Nickel metabolism is known to be altered in several common 
diseases, as well as in some physiological states.  Alonzo & Pell 
(1963) observed increased nickel concentrations in the serum of 19 
out of 20 patients with acute myocardial infarction, sampled within 
24 h of admission to the hospital.  Sunderman et al. (1970, 1971) 
reported increased nickel concentrations in the serum of 25 out of 
35 patients with acute myocardial infarction, sampled 12-36 h after 
onset of symptoms.  The frequent occurrence of hypernickelaemia 
after acute myocardial infarction has been confirmed by studies in 
the Federal Republic of Germany (Völlkopf et al., 1981), Pakistan 
(Khan et al., 1984), the United Kingdom (Howard, 1980), the USA 
(Leach et al., 1985), and the USSR (Nozdryukhina, 1978).  McNeely 
et al. (1971a) showed that hypernickelaemia is not specific for 
myocardial infarction, because nickel concentrations in serum are 
also increased in patients with cerebral stroke and thermal burns, 
as well as in patients with myocardial ischaemia without 
infarction.  Hypernickelaemia has been observed in patients with 
unstable angina pectoris, without infarction, and in patients 
suffering from coronary atherosclerosis, who developed cardiac 
ischaemia during treadmill exercise (Leach et al., 1985). 

    Volini et al. (1968) observed increased nickel concentrations 
in the liver in both the early and advanced stages of hepatic 
cirrhosis.  In a patient suffering from aspartylglycosaminurea, a 
10-fold increased concentration of nickel in the hepatic tissue was 
reported by Palo & Savolainen (1973). 

    Significantly decreased serum-nickel levels have been measured 
in steel-mill workers exposed to extreme heat (Szadkowski et al., 

    In an investigation by Rubanyi et al. (1982a), serum-nickel 
levels in postpartum mothers were found to be reduced by 60%.  
However, a significant 20-fold elevation in the concentration of 
nickel was observed immediately after delivery of the infant, but 
before delivery of the placenta.  Nomoto et al. (1983) did not 
confirm the occurrence of hypernickelaemia.  Post-operative 
hypernickelaemia and nickeluresis were observed in patients 
following total knee and hip arthroplasty with porous coated nickel 
alloy prostheses (Sunderman et al., 1989b). 

    Nickel concentrations in the serum, whole blood, and urine from 
61 patients with chronic alcoholism were elevated 17-, 15-, and 39-
fold, respectively, after 4 months to 4 years of disulfiram 
treatment.  Disulfiram (tetraethyl-thiuram-disulfide), a nickel-
chelating agent, is used in alcoholism therapy (Hopfer et al., 1987). 

6.3.  Elimination and excretion

    The elimination routes for nickel in human beings and animals 
depend, in part, on the chemical form of the compound and the mode 
of intake.  In general, relatively low gastrointestinal absorption 

explains the elimination of dietary nickel in the faeces.  In human 
beings and animals, urinary excretion is usually the major 
clearance route for absorbed nickel.  Other routes of elimination 
are of minor importance.  All body secretions appear to have the 
ability to excrete nickel; it has been found in saliva, sweat, 
tears, and milk.  Biliary excretion is minimal in animals, but may 
be significant in human beings.  Hair is an excretory tissue for 

6.3.1.  Experimental animals

    In experimental animals, urinary excretion is the main 
clearance route for nickel compounds, introduced parenterally.  
Only a small portion of an injected dose is excreted via the 
gastrointestinal tract.  Wase et al. (1954) studied the 
distribution and elimination of 63Ni in mice using a high dose (102 
µg 63Ni/animal), administered intraperitoneally, and found faecal 
and urinary elimination in the ratio of 30:70%.  The primary route 
of elimination of supplemental dietary nickel (carbonate) fed to 
calves was faecal (Tedeschi & Sunderman, 1957; O'Dell et al., 

    Biliary excretion of nickel was minimal following subcutaneous 
injection of 0.1 mg 63Ni, as nickel chloride, in rats (Marzouk & 
Sunderman, 1985). 

    In rats or rabbits, after inhalation of nickel carbonyl, 
Sunderman & Selin (1968) and Mikheyev (1971) found the lungs were 
the major excretory organ besides excretion via the urine, 2-4 h 
after exposure.  Other studies indicated that up to 90% nickel was 
excreted in the urine (Armit, 1908; Tedeschi & Sunderman, 1957; 
Sunderman & Selin, 1968; Mikheyev, 1971) and 38% was exhaled via 
the lungs as nickel carbonyl (Sunderman & Selin, 1968). 

    After intravenous injection of 14C-nickel carbonyl in rats, 
Kasprzak & Sunderman (1969) found that 30% of the 14C was excreted 
in the expired air as 14C-nickel carbonyl and 50% as 14C-carbon 

    Nickel is excreted in the urine, not as the free metal, but 
bound to a protein that is similar to, or a fragment of, the 
soluble low relative molecular mass glycoprotein associated with 
nickel in renal tissue (Verma et al., 1980; Abdulwajid & Sarkar, 

6.3.2.  Human beings

    As human beings take up most nickel via ingestion, it is 
eliminated unabsorbed, mainly in the faeces (Drinker et al., 1924; 
Tedeschi & Sunderman, 1957; Sunderman et al., 1963; Nodiya, 1972).  
Horak & Sunderman (1973) found that the faecal elimination of 
nickel in 10 healthy adults averaged 258 µg/day (SD 126) or 14.2 
mg/kg, (dry weight) (SD 2.7), thus, the normal faecal elimination 
of nickel was approximately 100 times greater than the normal 
urinary excretion (2.6 µg/day (SD 1.4) or 2.2 µg/litre (SD 1.2)). 

    The urinary nickel levels of persons occupationally exposed to 
appreciable nickel concentrations, via inhalation at the work-
place, are raised significantly.  Positive correlations have been 
reported between air and urinary nickel concentrations in workers 
in the nickel industry (section  Urinary nickel 
concentrations of normal and exposed persons are given in Tables 19 
and 20.  The large amounts of nickel also found in the faeces, in 
some cases, indicated that, either retrograde loss from the lung 
into the oesophagus, or considerable oral exposure via contaminated 
surfaces, had occurred. 

    Nickel concentrations in samples of human bile (section suggest that biliary excretion of nickel may be 
quantitatively significant in human beings (Rezuke et al., 1987).  
Sweat may constitute an excretory route of significance under 
conditions of physical exertion.  Hohnadel et al. (1973) 
demonstrated that, in sauna bathers, the mean concentrations of 
nickel in the sweat from healthy men and women were significantly 
higher than the mean concentrations in the urine (men: 52 µg/litre, 
SD=36; women: 131 µg/litre, SD=65).  Under conditions of profuse 
sweating, appreciable losses of nickel occurred.  This may account 
for the diminished concentrations of serum nickel that were 
reported by Szadkowski et al. (1969b) in blast-furnace workers who 
were exposed to extreme heat over a long period. 

    The role of nickel deposition in human hair as an excretory 
mechanism has been studied (section 

    Measurements of salivary nickel were performed by Catalanatto 
et al. (1977) on specimens of parotid saliva from 38 healthy 
adults.  The concentrations of nickel in saliva averaged 1.9 ± 1.0 
µg/litre (range 0.8-4.5 µg/litre).  There was no significant 
correlation between the concentrations of salivary nickel and 
protein.  No significant differences were observed between the mean 
concentrations of nickel in saliva samples from men and women. 


7.1.  Microorganisms

    Nickel is considered essential for certain metabolic processes 
in bacteria.  Bartha & Ordal (1965) demonstrated a nickel 
requirement in the "Knallgas" bacterium  Alcalignes entrophus.  A 
nickel requirement was reported by van Baalen & O'Donnell (1978) 
for the blue green algae  Oscillatoria sp. 

    Fungi and microorganisms demonstrate a fairly wide variety of 
sensitivity to nickel, but are generally more tolerant than the 
higher organisms.  The toxic effects of nickel on microorganisms, 
including eubacteria (non-marine and marine), actinomycetes, 
yeasts, and filamentous fungi, were studied by Babich & Stotzky 
(1982a,b; 1983).  Filamentous fungi varied considerably in their 
response to nickel, growth of  Achyla sp. being inhibited at 5 mg 
nickel/litre whereas  Aspergillus niger and  Gliocladium sp. were 
only affected at concentrations as high as 1000 mg nickel/litre.  
With actinomycetes and eubacteria, there was less variability in 
toxicity.  Concentrations of nickel inhibiting growth ranged from 5 
to 30 mg nickel/litre, with the exception of  Caulobacter leidyi, 
which exhibited some growth at 100 mg nickel/litre.  Growth 
inhibition in yeasts occurred at 1-40 mg nickel/litre.  In all 
microorganisms, toxicity increased as the pH decreased. 

    Babich & Stotzky (1983) investigated the influence of various 
factors on the toxicity of nickel for eubacteria, an actinomycete, 
and yeasts.  Reductions in cell number occurred at 5 or 10 mg/litre 
and viable cells were eliminated at 10-50 mg/litre, though some 
species were unaffected after 24 h at 100 mg/litre.  Reductions in 
pH from 6.8 to 5.3 enhanced the toxicity of 75 mg nickel/litre in 
some species, but not in others.  The toxicity of nickel (100 
mg/litre) for marine microbes was reduced by increasing the 
salinity and decreasing the temperature.  Addition of a simulated 
sediment (a mixture of organic and inorganic particles from soil) 
reduced toxic effects after exposure to 100 mg nickel/litre.  In 
freshwater microbes, addition of a clay mineral (50 mg/litre) 
provided protection against the toxicity of 10 mg nickel/litre.  
This effect was probably because of the adsorption of nickel on the 
particulates.  Increasing the hardness of the water, by adding 
calcium carbonate at 200 or 400 mg/litre, reduced the toxicity of 
10 mg nickel/litre.  Long-term studies indicated that microbial 
survival was greater in marine than in fresh water.  Bringmann et 
al. (1980) reported that, in fairly hard water (approximately 150 
mg CaCO3/litre) and a pH of 6.9, a nickel concentration of 0.82 
mg/litre reduced the numbers of the saprozoic flagellate  Chilomonas 

    Thus, fungi and microorganisms have a wide range of 
sensitivities to nickel, but are usually more tolerant than higher 

7.2.  Aquatic algae and plants

    Nickel at concentrations of 0.05-0.1 mg/litre inhibited the 
growth of algae, though some species may be more tolerant (Spencer, 
1980).  Upitis et al. (1980) reported growth inhibition in blue-
green algae at concentrations of 1-5 mg nickel/litre.  The 
chlorophyll content was found to be significantly reduced leading 
to discoloration of the cells.  Concentrations of 10-30 mg 
nickel/litre were lethal for  Chlorella sp.  The same authors 
investigated the influence of various environmental factors on the 
toxicity of nickel for  Chlorella.  Nickel inhibition could be 
overcome by the addition of ethylenediaminetetramine (EDTA) (40 
mg/litre) and also by the addition of zinc (10 mg/litre) to a 
medium containing 5 mg nickel/litre.  A synergistic effect of 
copper and nickel was demonstrated by Hutchinson (1973) for 
 Chlorella vulgaris, Scenedesmus acuminata, Haematococcus capensis, 
and  Chlamydomonas eugametos. 

    A nickel concentration of 0.1 mg/litre at 20 °C inhibited the 
growth of 4 species of green algae,  Pediastrum tetras, 
 Ankistrodesmus falcatus, Scenedesmus quadricauda, and  S. dimorpha.  
However, a concentration of 0.6 mg/litre did not affect the blue-
green alga  Anabaena cylindrica, though it reduced the rate of 
growth of  Anabaena flos-aquae (Spencer & Greene, 1981).  Stokes 
(1975) studied  Scenedesmus acutiformis var.  alternans, from a lake 
in a nickel-mining and smelting area.  The lake water contained 
about 2.5 mg nickel/litre.  At a nickel concentration of 1.9 
mg/litre, the  Scenedesmus grew at 53% of the rate of controls grown 
in clean water and, at 3.0 mg/litre, growth was still 18% of the 
control rate. 

    A nickel concentration of 0.125 mg/litre inhibited the growth 
of  Anabaena inequalis, but a concentration of 10 mg/litre was 
required to inhibit photosynthesis, and 20 mg/litre, to inhibit 
nitrogenase activity (Stratton & Corke, 1979). 

    Chiaudani & Vighi (1978) exposed  Selenastrum capricornutum to 
nickel in a standard medium with, and without, EDTA.  At 24 °C and 
a pH of 6.9-6.3 the 7-day EC50 (inhibition of growth to 50% of 
control values) was 0.9925 mg nickel/litre.  When 0.3 mg EDTA/litre 
was added to medium, the 7-day EC50 of nickel was increased to 
0.013 mg/litre.  In a further study, the addition of 0.04 mg 
nickel/litre to the water samples did not inhibit growth as much as 
was predicted from the laboratory studies. 

    When the diatom  Navicula pelliculosa was exposed to 0.1 mg 
nickel/litre (of which all but 0.2% was said to be Ni2+) for 14 
days, growth was retarded (50% of control value) (Fezy et al., 

    Hutchinson & Czyrska (1975) exposed  Lemna minor (Valdiviana), 
for 3 weeks, to nickel concentrations ranging from 0.01 to 1.0 
mg/litre in an artificial medium at pH 6.8, and a temperature of 
24±2 °C, with 16 h of light per 24 h.  They found that a 
concentration of 0.05 mg/litre stimulated growth, and that 

concentrations greater than 0.1 mg/litre inhibited growth.  At 1 mg 
nickel/litre, growth was prevented.  Nickel uptake and toxicity 
were enhanced by the presence of copper. 

    The same authors examined  Lemna minor from 23 sites, where the 
mean concentration of nickel in the water was 0.027 mg/litre.  The 
plants contained from 5.4 to 35.1 mg nickel/kg (dry weight), 
equivalent to bioaccumulation factors (BCFs) of 200 and 1300.  
 Lemna, grown on a culture medium containing 0.01-1 mg nickel/litre 
at pH 6.8 and a temperature of 24±2 °C for 3 weeks, accumulated 
nickel concentrations ranging from 40 mg/kg dry weight, at 0.01 
mg/litre, to 3067 mg/kg, at 0.5 mg/litre. 

    Clark et al. (1981) studied the accumulation and depuration of 
nickel by  Lemna perpusilla.  Plants collected from a fly ash basin 
(nickel concentration, 0.1 mg/litre) were allowed to depurate in 
dechlorinated tap water at 20 °C for a 14-day depuration period.  
Concentrations of nickel fell from about 160 mg/kg dry weight to 
about half of this value.  In the accumulation studies,  Lemna 
accumulated nickel readily, particularly at the lowest ambient 
concentration of 0.1 mg/litre, and levels reached 500-600 mg/kg in 
10 days.  After a return to depuration conditions, the nickel 
concentration in the plants fell to 160 mg/kg, in 8 days. 

     Euglena gracilis, exposed to 8.9 x 10-4 mg nickel/litre in 
spring-water, accumulated the metal to a concentration of 1.8 
mg/kg, a BCF of about 2000 (Cowgill, 1976). 

     Ipomea aquatica took up 200 mg nickel/kg dry plant in 48 h, 
mostly in the roots, from water containing 5 mg nickel/litre (BCF = 
40) (Low & Lee, 1981). 

    It is noted that, under laboratory conditions, the growth of a 
macrophyte  (Lemna) was inhibited at a concentration of 0.1 
mg/litre, but the growth of algae was inhibited at concentrations 
as low as 0.04 mg/litre.  However, in natural waters, a nickel 
concentration of 0.04 mg/litre had a less inhibiting effect. 

7.3.  Aquatic invertebrates

    Timourian & Watchmaker (1972) investigated the uptake of nickel 
chloride and its effects on the development of sea urchin embryos.  
After fertilization, sea urchin eggs exhibited increased rates of 
nickel uptake that appeared to be a result of an active transport 
mechanism.  When exposed to 59-590 mg nickel/litre, gastrulation of 
embryos was prevented.  Embryos grown in 0.59-5.9 mg nickel/litre 
were able to gastrulate, but failed to develop dorsoventral symmetry. 

    Acute and long-term toxicity studies performed by Powlesland & 
George (1986) revealed a different sensitivity to nickel in 
different developmental stages of  Chironomus riparis larvae.  First 
instar larvae were found to be significantly more sensitive to 
nickel than second instars with 48-h LC50 values of 79.5 mg/litre 
and 169 mg/litre, respectively.  Longer term toxicity tests (30 

days), in which larvae were allowed to develop from eggs until just 
prior to pupation, indicated that nickel concentrations up to 25 
mg/litre appeared to have little effect on the percentage hatch.  
However, the growth of larvae was significantly reduced at 2.5 
mg/litre.  A threshold concentration for the effect of nickel on 
growth was estimated to be 1.1 mg nickel/litre. 

    Bryant et al. (1985) investigated the effects of temperature 
and salinity on the toxicity of nickel in two estuarine 
invertebrates.  In the amphipod  Corophium volutator, and the 
bivalve  Macoma baltia, 96-h LC50 values varied from 5 to 54 mg 
nickel/litre and from 95 to 1100 mg nickel/litre, respectively.  A 
decrease in salinity from 35 to 5 mg/litre resulted in greater 
toxicity in both species.  Toxicity also increased in  Corophium 
 volutator with an increase in temperature from 5 to 15 °C. 

    Mathis & Cummings (1973) measured nickel levels in sediments, 
water, and biota in a river.  The water contained the lowest 
concentrations of nickel (<0.01 mg/litre) and the sediments, the 
highest (3-124 mg/kg).  Two species of tubificid worms  (Limnodrilus 
 hoffmeisteri and  Tubifex tubifex) contained 4-18 mg nickel/kg wet 
weight.  Three species of clam were examined: in order of 
increasing nickel content (mg/kg on a wet-weight basis) they were 
 Quadrula quadrula (0.4-1.6),  Amblema plicata (0.4-2.3) and 
 Fusconaia flava (0.7-3.0).  Neither worms nor clams were starved 
before being examined, and nickel may also have been present in 
their gut contents.  Brkovic-Popovic & Popovic (1977) studied the 
effects of nickel and other heavy metals on the survival of  Tubifex 
 tubifex in water of different pH and hardness.  At a hardness of 
0.1 mg CaCO3/litre, the 48-h LC50 was 0.082 mg nickel/litre.  
Increases in hardness to 34.2 mg CaCO3/litre and 261 mg CaCO3/litre 
increased the 48-h LC50 to 8.7 mg nickel/litre and 61.4 mg 
nickel/litre, respectively, thus decreasing the toxic effects. 

    A 64-h LC50 was determined for  Daphnia magna of 0.32 mg 
nickel/litre, at a temperature of 25 °C and a hardness of around 
100 mg CaCO3/litre (Anderson, 1950).  Baudouin & Scoppa (1974), 
using  Daphnia hyalina, estimated a 48-h LC50 value of 1.9 mg 
nickel/litre at a temperature of 10 °C, pH 6.2, and hardness of 58 
mg CaCO3/litre. 

    Exposure of  Daphnia magna to nickel sulfate at concentrations 
ranging from 5 to 10 µg nickel/litre for 3 generations resulted in 
extermination (Lazareva, 1985). 

    Hall (1982) exposed  Daphnia magna to 0.25 mg nickel/litre, 
including 63Ni, at pH 6.9, and a temperature of 18-21 °C in water 
with a hardness of 60 mg CaCO3/litre.  The uptake of nickel was 
initially rapid (about 12 mg in 80 h).  Depuration also occurred, 
and 25-33% of the nickel was lost from the animal in the exuviae, 
shed on moulting.  Gut tissue did not accumulate nickel until after 
the first 5 h of exposure, suggesting that the oral route was not 
important for nickel. 

     Daphnia, exposed for 3 weeks to 0.125 mg nickel/litre in water, 
at a temperature of 18±1 °C, hardness of 42.3-45.3 mg CaCO3/litre, 
and pH 7.74, had 43% lower weights than control  Daphnia, 9% less 
proteins, and the glutamic oxalacetic transaminase activity was 
reduced by 26%.  A 16% impairment of reproduction occurred at 0.03 
mg nickel/litre with a 50% impairment at 0.095 mg nickel/litre 
(Biesinger & Christensen, 1972). 

    Cowgill (1976) reared  Daphnia magna and  Daphnia pulex for 3 
months on  Euglena gracilis, which had been cultured in spring water 
containing 8.9 x 10-4 mg nickel/litre.  The algal cells contained 
1.8 mg nickel/kg, the  Daphnia magna, 3.6 mg nickel/kg, and the  D. 
 pulex, 4.2 mg nickel/kg, giving BCF values of 2020 and 4050. 

    The acute effects of nickel on the freshwater snails  Juga 
 plicifera and  Physa gyrina were studied by Nebeker et al. (1986).  
The 96-h LC50 values were 0.237 mg nickel/litre and 0.239 mg/litre, 
respectively.  A no-observed-effect-level of 0.124 mg nickel/litre 
was determined for  Juga plicifera.  Data published for other 
species of snails did not indicate a pronounced effect of hardness 
on nickel toxicity (Nebeker et al., 1986).  The eggs and adults of 
the snail  Amnicola were exposed to nickel in water at a temperature 
of 17 °C, pH 7.6, and a hardness of 50 mg/litre with 6.2 mg 
dissolved oxygen/litre.  The 24-h LC50s were 26.9 mg/litre for eggs 
and 21.1 mg/litre for adults, whereas at 96 h, the LC50s were 11.4 
and 14.3 mg/litre, respectively (Rehwoldt et al., 1973). 

    Nickel influenced the rate of filtration in the marine bivalve 
 Villorita cyprinoides (Abraham et al., 1986).  Rates of filtration 
decreased exponentially with increasing nickel levels.  The EC50, 
i.e., the concentration that reduced the rate of filtration by 50%, 
was 0.003 mg nickel/litre.  A 96-h LC50 was 0.061 mg nickel/litre. 
It is concluded that the nickel concentrations causing mortality in 
acutely exposed invertebrates were generally similar to those for 
fish, but that  Daphnia sp. appeared more sensitive, with LC50 
values of less than 2 mg nickel/litre. 

7.4.  Fish

    Sensitivity to nickel varies considerably among fish species.  
However, 96-h median lethal concentrations generally fall within 
the ranges of 4-14 and 24-44 mg nickel/litre for tests conducted in 
soft, and hard water, respectively.  For example, in water of 
hardness 100, 125, and 174 mg CaCO3/litre, the LC50s for rainbow 
trout, exposed from fertilization to 4 days after hatching, were 
0.05, 0.06, and 0.09 mg/litre, respectively (Birge & Black, 1980). 

    Pickering & Henderson (1966) compared the toxicity of nickel 
chloride in waters of 2 levels of hardness (total hardness 20 or 
300 mg CaCO3/litre).  The 96-h LC50 was 4.9 mg/litre for fathead 
minnow  (Pimephales promelas) and 5.3 mg/litre for bluegill sunfish 
 (Lepomis macrochirus) in soft water, and 43.5 mg/litre and 39.6 
mg/litre, respectively, in hard water.  Rainbow trout  (Salmo 
 gairdneri) showed a 4-fold increase in sensitivity between hard and 

soft water, the 48-h LC50 changing from about 80 to about 20 
mg/litre (Brown, 1968). 

    In rainbow trout, a 48-h LC50 for nickel sulfate of 263 
mg/litre was determined in a static test (Osterreichisches 
Forschungs-Zentrum Seibersdorf, 1983).  The water had a hardness of 
402 mg CaCO3/litre, a pH of 7.6, and a temperature of about 15 °C.  
The first signs of toxicity were observed at a concentration of 85 
mg nickel sulfate/litre. 

    Using the same test method and corresponding test conditions, 
Butz (1984) demonstrated that a decrease in water hardness from 270 
to 49 mg CaCO3/litre resulted in a 2.6-fold increase in toxicity. 

    Rehwoldt et al. (1971, 1972) studied the effects of temperature 
on the toxicity of nickel for 6 warm-water species of fish: banded 
killifish  (Fundulus diaphanus), striped bass  (Roccus saxatilis), 
pumpkin seed  (Lepomis gibbosus), white perch  (Roccus americanus), 
American eel  (Anguilla rostrata) and carp  (Cyprinus carpio).  There 
was a wide range of sensitivity among these species, with 96-h LC50 
values at 17 °C ranging from 6.2 to 46.2 mg nickel/litre.  However, 
each species showed very little variation in sensitivity at 
temperatures of 17 and 28 °C.  At 28 °C and a hardness of 55 mg 
CaCO3/litre,  Roccus saxatilis and  Lepomis gibbosus were the most 
sensitive, having 96-h LC50s of 6.3 and 8.0 mg nickel/litre, 
respectively, while  Fundulus diaphanus was the most tolerant (46.1 
mg nickel/litre).   Roccus americanus, Anguilla rostrata, and 
 Cyprinus carpio were intermediate in their response, but relatively 
sensitive, the 96-h LC50s being 13.7, 13.9, and 10.4 mg 
nickel/litre, respectively (Rehwoldt et al., 1972). 

    In static tests in softer water (20 mg CaCO3/litre),  Pimephales 
 promelas, Lepomis macrochirus, Carassius auratus, and  Lebistes 
 reticulatus showed similar levels of sensitivity in terms of 96-h 
LC50s with LC50 values of 4.9, 5.3, 9.8, and 4.5 mg nickel/litre, 
respectively (Pickering & Henderson, 1966). 

    In a flow-through test, rainbow trout  (Salmo gairdneri) were 
less sensitive than other fish species with a 48-h LC50 of 20 mg 
nickel/litre, in soft water (Brown, 1968).  In field studies, Hale 
(1977) reported a 96-h LC50 for rainbow trout of 35.5 mg 
nickel/litre in continuous-flow tests in water with a hardness of 
82-132 mg CaCO3/litre.  Arillo et al. (1982) found that rainbow 
trout  (Salmo gairdneri), exposed to nickel, showed a reduction in 
glucidic stores.  This effect is consistent with direct metal 
interaction on both membranes and enzyme thiolic groups of the 
pancreatic cells.  Other effects, similar to those found with other 
metals, such as damage to the secondary lamellae of gills (Hughes 
et al., 1979) and sialic acid depletion in the gills (Arillo et 
al., 1982) have been described. 

    A 96-h LC50 of 118.3 mg nickel/litre was determined for the 
marine grey mullet  (Chelon labrosus) (Taylor et al., 1985a). 

    The toxicity of nickel(II) chloride was studied in 2 estuarine 
fish species (US EPA, 1987).  In tidewater silverside  (Menidia 
 peninsulae) larvae, a 96-h LC50 was 38 mg/litre.  For adult spot- 
fish  (Leiostomus xanthums), the 96-h LC50 was 70 mg/litre. 

    In short-term tests in soft water, the most sensitive species 
of freshwater fish were killed by exposure to concentrations of 
about 4-20 mg nickel/litre.  Higher LC50 values of nickel have been 
found for different species of fish in harder waters, ranging from 
about 30 to 80 mg nickel/litre.  From the limited data available, 
it appears that hardness has the greatest effect on toxicity, while 
other determinants have not been proved to have any significant 
effects.  In acute tests, there are interspecies differences in 
sensitivity, but these are within a single order of magnitude. 

    Shaw & Brown (1971) did not observe any effects on rainbow 
trout eggs fertilized in water containing 1 mg nickel/litre and 
then maintained in clean water.  In a life-cycle study on fathead 
minnow, in water with a hardness of 210 mg CaCO3/litre, pH 7.8, and 
an average temperature of 18 °C, Pickering (1974) found that nickel 
concentrations of 0.38 mg/litre and less (0.18 and 0.08 mg/litre) 
did not have any adverse effects on survival, growth, and 
reproduction.  However, a concentration of 0.73 mg nickel/litre had 
a statistically significant effect on the number of eggs produced 
per spawning and on the hatchability of these eggs, though it did 
not affect the survival and growth of the first generation of fish. 

    In carp  (Cyprinus carpio) eggs and larvae, the 72-h LC50s were 
6.1 and 8.4 mg/litre, respectively, while the 257-h LC50 for larvae 
was 0.75 mg nickel/litre in water with a hardness of 128 mg 
CaCO3/litre, pH of 7.4, and a temperature of 25 °C.  A 
concentration of 3 mg nickel/litre caused an increased incidence of 
abnormal larvae (23% compared with 8.6% in the controls) and 32.7% 
of embryos failed to hatch, compared with 5.9% in the controls 
(Blaylock & Frank, 1979). 

    Birge et al. (1978) exposed rainbow trout and largemouth bass 
 (Micropterus salmoides) from fertilization to 4 days after 
hatching, to 11 trace metals found in coal, at a temperature of 12-
13 °C, equivalent to a period of exposure of 28 days for rainbow 
trout and 8 days for bass.  The LC50 values for these periods were 
0.05 mg nickel/litre for rainbow trout and 2.06 mg nickel/litre for 
bass.  The water used in the tests had a hardness of about 100 mg 
CaCO3/litre and a pH of 7.2-7.8.  For rainbow trout and goldfish, 
teratic larvae were observed at exposure levels that did not 
significantly affect egg hatchability.  In water from a natural 
source with a pH of 7.8 and 174 mg CaCO3/litre hardness, an LC50 
for rainbow trout was 0.09 mg nickel/litre whereas in dechlorinated 
tap water (pH 7.6, hardness 125 mg CaCO3/litre) the LC50 was 0.06 
mg nickel/litre. 

    Using water with a hardness of about 100 mg CaCO3/litre and pH 
7.2-7.8, Birge & Black (1980) found that the LC50 from 
fertilization to 4 days after hatching was 0.71 mg nickel/litre for 
channel catfish  (Ictalurus punctatus) and 2.78 mg nickel/litre for 
goldfish  (Carassius auratus). 

    Calamari et al. (1982) found that, during the long-term 
exposure of fish to 1 mg nickel/litre, continuous uptake of nickel 
occurred for 180 days.  The concentrations found were: liver, about 
2.9 mg nickel/kg wet weight, kidneys, 4.0 mg/kg, and muscle, 0.8 
mg/kg, while, at the beginning of the study, the levels had been 
1.5, 1.5, and 9.5 mg nickel/kg, respectively.  Toxicokinetic 
modelling indicated that theoretical asymptotic values for the 
liver, kidney, and muscle should be reached in 397, 313, and 460 
days, respectively, at which times the calculated bioconcentration 
factors (BCF tissue concentration/environmental concentration) were 
3.1, 4.2, and 1.9, respectively.  Release was slower in clean water 
and the proportions of nickel remaining after 90 days in the liver, 
kidney, and muscle were 25, 41, and 31%, respectively.  These data 
suggest that nickel had little capacity for accumulation in the 
tissues examined.  However, even these relatively low 
concentrations are toxic (Arillo et al., 1982). 

7.5.  Terrestrial organisms

7.5.1.  Plants

    Nickel is ubiquitous in plant tissues.  There is evidence that 
nickel is a required nutrient in a number of plant species.  The 
urease enzyme of jack bean  (Canavalia ensiformis) has been shown to 
be a nickel metalloenzyme (Dixon et al., 1975). 

    Although nickel levels above 50 mg/kg in plants are usually 
toxic, a number of plant species may tolerate higher levels 
(section 4.2.1). 

    In general, the effects of long-term, low-level exposure to 
nickel are only manifested in growth decrements with no visible 
signs.  Nickel toxicity in plants is characterized by chlorosis and 
necrosis of the leaves, stunting of the roots, deformation of 
various plant organs, and wilting (Brooks, 1980; Prokipcak & 
Ormrod, 1986). 

    Apart from the solubility of nickel ions or nickel complexes, 
other factors can affect nickel toxicity.  Of special interest is 
the presence of other heavy metals, which can act synergistically, 
and the ameliorating effects of calcium. 

    A synergistic effect of nickel and copper on the growth of bush 
beans was demonstrated by Wallace & Berry (1983).  When barley was 
grown on loam soil with an elevated level of each of the 6 trace 
elements, lithium (13 mg/kg soil, dry weight), zinc (200 mg/kg), 
copper (200 mg/kg), nickel (100 mg/kg), and cadmium (100 mg/kg) 
there was no reduction in yield when they were applied singly.  
However, when all 6 were applied together, at the concentrations 
applied singly, there was a 40% reduction in yield, probably 
because of depressed phosphorus levels (Wallace et al., 1980a). 

    Investigations by Prokipcak & Ormrod (1986) of the growth 
responses of tomato and soy bean to combinations of nickel, copper, 
and ozone, indicated that the nature of the joint action of these 

chemicals is very complex and depends on species, the 
concentrations of the metals and ozone, and, to a lesser extent, 
the duration of exposure.  In the first study, nickel was added to 
the nutrient solution of tomato and soy bean plants at 1.5, 7.5, or 
37.5 mg/litre for 6 days, beginning on day 14 after seeding.  The 
plants were then exposed to 0.15 or 0.30 µlitre atmospheric 
ozone/litre.  Growth variables were markedly reduced by nickel, but 
ozone response depended on the nickel level.  In the second study, 
0.3 or 1.5 mg nickel/litre was provided from the 5th or 14th day 
onwards.  There was little effect of duration of nickel treatment 
on growth.  Increasing nickel levels and increasing ozone levels 
decreased growth, but there was no interaction.  In the third 
study, treatments with 1.5 or 3.0 mg nickel/litre were combined 
with 3.0 or 6.0 mg copper/litre, prior to treatment with 0.25 ml 
atmospheric ozone/litre.  There were complex interactive effects of 
all 3 compounds on tomato plant growth, but not on soy bean plant 

    Calcium can reduce nickel toxicity.  For example, when soy 
beans were grown in nutrient solution containing 1.2 mg 
nickel/litre, leaf yield depression was 74% at 4 mg calcium/litre, 
but only 45% at 400 mg calcium/litre (Wallace et al., 1980b). 

7.5.2.  Animals

    Few data are available on the effects of nickel on terrestrial 
animals.  Most data are derived from laboratory animals and 
indicate that nickel is an essential element in some species. 

    As land application of wastes is a common method of 
fertilization, studies were performed to evaluate the impact of 
heavy metals on the soil ecosystem, using the earthworm  Eisenia 
 foetida as a test organism.  Following a 14-day exposure to nickel 
nitrate in artificial soil, the LC50 was calculated to be 757 mg/kg 
(Neuhauser et al., 1985).  Hartenstein et al. (1981) determined 
the level at which added concentrations of heavy metals would cause 
an activated sludge to induce toxic effects on  Eisenia foetida.  
Nickel was found to inhibit growth and to induce death at 
concentrations of 1200-12000 mg/kg dry weight.  These 
concentrations seemed very high and the authors concluded that 
nickel might have been accumulated by the large population of 
microorganisms in the rich organic matrix, part of which might not 
be ingestible or digestible by earthworms.  This would enable 
earthworms to grow in the presence of high nickel concentrations. 

7.5.3.  Essentiality of nickel for bacteria and plants

    Evidence for specific biochemical functions of nickel has come 
from studies of microbial systems.  Nickel is involved, in some 
way, in the "Knallgas" reaction, which is mediated by a number of 
bacteria of different genera (Tabillion et al., 1980; Friedrich et 
al., 1981; Albracht et al., 1982).  The reduction of carbon dioxide 
to acetate, carried out by acetogenic bacteria, is dependent on 
nickel, which is needed to activate the enzyme carbon monoxide 
dehydrogenase (Diekert & Thauer, 1980; Drake, 1982).  Diekert & 

Ritter (1982) demonstrated that  Acetobacterium woodii growth on 
fructose was stimulated by, but not dependent on, nickel, unlike 
CO2 reduction.  A number of studies have established that nickel is 
the core metal in the tetrapyrrole ("Factor F430"), found in 
methanogenic bacteria, and is essential for the growth of these 

    In plants, Dixon et al. (1975) showed that nickel is essential 
at the active site of urease in jack beans  (Canavalia ensiformis), 
for its enzymatic activity. 

7.6.  Population and ecosystem effects

    Few data are available that identify nickel as a specific cause 
for effects at the population level, because nickel is generally 
associated with other, often more toxic, trace metals or pollutants 
that could be involved in the effects. 

    Gradual ecological changes have been observed near sources 
emitting nickel and other trace metals, resulting in a decrease in 
the number and diversity of species (Hutchinson & Whitby, 1977; 
Gignac & Beckett, 1986).  Yan et al. (1985) investigated 39 lakes 
in Ontario and found that the tracheophyte richness of acidic lakes 
decreased with increasing nickel and copper levels. 

    In acidic copper-, and nickel-contaminated lakes near Sudbury, 
Ontario, species richness and community biomasses were reduced in 
Crustacean zooplankton communities (Yan & Strus, 1980). 

    DeCantazaro & Hutchinson (1985a,b) demonstrated that the 
addition of nickel to microecosystems and incubated soil samples 
from boreal jack pine forests could disrupt nitrogen cycling.  
Nickel additions of 100-500 mg/kg soil were shown to stimulate 
nitrification and nitrogen mineralization, resulting in loss of 
nitrogen by leaching.  The authors concluded that loss of nitrogen, 
which is probably the nutrient most limiting to growth in a boreal 
forest ecosystem, could have serious ecological consequences for 
forests in the vicinity of nickel smelters. 


    Various studies have indicated that nickel is an essential 
element in a number of experimental animal species and that it may 
also have a physiological role in human beings.  However, nickel 
deficiency has not been demonstrated in human beings, and the 
possible nickel requirement is probably very low.  While the 
elucidation of nickel essentiality is in progress, it has not 
reached the stage where it can be quantified in relation to nickel 

8.1.  Animals

8.1.1.  Essentiality

    Earlier studies in trace-element nutritional research did not 
demonstrate any consistent effects of nickel deficiency (Schroeder, 
1968; Smith, 1969; Nielsen & Säuberlich, 1970; Wellenreiter et al., 
1970; Nielsen & Higgs, 1971; Schroeder et al., 1974), in part, 
because of the technical difficulties of controlling nickel intake 
due to its ubiquity.  Since 1975, diets and environments have been 
devised for adequately controlled studies on nickel metabolism and 
nutrition, and the effects of deprivation have been described for 
17 animal species, including: chicken, cow, goat, mini-pig, pig, 
rat, and sheep. 

    Nickel is a component of several enzyme systems (certainly 
urease and some hydrogenases) and it seems essential for the well-
being of several animal species (Spears et al., 1978). Nickel deficiency symptoms 

 (a) Growth 

    In goats (Anke et al., 1977, 1978, 1980, 1986), pigs (Anke et 
al., 1977, 1986; Spears, 1984; Spears et al., 1984), and rats 
(Nielsen et al., 1975b; Schnegg & Kirchgessner, 1975a, 1980), a 
nickel-deficient diet resulted in significantly decreased growth.  
The growth depression depended on the nickel level and the duration 
of administration and only became evident after intrauterine nickel 
deficiency, i.e., in the second or later generations.  In addition, 
species-specific differences seemed to exist (Anke et al., 1977). 

 (b) Reproduction and mortality 

    In goats, mini-pigs, and rats, reproduction was decreased only 
insignificantly by intrauterine nickel deficiency (Anke et al., 
1977; Schnegg & Kirchgessner, 1975a, 1980).  Conception and 
abortion rates as well as the number of offspring were not 
influenced by nickel deficiency, but kidding in nickel-deficient 
goats and farrowing in nickel-deficient sows occurred later (Anke 
et al., 1974).  Furthermore, at the end of the lactation period, 
significantly fewer offspring of nickel-deficient goats were still 
alive compared with control animals.  Schnegg & Kirchgessner (1980) 

did not find any increase in mortality in intrauterinely nickel-
deficient rats, whereas Nielsen et al. (1975b) found it to a 
remarkable extent.  Smaller litter size has been observed in both 
rats and pigs (Anke et al., 1974; Nielsen et al., 1975b; Schnegg & 
Kirchgessner, 1975a). 

 (c) Histological parameters 

    Nielsen & Sauberlich (1970) described a nickel-deficiency 
syndrome in chickens, characterized by changes in the pigmentation 
of the shank skin, thicker bones, swollen joints, and a light-
coloured liver.  However, these findings are not consistent with 
those observed by other authors (Sunderman et al., 1972; Nielsen, 
1974).  Sunderman et al. (1972) and Nielsen & Ollerich (1974) 
observed ultrastructural lesions in the hepatocytes of chickens.  
In mini-pigs fed a nickel-deficient diet, Anke (1974) observed 
parakeratosis-like damage to the epithelium.  Skin eruptions were 
also seen in nickel-deficient goats; the hair of the animals was 
brittle, there were fissures of the mouth and legs (Anke et al., 
1976, 1980b).  Offspring of nickel-deficient rats had an anaemic 
appearance (Schnegg & Kirchgessner, 1975a, 1980a; Nielsen et al., 

 (d) Rumen activity 

    Nickel seems to be essential for ruminants, because urease 
activity in the rumen depends on nickel.  Spears & Hatfield (1977) 
demonstrated disturbances in metabolic parameters in lambs 
maintained on a low-nickel diet, including reduced oxygen 
consumption in liver homogenate preparations, increased activity of 
alanine transaminase, decreased levels of serum proteins, and 
enhanced urinary nitrogen excretion.  In a follow-up study, Spears 
et al. (1978) found that these animals had significantly lower 
microbial urease activity.  It was possible to increase urease 
activity in the rumen contents by means of nickel supplementation. 

 (e) Disturbance of iron metabolism 

    Schnegg & Kirchgessner (1975b; 1976a,b) showed that nickel 
deficiency in rats led to a reduced iron content in organs, reduced 
haemoglobin and haematocrit values, and anaemia.  Iron 
supplementation did not cure this anaemia (Nielsen et al., 1979a; 
Nielsen & Shuler, 1981), indicating a markedly impaired iron 
absorption.  Nickel-deficient goats eliminated 33% more iron via 
the faeces than control animals (Anke et al., 1980).  Spears et 
al., (1984) found that additional nickel could improve the iron 
status of neonatal pigs.  The mechanism through which nickel might 
enhance iron absorption is still unclear.  While nickel might act 
enzymatically to convert ferric to ferrous iron (a form more 
soluble for absorption), it might also promote the absorption of 
iron by enhancing its complexing with a molecule that can be 
absorbed (Nielsen, 1984). 

 (f) Nickel/calcium interaction 

    Anke (1974) found that nickel-deficient mini-pigs excreted more 
calcium renally than corresponding control animals.  The skeletons 
of nickel-deficient animals contained less calcium than those of 
animals on a nickel-rich diet.  Kirchgessner & Schnegg (1980a) 
confirmed this effect of nickel deficiency in 30-day-old rats and 
showed that more magnesium, instead of calcium, was incorporated 
into bones. 

 (g) Nickel/zinc interaction 

    Analysis showed that different organs and body fluids of 
nickel-deficient goats and pigs suffering from parakeratosis-like 
changes of the skin and hair, were not only poor in calcium, but 
also in zinc.  There were single cases of dwarfism in goats (Anke, 
1974; Anke et al., 1980, 1981).  In rats, nickel deficiency also 
resulted in a significantly decreased zinc concentration in organs, 
demonstrated by the reduced size of the organs (Nielsen & Shuler, 
1979; Kirchgessner & Schnegg, 1980a). 

 (h) Enzyme activities 

    The effects of nickel deficiency on enzyme activity have been 
studied in rats by Schnegg & Kirchgessner (1975b, 1977a,b,c,d) and 
Kirchgessner & Schnegg (1979, 1980b).  They found that, as a rule, 
the activity of a number of dehydrogenases and transaminases 
decreased by 40-75% (malate dehydrogenase (MDH), isocitrate 
dehydrogenase (ICDH), lactic dehydrogenase (LDH), glucose-6-
phosphate dehydrogenase (G6PDH), glutamate dehydrogenase (GLDH), 
glutamic oxalate transaminase (GOT), glutamic pyruvic transaminase 
(GPT)) with LDH and G6PDH being influenced by secondary iron 
deficiency.  Kirchgessner & Schnegg (1979, 1980b) also measured a 
significant 50% reduction in the activity of alpha-amylases in the 
liver and pancreas.  The results of other studies suggest that 
nickel may serve as a co-factor for the activation of calcineurin, 
a calmodulin-dependent phosphoprotein phosphatase (King et al., 

 (i) Substrate and metabolite concentrations 

    Nickel deficiency mainly affects carbohydrate metabolism, and 
this has been demonstrated in nickel-deficient rats by Schnegg & 
Kirchgessner (1977c).  The glucose and glycogen contents of the 
liver in nickel-deficient rats was reduced by 90% and the 
triglycerides decreased by 40% compared with those in control 
animals.  Similar values were found in the serum of the rats, and 
also in that of goats.  Anke et al. (1980b) reported a reduced 
triglyceride level in the serum of ruminants, but the cholesterol 
level was unchanged.  The significantly increased alpha-lipoprotein 
and reduced beta-lipoprotein concentrations were probably connected 
with a normal cholesterol level, and a disturbance of triglyceride 
metabolism, because the alpha-fraction was rich in cholesterol and 
the beta-fraction, rich in triglyceride. 

    The influence of nickel deficiency on the plasma cholesterol 
concentration and on the fat content of the liver has been studied 
(Nielsen, 1971; Sunderman et al., 1972; Nielsen et al., 1974, 
1975a,b; Schnegg & Kirchgessner, 1977c).  However, the results were 
inconsistent, because the cholesterol level was not affected in 
nickel-deficient animals.  Nielsen (1971) found a decrease in the 
fat content of the liver in chickens, but Anke et al. (1977) did 
not find this in mini-pigs. 

8.1.2.  Acute exposures Nickel carbonyl 

    Acute lethal concentrations of nickel carbonyl for laboratory 
animals are shown in Table 25.  The lethal doses range from an LC50 
of 0.1 mg nickel carbonyl/litre air for a 20-min inhalation 
exposure of the rat, to an LC50 of 2.5 mg/litre air for the dog 
following inhalation exposure of 30 min.  The LD50s via other 
routes range from 13 to 65 mg/kg, the intraperitoneal route being 
the most toxic. 

    Animals acutely exposed to nickel carbonyl vapour show 
pulmonary effects and lesions similar to those observed in human 
cases of industrial poisoning. The lung is the primary target organ 
for nickel carbonyl in animals, and pulmonary effects are rapid at 
high exposure levels, oedema occurring within 1 h of exposure.  
Subsequently, proliferation and hyperplasia of the bronchial 
epithelium and alveolar lining cells develop.  Several days after 
exposure, severe intra-alveolar oedema with focal haemorrhage and 
alveolar cell degeneration occur.  In animals that survive the 
acute effects, regression of cytological changes with fibroblastic 
proliferation within the alveolar interstitium occurs. 

    Pathological lesions in other organs after acute exposure of 
animals to nickel carbonyl are less severe than those in the lung.  
However, focal haemorrhage, congestion, oedema, hydropic 
degeneration, mild inflammation, and vacuolization have been 
reported in the brain, liver, kidney, adrenals, spleen, and 
pancreas.  In hepatic parenchymal cells, dilatation of rough 
endoplasmic reticulum is the most prominent and consistent 
ultrastructural abnormality.  Nucleolar alterations also develop in 
hepatocytes, 2-24 h after exposure to nickel carbonyl. 

    Pathological lesions of tubules and glomeruli have been seen in 
rats exposed to nickel carbonyl (Kincaid et al., 1953; Sunderman et 
al., 1961; Hackett & Sunderman, 1967). Other nickel compounds 

    LD50 data for some other nickel compounds are listed in Table 

Table 25.  Acute toxicity studies on nickel carbonyl in experimental animalsa
Species  Route        Lethal dose                      Observations in surviving        Observation   References
                                                       animals                          period after
Rabbit   inhalation   LC80 = 1.4 mg/litre 50 min        Lungs: intra-alveolar            1-5 days      Armit (1908)
Cat                   LC80 = 3.0 mg/litre 75 min       haemorrhage, oedema, and         (rabbit)
Dog                   LC80 = 2.7 mg/litre 75 min       exudate and alveolar cell
                                                        Adrenals: haemorrhages
                                                        Brain: perivascular
                                                       leukocytosis and neuronal

Rat      inhalation   LC80 = 0.9 mg/litre 30 min        Lungs: at 2-12 h, capillary      2 h-several   Barnes & Denz
                                                       congestion and interstitial      months        (1951)
                                                       oedema, at 1-3 days, massive
                                                       intra-alveolar oedema, at 
                                                       4-10 days, pulmonary 
                                                       consolidation and interstitial

Mouse    inhalation   LC50 = 0.067 mg/litre 30 min      Lungs: at 1 h, pulmonary         0.2 h-6 days  Kincaid et al.
Rat                   LC50 = 0.24 mg/litre 30 min      congestion and oedema, at        (rat)         (1953)
Cat                   LC50 = 0.19 mg/litre 30 min      12 h-6 days, interstitial
                                                       pneumonities with focal 
                                                       atelectasis and necrosis, and
                                                       peribronchial congestion;
                                                        Liver, spleen, kidneys, 
                                                        pancreas: parenchymal cellular
                                                       degeneration with focal 

Mouse    inhalation   LC100 = 0.2 mg/litre 120 min                                                    Sanotskii (1955)
Mouse                 LC100 = 0.01 mg/litre 120 min

Rat      inhalation   LC100 = 0.3 mg/litre 20 min                                                     Ghirinhgelli (1957)
Rat                   LC50 = 0.1 mg/litre 20 min

Table 25 (contd.)
Species  Route        Lethal dose                      Observations in surviving        Observation   References
                                                       animals                          period after
Mouse    inhalation   LC80 = 0.048 mg/litre 30 min                                                    West & Sunderman
Rat                   LC65 = 0.50 mg/litre 30 min                                                     (1958)

Dog      inhalation   LC90 = 2.5 mg/litre 30 min                                                      Sunderman et al.

Rat      inhalation                                     Lungs: at 1-2 days intra-        1-6 days      Sunderman et al.
Dog                                                    alveolar oedema and swelling     1-7 days      (1961)
                                                       of alveolar lining cells, at
                                                       3-5 days inflammation, 
                                                       atelectasis, and interstitial
                                                       fibroblastic proliferation;
                                                        Kidneys and adrenals: hyperaemia
                                                       and haemorrhage

Rat      inhalation   LC30 = 0.51 mg/litre 30 min                                                     Sunderman (1964)

Rat      intravenous  LD50 = 22 mg/kg                   Lungs: at 1-4 h, perivascular    1 h-21 days   Hackett & 
Rat      subcutaneous LD50 = 21 mg/kg                  oedema, at 2-5 days severe                     Sunderman (1967)
Rat      intraperi-   LD50 = 13 mg/kg                  pneumonitis with intra-alveolar 
         toneal                                        oedema, haemorrhage, subpleural
                                                       consolidation, hypertrophy and
                                                       hyperplasia of alveolar lining
                                                       cells, and focal adenomatous
                                                       proliferation, at 8 days, 
                                                       interstitial fibroblastic
                                                        Liver, kidneys, adrenals: 
                                                       congestion, vacuolization, 
                                                       and oedema

Table 25 (contd.)
Species  Route        Lethal dose                      Observations in surviving        Observation   References
                                                       animals                          period after
Rat      intravenous  65 mg/kg                          Lung: ultrastructural            0.5 h-8 days  Hackett & 
                                                       alterations, including                         Sunderman (1968)
                                                       oedema of endothelial cells
                                                       at 6 h and massive hypertrophy 
                                                       of membranous and granular 
                                                       pneumocytes at 2-6 days; 
                                                        Liver: ultrastructural 
                                                       alterations of hepatocytes 
                                                       including nucleolar distortions 
                                                       at 2-24 h, dilatation of rough 
                                                       endoplasmic reticulum at 1-4 
                                                       days, and cytoplasmic inclusion 
                                                       bodies at 4-6 days 

Mouse    inhalation   LC100 = 0.1 mg/litre 120 min                                                    Sanina (1968)
a  From: NAS (1975)
Table 26.  Acute toxicity of nickel compounds in experimental animals
Species (sex)     Substance         Route of          LD50 (mg/kg) and   References
                                    administration    confidence limits
Rat (male)        nickel acetate    oral              360 (410-316)      Haro et al. 
    (female)                                          350 (403-304)      (1968)

Mouse (male)                                          410 (500-336)
      (female)                                        420 (515-336)

Rat                                 intraperitoneal   23 (28-19)         Haro et al.

Mouse                                                 32 (37-28)

Rat (female)      nickel chloride   intraperitoneal   29                 Horak et al. 
    (pregnant                       intramuscular     71                 Sunderman et 
    female)                                           98                 al. (1978a)

                                    intraperitoneal   38 (34-41)         Mas et al.

Rat (male)        nickelocene       oral              490 (510-471)      Haro et al.
    (female)                                          500 (525-474)      (1968)

Rat                                 intraperitoneal   50 (59-42)

Mouse                               oral              600 (660-545)
                                    intraperitoneal   86 (102-72)


    Diarrhoea, respiratory distress, and lethargy were noted in 
rats and mice dying 2-3 hours after receiving nickel acetate or 
nickelocene by the oral or intraperitoneal route (Haro et al., 

    Benson et al. (1986) investigated the effects of single 
intratracheal doses of nickel subsulfide (3.2, 32, or 320 µg/kg 
body weight), nickel oxide (3, 30, or 300 µg/kg body weight), 
nickel sulfate (10.5, 105.2, or 1052 µg/kg body weight), and nickel 
chloride (9.5, 95.2, or 952 µg/kg body weight) on rats; 24 h after 
dosing, no effects were observed.  However, at 7 days, multifocal 
alveolitis with some type II hyperplasia was observed in animals 
treated with nickel chloride, nickel sulfate, or nickel subsulfide.  
Lung lavage fluid contained increased numbers of neutrophils and 
macrophages in the medium- and high-dose groups of nickel chloride 
and nickel sulfate and in the highest nickel subsulfide dose group.  
While increased levels of enzymes, total protein, and sialic acid 
occurred in rats exposed to nickel chloride, nickel sulfate, or 
nickel subsulfide, no such changes were seen in rats receiving 
nickel oxide. 

    Effects on kidney function in rabbits were studied by Foulkes & 
Blanck (1984), who reported a reduction in the maximum tubular 
transport rate for aspartase following ip injection of 20 µmol 
nickel chloride/kg body weight.  Intraperitoneal injection of 3 or 
6 mg nickel/kg body weight in male Wistar rats induced a decrease 
in Bowman's space, dilated tubules, loss of brush border, flattened 
epithelia, and some regenerative activity (Sanford et al., 1988). 

    Intraperitoneal administration of NiCl2 to mice and rats caused 
a rapid decrease of body temperature (Gordon, 1989; Gordon & Stead, 
1986; Gordon et al., 1989).  The nickel chloride treatment resulted 
in hypothermia that lasted for more than 1 h, with a reduction in 
colonic temperature of 3-4 °C at 20 °C ambient temperature.  The 
Ni2+-induced hypothermia was accentuated at lower ambient 
temperature (10 °C) and ameliorated at higher ambient temperature 
(30 °C). 

    Hopfer & Sunderman (1988) monitored core body temperature and 
physical activity by radiotelemetry from a thermistor probe 
implanted in the peritoneal cavity.  After injection of nickel 
chloride (250 µmol/kg body weight), core body temperature 
diminished to a minimum at 1.5 h and returned to baseline at 4 h; 
core body temperature at 1.5 h after dosing averaged 3.0 ± 0.5 °C 
below the simultaneous value in control rats.  During the 8-80 h 
following dosing, the mean body temperature of NiCl2-treated rats 
did not differ from that of the controls, but the amplitude of the 
diurnal cycle of body temperature was dampened and the acrophase of 
the temperature cycle was delayed from 10.32 pm to 03.00 am.  These 
parameters returned towards the control values during the 80-152 h 
period following dosing. 

    Acute thymic involution occurred in male Fischer 344 rats 
following a single subcutaneous injection of nickel chloride (500 
µmol/kg body weight) (Knight et al., 1987).  In nickel-treated 
rats, the mean thymic weight, which was significantly decreased at 
24 h, continued to diminish at 48 h and reached 24% of the control 
value at 72 h.  The concentration of lipoperoxides in the thymus 
increased 2-fold at 48 h and 7-fold at 72 h.  Histological 
examination showed marked degenerative changes.  Gitlitz et al. 
(1975) noted aminoaciduria and proteinuria in rats given single 
injections of nickel chloride (2 mg/kg body weight), the response 
being dose-dependent.  Proteinuria was seen initially with 
aminoaciduria at higher doses.  These effects, transitory in 
duration, were associated with morphological changes in the 
glomeruli. Possible mechanisms of acute nickel toxicity 

    The mechanisms of nickel toxicity are not well understood, but 
studies by Knight et al. (1987), Sunderman et al. (1987), and 
Sunderman (1987) suggest that acute Ni2+ toxicity in rats is 
associated with lipid peroxidation in target organs.  The chemical 
reactions whereby Ni2+ induces lipid peroxidation  in vivo have not 

yet been explained, however, Sunderman (1987) proposed the 
following four possible mechanisms: 

i.  An indirect mechanism owing to Ni2+ displacement of iron and 
copper from intracellular binding sites; 

ii.  An indirect mechanism, by which Ni2+ inhibits cellular 
defences against peroxidative damage, mediated by catalase, 
superoxide dismutase, glutathione peroxidase, aldehyde 
dehydrogenase, or other enzymes that protect against free-radical 
injury or that metabolize products of lipid peroxidation; 

iii. Generation of oxygen-free radicals by the redox couple: 


Ni2+ + H2 --> Ni3+ + OH- + OH- (Fenton reaction) 

Ni3+ + O-2 --> Ni2+ + O2 

H2O2 + O-2 --> OH- + OH- + O2 (Haber-Weiss reaction) 

iv. Ni2+ may accelerate the degradation of lipid hydroperoxides to 
form lipid-oxygen radicals, propagating autocatalytic peroxidation 
of polyenoic fatty acids. 

    Experiments performed by Inoue & Kawanishi (1989) using 
electron spin resonance (ESR) (spin traps 5,5-dimethylpyroline- N-
oxide and alpha-(4-pyridyl 1-oxide)- N-tert-butylnitrone) indicate 
that hydroxyl radical adducts are produced  in vitro by the 
decomposition of hydrogen peroxide in the presence of the nickel 
(II) oligopeptide Gly Gly His.  These investigators suggested that 
Gly Gly His plus hydrogen peroxide produce superoxide in addition 
to the hydroxyl radical.  The experimental findings support the 
conclusion that the nickel-dependent formation of an activated 
oxygen species is a primary molecular event in acute nickel 
toxicity and carcinogenicity. 

8.1.3.  Short- and long-term exposures Effects on the respiratory tract 

 (a) In vivo studies 

    Data on the chronic respiratory effects of nickel carbonyl are 
summarized in section 

    Long-term inhalation studies have been performed on guinea-
pigs, rats, and mice (Hueper, 1958), rats (Bingham et al., 1972), 
and hamsters (Wehner et al., 1975, 1981).  Exposure extended over 
more than one and a half years in all studies.  The compounds 
tested were metallic nickel powder, nickel subsulfide, nickel 
oxide, and nickel-enriched fly ash.  Hueper (1958) exposed animals 
to metallic nickel dust at 15 mg/m3, and noted nasal sinus 

inflammation and ulcers in rats, and signs of lung irritation in 
guinea-pigs and rats.  A common finding was an accumulation of 
adenomatoid cell formations.  In mice, there were signs of lung 
irritation, but not to the same extent as in guinea-pigs and rats. 

    Bingham et al. (1972) used aerosols of soluble nickel chloride 
at 109 µg/m3 and nickel oxide at 120 µg/m3 and observed hyperplasia 
of bronchiolar and bronchial epithelium with peribronchial 
lymphocyte infiltrates. 

    Ottolenghi et al. (1974) found a number of lung changes, such 
as abscesses as well as metaplastic changes, when rats were exposed 
for 78 weeks to nickel subsulfide by inhalation.  Wehner et al. 
(1975) exposed rats to a concentration of 53 mg nickel oxide/m3 
(type of oxide not specified) for the life span and found that 
particulate material accumulated on the alveolar septa.  Emphysema 
was observed early in the exposure period.  With longer exposure, 
the cellular response increased and pneumoconiosis developed 
gradually.  However, there was no reduction in the life span.  
Wehner et al. (1981) exposed hamsters through inhalation to nickel-
enriched fly ash or fly ash at concentrations of 17 or 70 µg/m3 for 
up to 20 months.  Lung weights and volumes were significantly 
increased in the 70 µg/m3 fly ash exposure group.  The severity of 
anthracosis, interstitial reaction, and bronchiolization was dose-

    Friberg (1950) exposed rabbits for 6 months to nickel-graphite 
dust (nickel hydrate, nickel content approx. 50%) at a 
concentration of 100 mg/m3 (3 h/day, 5 days/week) and found 
emphysematous and inflammatory changes in the nasal mucous 
membranes and the trachea, bronchitis, and sometimes slight 
fibrosis in the lung. 

    Port et al. (1975) reported that intratracheal injection of a 
suspension of nickel oxide (5 mg, particle size <5 µm, type of 
nickel oxide not specified) into Syrian hamsters, treated 48 h 
previously with influenza A/PR/8 virus, resulted in significantly 
increased mortality compared with controls.  Surviving animals at 
this and lower doses showed mild to severe acute interstitial 
infiltration by polymorphonuclear cells and macrophages, several 
weeks later.  Additional pathological changes included bronchial 
epithelial hyperplasia, focal proliferative pleuritis, and 

    Short-term inhalation studies (12 days) with nickel sulfate 
(3.5-60 mg/m3) and nickel subsulfide (0.6-10 mg/m3) were performed 
on rats and mice (Benson et al., 1987, 1988).  Nickel sulfate 
caused lesions in the lung, nose, bronchial, and mediastinal lymph 
nodes in the surviving animals at 3.5 mg/m3.  In the nickel 
subsulfide-exposed animals, similar changes occurred in the 
respiratory tract with extensive lesions in the lung, including 
necrotizing pneumonia.  Emphysema developed in rats exposed to 5 or 
10 mg/m3 and fibrosis was seen in mice exposed to 5 mg nickel 
subsulfide/m3.  Degeneration of the respiratory epithelium and 

atrophy of the olfactory epithelium occurred in all nickel 
subsulfide dose groups except in mice exposed to 0.6 mg/m3.  
Clinical signs included laboured respiration, emaciation, 
dehydration, and reduced body weight gain in rats and mice exposed 
to nickel sulfate or nickel subsulfide. A 12-day inhalation 
exposure of rats and mice to nickel oxide (1.2-30 mg/m3) also 
caused lung lesions in the higher dose groups.  Lung lesions 
included hyperplasia of alveolar macrophages, focal suppurative 
inflammation, focal interstitial cellular infiltrate and particles 
in alveoli and alveolar macrophages.  In mice, lung lesions were 
less severe (Dunnick et al., 1988).  On the basis of these 12-day 
studies, relative toxicity ranking was NiSO4 x 6H2O >Ni3S2 >NiO 
(Dunnick et al., 1988). 

    The effects of nickel on the cellular respiratory system 
defence mechanisms were studied by exposing guinea-pigs, rats, or 
rabbits to various concentrations (0.05-2 mg/m3, for 1-8 months) of 
nickel dust, nickel oxide, or nickel chloride (Waters et al., 1975; 
Graham et al., 1975a; Aranyi et al., 1979; Johansson et al., 1980, 
1981, 1983a,b; Castranova et al., 1980; Casarett-Bruce et al., 
1981; Lundborg & Camner, 1982, 1984; Wiernik et al., 1983; Murthy 
et al., 1983; Takenaka et al., 1985; Glaser et al., 1986).  It was 
concluded that the overall effects had some features in common with 
the pulmonary alveolar proteinosis described in human beings.  
There was no difference in the effect pattern between exposure to 
insoluble and soluble nickel compounds. Effects, such as changes in 
the morphology and function of alveolar macrophages and type II 
alveolar epithelial cells, and in the composition of lung lavage, 
were found, with the severity of effects depending on the 
concentration and duration of exposure. 

    The phagocytic activity of alveolar macrophages was increased 
in rabbits following 4 weeks inhalation of metallic nickel dust 
(0.5-2.0 mg/m3; Camner et al., 1978; Yarstrand et al., 1978) and in 
rats following 1-4 months inhalation of nickel oxide (produced by 
pyrolysis of nickel acetate at 550 °C) (Spiegelberg et al., 1984).  
No change in the phagocytic activity of alveolar macrophages was 
observed in rats following exposure to 0.13 mg metallic nickel 
dust/m3 for 4-8 months (Johansson et al., 1983a), and in rabbits 
following exposure to nickel chloride aerosols (0.3 mg/m3) for 1 
month (Wiernik et al., 1983). 

    Alveolar macrophages varied in size and, ultrastructurally, had 
an active cell surface with numerous slender microvilli and long 
protrusions.  Laminated structures were regularly found in the 
alveolar macrophages as well as in the lung fluid (Camner et al., 
1978; Johansson et al., 1980, 1983a; Wiernik et al., 1983).  
Spiegelberg et al. (1984) found an increase in size and number of 
polynucleated cells in the lungs of exposed rats.  Morphometric 
studies on the lungs of exposed rabbits showed an increase (up to 
3-fold) in the volume density of type II cells.  Cells contained 
many lamellar bodies and vesicles; the endoplasmic reticulum had a 
slightly dilated appearance (Johansson & Camner, 1980; Johansson et 
al., 1981, 1983b).  There were changes in the pulmonary lipid 
content and composition of the lung fluid of rabbits inhaling 

metallic nickel dust at levels ranging from 0.13 to 1.7 mg/m3 
(Casarett-Bruce et al., 1981; Curstedt et al., 1983, 1984).  There 
was a twofold increase in the concentration of total phospholipids, 
mainly due to an elevated level of phosphatidylcholines, especially 
disaturated species, and phosphatidylinositols.  Lundborg & Camner 
(1982, 1984) exposed rabbits to nickel dust (0.1 mg/m3, for 4 and 6 
months) and nickel chloride (0.2-0.6 mg/m3 for 4-6 weeks) and found 
markedly reduced lysosomal enzyme activity compared to control 
animals.  When rats were exposed to aerosols of nickel oxide (type 
of oxide not specified) at 120 µg/m3 or nickel chloride at 109 
µg/m3, Murthy et al. (1983) found that various hydrolytic enzymes 
were reduced in alveolar macrophages, but, in contrast, the enzyme 
activities were significantly increased in lung lavage. 

    Parenteral administration of nickel chloride can also cause 
toxic effects in alveolar macrophages, as demonstrated by Sunderman 
et al. (1989c) in rats that had received single subcutaneous 
injections of 8-65 mg (62-500 µmol) nickel chloride/kg.  Alveolar 
macrophages showed morphological and biochemical signs of 
activation, functional impairment, and lipid peroxidation.  In 
alveolar macrophages from 63NiCl2-treated rats, 63Ni was primarily 
located in the cytoplasm bound to high- and low-relative molecular-
mass constituents. 

    At the ciliated epithelium level, nickel significantly 
depressed normal ciliary activity in a hamster tracheal ring assay 
following  in vivo exposure to 100 µg nickel/m3 as nickel chloride 
for 2 h (Adalis et al., 1978; Olsen & Jonsen, 1979b). 

    Fisher et al. (1984) evaluated the effects of particle size and 
dose regimen on the toxicity of intratracheally instilled nickel 
subsulfide in mice, and showed the importance of physical form in 
the evaluation of pulmonary toxicity.  The median lethal dose for a 
single exposure to larger particles (MMAD 13.3 µm) was 12 times 
that of fine particles (MMAD 1.8 µm), i.e., 50 versus 4 mg/kg.  
Repeated exposures (once/week for 4 weeks) resulted in a 2-fold 
greater median lethal dose of coarse particles compared with fine 
particles, i.e., 2 versus 1 mg/kg.  Thus, repeated exposure to fine 
particles resulted in a cumulative lethality equivalent to the 
single exposure, while coarse particle lethality was enhanced with 
repeated exposure.  Alveolar macrophages from mice exposed to fine 
nickel subsulfide showed depressed cellular function, 14 days after 
a single administration. 

    Reichrtova et al. (1986a,b) performed 2 inhalation studies on 
rats to compare the effects of different types of exposure on 
alveolar macrophages.  In both studies, the nickel content of the 
aerosol was only 0.36% (NiO), thus, the effects are unlikely to be 
nickel-specific responses.  Increases in the alveolar macrophage 
count and lysosomal enzyme activities (acid phosphatase and beta-
glucuronidase) were found in Wistar rats, exposed to an aerosol of 
solid waste from a nickel refinery dump, under chamber conditions, 
for 6 months (aerosol concentration 0.1 g/m3, 4 h/day, 5 
days/week).  However, the activity of alveolar macrophage plasma 

membrane enzymes decreased.  Cells contained in lung lavage had a 
pleomorphic appearance. When rabbits were environmentally exposed 
at a biomonitoring station, situated in the direction of the 
prevailing wind from a nickel refinery dump, for 6 months, with an 
average dust fallout of 5.5 g/m2 in 30 days, the number of alveolar 
macrophages was significantly increased (Reichrtova et al., 1986b).  
A significant increase in lysosomal enzyme activity also occurred, 
but these changes were not as pronounced as the effects obtained in 
the chamber studies on rats.  In contrast to the increased alveolar 
macrophage activity, a significant reduction occurred in antibody-
mediated rosette formation by alveolar macrophages in the 
environmentally exposed rabbits. 

 (b) In vitro cytotoxicity studies 

    Alveolar macrophages exposed to nickel (1.1 mmol/litre)  in 
 vitro showed depressed phagocytic activity (Graham et al., 1975a; 
Aranyi et al., 1979).  Waters et al. (1975) correlated changes in 
cell viability with changes in the morphology and the specific 
activity of a lysosomal enzyme (acid phosphatase).  At 4.0 
mmol/litre, cell viability was reduced to approximately 50% of that 
of controls.  Castranova et al. (1980) demonstrated that nickel 
affected oxygen metabolism in the rat alveolar macrophages; at 
rest, and during phagocytosis, oxygen consumption and glucose 
metabolism were depressed. 

    The  in vitro cytotoxicity of nickel chloride on a human 
pulmonary epithelium cell line (A549) was reported by Dubreuil et 
al. (1984).  Nickel chloride in amounts ranging from 0.1 to 1.0 
mmol/litre produced decreases in cell growth rate and in the levels 
of cell adenosine triphosphate (ATP), and loss of viability, at the 
highest concentration.  No changes were seen in transmission 
electron microscopy preparations. 

     In vitro toxicity studies on bovine alveolar macrophages 
indicated that nickel subsulfide was 10 times more toxic than 
solubilized nickel subsulfide or soluble nickel chloride (Fisher et 
al., 1984). 

    Nickel subsulfide, nickel sulfate, nickel chloride and nickel 
oxide were tested for their relative toxicity in beagle dog and rat 
alveolar macrophages  in vitro.  Toxicity ranking was Ni3S2 >NiCl2 
ca NiSO4 >NiO (Benson et al., 1986). 

8.1.4.  Relationship of nickel toxicity and mixed metal exposure

    As both nickel production and some end uses of nickel involve 
mixed exposure of workers to nickel and copper, nickel and 
chromium, nickel, chromium, and manganese, and so on, the problem 
of the combined toxic effects of these metals is of great practical 
importance.  However, the relevant information is rather scarce. 

    Johansson et al. (1988) showed that the cytotoxic effects of a 
trivalent chromium salt on alveolar macrophages of the rabbit 
impaired their dealing with pulmonary surfactant, the latter being 

hyperproduced as a result of nickel's action on the type II 
alveolar epithelial cells.  However, analysis of these experimental 
data showed that, as far as the cytotoxicity of these metals for 
alveolar macrophages was concerned, their joint effect was 

    Davydova et al. (1981) demonstrated that subadditivity or even 
clear antagonism was the main type of combined acute toxicity for 
rats of nickel and chromium, nickel and manganese, and even a 
triple exposure of rats to nickel and cobalt.  On the contrary, the 
long-term exposure of rats to nickel and cobalt in the drinking-
water demonstrated the additive long-term toxicity of these two 
metals (Nadeenko et al., 1988). 

8.1.5.  Endocrine effects

    Bertrand & Macheboeuf (1926a,b) reported that parenteral 
administration of nickel chloride or nickel sulfate to rabbits or 
dogs antagonized the hyperglycaemic action of insulin.  Later 
investigators observed that after parenteral (iv or ip) injection 
to rabbits, rats, or chickens, or oral administration to rabbits, 
there was a rapid increase in plasma glucose concentrations, which 
returned to normal within 4 h (Kadota & Kurita, 1955; Gordynia, 
1969; Clary & Vignati, 1973; Freeman & Langslow, 1973; Horak & 
Sunderman, 1975a,b).  In the pancreatic islets of Langerhans, 
Kadota & Kurita (1955) noted marked damage of alpha-cells, and, to 
a lesser degree, degranulation and vacuolization of beta-cells. 
Ashraf & Sybers (1974) noted lysis of pancreatic exocrine cells in 
rats fed nickel acetate (0.1%).  In adrenalectomized or 
hypophysectomized rats, the hyperglycaemic effect was greatly 
depressed, but was not completely prevented.  Concurrent 
administration of insulin antagonized the hyperglycaemic effect 
(Horak & Sunderman, 1975a,b).  LaBella et al. (1973a,b) showed 
that nickel also affects the hypothalamus of animals.  Nickel salts 
specifically inhibited the release of prolactin  in vivo (in the 
rat) and  in vitro from bovine pituitary.  Subcutaneous injection of 
10 or 20 mg nickel chloride/kg in rats initially produced a drop in 
serum prolactin over the short term, but resulted in a sustained 
elevation of the hormone after 1 day, which lasted up to 4 days.  
The elevation was due to reduced levels of the prolactin-inhibiting 
factor (Clemons & Garcia, 1981).  Carlson (1984) demonstrated that 
nickel antagonized the stimulation of both prolactin and growth 
hormone by barium; thus, the basis of antagonism may be the 
competitive inhibition of calcium uptake.  Dormer et al. (1973) 
showed that the nickel ion is a potent inhibitor of secretion  in 
 vitro in the parotid gland, (amylase), the islets of Langerhans 
(insulin), and the pituitary gland (growth hormone).  Inhibition of 
growth hormone secretion at nickel concentrations comparable to 
those observed by LaBella et al. (1973b) to enhance release, may 
reflect differences in tissue preparation prior to assay.  Dormer 
et al. (1973) suggested that nickel may block exocytosis by 
interfering with either secretory granule migration or membrane 
fusion and microvilli formation. 

    The effects of nickel on thyroid function were reported by 
Lestrovoi et al. (1974).  Nickel chloride, given orally (0.5-5.0 
mg/kg per day, for 2-4 weeks) or by inhalation (0.05-0.5 mg/m3) to 
rats, significantly decreased iodine uptake by the thyroid, the 
effect being more pronounced with inhaled nickel. 

8.1.6.  Cardiovascular effects

    The serum nickel level increased in patients with acute 
myocardial infarction, stroke, and burns (D'Alonzo & Pell, 1963; 
McNeely et al., 1971; Leach et al., 1985). 

    Rubanyi & Kovach (1980) found that micromolar concentrations of 
nickel chloride (0.1-1 µmol/litre) increased cardiac contractility 
in the isolated rat heart.  At higher doses, there was depressed 
myocardial contractile performance. Ultrastructural damage was 
found (Rubanyi et al., 1980). 

    Nickel chloride at a concentration of 1 µmol/litre in the 
perfusate produced tonic contraction in the isolated canine 
coronary artery (Rubanyi et al., 1982b). 

    Nickel is released from the ischaemic dog myocardium (Rubanyi 
et al., 1981); exogenous nickel, in doses comparable to the amount 
released endogenously from the heart, induced coronary 
vasoconstriction in rat and dog hearts.  In further studies, the 
possible involvement of Na/K ATPase inhibition (Rubanyi et al., 
1982c) and/or stimulation of adrenergic receptors in the coronary 
vessels (Rubanyi et al., 1982d) were discussed as mechanisms of 
nickel-induced coronary vasoconstriction.  Rubanyi & Inovay (1982) 
studied the effects of nickel ions on spontaneous, electrically-, 
and norepinephrine-stimulated isometric contractions in the 
isolated portal vein of the rat.  They found that low 
concentrations of nickel (1-10 µmol/litre) inhibited spontaneous 
isometric force development and decreased basal tone, but 
significantly increased the frequency of contractions. Inhibition 
of the effect of selective stimulation of adrenergic nerves was 
significantly more pronounced than the depression of contractions 
evoked by exogenous norepinephrine. 

    In the  in situ heart (open-chest anaesthetized dogs), a 
decrease in coronary vascular flow with a low intravenous dose of 
nickel (0.02 mg nickel chloride/kg body weight) was reported, 
while, at higher dose levels (0.2, 2, or 20 mg nickel chloride/kg 
body weight), further reduction in coronary blood flow, depression 
of heart rate, and a decrease in left ventricular contractility 
were observed.  Coronary vasoconstriction may be regarded as a 
local action of nickel on coronary vessels (Ligeti et al., 1980). 

    In another  in situ study on dogs (intravenous bolus injection 
of 0.02 mg nickel/kg, or intracoronary infusion of 0.04 mg nickel 
chloride/min per kg body weight), Rubanyi et al. (1984) found that 
vasoconstriction was induced when coronary arteries were dilated by 
low-flow ischaemia, arterial hypoxaemia, and adenosine infusion.  

Nickel inhibited post-occlusion reactive hyperaemia and 
vasorelaxation in response to arterial hypoxaemia or intracoronary 
infusion of adenosine.  It was postulated that vasoactivity might 
be related to the existence of positive feedback loops triggered by 
alterations in the level of nickel. 

    Endogenous nickel release from damaged tissues and its 
implications for ischaemic heart disease have been examined with 
respect to the pathology of acute carbon monoxide poisoning and 
acute burn injury.  Significant endogenous nickel ion accumulation 
was noted in the heart muscle of rats and rabbits, when the CO-Hb 
level was above 30% (Balogh et al., 1983). 

8.1.7.  Effects on the immune system

    The effects of nickel on alveolar macrophages have been 
described in section 

    Koller (1980) noted that nickel exposure of animals could 
reduce host resistance to both viral and bacterial infections, and 
suppress the phagocytic capacity of macrophages. 

    Other cellular and humoral immune responses following nickel 
treatment were studied by Smialowicz et al. (1984, 1985).  Single 
or multiple intramuscular injections of nickel chloride in mice 
caused a significant reduction in a variety of T-lymphocytes and 
natural killer cell-mediated immune functions.  Suppression of the 
lymphoproliferative responses to the T-cell mitogens, 
phytohaemagglutinin and concanavalin A, and a reduction in the 
number of theta-positive T-lymphocytes were observed in the spleens 
of nickel chloride-injected mice (18.3 and 36.6 mg/kg body weight).  
Reductions in the primary antibody response to T-lymphocyte-
dependent antigen sheep red blood cells, but not T-lymphocyte-
independent antigen polyvinyl-pyrrolidone, were observed following 
a single injection of 18.3 mg nickel chloride/kg (Smialowicz et 
al., 1984). 

    Smialowicz et al. (1985) demonstrated that suppression of 
natural killer cell activity could be detected by  in vitro and  in 
 vivo assays and that reduction of natural killer cell activity was 
not associated with either a significant reduction in spleen 
cellularity or the production of suppressor cells.  A further 
demonstration of the effect of nickel chloride on natural killer 
cell activity was the enhancement of the development of lung tumour 
colonies in mice injected with B16-F10 melanoma cells, following a 
single injection of 18.3 mg nickel chloride/kg.  Unlike nickel 
chloride, manganese chloride was found to enhance natural killer 
cell activity, when injected into mice (Smialowicz, 1985).  No 
alteration in natural killer cell activity was observed in mice 
injected with magnesium, calcium, or zinc (Smialowicz et al., 
1987).  Manganese chloride was considered to have an antagonistic 
effect on nickel chloride-suppression of natural killer cell 

    The effects of nickel compounds on natural killer cells are of 
particular interest, because of the suspected function of these 
cells in nonspecific defence against certain types of infections 
and tumours. 

    The studies performed by Smialowicz et al. (1984, 1985, 1986, 
1987) confirmed the findings of other investigators on the immuno- 
suppressive effects of nickel salts on circulatory antibody titres 
to T1 phage in rats (Figoni & Treagan, 1975), on antibody response 
to sheep erythrocytes (Graham et al., 1975b), on interferon 
production  in vitro (Treagan & Furst, 1970) and  in vivo in mice 
(Gainer, 1977), and on susceptibility to induced pulmonary 
infection in mice following inhalation of nickel chloride (Adkins 
et al., 1979). 

    In cynomolgus monkeys that had been previously immunized and 
repeatedly challenged with sheep red blood cells, instillation of 
10.6 mg nickel subsulfide/kg lung in one immunized and one control 
lobe of each animal increased target cell killing by conjugate-
forming natural killer cells and decreased macrophage phagocytic 
activity (Haley et al., 1987). 

    The results of  in vitro studies have shown that nickel can 
replace magnesium, which is essential for the proper functioning of 
the complement system, in both the classical and the alternative 
pathway.  Nickel has been shown to result in a more efficient 
formation of the C3b,Bb enzyme, which theoretically may lead to 
disturbance of a well balanced complement cascade.  The 
significance of this finding  in vivo is not known (Fishelson et 
al., 1983). 

8.1.8.  Skin and eye irritation and contact hypersensitivity Skin and eye irritation 

    Repeated skin application of 40-100 mg nickel/kg (as nickel 
sulfate), daily for 30 days, produced skin atrophy, acanthosis, and 
hyperkeratinization in rats (Mathur et al., 1977).  No data are 
available on the eye irritancy of soluble nickel salts or on the 
skin and eye irritancy of insoluble nickel compounds. Contact hypersensitivity 

    Experimental sensitization to nickel in guinea-pigs has been 
reported (Walthard, 1926; Stewart & Cromia, 1934; Vinson & Choman, 
1960; Jansen et al., 1964; Gross et al., 1968; Magnusson & Kligman, 
1970).  Nilzén & Wikström (1955) reported a method for sensitizing 
laboratory animals to nickel by repeated topical applications of 
aqueous nickel sulfate solutions containing sodium lauryl sulfate.  
However, Samitz & Pomerantz (1958) were unable to demonstrate 
sensitization with this technique and attributed the effect to 
local irritation, rather than true allergenic reaction.  Samitz et 
al., (1975) were unable to induce sensitization in guinea-pigs 
using nickel compounds from the complexation of the nickel ion with 

amino acids or guinea-pig skin extracts.  Furthermore, 
sensitization of experimental animals was not found by Hunziker 
(1960) or Bühler (1965). 

    The sensitivity of guinea-pigs was increased by repeated intra-
dermal injections and skin painting with nickel sulfate solutions 
during the sensitization phase.  The responses were significantly 
greater than in control animals (Wahlberg, 1976). 

    Turk & Parker (1977) reported sensitization to nickel 
manifested as allergic-type granuloma formation.  This required the 
use of Freund's complete adjuvant followed by weekly intradermal 
injections of 25µg of the salt after 2 weeks.  Delayed 
hypersensitivity reactions developed in 2 out of 5 animals at 5 
weeks when a split-adjuvant method was used.  Suppression of the 
delayed hypersensitivity occurred when intratracheal intubation of 
nickel sulfate was also performed on these animals (Parker & Turk, 
1978).  Möller (1984) reported that mice could easily be sensitized 
to a potent antigen, such as picryl chloride, but response to 
nickel could only be achieved by repeated epicutaneous application 
of a strong (20%) nickel salt solution for 3 weeks. 

    The study of the allergic properties of nickel in experimental 
animals is a problem, because of difficulties involved in 
reproducing the phenomenon of allergodermatosis and because of lack 
of a uniform approach to reproducing the experimental contact 
allergic dermatitis model.  Duyeva (1983) recommended a single 
intracutaneous administration of 100-200 µg nickel chloride in the 
ear of the guinea-pig.  Sensitization developed as early as days 4-
10, reaching a peak on day 20. 

8.1.9.  Reproduction, embryotoxicity, and teratogenicity Effects on the male reproductive system 

    Data on the effects of nickel on the male reproductive system 
are limited.  Hoey (1966) examined the effects of nickel sulfate on 
the testis and epididymis of Fischer rats and reported histological 
changes in the testis and adnexae.  Following a single 
intracutaneous injection of 0.04 µmol nickel sulfate/kg body weight, 
histological examination, 18 h after exposure, revealed shrinkage 
of the tubules and complete degeneration of the spermatozoa.  
Infertility was observed in rats after 120 days of daily ingestion 
of 25 mg nickel sulfate/kg (Waltschewa et al., 1972). 

    Mathur et al. (1977) studied the dermal exposure of male rats 
to nickel sulfate at daily levels of 40, 60, or 100 mg nickel/kg 
body weight for 15 and 30 days.  Tubular damage and spermatozoal 
degeneration were observed in the testis following exposure to 60 
mg nickel/kg for 30 days.  These changes were more severe with 
exposure at 100 mg/kg for 30 days.  There were no effects on the 
testis following exposure to 40 mg/kg for 30 days or at any dose 
level after 15 days exposure. 

     In vitro embryo cultures were used to study the effects of 
nickel nitrate on male germ cells (Jacquet & Mayence, 1982).  
BALB/C mice were injected intraperitoneally with 40 or 56 mg nickel 
nitrate/kg body weight and were then allowed to mate with 
superovulated females, at weekly intervals, for 5 weeks following 
treatment.  The embryos were isolated and those at the 2-cell stage 
were cultured for 3 days.  These embryos were then classified 
according to their ability to develop to the blastocyst stage.  A 
dose of 40 mg/kg body weight did not affect the fertilizing 
capacity of the spermatozoa or the ability of the fertilized egg to 
cleave, but a dose of 56 mg nickel nitrate/kg body weight yielded a 
significant proportion of uncleaved unfertilized eggs.  Cleaved 
eggs from this treatment group were able to develop into 
blastocysts, suggesting that nickel nitrate treatment reduced the 
fertilizing capacity of the spermatozoa, presumably because of a 
toxic effect of nickel on spermatogenesis.  Deknudt & Leonard 
(1982) conducted a dominant lethal mutation test for nickel 
chloride and nickel sulfate in BALB/C mice.  Both compounds 
produced a reduction in implantations in the matings performed 2, 
3, or 4 weeks after treatment, but the post-implantation loss was 
not increased.  It was considered that this was attributable to a 
toxic effect of nickel treatment on male germ cells. Effects on the female reproductive system 

    Insertion of nickel wire into one uterine horn of rats on day 3 
of pregnancy produced a decrease in the number of implants and an 
increase in the number of resorption sites, compared with the 
untreated contralateral horn (Chang et al., 1970). 

    Nickel has been reported to localize within the pituitary and 
the hypothalamus of rats and to inhibit prolactin secretion (La Bella 
et al., 1973a,b).  It may, therefore, modify interactions between 
the hypothalamus and the pituitary, needed to maintain pregnancy. 

    No effects on fertility were observed in 3 generations, when 
breeding rats were exposed to 5 mg nickel/litre as a soluble salt 
(not specified) in the drinking-water (Schroeder & Mitchener, 1971). 

8.1.10.  Embryotoxicity and teratogenicity

    Nickel has been shown to cross the placental barrier and enter 
the fetus (section 6.1.5). 

    Sunderman et al. (1978a) studied the embryo- and fetotoxicity 
of nickel chloride and nickel subsulfide in Fischer 344 rats.  
Single intramuscular injection of nickel chloride (12 or 16 mg 
nickel/kg body weight) on day 8 of gestation significantly reduced 
the mean number of live pups per dam and resulted in reduced body 
weight in fetuses on day 20 of gestation and in pups, 4-8 weeks 
after birth.  When nickel chloride was administered in repeated 
intramuscular doses of 1.5 or 2.0 mg/kg body weight on days 6-10 of 

gestation, the higher dose caused significant intrauterine 
mortality, but did not cause any reduction in the mean body weight 
of live pups. Intramuscular injection of nickel subsulfide (80 mg 
nickel/kg body weight) reduced the mean number of live pups per 
dam.  Exposure to nickel chloride or nickel subsulfide did not 
produce any skeletal or visceral anomalies. 

    Lu et al. (1979) observed a dose-related increase in fetal 
deaths and a higher incidence of malformations in pregnant CD-1 
mice following intraperitoneal injection of single doses of nickel 
chloride (1.2, 2.3, 3.5, 4.6, 5.7, or 6.9 mg nickel/kg) between 
days 7 and 11 of gestation.  Fetal death and some general 
malformation (not described in detail) were reported in hamsters 
after intravenous injection of nickel acetate at 30 mg/kg body 
weight on day 8 of pregnancy (Ferm, 1972).  Nadeenko et al. (1979) 
demonstrated a dose-dependent embryotoxic effect of 27Ni given to 
female rats for 7 months (before and during pregnancy) in 
concentrations ranging from 5 x 10-1 to 5 x 10-4 mg/kg body weight. 

    The effects of nickel chloride on early embryogenesis were 
studied by Storeng & Jonsen (1980)  in vitro.  Mouse embryos at the 
2-, 4-, and 8-cell stages were cultured in media containing nickel 
chloride hexahydrate at a concentration of 10-1000 µmol/litre.  A 
concentration of nickel chloride hexahydrate of 10 µmol/litre 
adversely affected the development of 2-cell stage embryos whereas 
a concentration of 300 µmol/litre was needed to affect 8-cell stage 
embryos.  No effect was observed at 100 µmol/litre.  In a 
subsequent study (Storeng & Jonsen, 1981), a single intraperitoneal 
injection of nickel chloride hexahydrate (20 mg/kg) was given to 
mice on days 1-6 of gestation.  On day 19, implantation frequency 
in females treated with nickel chloride hexahydrate on day 1 was 
significantly lower compared with the controls.  Litter size was 
significantly reduced in females treated on days 1, 3, and 5 of 
gestation.  The incidence of abnormalities, such as haematomas and 
exencephaly, in the fetuses of treated females was higher 
(statistical significance not reported) than in the controls. 

    Sunderman et al. (1983) used intrarenal injection of nickel 
subsulfide to assess the effects on the progeny of rats.  
Administration of 30 mg nickel subsulfide/kg by intrarenal 
injection, 1 week prior to breeding, produced intense 
erythrocytosis in the dams, but not in the pups.  These findings 
indicate that the release of maternal erythropoietin by the 
maternal kidneys, caused by nickel subsulfide, did not stimulate 
erythropoiesis in the pups.  Nickel subsulfide was associated with 
a significant decrease in mean body weights of pups, 2 and 4 weeks 

    In a series of studies, Sunderman et al. (1978b,c, 1979a, 
1980, 1983) demonstrated that nickel carbonyl, administered by 
inhalation or injection before, or a few days after, implantation 
produced various types of malformations in hamsters and rats.  
Intravenous injection of nickel carbonyl (11 mg nickel/kg body 
weight) into Fischer rats on day 7 of gestation caused fetal 

mortality, reduced body weight in live pups, and a 16% incidence of 
fetal malformations, including anophthalmia, microphthalmia, cystic 
lungs, and hydronephrosis (Sunderman et al., 1983).  There was no 
maternal toxicity.  Similar effects were observed in rats following 
inhalation of nickel carbonyl at a concentration of 0.16 g/m3 on 
day 7 or 8 of gestation and a concentration of 0.3 g/m3 on day 7 of 
gestation (Sunderman et al., 1979a). 

    In a dominant lethal mutation test on male rats, administration 
of nickel carbonyl, by the inhalation route (50 mg nickel/m3 for 15 
min), 2-6 weeks prior to breeding, did not affect fertilization 
rates or reproductive yield; administration of nickel carbonyl by 
intravenous injection during the same period (22 mg nickel/kg) 
caused reduced numbers of live pups in litters sired during the 
fifth week (Sunderman et al., 1983).  In hamsters, inhalation 
exposure to 60 mg nickel carbonyl/m3, for 15 min on day 4 or 5 of 
gestation, led to decreased fetal viability and increased numbers 
of fetuses with malformations including cystic lungs, exencephaly, 
and haemorrhages in serous cavities (Sunderman et al., 1980). 

    Gilani & Marano (1980) injected nickel chloride into chicken 
eggs (0.02 and 0.7 mg per egg) on days 0, 1, 2, or 3 of incubation.  
Examination on day 8 revealed a number of malformations, such as 
exencephaly, everted viscera, short and twisted neck or limbs, 
microphthalmia, haemorrhage, and reduced body size.  The incidence 
of malformations was highest in embryos treated on day 2. 

    When rats were exposed long-term to nickel chloride or nickel 
sulfate in the diet or drinking-water, an increased frequency of 
runts and greater prenatal and neonatal mortality were observed 
(Schroeder & Mitchener, 1971; Ambrose et al., 1976; Nadeenko et 
al., 1979).  Berman & Rehnberg (1983) observed spontaneous 
abortions, loss of fetal mass in survivors, and loss of maternal 
mass in mice. 

8.2.  Mutagenicity and related end-points

    Genotoxicity data on nickel and nickel compounds are summarized 
in Table 27. 

    The data collectively show that nickel compounds are generally 
inactive in bacterial assays, but active in systems using 
eukaryotic organisms, and that positive responses were observed 
regardless of the nickel compounds used; particularly when these 
were compared at equitoxic concentrations (Hansen & Stern, 1983; 
Swierenga & McLean, 1985).  The ability of nickel compounds to 
inhibit DNA synthesis and excision repair should also be noted 
(Table 27).

Table 27.  Summary of the genotoxic effects of nickel compounds
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
Prophage           Prophage induction       Ni(CH3CO3)2   160-640 µmol/litre   + (weak)   Rossman et al.

T4 Bacteriophage   Bacteriophage-forward    NiSO4         300 mg/litre         -          Corbett et al.
                   mutation                                                               (1970)

TA1535              Salmonella typhimurium   NiCl2         0.01-0.1 g/litre     +          LaVelle & 
                   reverse mutation                                                       Witmer (1981)
                   (fluctuation test)

TA1535              S. typhimurium                                              -          Haworth et al.
                   reverse mutation                                                       (1983)

TA1525              S. typhimurium           NiCl2                              -          Arlauskas et
                   reverse mutation         NiSO4                                         al. (1985)

TA1537              S. typhimurium                                              -          Haworth et al.
                   reverse mutation                                                       (1983)

TA1537              S. typhimurium           NiCl2                              -          Arlauskas et
                   Reverse mutation         NiSO4                                         al. (1985)

TA1535              S. typhimurium           Ni salts      10-1000 µg/plate     + (weak)   Saichenko &
                   reverse mutation                                                       Sharapora 

TA98                S. typhimurium                                              -          Haworth et al.
                   reverse mutation                                                       (1983)

TA98                S. typhimurium           NiCl2                              -          Arlauskas et
                   reverse mutation         NiSO4                                         al. (1985)

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
TA100               S. typhimurium                                              -          Haworth et al.
                   reverse mutation                                                       (1983)

TA100               S. typhimurium           NiCl2                              -          Arlauskas et
                   reverse mutation         NiSO4                                         al. (1985)

Several strains     S. typhimurium           Ni(CH3CO2)2                        -          DeFlora et al.
                   reverse mutation         NiCl2                              -          (1984)
                                            Ni(NO3)2                           -

Frameshift         Co-mutagenesis with      NiCl2                              +          Ogawa et al.
tester strains     9-aminoacridine                                                        (1987)
                   Co-mutagenesis with      Ni(II)                             +          Dubins & 
                   alkylating agents (see                                                 Lavelle (1986)
                   pair substitution)

 Escherichia coli 
WP2                 E. coli, reverse         NiCl2         0, 5, 10, 25         -          Green et al.
                   mutation                               mg/litre                        (1976)

WP2                 E. coli (fluctuation)    NiCl2         50 mmol/litre        -          Nishioka (1975)
WP2 uvra            E. coli (fluctuation)    NiCl2         50 mmol/litre        -
CM571               E. coli (fluctuation)    NiCl2         50 mmol/litre        -

WP67               Differential toxicity    NiCl2         0, 200, 500,         + dose     Tweats et al.
                   assay                                  1000 mg/litre        response   (1981)

CM871              Differential toxicity    NiCl2         0, 200, 500,         + dose     Tweats et al.
                   assay                                  1000 mg/litre        response   (1981)

WP2 (repair        Differential toxicity    NiCl2         0, 200, 500,         + dose
deficient)         assay                                  1000 mg/litre        response
                   Differential toxicity    NiCl2         0, 200, 500,         + dose
                   assay                                  1000 mg/litre        response

WP2                 E. coli, reverse         NiCl2                              -          Arlauskas et
                   mutation                 NiSO4                              -          al. (1985)

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
 Bacillus subtilis 
H17 (rec+)          B. subtilis,             NiCl2         50 mmol/litre        -          Nishioka (1975)
M45 (rec-)         rec. strains 
                   differential toxicity
H17 (rec+)          B. subtilis,             NiCl2         5-50 mmol/litre      -          Kanematsu et
M45 (rec-)         rec. strains             NiO           5-50 mmol/litre      -          al. (1980)
                   differential toxicity    Ni2O3         5-50 mmol/litre      -

SP887              Reverse mutation         NiCl2         0.03-10 mg/litre     + dose     Pikalet &
                   fluctuation test                       8 doses              response   Necasek (1983)
                                                                               at > 5.0

G46 (his)          Host-mediated assay      NiCl2         50 mg/kg             -          Buselmaier et 
                   in mouse (NMRI strain)                                                 al. (1972)

 Serrati marcescens 
a21 (leu-)         Host-mediated assay      NiCl2         50 mg/kg             -          Buselmaier et
                   in mouse (NMRI strain)                                                 al. (1972)

                    Paramecium species       Ni3S2                              + at 0.5   Smith-Sonneborn
                   mutation                                                    µg/ml      et al. (1983)
                                            NiS particles                      + at 0.5
                                            (1.8 µm)                           µg/ml

                    Paramecium species       NiS particles                      + at 0.57  Smith-Sonneborn
                   chromosome aberration    (1.8 µm)                           µg/ml      et al. (1983)

 Yeast (Saccharomyces) 
D7 (diploid         S. cerevisiae, gene      NiCl2         3 or 10 mmol/litre   +          Fukunaga et al.
strain)            conversion                             24 h                            (1982)
D7 (diploid         S. cerevisiae, gene      NiSO4         5, 10, 20, 40        ?          Singh (1984)
strain)            conversion                             mmol/litre

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
Yeast 19 haploid    S. cervisiae, growth     NiCl2         26 mmol/litre        +          Egilsson et al.
strains            inhibition                                                             (1979)

 Vicia faba 
                   Chromosome aberrations   NiO                                +          Glaess (1956a)
                   Mitotic effects          NiO                                +          Glaess (1956b)

 Vicia faba         Mitotic effects          NiCl2                              +          Komczynski et
                                            Ni(NO3)2                           +          al. (1963)
                                            NiSO4                              +

 Pisum              Chromosome aberrations   Ni(NO3)2                           +          Van Rosen (1954)

 Allium cepa        Chromosome aberrations   NiO                                +          Levan (1945)

 D. melanogaster    Sex-linked recessive     NiSO4         200, 300, 400        +          Rodriguez-
white males        lethal mutations                       mg/litre in 5%                  Arnaiz & Ramos
BASC females                                              sucrose i.p.                    (1986)

 D. melanogaster    Sex chromosome           NiSO4         200, 300, 400        + (weak)   
XC2Y B/SC8Y        loss assay                             mg/litre in 5%
males                                                     sucrose i.p.
Y2Wa females

 D. melanogaster    Somatic eye colour       Ni(NO3)2      0.14 mmol/litre      -          Rasmuson (1985)
eggs from C(1)DX   test system              NiCl2         0.21 mmol/litre      -
y,w,f females X
SC Z W+f males

 D. melanogaster    mutation                 Ni(NO3)2      3.4-6.9 mmol/litre   +?         Vogel (1984)
                                            NiCl2         4.2 mmol/litre       -

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
Sprague-Dawley     DNA strand breaks,       NiCO3         5-40 mg/kg           +          Ciccarelli et 
 in vivo            X links, alkaline                                                      al. (1981)
                   elution,  in vivo                                                       Ciccarelli &
                   exposure                                                               Wetterhahn 

Primary            DNA strand breaks,                                          (+)        Sina et al.
hepatocyte         X links                                                                (1983)

CHO                DNA strand breaks        NiCl2         100-500 µmol/litre   +          Robison &
                   alkaline sucrose         Ni3S2         10 mg/litre          +          Costa (1982)
                   gradients                (cryst.)
                                            NiS (cryst.)  1-10 mg/litre        +
                                            NiS           10 mg/litre          -

CHO                DNA strand breaks                                           +          Costa et al.
                   X links                                                                (1982)

CHO                DNA strand breaks        Ni3S2         10 mg/litre, 24 h    +          Patierno &
                   X links                  NiCl2         0.25-1.0 mmol/litre  +          Costa (1985)

Normal human       DNA strand breaks        NiSO4         10-2000 mg/litre     -          Fornace (1982)
fibroblasts        alkaline elution
XP cells

Peripheral         DNA strand breaks        NiCl2         0.05 mmol/litre      ?          McLean et al.
lymphocytes        FADU technique                                                         (1982)

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
CHO                Binding to DNA  in        63NiS         10 mg/litre          +          Harnett et al.
                    vitro (radioactive       63NiCl2       10 mg/litre          + (10x     (1982)
                   precursor)                                                  less)

CHO                Binding to DNA  in vivo   63NiCl2                            + to       Hui & Sunderman
                                                                               liver &    (1980)
                                            63Ni(CO)4                          + kidney

CHO                Binding to RNA,          63NiS         10 mg/litre          +          Harnett et al.
                   protein                  63NiCl2       10 mg/litre          + (10x     (1982)

L132 pulmonary     Binding, X-ray           Ni3S2                              Ni bound   Chirali et
cells              microprobe analysis                                         to         al. (1982)
                                                                               groups of
                                                                               DNA, RNA 
                                                                               of cell

HeLa               Binding, colorimetric                                       Ni         Kovacs &
                   assay (dimethyl                                             localized  Darvas (1982)
                   glyoxime)                                                   in 

FM3A cells         Inhibition of DNA        Ni(CH3CO2)2   0.6, 0.8, 1.0        +          Umeda &
(mouse mammary     synthesis                              mmol/litre                      Nishimura 
carcinoma)                                                                                (1979)
                                                                                          Nishimura & 
                                                                                          Umeda (1979)

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
CBA strain         Inhibition of DNA        NiSO4         15-30% LD50          - kidney   Amlacher &
                   synthesis  in vivo                                           epithelium Rudolf (1981)
                                                                               + hepatic

Fischer rat        Inhibition of DNA        NiCl2                              +          Basrur &
embryo cells       synthesis; 3H TdR                                                      Gilman (1967)

Rat liver          Inhibition of DNA        Ni3S2         5, 10, 10, mg/litre  + equal    Swierenga &
epithelial cell    synthesis; 3H TdR        NiCl2         up to 150 mg/litre   + potency  McLean (1985)
line T51B          uptake                                                      at 

CHO                S-phase inhibition,      NiCl2         40-120 µmol/litre    +          Costa et al.
                   flow cytometry           Ni metal      10-20 mg/litre       +          (1980b, 1982)
                                            Ni3S2         1-10 mg/litre        +
                                            Ni3Se2        1-5 mg/litre         +
                                            NiO           5 mg/litre           +

HeLa               Inhibition of DNA        NiCl2                              -          Painter &
                   synthesis; 3H TdR uptake                                               Howard (1982)

Bronchial          Inhibition of DNA        NiSO4                              +          Lechner et al.
epithelial cells   synthesis; 3H TdR uptake                                               (1984)

Fischer rat        UDS                      NiCl2                              Inhibition Swierenga et
primary                                                                        of MMS-    al. (1987)
hepatocytes                                                                    induced 

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
CHO                Repair induction         NiCl2         100-1000 µmol/litre  +          Robison &
SHE                Cesium chloride          Ni3S2         10 mg/litre          +          Costa (1982)
                   gradients                (cryst.)
                                            NiS (cryst.)  1-10 mg/litre        +
                                            NiS           5-10 mg/litre        -

L5178Y mouse       Thymidine kinase locus   NiCl2         0.16-0.53 mmol/      + dose     Amacher &
lymphoma cells                                            litre (5 concs.)     response   Paillet 
                                                                               (toxic)    (1980)

L5178Y mouse       Thymidine kinase locus   NiSO4         300-800 mg/litre     + (weak)   McGregor et 
lymphoma cells                                                                 at toxic   al. (1988)

T51B rat liver     HPRT locus               Ni3S2         5-20 mg/litre        +          Swierenga &
epithelial cells                                                                          McLean (1985)

NRK, normal rat    Frameshift and base      NiCl2         20-40 µg/litre       +          Biggart &
kidney cells,      pair substitution                                                      Murphy (1988)
with integrated
viral gene

6m2 murine         Gene expression          NiCl2         20-160 µmol/litre    + dose
sarcoma virus-                                                                 dependent
infected cells

V79                HPRT locus               NiCl2         0.4, 0.8 mmol/litre  -          Miyaki et al.
V79                HPRT locus               NiCl2                              +          Hartwig &

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
V79, HGPRT with    HPRT locus               Ni(II)                             +          Christie &
integrated  E.coli                                                                         Tummolo (1988)
gpt gene

CHO                HPRT locus               NiCl2                              ?          Hsie et al.
CHO                HPRT locus               Ni3S2                              + (weak)   Costa et al.
                                            NiS                                + (weak)   (1980)

SHE Ouabain resistance                      NiSO4         0.019 mmol/litre     -          Rivedal &
                                                                               + as       Sanner (1980)
                                                                               with BaP

 Mouse                                                                          \
FM3A cells mouse   SCE                      NiCl2         6 x 10-4-10-3 mol/ + |          Nishimura &
mammary carcinoma                                         litre                |          Umeda (1979)
FM3A cells mouse                            Ni(CH3CO2)2   6 x 10-4-10-3 mol/ + | recovery
mammary carcinoma                                         litre                | period
                                            NiK2(CN)4     1-1.6 x 10-3 mol/  + | included
                                                          litre                |
                                            NiS           4-8 x 10-4 mol/    + |
                                                          litre                /
                                            NiSO4         2.3 x 10-6 to        +
                                                          2.3 x 10-3 mol/litre

P338D1 mouse       SCE                      NiSO4         10-4                 +          Andersen (1983)
macrophage line

Don cells          SCE                      NiSO4         0.19 mmol/litre      + at LC50  Ohno et al.
                                            NiCl2         0.13 mmol/litre      + at LC50  (1982)

CHO                SCE                      NiSO4         0.95, 2.85 µmol/     + at 0.75  Deng & Qu
                                                          litre                mg/litre   (1981)

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
CHO                SCE                      NiS (cryst.)  5-20 mg/litre        +          Sen & Costa
                                            NiCl2         1-1000 µmol/litre    +          (1985)

SHE                SCE                      NiSO4         3.8, 9.5, 19 µmol/   + dose     Larramendy 
                                                          litre                response   et al. (1981)

Peripheral blood   SCE                      NiCl2         0.0-1-1.0 mmol/      + dose     Newman et al.
lymphocytes,                                              litre                response   (1982)
 in vitro                                                                       at 0.1  

Peripheral blood   SCE                      NiSO4         0.0023-2.3 mmol/     + dose     Wulf (1980)
lymphocytes,                                              litre                response 
 in vitro                                                                       0.02, 0.2

Peripheral blood   SCE                      NiSO4         0.95, 2.85 µmol/     + dose     Deng & Qu
lymphocytes,                                              litre                response   (1981)
 in vitro 

Peripheral blood   SCE                      NiSO4         9.5, 19.0 µmol/      + dose     Larramendy et
lymphocytes,                                              litre                response   al. (1981)
 in vitro 

Peripheral blood   SCE                      Ni3S2         10-4 mol/litre       + (weak)   Andersen (1983)
 in vitro 

Peripheral blood   SCE                      Ni3S2         0.001-100 mg/litre   ?          Saxholm et al.
lymphocytes                                                                               (1981)

Peripheral blood   SCE                      nickel        2-20 mg/litre        + (weak)   Djachenko
lymphocytes                                                                               (1989)

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
 In vivo            CA, in Ni-induced        NiS (cryst.)                       + aneup-   Christie et al.
                   rhabdomyosarcomas                                           loidy,     (1988)

BalbC  in vivo      Micronucleus             Ni(NO3)2      56 mg/kg             -          Deknudt &
                                            NiCl2         25 mg/kg             -          Leonard (1982)

FM3A cells         CA                       Ni(CH3CO2)2   0.2, 0.3, 0.6,       + gaps     Umeda &
mammary carcinoma                                         1 mmol/litre; 24,               Nishimura 
                                                          48 h recovery                   (1979)

                                            NiCl2         0.2, 0.3, 0.6,       ? gaps
                                                          1 mmol/litre; 24,
                                                          48 h recovery

                                            NiS           0.2, 0.3, 0.6, 1     + gaps,
                                                          mmol/litre; 24,      breaks,
                                                          48 h recovery        exchanges

FM3A cells         CA                       Ni(CH3CO2)2   0.6, 0.8, 1.0 mmol/  + gaps,    Nishimura &
mammary carcinoma                                         litre; 6, 24, 48 h   breaks,    Umeda (1979)
                                                          recovery             exchanges

                                            NiCl2         0.6, 0.8, 1.0 mmol/  + gaps,
                                                          litre; 6, 24, 48 h   breaks,
                                                          recovery             exchanges

                                            NiS           0.6, 0.8, 1.0 mmol/  + gaps,
                                                          litre; 6, 24, 48 h   breaks,
                                                          recovery             exchanges

FM3A cells         CA                       Ni(CH3CO2)2   10-4 mol/litre       + gaps     Morita et al.
mammary carcinoma                                         (2-3 days)           breaks,    (1985)
                                            NiCl2                              exchanges

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
 In vivo            CA, rat bone marrow      NiSO4         3, 6 mg/kg for       -          Mathur et al.
                   CA, spermatogonial cells               7 and 14 days                   (1978)

Chinese hamster    CA                       NiCl2         1/5, 1/10, 1/25      + dose     Chorvatocvicova
 in vivo                                                   LD50                 response   (1983)
                                                                               1/10, 1/5

Chinese hamster    CA                       NiCl2         1-1000 µmol/litre    dose       Sen & Costa
 in vitro                                                  2 h + 24 h recovery  response   (1985)

                                            NiS (cryst.)  5-20 mg/litre        + at 20 mg/
                                                                               litre, gaps,

Syrian hamster     CA                       NiSO4         0.019 mmol/litre     + gaps,    Larramendy et
 in vitro                                                  24 hr                breaks,    al. (1981)

Peripheral blood   CA                       NiSO4         0.19 mmol/litre      + breaks,  Larramendy et
lymphocytes                                                                    rings,     al. (1981)
 in vitro                                                                       minutes

Peripheral blood   CA                       Ni powder                          -          Paton & Allison
lymphocytes                                 NiO                                           (1972)
 in vitro 

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
Peripheral blood   CA                       Ni(CH3CO2)2   10-100 mg/litre      -          Voroshilin et
lymphocytes                                                                               al. (1977)
 in vitro 

Peripheral blood   CA                       NiCl2         2-20 mg/litre        +          Djachenko 
lymphocytes                                                                               (1989)
 in vitro 

C3H10T             Transformed foci         Ni3S2         0.001, 0.1 mg/litre  +          Saxholm et al.

Mouse embryo       Inhibition of            NiS (cryst.)  1-20 mg/litre        +          Sonnenfeld et 
fibroblasts        interferon production    NiS (amorph.) 1-20 mg/litre        -          al. (1983)

HRT cells          Initiation & promotion   NiSO4         40 µmol/litre        +          Eker & Sanner
(hereditary renal  test                                                                   (1983)

Rat embryo cells   Transformed foci         NiSO4         0.19, 0.38 mmol/     +          Traul et al.
infected with                                             litre                           (1981)
Rauscher leukaemia

NRK (normal rat    Transformed foci         NiSO4         38-152 µmol/litre    + max at   Wilson &
kidney) cells,                                                                 10 mg/     Khoobyarian
infected with                                                                  litre      (1982)
Maloney murine
sarcoma virus

T51B rat liver     Calcium independence,    alphaNi3S2    2.5 mg/litre,        +          Swierenga et
epithelial cells   growth control and                     long-term                       al. (1989)
                   morphology, differen-                  exposure
                   tiation induction

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
Rat tracheal       Transformed foci         alphaNi3S2    5 mg/litre, 24 h     +          Feren & Reith
primary epithelial                                                                        (1988)

SHE                Transformed foci         NiSO4         10, 19, 38 µmol/     + dose     DiPaulo &
                                                          litre                response   Costa (1979)
                                            Ni3S2         1.0, 2.5, 5.0 mg/    + dose
                                                          litre                response
                                            NiS           up to 20 mg/litre    -

SHE                Transformed foci         NiSO4         3.8, 19, 76 µmol/    + at 19,   Rivedal &
                                                          litre                76 µmol/   Sanner (1980)
                                                                               litre co-     
                                                                               with BaP

SHE                Transformed foci         NiSO4         19 µmol/litre        + at 19,   Rivedal &
                                                          + BAP                76 µmol/   Sanner (1981)
                                                                               litre co-
                                                                               with BaP

SHE                Transformed foci         NiSO4         19 µmol/litre        + with     Rivedal et al.
                                                                               cigarette  (1980)

SHE                Transformed foci         Ni3S2         0.1, 1.0 mg/litre    + at       Costa et al.
                                            (crystalline)                      subtoxic   (1979)
                                                                               in nude 

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
SHE                Transformed foci         NiS           0.1, 1.0 mg/litre               Costa et al.
                                            (amorphous)                                   (1979)

SHE                Transformed foci         Ni            5, 10, 20 mg/litre   + |        Costa et al.
                                            NiO, Ni2O3                         + |        (1981a)b
                                            NiS (cryst.)                       + | crystalline
                                            NiS (amorph.)                      + | compounds
                                            Ni3S2 (cryst.)                     + | more
                                            Ni3S2 (cryst.)                     + | potent

SHE                Transformed foci         Inco Black    5, 10, 20 mg/litre   +          Sunderman et
                                            NiO (jet                                      al. (1987a)
                                            black, 5 µm
                                            particle size)

BHK-21 (baby       Anchorage independence   alphaNi3S2    5-20 mg/litre        + |        Hansen & Stern
hamster kidney)                             Ni2O3         5-20 mg/litre        + |        (1983)
                                            NiO           37.5-150 mg/litre    + | anchorage
                                            Ni(CH3CO2)2   100-400 mg/litre     + | independence
                                            MIG nickel    100-400 mg/litre     + | at equitoxic
                                            welding fume                         / concentrations

Bronchial          Growth control and       NiSO4         5-20 mg/litre        +          Lechner et al.
epithelial cells   morphology                                                             (1984)

Foreskin           Anchorage independence   Ni(CH3)CO2)2  10 µmol/litre        + |        Biedermann &
fibroblasts                                 NiO           50 µmol/litre        + |        Landolph (1986)
                                            NiSO4         10 µmol/litre        + | anchorage
                                            Ni3S2         10 µmol/litre        + | independence at
                                                                                 / LC50 concentrations

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
Balb/c mouse       Dominant lethal          NiCl2         25 mg/kg             - pre-     DeKnudt &
 in vivo                                     Ni(NO3)2      56 mg/kg             implant-   Leonard (1982)
                                                                               ation loss

Balb/c mouse       Dominant lethal          Ni(NO3)2      8.1, 11.3 mg/kg      - pre-     Jacquet &
 in vivo                                                                        implant-   Mayence (1982)
                                                                               ation loss

Rat                Dominant lethal          NiCl2         0.005-50 mg/kg       - pre-     Saichenko et
                                                          for 24 weeks         implant-   al. (1985)
                                                                               ation loss

Rat embryo cells   Spindle disturbance      NiCl2         1 mg Ni/litre        +          Swierenga &
 in vitro                                                  culture medium                  Basrur (1968)

Human lymphocytes  Spindle disturbance      NiSO4         10-3 mol/litre       +          Andersen (1985)

NIH3T3 cells       Inhibition of            NiSO4         0.5-20 mmol/litre    + dose     Miki et al.
                   intercellular                                               response   (1987)
                   (radioisotope transfer)

Table 27 (contd.)
Species/Strain     Test system              Compound      Concentrationa       Result     Reference
Human              Induction of free        Ni3S2                              + more     Evans et al.
polymorphonuclear  radicals                                                    potent     (1988)
leukocytes         (chemiluminescent        NiO                                +
a  No figures means no concentration data given.
b  Transformation experiments with this system have been repeated numerous times for mechanistic studies.
   Findings include:
   - crystalline but not amorphous nickel compounds are actively phagocytosed  in vitro (Costa & 
     Mollenhauer, (1980b);
   - reduction of amorphous compounds with LiA1H4 enchances phagocytosis (Costa & Mollenhauer, 1980b);
   - phagocytosis is Ca-dependent (Heck & Costa, 1982);
   - phagocytosed particles are contained in cytoplasmic vesicles where they slowly dissolve, releasing 
     nickel ions (Evans et al., 1982);
   - nickel compounds selectively damage heterochromatin (Sen & Costa, 1985);
   - NiS (cryst.) and NiCl2 preferentially transform male SHE cells (Costa et al., 1981a);
   - observed damage includes deletion of long arm of X chromosome (Conway & Costa, 1989).

8.2.1.  Mutagenesis in bacteria and mammalian cells

    Nickel compounds were generally inactive in bacterial mutation 
assays.  In some cases, where standard procedures were modified by, 
for example, using fluctuation assays (LaVelle & Witmer 1981; 
Pikalek & Necasek, 1983) or co-mutagenesis tests with other 
carcinogenic agents (Dubins & LaVelle, 1986; Ogawa et al., 1987), 
positive results were obtained. 

    The mutagenic effects of nickel chloride at the hypoxanthine-
guanine phosphoriboxyl transferase (HGPRT) locus were studied in 
cultured V79 Chinese hamster cells and Chinese hamster ovary (CHO) 
cells (Hsie et al., 1979).  Hsie et al. (1979) claimed positive 
results without reporting the detailed data.  Miyaki et al. (1979) 
obtained a negative response.  However, Hartwig & Beyersmann (1989) 
obtained a positive response with the same cell line, but the 
response occurred only in a serum-free medium. 

    Amacher & Paillet (1980) studied nickel chloride at the 
thymidine kinase (TK) locus in L51784Y mouse lymphoma cells and 
found a dose-dependent increase in the number of mutants of up to 4 
times that in the controls.  The possibility that this response was 
due to chromosome damage, also detected in this assay, cannot be 

    Swierenga & McLean (1985) used epithelial cells from rat liver 
(T51B) to study the genotoxic effects of nickel chloride and also 
of nickel subsulfide, either as an aqueous suspension of washed 
particles or as an aqueous solution.  All produced increased 
numbers of mutations at the hypoxanthine-guanine phosphoriboxyl 
transferase (HGPRT) locus, over a range of concentrations. 

    In all the gene mutation studies using mammalian cells, any 
response following exposure to nickel compounds was associated with 
considerable cell toxicity. 

8.2.2.  Chromosomal aberration and sister chromatid exchange (SCE)

    Nishimura & Umeda (1979) compared the effects of nickel 
chloride, nickel acetate, potassium cyanonickelate and nickel 
sulfide on the induction of chromosomal aberrations in cultured 
FM3A mouse mammary carcinoma cells.  The 4 compounds elicited 
similar inhibitory effects on the synthesis of protein, RNA, and 
DNA.  The chromosomal aberrations were manifested as breaks, 
exchanges, and fragmentations.  Treatment of Chinese hamster ovary 
(CHO) cells with crystalline nickel sulfide and nickel chloride 
induced chromosomal aberrations including gaps, breaks, and 
exchanges.  In both cases, the heterochromatic centromeric regions 
of the chromosomes were preferred; nickel sulfide also caused 
selective fragmentation at the heterochromatic long arms of the 

    Chromosomal damage and increased SCE were induced in Syrian 
hamster embryo (SHE) cells and human lymphocyte cultures treated 
with nickel sulfate (Larramendy et al., 1981). 

    Wulf (1980) showed that nickel sulfate and nickel subsulfide 
could produce SCE in human lymphocytes  in vitro.  A significant 
increase in SCE in human lymphocytes exposed to nickel subsulfide 
was reported by Saxholm et al. (1981).  Newman et al. (1982) 
observed increased SCE in human lymphocytes exposed to nickel 
chloride.  Ohno et al. (1982) investigated the induction of SCE by 
nickel sulfate and nickel chloride in Don Chinese hamster cells and 
found significantly increased frequencies of SCE. 

8.2.3.  Mammalian cell transformation

    These assays may not necessarily have a "genotoxic" endpoint as 
they also predict the carcinogenic potential of compounds that act 
by non-genotoxic mechanisms. 

    DiPaolo & Casto (1979) studied the capacity of nickel sulfate, 
nickel subsulfide, and amorphous nickel monosulfide to induce 
morphological transformation in Syrian hamster embryo (SHE) cells 
 in vitro.  Amorphous nickel monosulfide did not produce 
transformation at plate concentrations as high as 20 µg/ml medium.  
Nickel sulfate, tested at plate concentrations of 2.5, 5, and 10 
µg/ml medium, caused transformation in a dose-dependent manner.  
Nickel subsulfide produced a higher percentage of transformations, 
in a dose-dependent manner, than nickel sulfate, when tested at 
plate concentrations of 1.0, 2.5, and 5 µg/ml medium.  In a study by 
Costa et al. (1979), nickel subsulfide caused morphological 
transformation, in a dose-dependent manner, of Syrian hamster fetal 
cells, at plate concentrations of 0.1, 1.0, 5.0, and 10.0 µg/ml 
medium, but, under the same experimental conditions, nickel 
monosulfide, at plate concentrations of 0.1, 1.0, and 5.0 µg/ml 
medium, did not. 

    Costa et al. (1981) demonstrated that the incidence of 
morphological transformations of SHE and CHO cells, exposed to 
various nickel compounds, was directly correlated with 
phagocytosis.  Subcutaneous implantation of transformed SHE cells 
led to the development of fibrosarcomas in nude mice (Costa et al., 
1979). Nickel sulfate caused cell transformation in cultured Syrian 
hamster embryo cells (Pienta et al., 1977). 

    Sunderman et al. (1987a) compared nickel oxides with different 
physical and chemical properties in the SHE cell transformation 
assay, and  in vivo responses (Table 28).  Three out of the 4 
compounds that were active in the transformation assay were also 
positive  in vivo when injected intramuscularly. 

Table 28.  Comparison of activity of some nickel oxides with different physiochemical 
characteristics in  in vitro transformation assays and  in vivo carcinogenesis
Compound                                Concentration        Resulta   No. of tumours      
                                                                       observed (20 mg     
                                                                       Ni/rat im)b         
Nickel oxides             Calcination                                                      
INCO Black (jet black)    650 °C        5, 10, 20 mg/litre   +         6/15                
Grey black                735 °C        Particle size 5 µm   +         0/15                
Green                     1045 °C                            -         0/15                
Nickel copper oxides      Ni-Cu ratio                                                      
Maroon                    2.5:1         5, 10, 20 mg/litre   +         13/15               
Red-brown                 5.2:1         Particle size 5 µm   +         15/15               
alphaNiS (positive                                           +         15/15               
a  Sunderman et al. (1987a).
b  Sunderman et al. (1988a).
    Hansen & Stern (1984) compared the abilities of welding fume, 
nickel powder, nickel acetate, black nickel oxide, black nickel 
oxide catalyst (a commercial catalyst for organic reactions, which 
is a mixture of nickel(II) and nickel(IV) oxides (NiO1.4 x 3H2O), 
and nickel subsulfide, in the  in vitro transformation of Syrian 
baby hamster kidney BHK-21 cells.  Although a wide range of 
transformation potency was found, the compounds produced the same 
number of transformed colonies at the same degree of toxicity (50% 
survival).  The authors concluded that this indicated that if 
toxicity is a direct measure of net available nickel, then nickel 
or the nickel ion is the ultimate transforming agent.  In a 
subsequent BHK-21 mammalian cell assay, Stern et al. (1985) 
determined the 50% toxicity of the soluble and insoluble fraction 
of nickel welding fume and found that only the insoluble fraction 
showed a transformation potential. 

    Synergistic effects of nickel compounds and benzo (a)pyrene on 
morphological transformation of SHE cells have been reported.  
Costa & Mollenhauer (1980c) found that pretreatment of the cells 
with benzo (a)pyrene enhanced the cellular uptake of nickel 
subsulfide.  Treatment with nickel sulfate and benzo (a)pyrene 
resulted in a transformation frequency of 10.7% compared with 0.5% 
and 0.6%, respectively, for the individual substances (Rivedal & 
Sanner, 1980). 

8.3.  Other test systems

    Smith-Sonneborn et al. (1986) used the ciliated protozoan 
 Paramecium to quantify the effects of pure nickel powder, iron-
nickel powder, and nickel subsulfide.  Genotoxicity was indicated 

by significant increases in the fraction of non-viable offspring 
(presumed index of lethal mutation) found after autogamy in parents 
from the nickel-treated groups compared with the controls.  Only 
nickel subsulfide consistently induced a significant increase in 
offspring lethality. 

    Rodriguez-Arnaiz & Ramos (1986) studied the mutagenic potential 
of nickel sulfate in the  Drosophila sex-linked recessive lethal 
(SLRL) assay  in vivo.  Nickel sulfate induced SLRL in a dose-
dependent way, whereas sex chromosome loss was only detectable in 
significant numbers at the highest concentration. 

8.4.  Carcinogenicity

8.4.1.  Inhalation

    Studies on inhalation exposure are summarized in Table 29. 
Hueper (1958) and Hueper & Payne (1962) studied the effects of 
exposure to airborne concentrations of elemental nickel.  Hueper 
(1958) exposed 20 female C57BL mice, 50 male and 50 female Wistar 
rats, 60 female Bethesda black rats, and 32 male and 10 female 
guinea-pigs to an atmosphere containing 99% pure nickel powder 
(particle size 4 µm or less) at 15 mg/m3, for an exposure period of 
6 h/day, 4-5 days/week, for up to 21 months.  There were no control 
groups.  There were no lung tumours, but 2 lymphosarcomas were seen 
in the mice.  However, most animals died before 15 months.  Fifteen 
out of 50 rats of both strains that were studied histologically 
showed adenomatoid formations in the lung, which were classified as 
benign neoplasms.  At death, most of the guinea-pigs exhibited 
adenomatoid proliferations.  One animal had an intra-alveolar 
carcinoma.  The results of a later study (Hueper & Payne, 1962) on 
rats and hamsters did not reveal lung tumours following inhalation 
exposure to 99% pure nickel together with 56-98 mg sulfur 
dioxide/m3 (20-35 ppm) and powdered limestone. 

    In studies by Kim et al. (1969) a group of 77 male Wistar rats 
was exposed to metallic nickel dust, equivalent to 3.1 mg/m3 for 6 
h a day, 5 days/week, over 21 months, followed by exposure to air 
alone; 98% of the dust particles were less than 2 µm in diameter.  
Sub-groups were exposed to the dust for various periods followed by 
periods of recovery.  Two exposed rats developed lung tumours of a 
carcinoid pattern and a similar tumour was found in one rat in the 
unexposed control group. 

Table 29.  Experimental animal studies on the carcinogenicity studies of nickel compounds administered by inhalation or 
tracheal instillation
Nickel compound   Animal           Dosage schedule       Lung tumours detected    Comments             References
                  (group size)
Inhalation studies
Nickel powder     C57BL female     15 mg/m3, 6 h/day,    no lung tumours,         all animals died     Hueper (1958)
                  mice (20)        4-5 days/week for     2 lymphosarcomas         by week 60, no 
                                   60 weeks                                       control group

Nickel powder     Wistar rats      15 mg/m3, 6 h/day,    numerous multicentric    histology on 50      Heuper (1958)
                  (108); Bethesda  4-5 days/week, for    adenomatoid              animals only, no
                  black rats (60)  60 weeks              proliferations in 15     no control group

Nickel powder     Guinea-pigs      15 mg/m3, 6 h/day,    adenomatous alveolar     all animals died     Heuper (1958)
                  (42)             4-5 days/week, for    lesions in almost all    by 21 months
                                   60 weeks              animals

Nickel powder +   Bethesda black   level not specified   no lung tumours                               Heuper & Payne
powdered          rats (120)                                                                           (1962)
limestone +       Hamsters (100)
sulfur dioxide

Nickel powder     Wistar rats      3.1 mg/m3, 6 h/day,   carcinoid lung tumour                         Kim et al. 
                  (77)             5 days/week for 21    in 2 exposed and in 1                         (1969)
                                   months (?)            control rat

Ni(CO4)           Wistar rats      30 mg/m3, 30 min/     1 lung carcinoma         no lung tumours      Sunderman et al.
                  (64)             day, 3 days/week,                              in a control group   (1959)
                                   for 52 weeks                                   of 41 animals

Ni(CO4)           Wistar rats      60 mg/m3, 30 min/     1 lung carcinoma         9 animals survived   Sunderman et al.
                  (32)             day, 3 days/week,                              for 2 years          (1959)
                                   for 52 weeks

Ni(CO4)           Wistar rats      single exposure to    2 lung carcinomas                             Sunderman et al.
                  (80)             250 mg/m3 (30 min?)                                                 (1959)

Table 29 (contd.)
Nickel compound   Animal           Dosage schedule       Lung tumours detected    Comments             References
                  (group size)
Ni(CO4)           Wistar rats      30 mg/m3, 30 min/     1 lung adenocarcinoma                         Sunderman &
                  (64)             day, 3 days/week,                                                   Donelly (1965)
                                   for lifetime

Ni(CO4)           Wistar rats      single exposure to    1 lung adenocarcinoma    214/285 animals      Sunderman &
                  (285)            600 mg/m3 for 30 min                           died within 3 weeks  Donelly (1965)

Nickel            F344 rats        0.97 mg/m3, 6 h/day,  14 malignant and 15      survival: 5% in      Ottolenghi et
subsulfide        (226)            5 days/week, for 78   benign lung tumours in   nickel-exposed       al. (1974)
                                   weeks, followed by    the exposed, 1           rats; 31% in
                                   observation for 30    malignant and 1 benign   controls
                                   weeks                 in the control animals
                                                          P <0.01

Black nickel      Syrian golden    53.2 mg/m3, 7 h/day,  no significant increase  massive              Wehner et al.
oxide             hamsters (102)   5 days/week, for      in incidence of          pneumoconiosis in    (1975)
                                   2 years               respiratory tumours      exposed animals; 
                                                                                  part of animals also
                                                                                  exposed to tobacco

Green nickel      Wistar rats      0.6 mg/m3, 6 h/day,   1 adenocarcinoma and     5 control animals    Horie et al.
oxide             (6)              5 days/week, for 4    1 adenomatous pulmonary                       (1985)
                                   weeks, followed by    lesion
                                   observation for 80

Green nickel      Wistar rats      8 mg/m3, 6 h/day,     1 adenomatous lesion                          Horie et al.
oxide             (8)              5 days/week, for 4    in lungs                                      (1985)
                                   weeks, followed by
                                   observation for 80

Nickel-enriched   Syrian golden    fly ash containing    no lung tumours          20 of the animals    Wehner et al.
coal fly ash (Ni  hamster (102)    6% Ni, 70 mg/m3,                               removed from         (1981)
acetate added to                   6 h/day, 5 days/                               exposure for other
coal before                        week, for 20 months                            studies

Table 29 (contd.)
Nickel compound   Animal           Dosage schedule       Lung tumours detected    Comments             References
                  (group size)
Nickel-enriched   Syrian golden    fly ash containing    no lung tumours                               Wehner et al.
coal fly ash (Ni  hamsters         6% Ni, 17 mg/m3,                                                    (1981)
acetate added to                   6 h/day, 5 days/week,
coal before                        for 20 months
                                   fly ash containing    no lung tumours                               Wehner et al.
                                   0.3% Ni, 70 mg/m3,                                                  (1981)
                                   6 h/day, 5 days/week,
                                   for 20 months

Nickel oxide      Wister rats      60 µg/m3 continuous   no lung tumours          Alveolar             Glaser et al.
                  (60)             exposure for 18                                proteinosis in       (1986)
                                   months                                         nickel-exposed
                                   200 µg/m3 continuous  no lung tumours
                                   exposure, doe, 18

Intratracheal instillation
Nickel powder     Wistar rats      0.3 mg Ni x 20, at    1 adenoma, 1             no lung tumours in   Pott et al.
                  (39)             weekly intervals      adenocarcinoma, 8        in 40 control        (1987)
                                                         squamous cell            animals

                  Wistar rats      0.9 mg Ni x 10, at    3 adenocarcinomas,                            Pott et al.
                  (32)             weekly intervals      4 squamous cell                               (1987)
                                                         carcinomas, 1 mixed

Nickel oxide      Wistar rats      5 mg x 10, at         4 adenocarcinomas,                            Pott et al.
(not specified)   (37)             weekly intervals      4 squamous cell                               (1987)
                                                         carcinomas, 2 mixed

                  Wistar rats      15 mg x 10, at        12 squamous cell
                  (38)             weekly intervals      carcinomas

Table 29 (contd.)
Nickel compound   Animal           Dosage schedule       Lung tumours detected    Comments             References
                  (group size)
Black nickel      Hamsters         4 mg x 30, at         no lung tumours          3 hamsters in both   Farrell & Davis
oxide             (50)             weekly intervals                               groups survived for  (1974)
                                                                                  12 months

Black nickel      Rats (26)        single                1 squamous cell          the nickel oxide     Saknyn & Blokhin
oxide                              administration        carcinoma of the         dust contained       (1978)
                                   20-40 mg              lung                     64.7% NiO, 0.13%
                                                                                  NiS, 0.18% Ni; no
                                                                                  pulmonary tumours
                                                                                  in 47 controls

Nickel            B6C3F1 mice      0.024, 0.056, 0.156,  no neoplastic or                              Fisher et al.
subsulfide        (20)             0.412, or 1.1 mg/kg,  non-neoplastic                                (1986)
                                   four doses at weekly  lesions
                                   intervals, follow-up
                                   of 27 months

Ni3S2             Rats (47)        0.063 mg x 15, at     2 adenocarcinomas,       no pulmonary         Pott et al.
                                   weekly intervals      5 squamous cell          tumours in control   (1987)
                                                         carcinomas               rats

Ni3S2             Rats (45)        0.125 mg x 15, at     3 adenocarcinomas, 6     no pulmonary         Pott et al.
                                   weekly intervals      squamous cell            tumours in control   (1987)
                                                         carcinomas, 4 mixed      rats

Ni3S2             Rats (40)        0.25 mg x 15, at      7 adenocarcinomas,       no pulmonary         Pott et al.
                                   weekly intervals      4 squamous cell          tumours in control   (1987)
                                                         carcinomas, 1 mixed      rats

Powder            Hamsters,        0.8 mg powder,        1 lung tumour (nickel    no pulmonary         Muhle et al.
Ni3S2             (30-40 per sex)  0.1 mg alphaNi3S2,    powder group)            tumours in positive  (1988)
Pentlandite                        3 mg pentlandite,     1 lung tumour            control group
Cr-Ni(55) Alloy                    3 or 9 mg Cr-Ni(55)   (pentlandite group)
Cr(55) Alloy                       alloy, 9 mg Cr(55)
                                   alloy; 12 times at
                                   14-day intervals
    Ottolenghi et al. (1974) found a significantly higher incidence 
of pulmonary hyperplastic and neoplastic lesions in 226 Fischer 344 
rats of both sexes exposed to nickel subsulfide (0.97 mg nickel/m3; 
70% of particles smaller than 1 µm) for 6 h/day, 5 days/week, over 
78 weeks.  The overall incidence of lung tumours (adenoma and 
adenocarcinomas) in treated animals was 14% compared with 1% in the 
controls.  The nickel sulfide-exposed rats also had a higher 
incidence of respiratory tract inflammation. 

    The pathogenic effect of inhaled black nickel oxide was 
investigated in hamsters by Wehner et al. (1975).  Random-bred ENG: 
ELA Syrian golden hamsters (102 males) were exposed to respirable 
aerosols of nickel oxide (count median diameter 0.3 µm) at a 
concentration of 53.2 mg/m3 for 7 h/day, on 5 days/week, for up to 
2 years.  Half of the animals were also exposed (nose-only) to 
cigarette smoke for 10 min, 3 times a day.  Histopathological 
examination revealed increasing cellular response, proliferative 
and inflammatory, in animals dying late in the study.  
Histopathologically, there were no marked differences between the 
nickel-oxide-plus cigarette smoke and the nickel-oxide-only exposed 
groups.  It was concluded that there was neither a significant 
carcinogenic effect of nickel oxide nor a co-carcinogenic effect of 
cigarette smoke.  However, though not statistically significant, 3 
malignant musculoskeletal tumours were found among nickel oxide-
exposed hamsters (Wehner et al., 1975). 

    Wehner et al. (1981) exposed 4 groups, each of 102 male Syrian 
golden hamsters (outbred LAK:LVG), through inhalation to nickel-
enriched fly ash (NEFA) for 6 h/day, 5 days/week, for up to 20 
months.  The first group was exposed to 70 mg NEFA/m3 aerosol (4 mg 
nickel/m3), the second group to 17 mg NEFA/m3 aerosol (1 mg 
nickel/m3), the third group was exposed to 70 mg fly ash (FA)/m3 
aerosol containing 0.21 mg nickel/m3, and the fourth group was 
exposed to filtered air (control group).  Five animals from each 
group were killed after 4, 8, 12, and 16 months of exposure.  
Additional groups of 5 animals were withdrawn from exposure at the 
same time intervals and maintained for observation up to the 
twentieth month of the study, when all the animals were killed.  
Dust deposition, interstitial reaction, and bronchiolization in the 
lungs were higher in the high-NEFA and FA groups than in the low-
NEFA group, indicating that dust quantity rather than actual nickel 
content may be the major factor in determining tissue response.  
While 2 malignant pulmonary tumours were found in 2 hamsters of the 
high-NEFA group, no statistically significant carcinogenesis was 

    Horie et al. (1985) studied the carcinogenic effects of 
inhalation of 8.0 or 0.6 mg green nickel oxide/m3 on male Wistar 
rats (5-8 rats/dose group).  The exposure time was 6 h/day, 5 
days/week, for 1 month.  Animals were killed 20 months after 
exposure.  There was one adenocarcinoma in a low-dose animal.  In a 
study by Glaser et al. (1986), male Wistar rats were exposed 

continuously for 18 months to nickel oxide aerosols (60 or 200 µg 
nickel/m3).  The nickel oxide aerosols were generated by 
atomization of aqueous nickel acetate solutions and subsequent 
pyrolysis.  No lung tumours were observed. 

    Sunderman et al. (1959) and Sunderman & Donelly (1965) reported 
carcinogenesis in rats following inhalation exposure to nickel 
carbonyl.  In the first study (Sunderman et al., 1959), groups of 
64 and 32 male Wistar rats were exposed to 30 and 60 mg nickel 
carbonyl/m3, respectively, for 30 min, 3 days/week, for one year.  
A further group was exposed once to 250 mg nickel carbonyl/m3.  
Four out of the 9 animals that survived 2 years developed neoplasms 
of the lung; 2 of these animals were in the single-exposure group, 
the other 2 rats were in the repeated-exposure groups.  No 
pulmonary tumours were seen in 41 control animals, the death rate 
of which was similar to that in the animals exposed to nickel 
carbonyl.  Sunderman & Donelly (1965), using 285 male Wistar rats, 
observed pulmonary adenocarcinoma with metastases in one of the 35 
rats that survived 2 or more years after a single 30-min inhalation 
of 600 mg nickel carbonyl/m3.  In a further group of 64 male rats, 
exposed to repeated inhalation of nickel carbonyl (30 mg/m3 for 30 
min, 3 days/week, until death), one pulmonary adenocarcinoma with 
metastases developed among 8 rats that survived 2 or more years.  
The control animals did not show any tumours.  Because of the 
rarity of spontaneous pulmonary malignancies in Wistar rats, it was 
suggested that the tumours observed in the two studies were due to 
inhalation of nickel carbonyl.  Survivability of treated and 
control animals was poor in both studies.  Statistical analysis 
could not be performed because of small sample size. 

    Kasprzak et al. (1973) did not find any lung tumours in 13 rats 
following intratracheal instillation of 5 mg nickel subsulfide.  
Thirty weekly intratracheal injections of 4 mg black nickel oxide 
did not produce lung tumours in 50 hamsters, but only 3 animals 
survived (Farrell & Davis, 1974).  In a study by Saknyn & Blokhin 
(1978) 26 rats were exposed to 20-40 mg nickel oxide by 
intratracheal instillation; 1 lung carcinoma was found.  In a 
series of studies, Pott et al. (1987) examined the potential 
carcinogenic effect of a number of dusts, including nickel oxide, 
nickel powder, and nickel subsulfide, at various concentrations, in 
rats.  All 3 nickel compounds produced lung tumours, including 
adenocarcinomas and squamous cell carcinomas, nickel subsulfide 
exhibiting the strongest effect in relation to dose.  Lung tumour 
incidence was 14.9% (7 out of 47 animals), 28.9% (12 out of 45 
animals), and 30% (12 out of 40 animals) following 15 weekly 
intratracheal injections each containing 0.063 mg, 0.125 mg, and 
0.25 mg nickel, respectively.  Nickel powder was given 
intratracheally in 20 weekly doses of 0.3 mg nickel; an additional 
group was given 10 weekly doses of 0.9 mg nickel.  Lung tumours 
occurred in 10 out of 39 animals (25.6%) and in 8 out of 32 animals 
(25.0%), respectively.  Ten weekly instillations of nickel oxide, 
each corresponding to a nickel content of 5 or 15 mg, produced 
27.0% (10/37 animals) or 31.6% (12/38 animals) lung tumours, 
respectively.  No lung tumours occurred in the controls (40 

animals).  In a study with nickel subsulfide using the 
intratracheal route, no increase in tumour incidence was observed 
compared with the controls.  Doses ranged from 0.024 to 1.1 mg/kg, 
administered once a week for 4 weeks (Fisher et al., 1984). 

    Muhle et al. (1988) administered nickel powder (cumulative dose 
9.6 mg), nickel subsulfide (cumulative dose 1.2 mg), pentlandite 
(cumulative dose 36 mg), chromium-nickel-steel (cumulative dose 36 
or 108 mg) and chromium-containing stainless steel (cumulative dose 
108 mg) to Syrian golden hamsters (30-40 animals per sex and dose 
group) by intratracheal instillation, 12 times every 14 days.  One 
lung tumour was found after treatment with nickel powder and one 
tumour after treatment with pentlandite. 

8.4.2.  Oral

    Schroeder et al. (1964, 1974) and Schroeder & Mitchener (1975) 
studied the carcinogenic potential for mice and rats of nickel 
salts in the drinking-water.  Levels of 5 mg nickel/litre in the 
drinking-water did not produce a significantly higher incidence of 
tumours compared with controls. 

    Ambrose et al. (1976) added nickel sulfate hexahydrate fines 
(22.3% nickel) to the diet of Wistar derived rats for 2 years, at 
concentrations of 0, 100, 1000, or 2500 mg nickel/kg.  There was no 
carcinogenic response. 

8.4.3.  Other routes

    The results of carcinogenesis studies of nickel compounds in 
rodents are summarized in Table 30. 

Table 30.  Experimental carcinogenesis studies of various nickel compounds
Nickel      Animals     Routea                 Tumours               Comments           Reference        
Ni3S2       Fischer     im                                           Form of implant    Gilman & Herchen 
            rats        - implants 500 mg      14/17                 is important       (1963)           
                        - diffusion chambers                                                             
                          10 mg                14/17                                                     
                        - powder 10 mg         19/20                                                     
                        - chips 500 mg         5/7                                                       
Ni3S2       Rat         1 or 3 mg Ni3S2/       1 mg: 9/60 tumour     No tumours in      Yarita &         
                        gelatin pellet         (6 carcinomas, 3      control            Nettesheim       
                        implanted 4 weeks      sarcomas)             transplanted       (1978)           
                        post-grafting in       3 mg: 45/60 tumours   tracheas                            
                        tracheas grafted       (1 carcinoma, 44
                        under dorsal skin of   sarcomas) 
                        isogenic recipients    

Ni3S2       Rats        Intratesticular,       16/19 (fibrosarcomas, No tumours in      Damjanov et al.
                        0.6-10 mg              rhabdomyosarcomas,    controls           (1978)

Ni3S2       Fischer     intrarenal             Renal cancers in      No tumours in      Sunderman et al.
            rats                               18/24 rats at 10 mg   controls           (1979b)
                                               dosage and 5/18 rats
                                               at 5 mg dosage

Ni3S2       NMRI mice   im, sc                 Local sarcomas in 19                     Oskarsson et al.
                                               of 32 mice at 10 mg                      (1979)

Ni3S2       Pregnant    im, on day 6           Local sarcomas in                        Sunderman et al.
            rats                               all dams; no excess                      (1981)
                                               tumours in progeny

Table 30 (contd.)
Nickel      Animals     Routea                 Tumours               Comments           Reference        
Ni3S2       Rabbits     im                     Leiomyosarcomas with                     Hildebrand & 
                                               myosin light-chains                      Tetaert (1981);
                                               typical of fetal                         Hildebrand &
                                               smooth muscle,                           Biserte (1979a,b)

Ni3S2       Fischer     intraocular            Retinoblastomas,                         Albert et al.
            rats                               gliomas, and                             (1980, 1982)

Ni3S2       Fischer &   im                     Rhabdomyosarcomas,                       Yamashiro et al.
            hooded                             leiomyosarcomas,                         (1980, 1983)
            rats                               fibrosarcomas and

Ni3S2       Fischer     im                     Ni3S2 carcinogenesis                     Sunderman &
            rats                               inhibited by                             McCully (1983)
                                               simultaneous injection
                                               of manganese dust

Ni3S2,      Wistar      im                     Sarcomas induced by                      Kasprzak et al.
Ni(OH)2,    rats                               Ni3S2 and crystalline                    (1983)
NiSO4                                          Ni(OH)2, but not by
                                               NiSO4 or amorphous

Various     Fischer     im                     Sarcomas induced by                      Sunderman
nickel      rats                               nickel compounds                         (1984)

Ni3S2, NiO  Wistar &    intrapleural           Rhabdomyosarcomas,                       Skaug et al. 
Ni3S2       Fischer     implantation           malignant tumours of                     (1985)
            rats                               pluripotential origin                    Lumb et al.

Ni3S2       Fischer     im                     Rhabdomyosarcomas,                       Kasprzak &
            rats                               fibrosarcomas                            Poirier (1985)

Table 30 (contd.)
Nickel      Animals     Routea                 Tumours               Comments           Reference        
Ni3S2       F344 rats   sc, im, if, ia         Malignant soft        No synovial        Shibata et al.
                                               tissue tumours in     sarcomas           (1985a)
                                               18/19 (sc), 19/20
                                               (im), 9/20 (if),
                                               16/19 (ia)

Ni3S2       Male        im (single dose)       Mg carbonate          A possible         Kasprzak et al.
            Fischer                            inhibited Ni3S2       involvement of     (1987)
            rats                               carcinogenicity       NK and phagocytic
            10 groups                          from 100 to 55%       cells in this
            20 each                                                  inhibition

Ni3S2       Fischer     im                     Local sarcomas        Simultaneous       Kasprzak et al.
            rats                                                     admin. of ZnO      (1988)
                                                                     or Zn acetate 
                                                                     delayed the onset
                                                                     of sarcomas

Ni3S2       F344 NCT    im                     Local sarcomas                           Kasprzak &
                                               100%                                     Rodriguez (1988)

Ni3S2 +     Rat         im                     Local sarcomas        Interaction role   Kasprzak &
iron:                                                                of inflammation,   Rodriguez
Fe-/Ni = 0.5                                   60%                   active oxygen      (1988)
Fe-/Ni = 1.0                                   40%                   species, enzyme
Fe-/Ni = 2.0                                   10%                   system
                                               Local sarcomas

Fe3+ = 0.5                                     95%                                      Kasprzak &
Fe3+ = 1.0                                     45%                                      Rodriguez
Fe3+ = 2.0                                     35%                                      (1988)

Table 30 (contd.)
Nickel      Animals     Routea                 Tumours               Comments           Reference        
Ni3S2 +                                        100%                  Iron effect is     Kasprzak &
remote                                                               purely local       Rodriguez 
Fe- or                                                                                  (1988)
Fe3+/Ni = 2

Ni3S2        in vitro                                                 Deactivation of    Kasprzak &
            cell free                                                catalase and       Rodriguez 
                                                                     glutathione        (1988)

Ni3S2       Japanese    intraocular            Malignant                                Mitsumasa
            common                             melanoma-like                            (1987)
            newts                              tumour in 7/8
             (Cynops)                           at 400-1100
             pyrrhogaster                       µg/newt

NiO         Wistar      im                     26 local tumours      No controls used   Gilman 
            rats        20 mg                  in 32 rats (80%)                         (1962)

NiO         Swiss       im                     35% mice with
            mice        5 mg                   tumours

NiO         C3H mice    im                     23% mice with
                        5 mg                   tumours

NiO         NIH black   im implants            4 sarcomas in 35                         Payne 
            rats        7 mg                   rats after 18 months                     (1964)

Nickel      Rats        Instillation in        Rhabdomyosarcomas     Negative study     Eilertsen 
oxides and              pleural cavity         in 8/220 (4/20 in                        et al.
nickel-                                        positive control)                        (1988)

Table 30 (contd.)
Nickel      Animals     Routea                 Tumours               Comments           Reference        
Nickel      Hooded      im,                    52/66 rats with                          Gilman &
refinery    Wistar                             sarcomas                                 Ruckerbauer
flue dust   rats        20 or 30 mg, one or    8/20 rats with                           (1962)
                        thighs                 sarcomas

            Mice        im,                    23/40 mice with
                        10 mg each thigh       sarcomas

Feinstein   Rats        ip                     6/39 rats with injection                 Saknyn &
dust                    90-150 mg dust/rat     site sarcomas                            Blokhin (1978)

Nickel      Hooded      im, 28.3 mg in         10/10 rats with                          Heath &
powder      rats        0.4 ml fowl serum      local rhabdomyosarcomas                  Daniel (1964)

Nickel      Osborne-    Intrafemoral,          4/17 rats with                           Hueper (1952)
powder      Mendel      21 mg                  tumours, 1 squamous
            rats                               cell carcinoma,
                                               3 osteosarcomas

            Wistar      Intrafemoral           28% of treated rats   No tumours in
            rats        implant, 50 mg         with tumours of       control rats
                                               injected thighs

            Dutch       Intrafemoral           1/6 rabbits with
            rabbits     implant, 54 mg/kg      fibrosarcomas

            C57BL       iv,                    No tumours
            mice        weekly for 2 weeks

            Rabbits     iv,                    No tumours
                        6 times of a 1% Ni
                        suspension in 2.5%
                        gelatin at a rate
                        of 0.5 ml/kg

Table 30 (contd.)
Nickel      Animals     Routea                 Tumours               Comments           Reference        
            Wistar      iv,                    7/25 rats with
            rats        6 times of 0.5% Ni     tumours
                        suspension in saline
                        at 0.5 ml/kg

Nickel      Fischer     im, 5 monthly          38/50 rats with                          Furst &
powder      rats        injections of 5 mg     fibrosarcomas                            Schlauder 
                        Ni in 0.2 ml                                                    (1971)

            Hamsters    im, 5 monthly          2/50 hamsters with                       Furst &
                        injections of 5 mg     fibrosarcomas                            Schlauder 
                        Ni in 0.2 ml                                                    (1971)

Nickel      Fischer     im, 3.6 mg/rat         0/10 rats with local                     Sunderman &
powder      rats                               tumours                                  Maenza (1976)
                        14.4 mg/rat            2/10 rats with local

Nickel      Fischer     Intrathoracic,         Mesothelioma,         Only 10 animals    Furst et al.
powder      344 rats    5 monthly doses of     pleural cavity in                        (1973)
                        5 mg/animal            2 out of 10 rats

Nickel      Fischer     ip, 16 injections      30-50%                                   Furst &
powder      344 rats    twice monthly, 5 mg/   intraperitoneal                          Cassetta 
                        animal                 tumours                                  (1973)

Nickel      Fischer     Intrathoracic          40% mesothelioma                         Furst &
powder      344 rats    5 monthly doses, of                                             Cassetta 
                        5 mg/animal                                                     (1973)

Table 30 (contd.)
Nickel      Animals     Routea                 Tumours               Comments           Reference        
Ni(CO)4     Sprague-    iv, 6 x 50 µl/kg       19/21 rats with                          Lau et al.
            Dawley      (9 mg Ni/kg)           malignant tumours                        (1972)
            rats                               at various sites,
                                               2/47 rats with 
                                               pulmonary lymphomas
                                               < 0.05

NiCO3       NIH black   Muscle implant,        4/35 implant site                        Payne
            rats        7 mg                   sarcomas                                 (1964)

Nickelocene Fischer     im injections,         18/50 rats or 21/50   No tumours         Furst &
            rats        12 x 12 mg or          rats with             in controls        Schlauder
                        12 x 25 mg             fibrosarcomas                            (1971)

            Hamsters    im injections,         4/29 hamsters with    No tumours at
                        1 x 25 mg or           fibrosarcomas at      8 x 5 mg
                        8 x 5 mg               1 x 25 mg

Ni(CH3CO2)2 Mice,       ip, 24 injections,     Lung adenomas and                        Stoner
            Strain A    3/week at 72, 180,     adenocarcinomas                          et al. 
                        360 mg/kg              (significant for                         (1976)
                                               360 mg/kg group)

Ni(CH3CO2)2 Mice,       ip                     Average 1.5 lung                         Poirier 
            Strain A                           adenomas per mouse                       et al. (1984)

Ni(CH3CO2)2 F344 rats   sc, 150 mg/kg          Injection site                           Teraki &
                                               sarcomas                                 Uchiumi (1988)

Table 30 (contd.)
Nickel      Animals     Routea                 Tumours               Comments           Reference        
Nickel      Wistar      ip                     46/48, 48/47 and                         Pott et al.
powder      rats                               27/42 rats with                          (1987)
NiO, Ni3S2                                     sarcomas, 
                                               mesotheliomas, or

Nickel      Wistar      ip                     High incidence of                        Pott et al.
powder      rats                               sarcomas and                             (1987)
NiO, Ni3S2                                     mesotheliomas in
NiCl2,                                         Ni3S2-, nickel
Ni(CH3CO2)2                                    powder-, nickel
NiSO4,                                         alloy-, and NiO-
NiCO3 nickel                                   groups
a  ia = intra-articular
   if = intra-retroperitoneal fat
   im = intramuscular
   ip = intraperitoneal
   iv = intravenous
   sc = subcutaneous.
    Nickel subsulfide is the nickel compound that has been most 
studied.  All routes of administration, except submaxillary gland 
injection into Fischer rats and local application to the cheek 
pouches of Syrian hamsters (Sunderman et al., 1978d), produced 
tumours.  Sunderman (1983b) and Gilman & Yamashiro (1985) reviewed 
experimental data on factors influencing the carcinogenetic 
activity of nickel subsulfide and other nickel compounds, including 
species and strain, susceptibility of organs, route of 
administration, physical form of nickel compound, and dose-response 
characteristics.  Dose-effect relationships could be demonstrated 
for nickel subsulfide in rats following intramuscular and 
intrarenal injections and in hamsters following intramuscular and 
intratesticular injections.  Intraocular and intramuscular routes 
of administration yielded the highest tumour incidence.  Local 
tumours after intraocular injection included malignant melanomas, 
retinoblastomas, gliomas, a phakocarcinoma, and unclassified 
tumours.  Following intramuscular injection, local tumours were 
mostly rhabdomyosarcomas, fibrosarcomas, and undifferentiated 
sarcomas.  Rats are more susceptible to the induction of sarcomas 
by nickel subsulfide than mice, hamsters, or rabbits, though 
Sunderman (1983b) considered that absolute species susceptibility 
could not be defined, because of differences in experimental 
conditions.  For strain differences in rats, Gilman & Yamashiro 
(1985) ranked susceptibility to tumour induction by nickel 
subsulfide as: Hooded > Wistar > Fischer > Sprague-Dawley.  
Yarita & Nettesheim (1978) implanted nickel subsulfide pellets into 
heterotopic tracheas grafted in Fischer 344 rats and reported 
tracheal tumours including sarcomas (2 fibrosarcomas, 1 
leiomyosarcoma) and carcinomas (5 squamous cell carcinoma, 1 
undifferentiated carcinoma).  Malignant testicular neoplasms 
developed in Fischer 344 rats after intratesticular injection of 
10 mg nickel subsulfide (Damjanov et al., 1978).  Gilman & Herchen 
(1963) found corresponding numbers of rhabdomyosarcomas in rats 
after intramuscular implantation of Ni2S3 in implants of different 
forms, injection of powder, or exposure in a diffusion chamber.  
Shibata et al. (1989) injected nickel subsulfide (single injection, 
0.5 mg) subcutaneously (sc), intramuscularly (im), in 
retroperitoneal fat, and intra-articularly (ia), in male Fischer 
rats, and observed the animals for 48 weeks.  Malignant soft-tissue 
tumours developed in 18/19 (sc) 19/28 (im) 9/20 (retroperitoneally), 
and 16/19 (ia) animals.  No synovial sarcomas were detected. 
Magnesium carbonate was observed to decrease sarcoma incidence due 
to Ni3S2 from 100 to 55% in a dose-related manner, when both 
compounds were injected into the thigh muscles of male Fischer 344 
rats (Kasprzak et al., 1987).  Kasprzak et al. (1988) found that, 
40 weeks after injection, zinc, either as zinc oxide or zinc 
acetate, delayed the onset, but not the final incidence of local 
sarcomas when injected intramuscularly with Ni3S2.  All of the rats 
given Ni3S2 developed tumours compared with only 60% of those that 
received Ni3S2 plus zinc.  Kasprzak & Rodriguez (1988) found that 
iron counteracted the ability of nickel subsulfide to induce cancer 
and that it inhibited catalase and glutathione peroxidase, leading 
to a build up of hydrogen peroxide (H2O2), which may be related to 

    Iron can decompose H2O2 so reversing the action of nickel 
subsulfide.  Mitsumasa (1987) administered Ni3S2 to lentectomized 
Japanese common newts  (Cynops pyrrhogaster).  A single injection of 
40-100 µg/newt produced malignant melanoma-like tumours in the 
injected eyes of 7 or 8 newts. 

    Nickel oxide produced local tumours (mainly rhabdomyosarcomas, 
fibrosarcomas, and undifferentiated sarcomas) following intramuscular 
injections in rats and mice (Gilman, 1962; Sunderman, 1984) and a 
few tumours (not specified) following implantation in rats (Payne, 
1964).  It was also carcinogenic when administered by intrapleural 
injection in Wistar rats (Skaug et al., 1985).  Eilertsen et al. 
(1988) tested the carcinogenicity in the rat of a variety of nickel 
oxides given by the intrapleural route but obtained negative 

    When Gilman & Ruckerbauer (1962) injected nickel refinery flue 
dust (20% nickel sulfate, 57% nickel subsulfide, 6.3% nickel oxide) 
into the thigh muscles of rats and mice, they found a high 
induction rate of sarcomas.  Saknyn & Blokhin (1978) injected 
"feinstein" dust (an intermediate product of nickel refining 
containing nickel sulfide, nickel oxide, and metallic nickel) 
intraperitoneally at a dose of 90-150 mg/rat and found sarcomas at 
the injection sites in 6 out of 39 rats. 

    Intramuscular injection of nickel powder produced sarcomas in 
rats at the injection sites (Heath & Daniel, 1964; Furst & 
Schlauder, 1971; Sunderman & Maenza, 1976; Sunderman, 1984).  In 
hamsters, intramuscular injection of nickel powder produced 
sarcomas at the site of injection, but the incidence was low (2 out 
of 50 animals) (Furst & Schlauder, 1971).  Intravenous injection of 
nickel powder produced local sarcomas in rats, but not in mice and 
rabbits (Hueper, 1955).  No controls were used.  Hueper (1952, 
1955) injected nickel powder into the femurs of rats and rabbits 
and observed sarcomas at the site of injection.  Intrathoracic 
injections of nickel powder produced mesotheliomas in Fischer 344 
rats (Furst et al., 1973; Furst & Cassetta, 1973).  Following 
intraperitoneal injection of nickel powder, tumours were seen in 
Fischer 344 rats (Furst & Cassetta, 1973). 

    Besides its carcinogenic potential in inhalation studies, 
administration of nickel carbonyl to rats by repeated intravenous 
injection was also associated with an increased tumour rate (Lau et 
al., 1972).  Malignant tumours included pulmonary lymphomas, 
undifferentiated sarcomas in the lung, pleura, liver, pancreas, 
uterus, and abdominal wall, fibrosarcomas in the neck, pinna, and 
orbit, carcinomas of liver, breast, and kidney, and one 

    Local sarcomas were induced in rats with repeated intramuscular 
injections of crystalline nickel hydroxide, but not with colloidal 
nickel hydroxideor nickel sulfate, under similar experimental 
conditions (Kasprzak et al., 1983). 

    Implantation of 7 mg nickel carbonate hydroxide/rat produced 
local sarcomas in 4 out of 35 rats (Payne, 1964). 

    Nickelocene, an organic nickel compound used as a laboratory 
reagent, induced fibrosarcomas in rats and hamsters, when injected 
intramuscularly (Furst & Schlauder, 1971). 

    It was reported by Stoner et al. (1976) that 24 intraperitoneal 
injections of nickel acetate to strain A mice (total dose 72-360 
mg/kg body weight) induced lung tumours at the highest dose.  
Poirier et al. (1984) observed an increased incidence of lung 
adenomas in Strain A mice following intraperitoneal administration 
of nickel acetate, though these authors also observed an increase 
in tumour incidence in animals treated with calcium acetate or lead 
acetate.  Teraki & Uchiumi (1988) reported that nickel acetate 
causes injection site tumours in rats. 

    Single intraperitoneal doses of nickel powder, nickel 
subsulfide, or an unspecified nickel oxide induced a high frequency 
(46 out of 48 animals, 27 out of 42 animals, and 46 out of 47 
animals, respectively) of abdominal cavity tumours in Wistar rats 
(Pott et al., 1987).  Pott et al. (1988) investigated nickel 
carcinogenicity by intraperitoneal injection in rats and produced 
a variety of responses (see Table 30).  They concluded that the 
model is good for screening nickel compounds and alloys for 

    In a study by Sunderman (1984), 18 nickel compounds were 
investigated under standardized experimental conditions to relate 
their physical, chemical, and biological properties to their 
carcinogenic activity.  Marked differences were observed in the 
incidence of sarcomas in male Fischer rats within 2 years following 
single intramuscular injections of equivalent doses (14 mg 
nickel/rat).  The results of these bioassays are summarized in 
Table 31.  They provide an adequate basis for ranking the relative 
carcinogenicity of different nickel compounds in animals.  Sarcoma 
incidences in these bioassays were significantly correlated with 
the mass-fractions of nickel in the respective compounds.  They 
were not significantly related to the dissolution half-times of the 
nickel compounds in rat serum or renal cytosol (Kuehn & Sunderman, 
1982), or to the susceptibilities of the compounds to phagocytosis 
by rat peritoneal macrophages  in vitro (Kuehn et al., 1982).  On 
the other hand, there was a strong correlation between the sarcoma 
incidences and the capacity of nickel compounds to induce 
erythrocytosis after intrarenal administration to rats, suggesting 
that nickel-stimulated production of erythropoietin and nickel 
carcinogenesis may be related in some way (Sunderman & Hopfer, 

Table 31.  Summary of survival data and sarcoma incidences in carcinogenesis tests of 18 nickel compoundsa
Category   Test substance                  Survivors at         Rats with local    Median    Median    Rats with metastases/
                                           2 years/total        sarcomas/total     tumour    survival  rats with sarcomas
                                           number of rats       number of rats     latency   period    (% survival)
                                           (% survival)         (% survival)       (weeks)   (weeks)
Controls   Glycerol vehicle                25/40 (63%)          0/40 (0%)          -         >100      -
           Penicillin vehicle              24/44 (55%)          0/44 (0%)          -         >100      -
           All controls                    49/84 (58%)          0/84 (0%)          -         >100      -

Class A    Nickel subsulfide (alphaNi3S2)  0/9d (0%)            9/9d (100%)        30        39c       5/9 (56%)
           Nickel monosulfide (BNiS)       0/14d (0%)           14/14d (100%)      40        48c       10/14 (71%)
           Nickel ferrosulfide (Ni4FeS4)   0/15d (0%)           15/15d (100%)      16        32c       10/15 (67%)

Class B    Nickel oxide (NiO)              0/15d (0%)           14/15d (93%)       49        58c       4/14 (29%)
           Nickel subselenide (Ni3Se2)     0/23d (0%)           21/23d (91%)       28        38c       18/21 (86%)
           Nickel sulfarsenide (NiAsS)     0/16d (0%)           14/16d (88%)       40        57c       10/14 (71%)
           Nickel disulfide (NiS2)         0/14d (0%)           12/14d (86%)       36        47c       6/12 (50%)
           Nickel subarsenide (Ni5As2)     0/20d (0%)           17/20d (85%)       22        44c       9/17 (53%)

Class C    Nickel dust                     4/20c (20%)          13/20d (65%)       34        42c       6/13 (40%)
           Nickel antimonide (NiSb)        9/29c (31%)          17/29 (59%)        20        66c       10/17 (59%)
           Nickel telluride (NiTe)         12/26 (46%)          14/26d (54%)       17        80c       8/14 (57%)
           Nickel monoselenide (NiSe)      7/16 (44%)           8/16d (50%)        56        72c       3/8 (38%)
           Nickel subarsenide (Ni11As8)    5/16b (31%)          8/16d (50%)        33        88c       6/8 (75%)

Class D    Amorphous nickel monosulfide    5/25c (20%)          3/25c (12%)        41        71c       3/3 (100%)
           Nickel chromate (NiCrO4)        10/16 (63%)          1/16 (6%)          72        >100      1/1 (100%)

Class E    Nickel monoarsenide (NiAs)      13/20 (65%)          0/20 (0%)          -         >100      -
           Nickel titanate (NiTiO3)        11/20 (55%)          0/20 (0%)          -         >100      -
           Feronickel alloy (NiFe1,6)      11/16 (75%)          0/20 (0%)          -         >100      -
a  From Sunderman (1984d).
b   P < 0.05 versus corresponding vehicle controls.
c   P < 0.01 versus corresponding vehicle controls.
d   P < 0.001 versus corresponding vehicle controls.
    Six nickel oxides and 4 nickel-copper oxides were categorized 
according to the criteria shown in Table 32 (Sunderman et al., 
1987a).  These compounds were assayed as follows: (a)  in vitro 
dissolution in water and body fluids; (b)  in vitro phagocytosis 
tests in Chinese hamster ovary and C3H-10T1/2 cells; (c) 
morphological transformation and cytotoxicity tests in cultured 
Syrian hamster embryos (SHE) cells; (d) erythropoiesis stimulation 
assay by intrarenal administration to Fischer 344 rats; and (e) 
scoring the renal histopathological responses in rats killed 3 
months after injection.  The extent of agreement among the 
physical, chemical, and biological attributes of the test compounds 
was tested by Kendalls' non-parametric test for concordance of 
rankings.  On the basis of a highly significant concordance of 
ranked results in the assays ( P <0.001), 6 biological attributes of 
the compounds were identified: (i) dissolution half-times in rat 
serum and renal cytosol; (ii) phagocytosis by C3H-10T1/2 cells; 
(iii) morphological transformation of SHE cells; (iv) 
erythropoiesis stimulation in rats; (v) induction of tubular 
hyperplasia in rat kidneys; and (vi) induction of arteriosclerosis 
in rat kidneys.  A strong rank correlation between results of the 
cell transformation and erythropoiesis stimulation was observed.  
The presence of high surface area and demonstrable Ni(III) were 
the two physicochemical characteristics associated with the 
greatest biological effects of the nickel oxides. 

    Compounds A, B, and F (nickel oxides) and compounds H and I 
(nickel-copper oxides) were selected for carcinogenesis testing in 
male Fischer 344 rats (20 mg, intramuscular injection, right thigh) 
(Sunderman et al., 1988a). Injection site sarcomas (524 months) 
developed in 6 out of 15 rats that received compound A (INCO black 
NiO), versus 0 out of 15 rats that received compound B (NiO 
calcined at 735 °C), and 0 out of 15 rats that received compound F 
(NiO calcined at 1045 °C). Sarcomas developed in 13 out of 15 rats 
that received compound H (NiO/CuO, 2.5/1 ratio) and 15 out of 15 
rats that received compound I (NiO/CuO, 5.2/1 ratio).  Injection 
site sarcomas developed in 0 out of 15 vehicle control rats and 15 
out of 15 positive controls that received intramuscular injection 
of Ni3S2. 

8.4.4.  Interactions with known carcinogens

    Several studies have been performed to investigate the possible 
interactions of different nickel species with known carcinogens, 
either in classical two-stage carcinogenesis studies, or using 
simultaneous administration. 

    In a two-stage carcinogenesis assay, orally administered nickel 
chloride enhanced the renal carcinogenicity of  N-ethyl- N-hydroxyethyl 
nitrosamine in rats, but not the hepatocarcinogenicity of  N-
nitrosodiethylamine, the gastric carcinogenicity of  N-methyl-
 N-nitro- N-nitrosoguanidine, the pancreatic carcinogenicity of  N-
nitrosobis(2-oxopropyl)amine, or the skin carcinogenicity of 7,12-
dimethylbenzanthracene (Hayashi et al., 1985). 

Table 32.  Physical and chemical characteristics of some test compounds: 6 Ni oxides and 4 Ni-Cu oxidesa
Test              Calcin- Surface   Elemental composition (% by weight)              Constitutents and         Relative
compound          ation   area                                                       speciation (% by weight)  height of
and colour        temp.   (m2/g)                                                                               XRD peaks
                  (°C)              Ni    Cu     Ob    S      Fe     Co     Ni(III)  SO4    Ni3S2  CuO  NiOc   for Ni 
A (jet black)     <650    41.5      77.7  <.001  22.3  <0.02  <0.01  <0.01  0.81     <0.06  NDe    ND   SSf    0.31
B (grey-black)    735     3.0       78.1  <.001  21.9  <0.02  <0.01  <0.01  0.05     <0.06  ND     ND   SS     0.74
C (grey)          800     1.4       78.2  <.001  21.8  <0.02  <0.01  <0.01  0.03     <0.06  ND     ND   SS     0.87
D (grey)          850     0.7       78.2  <.001  21.8  <0.02  <0.01  <0.01  <0.03    <0.06  ND     ND   SS     0.88
E (dark green)    918     0.2       78.4  <.001  21.6  <0.02  <0.01  <0.01  <0.03    <0.06  ND     ND   SS     0.90
F (green)         1045    <0.2      78.6  <.001  21.4  <0.02  <0.01  <0.01  <0.03    <0.06  ND     ND   SS     1.00
G (dark maroon)   850     <0.2      43.8  27.9   23.4  0.69   2.98   1.17   g        1.86   0.3    14   77
H (maroon)        850     <0.2      51.7  20.6   23.6  1.02   2.02   1.09   g        2.67   0.5    3    89
I (red-brown)     850     <0.2      62.6  12.6   22.3  0.30   1.20   1.04   g        0.06   1.0    ND   95
J (brown)         850     <0.2      68.8  6.9    22.1  0.42   0.75   0.97   g        0.06   1.5    ND   96
a  From: Sunderman et al. (1987a)
b  Estimated by subtracting the percentages for other elemental constituents from 100%.
c  NiO (bunsenite) can accommodate up to 25% CuO (tenorite) as a solid solution within its crystal lattice at 850C.
d  Heights of XRD peaks of NiO (bunsenite) at 1.48, 2.09, and 2.41 angstrom, relative to peak heights obtained with 
   compound F.
e  ND = not detected by XRD.
f  SS = sole species detected by XRD.
g  Presence of sulfur in compounds G-J precluded assays for Ni(III).
    Single intratracheal injections of nickel subsulfide did not 
increase the carcinogenicity of benzo (a)pyrene, also instilled 
intratracheally, in rats (Kasprzak et al., 1973). 

    Metallic nickel powder seemed to enhance the lung 
carcinogenicity of 20-methylcholanthrene (MC) when both were 
administered intratracheally to rats.  The tumour incidences in 
different groups, 12 weeks after the instillation were: (i) 5 mg 
MC: 2/7; (ii) 5 mg MC + 10 mg Ni: 3/5; (iii) 1 mg MC: 1/8; (iv) 1 
mg MC + 10 mg Ni 2/7; and (v) 10 mg Ni only: 0/7 (Mukubo, 1978).  
Nickel oxide, administered intratracheally, did not enhance the 
carcinogenic response to diethylnitrosamine in the lungs or nasal 
cavity of hamsters (Farrell & Davis, 1974). 

    In studies on combined intramuscular injection of nickel 
subsulfide and benzo (a)pyrene, latency times to local tumour 
development were shorter, and the proportion of malignant tumours 
higher, than when either carcinogen was injected alone (Maenza et 
al., 1971). 

    In a two-stage carcinogenicity study, Ou et al. (1981) gave a 
single injection of dinitrosopiperazine (9 mg) to rats, followed by 
administration of nickel sulfate, either in the drinking-water (3.7 
mg/day), or topically in the nasopharynx as a gelatin solution 
(0.02 ml of 0.5% NiSO4).  Two out of 12 rats in both groups 
receiving both nickel and the nitrosamine developed nasopharyngeal 
tumours (1 squamous cell carcinoma, 1 fibrosarcoma, 1 papilloma, 1 
"early carcinoma"), while none was seen in the 24 animals treated 
with the nitrosamine alone, or in the two groups of 12 animals 
treated with nickel sulfate.  The same authors (abstract only) 
reported an extension of the study, using topical nickel sulfate as 
a promoter.  Five out of 22 rats given the combined treatment 
developed carcinomas of the nasopharynx, nasal cavity, or hard 
palate, while these tumours were not found in the other groups (Liu 
et al., 1983). 

    Ou et al. (1983) reported a study in which  N-nitrosopiperazine 
was given to female rats on the 18th day of pregnancy, and the pups 
were given nickel sulfate orally.  Five out of 21 pups with 
combined treatment, and 1 out of 4 with nitrosamine treatment only 
developed nasopharyngeal carcinoma, and two other pups developed 
other tumours. 

8.4.5.  Possible mechanisms of nickel carcinogenesis

    Both  in vivo and  in vitro studies have shown varying 
carcinogenic responses, depending on the bioavailability of certain 
nickel compounds.  Several factors influencing bioavailability have 
been suggested, such as the physical form of the compound 
(crystalline or amorphous), solubility in water or serum, and its 
ability to be phagocytosed by target cells (Costa et al., 1982) or 
pass through calcium channels (Sunderman, 1989a).   In vitro studies 
have shown that various nickel compounds had similar transforming 
potencies at equitoxic concentrations (Hansen & Stern, 1984). 

    The transformation potency of a number of particulate nickel 
compounds has been correlated with phagocytosis (Costa et al., 
1981b).  The incidence of sarcomas and the capacity of nickel 
compounds to produce erythrocytosis are also related (Sunderman & 
Hopfer, 1983; Sunderman et al., 1987a).  Erythrocytosis can be 
induced in rats by intrarenal injection of nickel subsulfide, 
probably due to increased production of the stimulating hormone 
erythropoietin (Jasmin & Ripolle, 1976; Morse et al., 1977; Hopfer 
et al., 1978).  Intrarenal injection of nickel subsulfide caused 
renal cancers (Sunderman et al., 1984b).  Induction of 
erythrocytosis and carcinogenesis in rats by nickel subsulfide were 
both inhibited by the administration of manganese dust (Sunderman 
et al., 1976b).   In vitro studies have demonstrated that nickel 
compounds cause (a) DNA damage in a wide variety of organisms, (b) 
mutagenicity, possibly related to cytotoxicity, in mammalian cells, 
and (c) clastogenicity and morphological transformation in 
mammalian cells including human cells.  From  in vitro and  in vivo 
studies, it is known that nickel interacts with DNA and proteins, 
causing lesions, such as DNA-protein (possibly heterochromatin) 
cross-links and DNA single strand breaks (Ciccarelli et al., 1981; 
Ciccarelli & Wetterhahn, 1982; Robison et al., 1982; Patierno et 
al., 1985), resulting in DNA damage and other cytotoxic effects 
that can lead to altered gene expression in surviving cells.  For 
example, Sen & Costa (1986) showed that nickel preferentially 
induced decondensation (presumably by DNA-protein cross-linking) 
and fragmentation of the long arm of the X-chromosome in CHO cells.  
Other consequences of cross-linking, such as the appearance of 
irreversible, but heritable, lesions of intermediate filaments (a 
family of cytoskeletal proteins linking the nucleus with the cell 
membrane), related to disturbance of normal growth control 
processes, have been observed early after nickel intoxication  in 
 vitro (Swierenga & McLean, 1985; Swierenga et al., 1987, 1989). 
Nickel-induced DNA damage/alterations that have been reported 
include: conformational transitions of the DNA from the normal 
right-handed B-helix to the left-handed Z helix (van de Sande et 
al., 1982; Boutayre et al., 1984), infidelity of DNA synthesis, as 
shown with cell-free systems using synthetic templates (Sirover & 
Loeb, 1977; Zakour et al, 1981), and inhibition of DNA synthesis in 
a wide variety of organisms extending to inhibition of DNA excision 
repair (Table 27).  The latter may be an important mechanism in the 
ability of nickel to enhance the carcinogenic activity of other 
compounds (Maenza et al., 1971; Kurokawa et al., 1985).  Other  in 
 vitro evidence indicates that nickel disrupts intercellular 
communication, a property of tumour promoters (Miki et al., 1987). 

    Studies by Nieboer et al. (1986) indicated that, in the 
presence of certain peptides, the Ni3+/Ni2+ redox couple can 
participate in dioxygen radical reactions  in vitro.  As chemical 
promoters of cancer appear to have the capacity to stimulate 
phagocytic cells to produce dioxygen radicals, which may damage 
DNA, proteins and lipids, and as metal ions catalyze processes 
involving molecular oxygen, this observed effect of nickel may have 
implications for nickel carcinogenesis. 

    Sunderman & Barber (1988) have suggested a mechanism for the 
interaction of nickel with DNA.  This model proposes that the Zn2+ 
binding sites of DNA binding proteins known as "finger loop 
domains", which have been identified on some proto-oncogens, are 
likely molecular targets for metal toxicity.  As Ni2+ has a similar 
ionic radius to Zn2+, substitution is possible, interfering with 
regulation of gene expression.  The replacement of Zn2+ in finger 
loops might affect the conformation and stability of DNA-binding 
structures interfering with expression and induce site-specific 
free radical reactions, causing cleavage of DNA, formation of DNA-
protein cross links, and disturbances of mitosis. 

8.4.6.  Factors influencing nickel carcinogenesis

    Maenza et al. (1971) reported a synergistic action between 
nickel subsulfide and benzo (a)pyrene.  After intramuscular 
injection, the latency period for sarcoma induction was 
significantly reduced.  Kasprzak et al. (1973) found an increased 
incidence of premalignant changes in the lungs of rats receiving 
intratracheal injections with a mixture of benzo (a)pyrene and 
nickel subsulfide compared with groups receiving one compound at a 

    Manganese in metallic form has been shown to antagonize the 
tumourigenic effect of nickel subsulfide by intramuscular injection 
(Sunderman et al., 1976b) and intrarenal injection (Sunderman et 
al., 1979b).  Kasprzak & Poirier (1985) found that simultaneous 
intramuscular injection of magnesium carbonate inhibited the 
development of muscle tumours induced by nickel subsulfide.  
Calcium carbonate, under the same experimental conditions, was 
ineffective.  Poirier et al. (1984) reported that both magnesium 
acetate and calcium acetate inhibited lung adenoma formation in 
Strain A mice treated with intraperitoneal nickel acetate.  
Manganese, magnesium, calcium, copper, and zinc were shown by 
Kasprzak & Poirier (1985) and Kasprzak et al. (1986) to inhibit 
binding of nickel to DNA.  They also found that amino acids were 
very effective inhibitors of nickel binding to DNA, but their 
eventual role in moderating nickel carcinogenicity has not been 

    When rats with muscular implantations of nickel subsulfide were 
injected intraperitoneally with sodium diethyldithiocarbamate, 
tumour incidence was significantly reduced compared with that in 
rats that had received the nickel subsulfide implant alone 
(Sunderman et al., 1984b). 


9.1.  Systemic effects

9.1.1.  Acute toxicity - poisoning incidents Nickel carbonyl 

    In terms of human health, the most acutely toxic nickel 
compound is nickel carbonyl.  The clinical manifestations of nickel 
carbonyl poisoning have been described in detail by Sunderman 
(1970) and Vuopala et al. (1970).  A summary of 179 cases of nickel 
carbonyl poisoning in China since 1961 has been published by Shi 

    The acute toxic effects occur in 2 stages, immediate and 
delayed.  The immediate symptomatology includes frontal headache, 
vertigo, nausea, vomiting, insomnia, and irritability, followed by 
an asymptomatic interval before the onset of delayed pulmonary 
symptoms.  These include constrictive chest pains, dry coughing, 
dyspnoea, cyanosis, tachycardia, occasional gastrointestinal 
symptoms, sweating, visual disturbances, and weakness.  The 
symptomatology resembles that of a viral pneumonia.  In men who 
died, pulmonary haemorrhage and oedema or pneumonitis were observed 
accompanied by derangement of alveolar cells, degeneration of the 
bronchial epithelium, and the appearance of a fibrinous intra-
alveolar exudate.  The pathology of the pulmonary lesions was 
similar to that observed in animal studies.  Other affected organs 
included the liver, kidneys, adrenal glands, and spleen, where 
parenchymal degeneration was observed.  Cerebral oedema and 
punctate cerebral haemorrhages were noted in men dying after 
inhalation of nickel carbonyl.  Shi (1986) reported leukocytosis in 
25 out of 179 cases.  Urinary nickel concentrations were determined 
in 27 cases and ranged from 0.003 to 0.66 mg/litre.  Air 
concentrations were measured and were reported to have exceeded 50 
mg nickel carbonyl /m3 with exposure periods ranging from 30 min to 
more than 2 h.  Recovery time was 7-40 days, depending on the 
severity of exposure.  In some cases, symptoms persisted for 3-6 
months.  In lethal cases, death occurred between the third and 
thirteenth days following exposure. Other nickel compounds 

    Information on poisoning with other nickel compounds is 
limited.  Daldrup et al. (1983) reported a case of fatal nickel 
poisoning.  A 2 1/2-year-old girl ingested about 15 g of nickel 
sulfate crystals.  On admission to hospital, she was somnolent with 
wide and unresponsive pupils, a high pulse rate, and pulmonary 
rhonchi.  Cardiac arrest occurred after 4 h.  Autopsy findings 
revealed increased nickel levels (7.5 mg/kg in blood, 50 mg/litre 
in urine, 25 mg/kg in liver tissue).  Nickel poisoning was reported 
in a group of 23 dialysed patients, when leaching from a nickel-
plated stainless steel water heater tank contaminated the 
dialysate.  Symptoms occurred during, and after, dialysis, at 
plasma-nickel concentrations of approximately 3 mg/litre.  Symptoms 

included nausea (37 out of 37), vomiting (31 out of 37), weakness 
(29 out of 37), headache (22 out of 37), and palpitation (2 out of 
37).  Recovery occurred spontaneously, generally 3-13 h after 
cessation of dialysis (Webster et al., 1980). 

    Thirty-two workers in an electroplating plant accidentally 
drank water contaminated with nickel sulfate and nickel chloride 
(1.63 g nickel/litre).  Twenty workers rapidly developed symptoms 
(e.g., nausea, vomiting, abdominal discomfort, diarrhoea, 
giddiness, lassitude, headache, cough, shortness of breath) that 
typically lasted a few hours, but persisted for 1-2 days in 7 
cases.  The nickel doses in workers with symptoms were estimated to 
range from 0.5 to 2.5 g.  In 15 exposed workers, who were 
investigated on day 1 after exposure, serum-nickel concentrations 
ranged from 12.8 to 1340 µg/litre (average 286 µg/litre) with 
urinary nickel concentrations ranging from 0.23 to 37.1 mg/litre 
(average 5.8 mg/litre) compared with control values for nickel-
plating workers of 2.0-6.5 µg/litre (average 4.0 µg/litre) for 
serum nickel and 22-70 µg/litre (average 50 µg/litre) for urinary 
nickel.  Laboratory tests showed transiently elevated levels of 
blood reticulocytes (7 workers), urine-albumin (3 workers), and 
serum-bilirubin (2 workers) (Sunderman et al., 1988b). 

9.1.2.  Short- and long-term exposure Respiratory effects 

    A chemical engineer, who had been exposed for a long period to 
low levels of nickel carbonyl, developed asthma and Löffler's 
syndrome.  In addition to pulmonary infiltrations and eosinophilia, 
which are markers in Löffler's syndrome, the patient had an 
eczematous dermatitis of the hands (Sunderman & Sunderman, 1961b). 

    There have been systematic investigations of the health state 
of the respiratory tract of workers in the nickel industry.  
Tatarskaya (1960) examined 486 workers from nickel-refining plants, 
exposed mainly to nickel sulfate during electrorefining operations.  
Exposure levels were not given.  Rhinitis was observed in 10-16%, 
chronic rhinitis in 5.3%, nasal septal erosions in 13%, 
perforations in 6.1%, and ulceration in 1.4% of the workers.  The 
frequencies of hypo-osmia and anosmia were 30.6 and 32.9%, 
respectively.  Kucharin (1970) studied 302 workers who had been 
exposed to nickel sulfate, accompanied by sulfuric acid vapour, for 
at least 10 years, at concentrations of 0.02-4.5 mg/m3.  Clinical 
and radiological examination revealed chronic sinusitis in 83% of 
the workers.  Among these workers, severe injuries were apparent, 
such as septal erosion and perforation in 41.4 and 5.6%, respectively. 

    Hypo- or anosmia was noted in 46% of the workers with chronic 
sinusitis.  In a nickel refinery where hydrometallurgical methods 
were used, 37 out of 151 workers (24.5%) exhibited pathological 
changes of the nasopharynx.  Septal erosions were noted in 14 
workers (9.3%).  Exposure concentrations of soluble nickel salts, 
during the years 1966 and 1970, ranged from 0.035 to 1.65 mg/m3 
(Sushenko & Rafikova, 1972). 

    Other studies on the nasopharyngeal effects of inhalation of 
nickel salt aerosols, conducted in order to detect precancerous 
lesions, are described in the section 9.5. 

    Data are available on the development of pulmonary changes with 
fibrosis in workers inhaling nickel dust or fumes.  Zislin et al. 
(1969) studied respiratory function in 13 workers, who had been 
exposed to nickel dust for periods of 12.9-21.7 years.  Exposure 
levels were not given.  There was decreased pulmonary residual 
capacity, increased respiratory frequency, and radiography showed a 
diffuse fibrosis, considered to be nickel pneumoconiosis. 

    Industrial dusts, collected in the workrooms of nickel 
refineries, induced the development of pneumoconiosis of an 
interstitial type, together with bronchitis, in experimental 
animals (Saknyn et al., 1978; Grebnev & Yelnichnykh, 1983).  The 
fibrogenicity of these dusts did not depend on their silica 
content, and the dust that was almost pure nickel suboxide (Ni2O3) 
was fibrogenic, when instilled intratracheally.  Pneumoconiosis of 
an interstitial and micronodular type had been detected in a number 
of workers in the same industry (Zislin et al., 1969). 

    Peto et al. (1984) reported mortality experience in Welsh 
nickel refinery workers.  Men first employed before 1925, who had 
worked for 5 or more years in the process areas where lung and 
nasal cancer risks were highest, also suffered a significantly 
elevated mortality from non-malignant respiratory disease (20 
deaths, 11.1 expected); less heavily exposed workers suffered no 
such excess (43 deaths, 51.2 expected). 

    Jones & Warner (1972) studied respiratory symptoms, chest X-
rays, and lung ventilation capacities in 12 steelworkers, who had 
been employed as de-seamers of steel ingots for periods of up to 16 
years.  Total fume concentration at the workplace ranged from 1.3 
to 294.1 mg/m3, either from iron oxide, chromium oxide, and nickel 
oxide in proportions of 6:1:1 (stainless steel fume) or 98.8% iron 
oxide (special steel fume).  Airborne nickel oxide concentrations 
of 0.15-34 mg/m3 were calculated from these values.  Two of the 
workers had measurable loss of pulmonary function.  In 5 men, 
definite signs of pneumoconiosis were detected radiographically. 

    Effects on the respiratory system have also been observed in 
welders.  Between 1955 and 1979, Zober (1981a,b) found a total of 
47 cases of histologically verified fibrotic changes in the lungs 
of electric arc welders.  Though the findings were very 
heterogeneous, indicating a diversity of causes, welding fumes were 
found to be a concomitant cause of fibrotic changes in 20 cases.  
Zober (1982) studied 40 welders (22, non-smoking and 18, smoking), 
who were using metal inert gas and electric arc welding techniques 
on chromium- and nickel-containing materials.  Concentrations of 
airborne nickel did not exceed 0.5 mg/m3, except in one working 
process, where there was a concentration of 1.2 mg nickel/m3.  
Respiratory-tract effects, including acute bronchitis and 
bronchitic pulmonary rhonchi, were increased, mainly in welders who 
smoked tobacco. 

    Asthmatic lung disease in nickel-plating workers exposed to 
soluble nickel has been reported (Tolot et al., 1956; McConnell et 
al., 1973; Block & Yeung, 1982; Malo et al., 1982; Dolovich et al., 
1984).  Cirla et al. (1985) examined 12 workers with respiratory 
problems in a nickel-plating industry.  In 6 workers, allergic 
asthma could be provoked by the inhalation of nickel sulfate 
aerosols.  Novey et al. (1983) reported that a metal-plating 
(chromium and nickel) worker developed acute asthma in response to 
inhalational challenge with nickel sulfate and chromium sulfate.  
Radioimmuno-assays incorporating the challenge materials revealed 
specific IgE antibodies to the provocative agents. 

    Five stainless steel welders, suffering from respiratory 
distress, developed asthmatic symptoms during provocation tests 
with stainless steel fumes (Keskinen et al., 1980). 

    Inhalation testing using 0.01-0.001% nickel chloride solution 
has been carried out to detect hypersensitivity to nickel and its 
compounds in patients occupationally exposed to nickel and 
suffering from atopic bronchial asthma.  In inhalation testing, it 
is necessary to take pneumotachometric readings before, and after, 
the test, at various times over a period of 24 h (Izmerov, 1983). Renal effects 

    Sanford et al. (1988) assessed different parameters for kidney 
dysfunction in urine samples from electrolytic nickel refinery 
workers (renal clearance, protein, specific gravity, and 
qualitative "dipstick" tests).  In male workers who accidentally 
ingested drinking-water contaminated with nickel sulfate and 
chloride, Sunderman et al. (1988b) found elevated urine-albumin 
concentrations (68, 40, and 27 mg/g creatinine), which returned to 
normal on the fifth day after exposure.  The findings suggested a 
mild transient nephrotoxicity (section 9.1.1). Cardiovascular effects 

    Patients with acute myocardial infarction and unstable angina 
pectoris develop high serum-nickel levels, which may be followed by 
coronary vasoconstriction (Leach et al., 1985).  The mechanism and 
source of nickel release are not yet known, but Sunderman (1983a) 
recommended that the amount of nickel in intravenous solutions 
should not exceed 5 µg/kg per day.  Peto et al. (1984) observed 
elevated cerebrovascular mortality (16 deaths, 8.5 expected) among 
nickel refinery workers who had worked for 5 years in the process 
area, where lung and nasal cancer rates were highest.  Mortality 
from all other cardiovascular causes was similar to local 
population rates. Other effects 

    In a study by Shi et al. (1986), nickel carbonyl refinery 
workers were compared with a control group.  Exposure ranged from 
0.007 to 0.52 mg Ni(CO4)/m3.  A decrease in the MAO (serum 
monoamine oxidase) activity, and EEG abnormalities were observed in 

the most severely exposed.  A number of non-specific symptoms in 
persons exposed for long periods to low concentrations 
(unspecified) were reported, but no details were given. 

    Immune reactions elicited in the sera of individuals exposed to 
nickel and cobalt were assessed according to changes in the 
concentrations of the serum immunoglobulins, IgG, IgA, and IgM, and 
the serum proteins, alpha2 macroglobulin (A2M), transferin (TRF), 
alpha1-antitrypsin (A1AT), ceruloplasmin (CPL), and lysozyme 
(LYS) (Bencko et al., 1983).  Examinations were carried out on 
workers occupationally exposed to nickel (38 individuals) or cobalt 
(35 individuals) and in groups of non-occupationally exposed 
children living in areas with different levels of air pollution 
from a nearby source of nickel and cobalt emissions. 

    Non-exposed controls were represented by a group of 42 male 
adults, matched by age, and by a group of 48 children from a non-
polluted area.  Significantly increased average values were 
obtained for IgG, IgA, and IgM, in the group of workers exposed to 
nickel, for IgA, in workers exposed to cobalt, and for A1AT, A2M, 
CPL and LYS, in both groups of occupationally-exposed adults 
( P >0.001 and  P >0.005, respectively).  Among non-occupationally 
exposed children, the most highly exposed group had significantly 
elevated average values for A2M and A1AT, which were higher than 
those recorded in the groups of "less exposed" and control children 
( P >0.02 and  P >0.05, respectively) (Bencko et al., 1983). 

9.2.  Skin and eye irritation and contact hypersensitivity

9.2.1.  Skin and eye irritancy

    Primary skin irritation reactions to nickel salts in solution 
were observed when human volunteers were patch tested.  When 
aqueous solutions of nickel chloride were applied to the back, the 
threshold concentrations for irritancy were 1% with occlusion and 
10% without occlusion (Vandenberg & Epstein, 1963). 

    A 5% aqueous solution of nickel sulfate was also irritant in 
some individuals, when applied to the back, under occlusion (Kalimo 
& Lammintausta, 1984).  On the unoccluded human forearm, the 
threshold concentrations of aqueous nickel sulfate producing 
irritation were 20% on unbroken skin and 0.13% on scarified skin, 
the nickel solutions being applied once daily for 3 days (Frosch & 
Kligman, 1976). 

9.2.2.  Contact hypersensitivity

    Nickel and its water-soluble salts are potent skin sensitizers.  
Nickel ions pass the skin barrier and bind to carrier proteins to 
form the allergen.  In the pathogenesis of allergic contact 
dermatitis (a type IV reaction), two steps can be recognized.  
First, sensitization, after which, subsequent exposure of fully 
sensitized skin, even to minute quantities of nickel or its water-
soluble salts, will elicit or provoke an eczematous response which 
begins within 12 h, is fully developed at 48-72 h, and then 

subsides.  After the elicitation phase, the sensitivity will 
remain, usually for years, and frequently for a lifetime.  
Sensitization is only known to occur after dermal exposure to 
nickel, whereas provocation can take place after exposure of the 
skin and after ingestion of nickel.  The clinical manifestations of 
nickel-associated allergic contact dermatitis comprise both primary 
and secondary eruptions.  The primary eruptions usually appear at 
the site of sensitization, and the secondary eruptions will 
frequently be more or less generalized, often symmetrical, 
maculopapular vesicules of the pompholyx type eczema, which affects 
the flexures of the elbows, the sides of the neck, the axillae, the 
eyelids, and the genital area.  A vesicular hand eczema can also 
develop. Nickel contact dermatitis has been documented in the 
general population and in nickel workers, especially in the nickel-
plating industry (NAS, 1975).  Nickel contact hypersensitivity was 
originally considered to be a problem in occupational medicine, but 
more recent epidemiological and clinical data indicate that it 
could also be a problem in the general population, because of the 
increasing number of nickel-containing commodities in everyday use.  
The prevalence of nickel sensitivity in the general population can 
be evaluated by patch-testing with 5% nickel sulfate in petrolatum 
or by an interview technique.  Peltonen (1979) and Prystowsky et 
al. (1979) studied volunteers from different subpopulations in 
Finland and the USA.  The prevalence of nickel sensitivity was 
about 10% for women and about 1% for men.  In women, Prystowsky et 
al. (1979) found a high correlation of sensitivity to nickel with 
the practice of ear piercing.  Peltonen (1979) reported that hand 
eczema is very common in patients with nickel sensitivity.  
Christensen & Möller (1975a) reported that pompholyx was the 
predominant type of hand eczema.  Nickel allergy was investigated 
in a stratified sample of the Danish female population using an 
interview technique (Menné et al., 1982).  Of those responding, 
14.5% reported a history of nickel allergy.  The prevalence rate 
was highest in the younger age groups and declined after the age of 
50 years.  Although the use of the interview technique had certain 
limitations, the data were in good agreement with data obtained 
through other test methods (e.g., patch testing). 

    Edman & Möller (1982) reported a study on a patient population 
of 8933, who had been patch-tested over a 12-year period.  Nickel 
sensitization increased during this period in both male and female 
patients, females producing a higher rate of positive reactions 
than males. 

    Oral provocation of hand eczema in nickel-allergic patients 
with vesicular hand eczema has been studied (Nielsen, in press).  
Oral provocation, using nickel sulfate in lactose capsules, was 
performed by Christensen & Möller (1975), Kaaber et al. (1978), 
Cronin et al. (1980), Jordan & King (1979), Burrows et al. (1981), 
and Gawkrodger et al. (1986).  The last three studies were double-
blind, weeks with provocation and weeks with placebo following each 
other randomly.  Evaluation of the eczema was performed in the 3 
days following exposure and it was assumed that no delayed response 
occurred.  The doses ranged from 0.5 to 5.6 mg nickel; lower doses 
were used in the double-blind studies. An exacerbation of the 

eczema was observed with doses of 2.5 mg nickel or more.  The 
response to nickel sulfate in lactose differed from nickel 
contained in the diet.  A provocation study was performed with a 
diet naturally containing about 500 µg nickel.  Two conclusions were 
drawn: (i) a diet naturally high in nickel content (chocolate cake, 
soya bean stew, and oatmeal) resulted in an exacerbation of 
vesicular hand eczema, when ingesting the diet daily for 4 days, 
(ii) exacerbation of hand eczema was observed on day 7 after 
finishing the 4-day provocation period.  This delayed reaction may 
be the reason why reactions to nickel were not reported in previous 
double-blind studies in which weeks with nickel exposure and weeks 
with placebo randomly followed each other. 

    The response to oral intake of nickel salts may not be uniform 
and hyposensitization may be possible.  In 2 controlled studies, 
doses of 5.0 mg nickel sulfate given once a week, for 6 weeks, 
significantly lowered the degree of contact allergy, as measured by 
patch test reactions before, and after, nickel administration 
(Sjövall et al., 1987).  Further adaptation to oral doses of 2.24 
mg nickel sulfate was observed after the volunteer subjects were 
given gradually increasing daily doses over a 3-month period 
(Santucci et al., 1988).  These reported responses to the oral 
intake of inorganic nickel do not necessarily contradict one 
another, but the mechanisms are not known.  However, they indicate 
that hand eczema can benefit from a diet low in nickel. 

    Allergic reaction as well as urticarial and eczematous 
dermatitis in nickel-sensitive persons can be produced by implanted 
prostheses and other surgical devices made from nickel-containing 
alloys (NAS, 1975; Fisher, 1977).  Deutman et al. (1977) found 
nickel sensitivity in 11 out of 85 patients following hip 
prosthesis implantation.  Three of the patients had had previous 
implants.  Oakley et al. (1987) described 4 patients with a history 
of metal intolerance, who developed dermatitis following surgical 
wound closure with disposable skin clips (nickel content about 
10%).  Two positive reactions were reported by Waterman & Schrik 
(1985) in 85 patch-tested patients, who had undergone hip 

    Metal alloys, used in dental surgery, contain various amounts 
of nickel.  Data on the relationship between nickel allergy and 
dental alloys are limited.  In a retrospective study, Moffa et al. 
(1983) found that the incidence of nickel allergy in patients with 
intraoral exposure to nickel alloys was not significantly higher 
than that in patients with no intraoral exposure. 

    Treatment of nickel-sensitive patients who were suffering from 
hand eczema of the pompholyx type, with the nickel-chelating agent 
diethyldithiocarbamate was successful in 10 out of 11 patients 
(Christensen & Kristensen, 1982).  However, hepatotoxicity was 
observed in some patients, and this form of treatment is no longer 

9.3.  Reproduction, embryotoxicity, and teratogenicity

    No data are available on the reproductive and developmental 
effects of nickel in human beings. 

9.4.  Genetic effects in exposed workers

    Elevated levels of chromosome aberrations, mainly gaps, were 
reported by Waksvik & Boysen (1982) in 2 groups of nickel workers, 
but SCE was not observed; one group was involved in nickel 
crushing/roasting/smelting processes and exposed mainly to nickel 
oxide and nickel sulfide, and the other was involved in 
electrolysis and exposed mainly to nickel chloride and nickel 
sulfate.  In a further study on 9 ex-nickel workers, who had been 
exposed for an average duration of 25 years, but retired for at 
least 8 years, Waksvik et al. (1984) showed the persistence of a 
low level of gaps, as well as chromatid breaks, when plasma nickel 
levels were still 2 µg/litre.  Deng et al. (1983, 1988) showed 
elevated levels of both SCEs and chromosome aberrations (gaps, 
breaks, fragments) in electroplating workers.  However, these 
effects were not observed in a study by Decheng et al. (1987) on 
workers exposed to nickel carbonyl.  Low exposure and good 
workplace conditions were cited by the latter authorities. 

9.5.  Carcinogenicity

9.5.1.  Epidemiological studies Nickel refining industry 

 (a) Clydach nickel refinery, Clydach (Wales) 

    The existence of an increased risk of nasal cancer in workers 
from the Clydach nickel refinery was recognized in 1928.  Processes 
at Clydach involved: the crushing and grinding of nickel copper 
matte, received from Canada, which consisted of the phases Ni3S2, 
CuS, and metallic nickel and copper, in a 3:4:1 ratio (Boldt & 
Queneau, 1967); the calcining of the crushed matte to produce 
nickel and copper oxides (the copper oxide is dissolved in the 
metal oxide and described as (Ni,Cu)O (Boldt & Queneau, 1967)); the 
extraction of the copper by sulfuric acid; reduction to nickel 
oxide; and refining with nickel carbonyl.  The first 
epidemiological study on Clydach plant workers was carried out by 
Hill in 1939 (quoted by Morgan, 1958).  Hill found that the 
observed to expected ratios (O/E) of deaths were 16:1 for lung 
cancer and 22:1 for nasal cancer in the period 1929-38.  Morgan 
(1958) and Doll (1958) extended the observation period from 1902 to 
1957 and identified 131 deaths from lung cancer and 61 deaths from 
nasal cancer in 9340 workers.  Excess mortality occurred only in 
workers first employed before 1924.  The highest risk of lung 
cancer appeared to have occurred in the calcination and copper 
sulfate departments.  Deaths from nasal cancer occurred most 
frequently in the calcination department. There were no nasal 
cancers among workers entering employment after 1924.  The decline 
in the numbers of deaths from nasal and lung cancer was attributed 

to improvements in work practices and refinery processes in the 
early 1920s.  These improvements included the wearing of gauze 
masks, improvements in ventilation, and the use of arsenic-free 
sulfuric acid in refining.  Follow-up studies were carried out by 
Doll et al. (1970) on a cohort of 819 workers, who had been 
employed for at least 5 years at Clydach between 1902 and 1944, and 
who were still employed in 1934. Thirty-nine cases of nasal cancer 
and 113 cases of lung cancer were identified.  The reported O/E 
ratio for lung cancer was 10.5 for workers starting between 1910 
and 1915, 1.8 for workers employed between 1925 and 1929, and 1.1 
for those employed between 1930 and 1944.  In this study, no nasal 
cancer was reported in workers starting employment after 1925.  
Doll et al. (1977) extended the follow-up period to 1971 and 
confirmed that, since 1925, the risk of respiratory cancer had 
decreased sharply; they attributed this to the improvements in work 
practices and refinery processes. 

    Cuckle et al. (1980) studied the causes of death in a small 
cohort of 297 men who were mainly exposed to soluble nickel salts 
between 1937 and 1960.  They did not find any nasal sinus cancers.  
Thirteen cases of lung cancer were found, a significant excess 
above regional rates (expected number 7.54), but not significant 
when compared with the rates for England and Wales.  The small size 
of the group limited this study. 

    Estimated concentration data for different nickel species in 
different areas of Clydach nickel refinery are shown in Table 33. 

Table 33.  Estimated concentration (mg/m3) 
before 1930, of major forms of nickel in 
high-risk areas of the Clydach nickel refinery, 
South Walesa
                  Metal   Oxide  Ni3S2   Soluble
Calcining         5.3     18.8   6.8     0.8
Furnaces          5.6     6.4    2.6     0.4
Copper plant      -       13.1   0.4     1.1
Hydrometallurgy   0.5     0.9    0.1     1.4
a  From: Peto (1988).

    Peto et al. (1984) extended the follow-up to 1981.  The cohort 
included 968 men.  One hundred and fifty-nine lung cancer deaths 
and 56 nasal cancer deaths were identified.  The duration of 
employment in 4 areas showed a statistically significant 
association with lung or nasal cancer or both.  These were the 
calcining furnace area, the calcining/crushing area, the copper 
sulfate area, and the furnace area.  Peto et al. (1984) also 
related age, time of exposure, and exposure levels, to lung and 
nasal sinus cancer incidence in pre-1925 workers.  Exposure level 
was defined on the basis of duration of work in high-risk areas.  
Both lung and nasal cancer showed increasing risk with increasing 
duration of work in high-exposure areas.  Nasal cancer showed a 

strong positive relationship with age at first exposure, whereas 
lung cancer did not.  The latency period was 20-50 years for nasal 
cancer and somewhat shorter for lung cancer.  The risk of nasal 
cancer was highest for workers with first exposure between 1910 and 
1915 and declined thereafter, whereas the risk for lung cancer was 
highest for workers between 1920 and 1925. 

 (b) Falconbridge refinery, Kristiansand (Norway) 

    Loken (1950) reported 3 cases of lung cancer in workers from 
the Falconbridge refinery.  This plant began operations in 1910, 
processing matte from Ontario via roasting, smelting, and 
electrolysis.  Although workers in the roasting/smelting 
departments were, and are, exposed to sulfides, oxides, and nickel-
copper oxides in dust and fumes, the processes have changed in 
recent years and exposure levels have been reduced dramatically.  
The electrolytic workers are exposed to aerosols containing,  inter 
 alia, nickel sulfate and nickel chloride (Hogetveit & Barton, 
1976).  These workers are, as cited by Hogetveit & Barton (1976), 
"exposed largely to soluble nickel aerosols".  That the soluble 
form predominates in the exposure of electrolysis workers is also 
supported by the results in Table 34.  This table shows that, even 
when the air values are lower in the electrolysis department than 
in roasting/smelting department, the plasma and urine values are 

Table 34.  Summary of biological tests and personal sampler measurementsa
Departments      Number of   Mean          Mean            Mean
                 employees   plasma ± SD   urine ± SD      concentration
                             (µg Ni/litre) (µg Ni/m3)      in air ± SD
                                                           (µg Ni/m3)
No. 01-19        24          72 ± 2.8      65.0 ± 57.6     0.86 ± 1.20

No. 22-44        90          11.9 ± 8.0    129.2 ± 105.6   0.23 ± 0.42

Other process    13          6.4 ± 1.9     44.6 ± 26.7     0.42 ± 0.49


Departments   Number of   Plasma vs. air   Plasma vs. air   Plasma vs. urine
              employees   Corr. factor  R   Corr. factor  R   Corr. factor  R 
No. 01-19     24          -0.55    -0.11   -0.71    +0.14   3.72     +0.76
No.22-44      90          1.98     0.21    2.99     0.31    7.30     0.77
Other         13          2.41     0.67    1.70     0.47    2.27     0.63
a  Modified from Hogetveit et al. (1978).

    The first epidemiological study was carried out on a cohort of 
1916 workers who were employed for at least 3 years before 1961 
(Pedersen et al., 1973).  Exposure was defined according to 
department or work in which there had been the longest employment.  
The authors used 4 work categories: roasting and smelting, 
electrolysis, other processes, other work groups.  All occupational 
groups were associated with an excess risk of respiratory cancer.  
Risk was greatest in the roasting and smelting department and the 
electrolysis department.  Workers in the electrolysis department 
showed the highest risk of lung cancer (O/E=26/3.6) and an excess 
risk of nasal cavity cancer (O/E=6/0.2).  The risk of nasal cancer 
was greatest (O/E=5/0.1) in the roasting and smelting department, 
but there was also an increased risk of lung cancer in this 
department (O/E=12/2.5). 

    Magnus et al. (1982) updated the study of Pedersen et al. 
(1973) and confirmed the results.  They also analysed data on 
smoking habits and found evidence for an additive effect of smoking 
and nickel exposure. 

    The cohort was further followed up by Andersen (1988).  During 
the follow-up period 1953-87, 163 new cases of respiratory cancer 
were observed against 42 expected.  There was a decreasing trend in 
ratio between observed/expected from 6.9 in 1926-35 to 2.4 among 
those first employed in 1956-65.  No risk for any other cancer was 
recorded, in fact, the observed number is lower than the expected 
number in all periods (207/248 all periods combined).  No cases of 
nasal cancer have been observed in workers employed after 1955, but 
the expected number is only 0.20. 

    Following technological improvements in the plant, Andersen 
(1988) formed a new cohort of 1237 employees with a total 
employment of one year or more, the first entry in 1968 or later, 
and exposure estimated according to nickel species and exposure 
concentration.  For entry in the period 1968-72, 7 new cases of 
lung cancer were found, versus 1 expected.  Actual measurements 
reported in 1979 (Torjussen & Andersen, 1979) were 0.1-0.5 mg/m3 
for electrolysis workers and 0.1-1.0 mg/m3 for the roasting/
smelting category.  Estimated concentrations for the period 1968-77 
were about 0.5-2.0 mg/m3 and about 2.0-5.0 mg/m3, respectively.  In 
the electrolysis department, the exposure was mainly to soluble 
nickel, even if there might have been up to 60% NiS and NiO present 
in some working areas.  No exposure to soluble compounds was 
considered to take place in the roasting/smelting department, but 
the possible presence of NiSO4, as an intermediate, was not 

    The risk of lung cancer for a 1953-84 cohort of 3250 workers 
was also estimated according to department and to cumulative 
exposure to different nickel species (nickel subsulfide, nickel 
oxide, soluble nickel).  Although an increased risk was found for 
both electrolysis and roasting, smelting, and calcining, the 
highest risk and steepest dose-response relationship (based on 
exposure time) was found for electrolysis, and the highest risk was 

found for the highest cumulative exposure to soluble nickel.  It 
must be remembered, however, that most workers were exposed to more 
than one form of nickel. 

    Torjussen et al. (1979a,b) examined nasal biopsy specimens from 
318 active and 15 retired workers with at least 8 years of 
employment.  Epithelial dysplasia was found in 14 (14%) of the 97 
roasting/smelting workers, in 16 (11%) of the 144 electrolysis 
workers, in 8 (10%) of the 77 non-process workers and in 7 (47%) of 
the retired workers.  One out of 57 controls, a carpenter, had 
dysplasia.  Two co-workers from the roasting/smelting department 
had nasal carcinoma.  Based on the methods employed by Torjussen et 
al. (1979a,b), histopathological reinvestigations of nasal biopsy 
specimens from workers, previously included in the Torjussen study, 
were carried out by Boysen et al. (1980, 1982, 1984) and similar 
results were found.  The histopathological changes in the nasal 
epithelium, including dysplasia, persisted in active workers, 
despite reduction of airborne nickel concentrations in the working 
environment.  The frequency of dysplasia was also still elevated in 
retired workers.  The real significance of nasal epithelial 
dysplasia is not known, but it could be considered as a 
precancerous lesion because of its prevalence in groups with 
increased risk of nasal cancer. The role of nasal biopsies in 
identifying and monitoring occupational nickel exposure is unclear. 

 (c) International Nickel Company (INCO), Ontario 

    Sulfide nickel ore is mined and refined at several locations 
using different processes.  The Ontario Health Department studied a 
cohort of 2355 refinery workers followed from 1930 to 1957 
(Sutherland, 1959, reviewed by Mastromatteo, 1967).  There were 7 
deaths from sinus cancer (0.19 expected) and 19 from lung cancer 
(8.45 expected).  Nearly all excess deaths from sinus cancer and 
lung cancer occurred in workers exposed to furnace dusts in 
calcining and sintering.  Mastromatteo (1967) extended Sutherland's 
study to the period between 1930 and 1960.  The risk of nasal 
cancer was still elevated (16 sinus cancer deaths observed, 0.166 
expected) as well as the risk of lung cancer (37 lung cancer deaths 
observed, 12.71 expected).  According to Mastromatteo (1967), the 
investigations of Sutherland led to major process changes, among 
them the termination of the sinter plant operations, in 1962.  The 
Sutherland study was updated by Rigaut(1986 ) and the US EPA, 
(1986a) to cover the period between 1930 and 1970.  By this time, 
sinus and lung cancer deaths amounted to 24 (SMR=5106) and 76 (SMR= 
1861), respectively. 

    On the basis of the unpublished work by Sutherland (1959), 
Chovil et al. (1981) identified a cohort of 495 men, who had been 
employed at the Copper Cliff sinter plant for a period between 1948 
and 1962, and were alive in 1963.  However, only 75% of the cohort 
were successfully followed through 1977 and 1978.  Six cases of 
sinus cancer were identified (no expected numbers given), and 54 
cases of lung cancer of which 37 were fatal, compared with 4.25 
expected deaths.  Despite some methodological weaknesses, an excess 
risk of lung and sinus cancer is suggested. 

    A large cohort study was carried out by Roberts et al. (1984).  
The cohort consisted of 54724 INCO workers employed in Port 
Colborne refinery and in the extraction and refining of copper and 
nickel in two Sudbury sinter plants (Coniston smelter and Copper 
Cliff plant).  The cohort was followed for mortality between 1950 
and 1976.  In Sudbury workers not exposed to sintering operations, 
the SMRs for nasal and lung cancer were 144 (O/E=3/2.08) for nasal 
cancer and 108 (O/E=222/204.98), respectively, compared with SMRs of 
2174 (O/E=2/0.09) for nasal cancer and 463 (O/E= 42/9.08) for lung 
cancer in workers exposed to sintering operations.  In workers from 
the Port Colborne leaching, calcining, and sintering departments, 
SMRs for nasal and lung cancer were 9412 (O/E=16/0.17) and 298 
(O/E=49/16.44), respectively, compared with SMRs of 78 
(O/E=13/16.65) for lung cancer in men who had never worked in this 
department.  A single case of nasal cancer was observed compared to 
0.16 expected, but, on further investigation, it was found that 
this man had had 20 years exposure to roasting/calcining operations 
elsewhere.  Nasal and lung cancer mortality was found to increase 
with increasing duration of exposure.  Lung cancer was already seen 
in excess 5-10 years after first exposure in Sudbury, but, in Port 
Colborne, it did not become apparent until 20 years after the first 
exposure.  Nasal cancer began to appear after 15 years.  Apparently 
the nasal cancer risk was higher at Port Colborne than at Sudbury, 
while lung cancer was more frequent at Sudbury. 

    Airborne nickel levels were much higher in the sintering 
department than in other areas of these refineries.  Warner (1985) 
reported that a 40-h sample, taken on the operating floor of the 
Copper Cliff Sinter Plant in 1960, contained 46.4 mg total dust/m3.  
The major nickel compounds in the dust were Ni3S2, NiO, and NiSO4.  
Samples taken between 1948 and 1952 from dusty air escaping from 
roof monitors contained over 100 mg total dust/m3, but it is not 
known if these were representative of exposures in working areas.  
Other processes are believed to have been very much less dusty.  
Mean levels in most areas were generally well below 1 mg nickel/m3 
in later years, though substantially higher levels occasionally 
occurred, particularly in matte grinding and in the handling of 
metallic nickel powders (Warner, 1984). 

    The composition of a sample of dust collected in 1959 from the 
calcining and sintering rooms of the Port Colborne, Ontario, 
refinery is shown in Table 35 (Gilman & Yamashiro, 1985).  The 
major constituents were nickel subsulfide (57%), nickel sulfate 
(20%), nickel oxide (6%), and copper oxide (3%). 

Table 35.  Composition of dust collected in 
1959 in the calcining and sintering of the 
Port Colborne (INCO) nickel refinery Ontarioa
Compound                Percentage
CuO                     3.4
NiSO4 x 6H2O            20.0
Ni3S2                   57.0
NiO                     6.3
CoO                     1.0
Fe2O3                   1.8
SiO2                    1.2
Miscellaneous           2.0
Moisture                7.3
a  From: Gilman & Yamashiro (1985).

    Kaldor et al. (1986) analysed the same data using a case-
control approach.  In addition to the four areas identified by Peto 
et al. (1984), employment in nickel sulfate production was 
associated with increased lung and nasal cancer risk.  Lung and 
nasal cancer mortality and exposure levels for various nickel 
compounds for men employed in major production areas were reported 
by Peto (1988).  There were 5 lung cancer deaths (1.5 expected) and 
4 nasal cancer deaths among men, employed for 5 or more years in 
hydrometallurgy (nickel sulfate production), who had spent less 
than a year in other high-risk areas (copper sulfate, calcining, 
furnaces).  The principal exposure in hydrometallurgy was to 
soluble nickel (about 1.4 mg/m3) with lower levels of nickel oxide 
(0.9 mg/m3), nickel subsulfide (0.1 mg/m3), and metallic nickel 
(0.5 mg/m3).  These estimates were provided by the technical staff 
of the refinery, but no measurements were made to verify them. 

 (d) Falconbridge, Ltd., Falconbridge (Ontario) 

    A mortality study was carried out on a cohort of 11 594 
workers, employed for at least 6 months by the Falconbridge nickel 
mines, Sudbury, Ontario, between 1950 and 1976 (Shannon et al., 
1984).  In this plant, sintering techniques included a low 
temperature step.  Nasal cancer was not observed.  A slight excess 
of lung cancer (SMR=123, O/E=46/37.5) in both mines and service 
occupations was not statistically significant.  However, laryngeal 
cancer deaths were significantly increased in miners (SMR=261, 
O/E=5/1.92).  A slight, though not significant, increase in deaths 
from prostate cancer was noted in smelter workers. 

 (e) Sherritt Gordon Mines Ltd., Fort Saskatchewan, Alberta 

    Sherritt Gordon Mines, Ltd., established hydrometallurgical 
nickel refining in 1954.  Nickel exposures were mainly in the form 
of oxide ore concentrate, nickel metal, and some soluble compounds.  
Egedahl & Rice (1984) conducted a study of cancer incidence and 
mortality with a cohort of 720 workers employed in 

hydrometallurgical refining and did not find any excess of 
respiratory cancer.  Two cases of renal cancer occurred in workers 
with 11 and 16 years exposure to nickel concentrate, soluble nickel 
substances, and nickel metal, prior to developing their illness.  
Both were cigarette smokers. 

 (f) Nickel refinery, Huntington (West Virginia) 

    Copper-nickel matte was refined in Huntington during 1922-47 
and a mortality study was performed on 1855 men, employed before 
1947 who had worked for at least one year at the plant (Enterline & 
Marsh, 1982).  Concentrations of airborne nickel in the area where 
nickel was crushed, ground, and handled, were estimated to range 
from 20 to 350 mg/m3 and from 5 to 15 mg/m3 in the calcining area.  
The SMR for nasal cancer was 2443.5 with 2 observed and 0.08 
expected cases.  Two nasal cancers were observed among nickel-
exposed non-refinery workers.  There was no significant increase in 
deaths from lung cancer among refinery workers (SMR=118.5 with 8 
observed and 6.75 expected cases) and it was suggested that the 
nickel exposures at the plant may have been considerably lower than 
in other plants.  However, for refinery and non-refinery workers 
combined, and for all respiratory cancer cases combined, there was 
a dose-relationship with accumulated nickel exposure. 

 (g) Oxide ore refinery, New Caledonia 

    Nickel oxide ore has been mined on the South Pacific Island of 
New Caledonia since 1866 and smelted there since 1885.  Lessard et 
al. (1978) identified 92 cases of lung cancer that had occurred in 
this area between 1970 and 1974.  The observed rate was 3-7 times 
higher than rates in other Central or South Pacific areas, but 
similar to those seen in industrialized countries.  A significant 
increase in lung cancer rates was observed with decreasing distance 
from the refinery.  The authors found that, in New Caledonia, there 
was a 3-fold risk of lung cancer among workers compared with non-
workers, independent of age and tobacco smoking, and considered 
that these results supported the etiological role of nickel in lung 
cancer.  Goldberg et al. (1985a,b) carried out a retrospective 
cohort study and a case-control study and reported no excess of 
respiratory cancer in workers of the Society Le Nickel (SLN) 
compared to the general population of New Caledonia; however, these 
studies have weaknesses in statistical power and definition of the 
control population.  Goldberg et al. (1988) concluded that, in a 
10-year period, there was no excess of either lung or sinonasal 
cancer in the nickel workers, when compared with the island 
population on an age-matched basis.  Both studies were considered 
to have methodological problems, but the Goldberg et al. (1988) 
study had more comprehensive health data. 

 (h) Other nickel refineries 

    In the Soviet Union, Saknyn & Shabynina (1970, 1973) reported 
an increase in lung and gastric cancer in workers in a nickel 
refinery plant in the Urals.  The refinery was engaged in the 

preparation of nickel oxide ore, roasting, and smelting. They 
stated that the lung cancer death rate from 1955 to 1967 exceeded 
that of the nearby urban population by 180% and that the death rate 
from sarcomas and stomach cancer was also increased.  Excess lung 
cancer was seen in workers in roasting/reducing and smelting, but 
also in electrolysis, where exposure was principally to nickel 
sulfate and nickel chloride, and, in the cobalt shop, where 
exposure was to various soluble salts of nickel and cobalt. 

    Tatarskaya (1965) reported 2 cases of nasal cancer among 
workers engaged in the electrolytic refining of nickel. 

    In workers in a Czech plant, where nickel oxide ore had been 
refined since 1963, 8 lung tumours were diagnosed between 1971 and 
1980 (Olejar et al., 1982).  All workers had smoked more than 25 
cigarettes per day.  These results must be treated with caution as 
the latency period from 1963 was very short. 

    Rockstroh (1959) reported 45 cases of lung cancer in workers in 
a nickel refinery in Aue in the German Democratic Republic between 
1928 and 1956.  Exposure was very complex: nickel, arsenic, cobalt, 
copper, bismuth, and benzo (a)pyrene, and workers were often 
involved in different processes, during their employment.  One case 
of lung cancer was found among office personnel, but the size of 
the comparison group was not indicated. Nickel alloy manufacturing 

    In a nickel alloy manufacturing plant in Hereford, England, the 
alloys are manufactured from materials consisting of metallic 
nickel and other metals (iron, copper, cobalt, chromium, 
molybdenum).  Workers are exposed to metallic nickel and oxidic 
nickel.  The average airborne nickel concentrations ranged from 
0.84 mg/m3 in the melting, fettling, and pickling area to 0.04 
mg/m3 in the process, stock handling, distribution, and warehouse.  
Cox et al. (1981) studied a cohort of 1925 men with at least 5 
years of employment between 1953 and 1978.  He did not find any 
cases of nasal sinus cancer.  The lung cancer death rate was not 
increased compared with the numbers expected from national and 
local mortality rates.  However, the study period was too short to 
exclude the risk of respiratory cancer completely. 

    Redmond (1984) reported a cohort mortality study on 28 261 
workers employed at 12 high nickel alloy production plants between 
1956 and 1960, including a follow-up to 1977.  The predominant 
nickel species, to which the workers were exposed, appeared to have 
been nickel dust and nickel oxide.  Average levels of airborne 
nickel ranged from 0.064 mg/m3 in the cold working area to 1.5 
mg/m3 in the powder metallurgy area (Redmond et al., 1983, internal 
report).  Overall, no statistically significant increased risk was 
observed for cancers of the lung, nasal sinuses, larynx, or kidney. 

    Another study dealt with the standardized proportionate 
mortality ratios of 851 foundrymen from 26 nickel/chromium alloy 
foundries compared with 141 unexposed foundrymen during the period 

1968-79 (Cornell & Landis, 1984).  There were no cases of nasal 
cancer.  The percentages of respiratory cancer in the exposed group 
were not significantly different from the percentages of 
respiratory cancer in the unexposed group.  When compared to 
national mortality data, the observed numbers of lung cancer and 
all cancer deaths in exposed men were not significantly different 
from the expected values. 

    Cornell (1984) performed a proportional mortality analysis on 
4487 workers in 12 US plants engaged in the production of stainless 
steel and low nickel alloys. All deaths were included for, at 
least, a 5-year period, up to 1977.  No cases of nasal cancer were 
observed and there was no excess of lung cancer.  However, details 
of the study, such as the definition of exposure and latency 
period, were not provided. Nickel plating industry 

    Silverstein et al. (1981) conducted a case-control study on 
deaths among workers at a Scandinavian die-casting and 
electroplating plant.  The major operations in the plant were zinc 
alloy die-casting, buffing, polishing of zinc and steel parts, and 
electroplating with copper, nickel, and chrome.  There were 238 
deaths among workers with at least 10 years of employment.  The 
proportionate mortality ratio (PMR) (38 deaths, PMR=209) for lung 
cancer was significantly increased.  However, because of 
heterogeneous exposure, the increased risk of lung cancer 
mortality could not be exclusively associated with nickel exposure. 

    The authors subsequently initiated a case-control study on the 
28 white male and 10 white female lung cancer deaths.  Cases and 
controls were compared for length of employment in individual 
departments.  Odds ratios were estimated for work in 14 different 
departments.  For males in three departments, the odds ratio 
increased with duration of work in the departments.  This trend was 
most significant for the department where die-casting and plating 
were the major activities. 

    A study was carried out by Burges (1980) on a group of 508 
nickel platers in an engineering firm in England.  Nickel plating 
was done in a separate shop from chrome plating.  The cohort was 
divided into groups: nickel bath workers with less than one year of 
exposure, more than one year of exposure, and other exposed 
workers.  In the short-exposure group (less than one year), no 
excess mortality was found, whereas, in the longer-exposure group 
(more than one year), a significant excess of deaths was found for 
stomach cancer (O/E = 4/0.6, SMR = 623) and for non-malignant 
respiratory disease (O/E = 8/2.8, SMR = 286).  Only one lung cancer 
death was observed in the longer-exposure group compared with 1.7 
expected cases.  The results of the study suggest a higher incidence 
of gastric cancer in nickel platers. Sorahan et al. (1987) reported 
a study on mortality in nickel and chromium platers in the United 
Kingdom.  While an excess of certain cancers was associated with 
chromium bath workers, it was stated that nickel exposure was not a 
confounding factor. Welding 

    Stern (1983) and Langard & Stern (1984) concluded that the 
excess risk of lung cancer in welders is approximately 30% greater 
than that in the non-welding population.  It was suggested that the 
greater risk of lung cancer found among stainless steel welders, in 
some studies, could be related to high concentrations of nickel and 
hexavalent chromium in stainless steel welding fumes. 

    The role of nickel compounds as a cause of respiratory cancer 
is difficult to assess, because chromates and other carcinogens may 
occur in the work-place air during the welding of stainless steel 
and other nickel-containing alloys (IARC, 1990). Nickel powder 

    In the Oak Ridge Gaseous Diffusion Plant, Tennessee, metallic 
nickel is used in the production of barrier material for the 
isotopic enrichment of uranium by gaseous diffusion.  The median 
nickel concentration in air between 1948 and 1963 ranged between 
0.1 and 1.0 mg/m3 (Godbold & Tompkins, 1979).  In a cohort of 814 
workers, Godbold & Tompkins (1979) did not find any increased risk 
of respiratory cancer during the period 1948-72.  In a follow-up 
study by Cragle et al. (1984) covering the years from 1972 to 1977, 
the lung cancer rate did not increase.  The SMR for men employed 
for more than 5 years was 91, based on 8 deaths. Nickel-cadmium battery manufacturing 

    Sorahan & Waterhouse (1983) examined 3025 nickel-cadmium 
battery workers for a possible excess of cancer mortality.  
Overall, the SMRs showed a statistically significant excess of 
respiratory cancer deaths, but it was not possible to attribute the 
excess to nickel or to cadmium, since exposure to both occurred at 
high levels.  In studies by Kjellstrom et al. (1979) and Andersen 
et al. (1983), the mortality was examined in men working at a 
nickel-cadmium battery-manufacturing plant with mixed exposure to 
both metals and nickel hydroxide.  Increased respiratory, renal, 
and prostate cancer mortality were noted, though there was no 
increase in overall cancer mortality.  There were two cases of 
nasopharyngeal cancer.  One started employment before 1948, the 
other between 1948 and 1961, when exposure to nickel powder was 
very high, exceeding 100 mg nickel/m3 in the work area.  The low 
risk ratio for lung cancer rendered the studies inconclusive for 
the effects of nickel compounds. Case-control studies 

    The case-referent design has been used to associate the 
incidence of certain cancer types with occupations in nickel-
producing or nickel-using industries. 

    In a British study (Acheson et al., 1981), an excess risk for 
nasal cancer was found in furnace and foundry workers, partly, 
because of several cases among Clydach refinery workers. 

    Bernacki et al. (1978b) carried out a small case-control study 
at an aircraft-engine factory where high nickel alloys were used.  
Nickel exposure was not found to be associated with lung cancer 
cases.  Roush et al. (1980), using data from the Connecticut Tumor 
Registry and from City Directories, determined the occupational 
exposures of individuals reported to have cancer of the nasal 
sinuses in the years 1935-75.  The study did not reveal any 
increase in nasal cancer deaths in occupations classified as having 
nickel exposure.  A case-control study of 204 laryngeal cancer 
patients and 204 neighbourhood controls did not show any relation 
to occupational exposure to nickel, while tobacco, alcohol, and 
asbestos were major risk factors (Burch et al., 1981).  However, 
Olsen & Sabroe (1984) found a statistically significant excess risk 
of laryngeal cancer related to potential nickel exposure from 
alloys, battery chemicals, and chemicals used in the production of 
plastics.  A case-referent study covering the entire Montreal 
population showed a statistically significant odds ratio of 3.1 for 
lung cancer and nickel exposure and some indication of a dose-
response relationship (Gerin et al., 1984), though individuals 
exposed to nickel were always exposed to chromium as well. 

9.5.2.  Carcinogenicity of metal alloys in orthopaedic prostheses

    It was concluded by Sunderman (1989b) that case reports of 
sarcomas at sites of metal implants in human beings and domestic 
animals have implicated carcinogenesis as a potential, albeit rare, 
complication of metal orthopaedic prostheses (Table 36).  Since 
physicians and veterinarians are not obliged to report adverse 
reactions to prostheses, the actual incidences of sarcomas in 
association with metal implants cannot be reliably estimated, and 
the possibility that the apparent associations are coincidental 
cannot be excluded.  Carcinogenesis bioassays in rodents have shown 
that pure nickel or cobalt powders induce sarcomas at injection 
sites, and transformation assays in mammalian cells have yielded 
positive results with nickel powder, suggesting that surgical 
implantation of alloys containing these metals may pose 
carcinogenic risks. 

Table 36.  Patients with tumours at sites of metal implantsa
Patient age   Time lapse   Implant type                   Tumour type           Reference
[years]       to tumour
implant       (years)
12 (humerus)  30           Steel plate (FeCrNi) and 4     Ewing's sarcoma       McDougall (1956)
                           screws (FeCr), much corrosion

37 (tibia)    3            Osteosynthesis plate and 2     Osteochondrosarcoma   Delgado (1958)
                           screws, alloy unknown

53 (femur)    3            Steel plate and nail (6        Giant cell tumour     Castleman &
                           months) then Moore                                   McNeely (1956)
                           prosthesis and trochanteric

58 (tibia)    26           Steel (Type 316) plate and     Haemangiosarcoma      Dube & Fisher
                           screws (Types 304 and 316)                           (1972)

56 (hip)      2.5          Mckee metal-to-metal           Fibrosarcoma          Arden & Bywaters
                           arthroplasty, alloy not                              (1978)

4 (hip)       7            Sherman (CoCrMo) plate and     Ewing's sarcoma       Tayton (1980)
                           6 screws (implanted 1 year)

31 (tibia)    17           Sherman (CoCrMo) plate and     Histiocytic           McDonald (1981)
                           screws                         lymphoma

75 (hip)      2            Charnley-Muller arthroplasty   Malignant fibrous     Bago-Granell et
                           and trochanteric wires, alloy  histiocytoma          al. (1984)
                           not stated

63 (hip)      2.4          McKee-Farrar arthroplasty      Malignant fibrous     Swann (1984)
                           (CoCrMo)                       histiocytoma

Table 36 (contd.)
Patient age   Time lapse   Implant type                   Tumour type           Reference
[years]       to tumour
implant       (years)
75 (hip)      5            Ring arthroplasty (CoCrMo)     Osteogenic sarcoma    Penman & Ring

76 (knee)     4.5          CoCrMo arthroplasty            Epithelioid sarcoma   Weber (1986)

14 (hip)      29           Sherman screw (CoCrMo)         Malignant fibrous     Hughes et al.
                                                          histiocytoma          (1987)

40 (hip)      13           2 Screws (unspecified alloy)   Undifferentiated      Ryu et al.
                           for 12 years; then hip         sarcoma               (1987)
                           prosthesis (CoCrMo stem and
                           Al2O3 head)
a  Modified from: Sanderman (1989b).


10.1.  Exposure

    Nickel is an ubiquitous element and has been detected in 
different media in all parts of the biosphere. 

    Nickel is introduced into the environment from both natural and 
man-made sources and is circulated throughout all environmental 
compartments by means of chemical and physical processes, as well 
as through the biological transport mechanisms of living organisms. 

    Acid rain may leach nickel as well as other metals from plants 
and soil. 

    Atmospheric nickel is considered to exist mainly in the form of 
particulate aerosols. 

    Nickel is introduced into the hydrosphere by removal from the 
atmosphere, by surface run-off, by discharge of industrial and 
municipal wastes, and also following the natural erosion of soils 
and rocks. 

    A major source of nickel in the environment is the combustion 
of fossil fuels, particularly coal. 

    Uncontrolled emissions and waste disposal may have adverse 
effects on the environment. 

    Both the chemical and physical forms of nickel and its salts 
strongly influence bioavailability and toxicity. 

    Nickel from soil and water is absorbed and metabolized by 
plants and microorganisms and these small quantities of nickel are 
widely present in all foods and water. 

    Some foods, such as pulses and cocoa products, contain 
relatively high amounts of nickel, but these quantities have not 
been correlated with adverse health effects. 

10.2.  Human health effects

    Nickel is normally present in human tissues and, under 
conditions of high exposure, these levels may increase 

    The general population is exposed to nickel via the diet and 
objects containing nickel, especially jewellery and coins. 

    Occupational exposure to nickel is important. 

    Inhalation is an important route of exposure to nickel and its 
salts in relation to health risks.  The gastrointestinal route is 
of lesser importance. 

    Nickel absorption from the gastrointestinal tract is poor, 
though nickel in the drinking-water is absorbed to a greater extent 
in an empty stomach.  This may be a risk for sensitized persons. 

    Smoking tobacco may contribute to nickel intake, but there is 
no agreement on the chemical nature of nickel in tobacco smoke and 
its health significance. 

    Target organs are the respiratory system, especially the nasal 
cavities and sinuses, and the immune system. 

    The percutaneous absorption of nickel is minor, but it is 
important in sensitization. 

    Nickel and its salts are potent skin sensitizers and possible 
respiratory sensitizers in human beings.  Nickel dermatitis is a 
common result of nickel exposure, especially in women. 

    Primary skin and eye irritation reactions to high 
concentrations of soluble nickel salts have also been reported. 

    Acute toxicity is a minor risk from nickel or its compounds, 
with the exception of nickel carbonyl. 

    There is no convincing evidence that nickel salts produce point 
mutations in bacterial systems.  However, some nickel salts are 
clastogenic  in vitro, producing chromosome aberrations, 
(transformation) and sister chromatid exchanges in mammalian cells. 

    There is a lack of evidence of a carcinogenic risk from oral 
exposure to nickel, but the possibility that it acts as a promoter 
has been raised. 

    There is evidence of a carcinogenic risk through the inhalation 
of nickel metal dusts and some nickel compounds. 

    Very high concentrations of nickel are required to produce 
teratogenic or genotoxic effects. 

    The consequences of the effects of nickel on the immune system 
are not clear. 

10.3.  Environmental effects

    Nickel is accumulated by plants.  Growth retardation has been 
reported in some species, at high nickel concentrations. 

    There is no evidence that nickel may undergo biotransformation, 
though it does undergo complexation. 

    Nickel has been shown to be essential for the nutrition of many 
microorganisms, a variety of plants, and for some vertebrates. 


1.  The nomenclature for nickel compounds should be further 

2.  Analytical methods should be developed and standardized to 
    facilitate speciation of nickel compounds in environmental 
    media, biological materials, the workplace, and atmospheric 

3.  Studies are recommended on the kinetics and mass transfer of 
    nickel, in order to elucidate the biogeochemical cycle on a 
    global scale and its potential for long-range transport. 

4.  The use of nickel in consumer products that may release nickel 
    when in contact with skin should be regulated.  The 
    specification and testing requirements should be standardized. 

5.  Studies should be performed on the absorption and cellular 
    uptake, transport, and metabolism of well characterized nickel 
    species, following different routes and types of administration. 

6.  Nickel compounds, to which human beings are exposed, should be 
    tested for carcinogenicity in adequate, long-term, inhalation 
    studies on animals. 

7.  Further large-scale cohort studies with well characterized 
    exposures, including biological monitoring, are needed in all 
    sectors of industry, to establish more accurate upper limits of 
    cancer risk. 

8.  Priority should be given to improving industrial hygiene in 
    occupations where exposure to high levels of soluble nickel 
    compounds may occur. 


    The carcinogenic risk of nickel and inorganic nickel compounds 
has been evaluated by the International Agency for Research on 
Cancer (IARC).  An International Working Group evaluated 
epidemiological and experimental carcinogenicity data on nickel and 
certain nickel compounds encountered in the nickel refining 
industry (IARC, 1990).  The evaluations are summarized below: 

                                     Degree of evidence    Overall 
                                     for carcinogenicitya  evaluation
                                     Human      Animal     
Nickel and nickel compounds
  Nickel compounds                                         1
    Nickel salts                                L
      Nickel sulfate                 S
    Combination of nickel oxides
      and sulfides encountered in
      the nickel refining industry   S
      Nickel monoxides                          S
      Nickel trioxides                          I
      Nickel sulfide, amorphous                 I
      Nickel sulfides, crystalline              S
    Nickel antimonide                           L
    Nickel arsenides                            L
    Nickel carbonyl                             L
    Nickel hydroxides                           S
    Nickelocene                                 L
    Nickel selenides                            L
    Nickel telluride                            L
    Nickel titanate                             I
Metallic nickel                      I          S          2B
    Nickel alloys                    I          L
a  S  :  Sufficient evidence of carcinogenicity.
   L  :  Limited evidence of carcinogenicity.
   I  :  Inadequate evidence of carcinogenicity.
   1  :  The agent is carcinogenic for human beings. 
   2B :  The agent is possibly carcinogenic for human beings. 

    In the  Guidelines for drinking-water quality (WHO, 1984), no 
guideline value was set for nickel in drinking-water, as the 
toxicological data available at the time indicated that a guideline 
value was not necessary. 

    In the  Air quality guidelines for Europe (WHO, 1988), no safe 
level was recommended for nickel, because of its carcinogenic 
properties.  At an air concentration of nickel dust of 1 µg/m3, a 
conservative estimate of the lifetime risk is 4 x 10-4. 


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1. Identité, propriétés physiques et chimiques et méthodes

    Le nickel est un élément métallique qui appartient au groupe 
VIIIb de la classification périodique.  Il résiste aux alcalis mais 
se dissout en général dans les acides oxydants dilués.  Le 
carbonate, le sulfure et l'oxyde sont insolubles dans l'eau, alors 
que le chlorure, le sulfate et le nitrate sont solubles.  Le nickel 
carbonyle est un liquide volatil incolore qui se décompose au-
dessus de 50 °C.  Sous forme ionique, le nickel existe 
essentiellement à l'état de nickel(II).  Dans les systèmes 
biologiques, le nickel une fois dissous peut former des complexes 
avec divers ligands et se fixer aux matières organiques. 

    L'analyse des échantillons biologiques et environnementaux se 
fait le plus fréquemment par spectroscopie d'absorption atomique et 
voltammétrie.  Pour obtenir des résultats fiables, en particulier 
dans le domaine des ultratraces (ultramicrotraces), il faut suivre 
un mode opératoire précis pour réduire au minimum le risque de 
contamination lors des prélèvements, de la conservation, du 
traitement, et de l'analyse des échantillons.  Selon les 
traitements préalables subis par l'échantillon et les méthodes 
d'extraction ou d'enrichissement utilisées, on peut atteindre des 
limites de détection de 1 à 100 ng/litre dans les produits 
biologiques et l'eau. 

2. Sources d'exposition humaine et environnementale

    Le nickel est présent à l'état de traces un peu partout dans le 
sol, l'eau, l'air et la biosphère.  La teneur moyenne de la croûte 
terrestre en nickel est d'environ 0,008%.  Les terrains agricoles 
en contiennent entre 3 et 1000 mg/kg.  Dans les eaux naturelles, 
les concentrations varient de 2 à 10 µg/litre (eau douce) et de 0,2 
à 0,7 µg/litre (eau de mer).  Dans l'atmosphère, les concentrations 
en nickel varient de 0,1 à 3 ng/m3, au-dessus des zones écartées. 

    Les gisements de nickel consistent en accumulations de minéraux 
sulfurés (essentiellement de la pentlandite) et en latérites.  Le 
nickel est extrait de ces minerais par affinage pyro- et hydro-
métallurgique.  Le nickel est principalement utilisé pour la 
production d'aciers inoxydables qui sont très résistants à la 
corrosion et aux températures élevées.  On l'utilise sous forme 
d'alliages et de dépôts galvaniques pour la confection de pièces 
d'automobiles, de machines-outils, d'armements, d'outils, de 
matériel électrique, d'appareils ménagers, et de pièces de monnaie.  
Les dérivés du nickel sont également utilisés comme catalyseurs, 
comme pigments, et dans les batteries d'accumulateurs.  En 1985, la 
production minière mondiale de nickel a été d'environ 67 millions 
de kg.  Les principales émissions de nickel dans l'air ambiant 
proviennent de la combustion du charbon et du mazout pour le 
chauffage et la production d'énergie,de l'incinération des déchets 
et des boues de stations d'épuration, de la production minière et 
de la métallurgie du nickel, de la fabrication de l'acier, du 

nickelage, et de diverses autres sources, comme les cimenteries.  
Dans les polluants atmosphériques, le nickel est présent 
principalement sous forme de sulfates, d'oxydes, de sulfures, et, 
dans une moindre mesure, de nickel métallique. 

    Le nickel rejeté lors de diverses opérations industrielles ou 
autres finit par aboutir dans les eaux usées.  Après traitement de 
ces dernières, les résidus sont éliminés par injection dans des 
puits profonds, décharge en mer, enfouissement dans le sol et 
incinération.  Les effluents rejetés par les usines de traitement 
des eaux usées contiendraient jusqu'à 0,2 mg de nickel par litre. 

3. Transport, distribution, et transformation dans l'environnement

    Le nickel qui pénètre dans l'environnement peut être d'origine 
naturelle ou artificielle et il circule à travers tous les 
compartiments du milieu, soit sous l'effet de processus 
physicochimiques, soit par transport biologique au sein 
d'organismes vivants. 

    On estime que le nickel atmosphérique est essentiellement 
présent sous forme d'aérosols particulaires dont la teneur en 
nickel varie en fonction de leur origine.  C'est en général les 
particules les plus petites qui présentent les teneurs les plus 
élevées en nickel.  Le nickel carbonyle est instable à l'air et il 
se décompose pour former de l'oxyde de nickel. 

    Le transport et la distribution des particules de nickel en 
direction ou à l'intérieur des divers compartiments du milieu 
dépend beaucoup de la granulométrie des particules et des 
conditions météorologiques.  Cette granulométrie dépend à son tour 
principalement de la source émettrice.  En général, les particules 
d'origine artificielle sont de dimension plus réduite que celles 
qui proviennent de la poussière naturelle. 

    Le nickel peut pénétrer dans l'hydrosphère soit à partir de 
l'atmosphère, soit par lessivage superficiel, soit encore par 
décharge de déchets industriels ou municipaux ou érosion naturelle 
des sols et des roches.  Dans les cours d'eau, le nickel est 
principalement transporté par des particules enrobées de matières 
précipitées ou en association avec des matières organiques; dans 
les lacs, le transport est assuré sous forme ionique, 
essentiellement en association avec des matières organiques.  Le 
nickel peut également s'adsorber sur des particules d'argile ou 
être fixé par des organismes vivants.  A l'inverse, il peut se 
désorber et s'échapper ainsi des sédiments où il était fixé.  Une 
partie du nickel ainsi transporté par les cours d'eau aboutit à 
l'océan.  On estime que l'apport sous forme de particules en 
suspension dans les cours d'eau est d'environ 135 x 107 kg/an. 

    Selon le type de sol, le nickel peut présenter une forte 
mobilité et parvenir jusqu'aux eaux souterraines, puis aux lacs et 
aux rivières.  C'est principalement par leurs racines que les 
plantes terrestres fixent le nickel présent dans le sol.  La 
quantité ainsi fixée dépend de divers paramètres géochimiques et 

physiques, notamment le type de sol, son pH, sa teneur en eau et en 
matières organiques, ainsi que la concentration en nickel extractible.  
L'exemple le mieux connu d'accumulation de nickel est fourni par un 
certain nombre d'espèces végétales "hyperaccumulatrices", qui 
concentrent le nickel à raison de plus de 1mg/kg de poids sec, et 
qui poussent sur des sols serpentinifères relativement stériles.  A 
partir de 50 mg/kg de poids sec, le nickel est toxique pour la 
plupart des végétaux.  On a observé une accumulation de nickel et 
des effets toxiques chez les végétaux cultivés sur sols traités par 
des boues de stations d'épuration ainsi que dans la végétation 
située à proximité de sources d'émission.  Certaines plantes 
aquatiques concentrent fortement le nickel.  Des études de 
laboratoire portant sur des poissons ont montré que le nickel 
n'avait guère tendance à s'accumuler, quelques que soient les 
espèces étudiées.  Dans des eaux non polluées, les concentrations 
relevées dans le poisson entier (et rapportées au poids de tissus 
frais), variaient de 0,02 à 2 mg/kg.  Ces valeurs pourraient être 
jusqu'à 10 fois supérieures dans les poissons qui vivent en eau 
polluée.  Toutefois rien n'indique que le nickel subisse une 
bioamplification tout au long de la chaîne alimentaire. 

    Les animaux sauvages, par exemple, les herbivores et leurs 
prédateurs carnivores, absorbent du nickel par voie alimentaire, 
qui se retrouve ensuite dans de nombreux organes et tissus. 

4. Concentrations dans l'environnement et exposition humaine

    Dans les organismes terrestres et aquatiques, les 
concentrations de nickel peuvent varier de plusieurs ordres de 
grandeur.  L'homme est exposé à des concentrations atmosphériques 
dont les valeurs caractéristiques vont de 5 à 35 ng/m3 en zones 
rurales et urbaines, d'où une absorption par inhalation de 0,1 à 
0,7 µg de nickel par jour.  L'eau de boisson en contient 
généralement moins de 10 µg/litre mais il arrive que du nickel soit 
libéré dans l'eau d'adduction par les éléments de la plomberie et 
atteigne des concentrations de 500 µg/litre. 

    Dans les produits alimentaires, les concentrations sont 
généralement inférieures à 0,5 mg/kg en poids de substance fraîche.  
Le cacao, les graines de soja, certains légumes secs, diverses 
noix, et la farine d'avoine en contiennent de fortes 
concentrations.  L'ingestion journalière de nickel par la voie 
alimentaire est très variable du fait de la diversité des habitudes 
alimentaires: les quantités ingérées peuvent varier de 100 à 800 
µg/jour; en moyenne l'apport alimentaire dans la plupart des pays 
est de 100 à 300 µg/jour.  La libération de nickel par les 
ustensiles de cuisine peut augmenter sensiblement les quantités 
ingérées.  Chez les fumeurs, les quantités absorbées par voie 
pulmonaire peuvent aller de 2 à 23 µg/jour pour une consommation 
quotidienne de 40 cigarettes. 

    L'exposition cutanée dans l'environnement général joue un rôle 
important dans l'apparition et l'entretien d'une hypersensibilité 
de contact qui peut être due à un contact quotidien avec des objets 
nickelés ou en alliage de nickel (par exemple des bijoux, des 
pièces de monnaie, des agrafes). 

    Les implants et prothèses en alliage de nickel, les liquides 
pour injection intraveineuse ou dialyse, et les produits de 
contraste utilisés en radiographie peuvent entraîner une exposition 
iatrogène au nickel.  On estime qu'un malade sous dialyse reçoit à 
chaque traitement environ 100 µg de nickel en moyenne par voie 

    Dans les ambiances de travail, les concentrations de nickel en 
suspension dans l'air peuvent varier de quelques µg jusqu'à, 
parfois, plusieurs mg/m3, selon le processus industriel et la 
teneur en nickel des produits manipulés. 

    Partout dans le monde, des millions de travailleurs sont 
exposés à des poussières et des fumées contenant du nickel lors de 
travaux tels que le soudage, le nickelage, le broyage, l'extraction 
minière, l' affinage du nickel ainsi que dans les aciéries, 
fonderies, et autres industries métallurgiques.Une exposition 
cutanée au nickel peut intervenir à l'occasion des activités 
professionnelles les plus diverses, qu'il s'agisse d'une exposition 
directe à du nickel dissous, par exemple, lors de l'affinage, du 
nickelage ou de l'électroformage ou lors de la manipulation 
d'outils contenant du nickel.  Le nettoyage par voie humide peut 
comporter une exposition au nickel qui s'est dissous dans les eaux 
de lavage. 

5. Cinétique et métabolisme chez l'homme et l'animal

    Chez l'homme et l'animal le nickel peut être absorbé par 
inhalation, ingestion, ou par voie percutanée.  En cas d'exposition 
professionnelle, la principale voie de pénétration dans l'organisme 
est l'absorption respiratoire avec résorption gastro-intestinale 
secondaire (formes solubles et insolubles).  Une proportion 
importante des matières inhalées est avalée après avoir été 
éliminée des voies respiratoires sous l'action de l'ascenseur 
mucociliaire.  Une hygiène personnelle insuffisante et de mauvaises 
habitudes de travail peuvent accroître l'exposition par voie 
digestive.  L'absorption percutanée est négligeable 
quantitativement mais joue un rôle important dans la pathogénèse de 
l'hypersensibilité de contact.  La résorption dépend de la 
solubilité du composé et elle décroît en général dans l'ordre 
suivant: nickel carbonyle > composés solubles > composés 
insolubles.  De tous les dérivés du nickel, c'est le nickel 
carbonyle qui est le plus rapidement et le plus complètement 
résorbé dans l'organisme de l'homme et des animaux.  Les études 
comportant sur l'administration de nickel par voie respiratoire 
sont limitées.  Des études au cours desquelles on a administré à 
des hamsters et à des rats de l'oxyde de nickel insoluble ont 
montré que celui-ci était faiblement résorbé, la plus grande partie 
du produit étant retenue dans les poumons après plusieurs semaines.  
En revanche, la résorption du chlorure de nickel soluble et du 
sulfure de nickel amorphe ont été rapides.  Dans le sang, le nickel 
est principalement transporté par l'albumine. 

    Le nickel est plus ou moins résorbé au niveau gastrointestinal 
en fonction de la composition de l'alimentation.  Lors d'une étude 
récente sur des volontaires humains, on a constaté que le nickel 

était résorbé à hauteur de 27% à partir de l'eau, contre moins de 
1% à partir de la nourriture.  L'excrétion peut s'effectuer en 
principe dans toutes les sécrétions et notamment l'urine, la bile, 
la sueur, les larmes, le lait et le liquide muco-ciliaire.  Le 
nickel qui n'est pas résorbé est éliminé dans les matières fécales.  
On a mis en évidence l'existence d'un transfert transplacentaire 
chez des rongeurs.  Après administration parentérale de sels de 
nickel, on a constaté que c'est au niveau des reins, des glandes 
endocrines, des poumons et du foie que l'accumulation de nickel 
était la plus importante: des concentrations élevées ont été 
également observées dans l'encéphale après administration de nickel 
carbonyle.  Les données relatives à l'excrétion correspondent à un 
modèle bicompartimental.  Chez des adultes en bonne santé exposés 
en dehors de leur activité professionnelle, on a observé des 
concentrations sériques et urinaires de 0,2 µg/litre (limites: 
0,05-1,1 µg/litre) et de 1,5 µg/g de créatinine (limites: 0,5-4,0 
µg/g de créatinine), respectivement.  Après exposition 
professionnelle, on a constaté une augmentation des concentrations 
de nickel dans ces deux liquides.  Pour un adulte non exposé de 70 
kg, la charge de l'organisme en nickel est de 0,5 µg. 

6. Effets sur les êtres vivants dans leur milieu naturel

    Chez les microorganismes, on a constaté une inhibition de la 
croissance lorsque la concentration en nickel dans le milieu était 
de 1 à 5 mg/litre (cas des actinomycètes, des levures et des 
eubactéries marines ou non marines) ou de 5 à 1000 mg/litre (cas des 
champignons filamenteux).  Dans le cas des algues, on n'a pas 
observé de croissance à des concentrations d'environ 0,05-5 mg de 
nickel par litre.  La toxicité du nickel dépend également de 
facteurs abiotiques tels que le pH, la dureté, la température et la 
salinité du milieu ainsi que de la présence de particules 
organiques ou minérales. 

    Chez les invertébrés aquatiques, la toxicité du nickel varie 
dans de très importantes proportions selon l'espèce et les facteurs 
abiotiques.  Chez la daphnie, on a observé une CL50 à 96 h. de 0,5 
mg/litre alors que chez trois mollusques, deux gastéropodes d'eau 
douce et un bivalve, ce paramètre était respectivement égal à 0,2 
mg/litre et 1100 mg/litre. 

    Chez les poissons, les valeurs de la CL50 à 96 h. sont 
généralement comprises entre 4 et 20 mg/litre mais elles peuvent 
être plus élevées chez certaines espèces.  Des études à long terme 
sur les poissons et leur développement effectuées dans des eaux 
douces ont montré qu'à des concentrations ne dépassant pas 
0,05 mg/litre, le nickel exerçait certains effets, en particulier 
sur la truite arc-en-ciel.  Pour les plantes terrestres, des 
concentrations de nickel dépassant 50 mg/kg de poids à sec sont 
généralement toxiques.  On a observé que le cuivre potentialisait 
la toxicité du nickel alors que le calcium la réduisait.  On ne 
dispose que de données limitées au sujet des effets du nickel sur 
les animaux terrestres. 

    Les lombrics paraissent être relativement insensibles au 
nickel, du moins si le milieu abonde en microorganismes et matières 
organiques qui captent une partie du nickel aux dépens des vers.  
On n'a pas envisagé la possibilité que le nickel constitue un 
polluant majeur à l'échelon planétaire encore que des modifications 
écologiques, par exemple une diminution du nombre et de la 
diversité des espèces ait été observée à proximité de sources de 
nickel.  En outre, des études portant sur les microécosystèmes ont 
montré qu'un apport de nickel dans le sol perturbait le cycle de 

7. Effets sur les animaux d'experience et sur les systemes
d'épreuve  in vitro 

    Le nickel joue un rôle essentiel dans l'activité catalytique de 
certaines enzymes végétales et bactériennes.  Chez certaines 
espèces animales on a observé, après administration d'un régime 
carencé en nickel, un ralentissement du gain de poids, de l'anémie 
et une moindre viabilité de la progéniture. 

    Le dérivé du nickel qui présente la plus forte toxicité aiguë 
est le nickel carbonyle dont le poumon constitue l'organe cible.  
Ce composé peut provoquer un oedème pulmonaire en l'espace de 4 
heures.  Les autres dérivés du nickel présentent une faible 
toxicité aiguë. 

    Si les allergies de contact sont très fréquentes chez l'homme, 
on ne parvient à produire une sensibilisation expérimentale chez 
l'animal que dans certaines conditions particulières.  Chez le rat, 
la souris et le cobaye on a provoqué des lésions des muqueuses et 
des réactions inflammatoires des voies respiratoires en faisant 
inhaler pendant une longue période à ces animaux du nickel 
métallique, de l'oxyde et du sous-sulfure de nickel.  On a observé 
une hyperplasie de l'épithélium chez des rats après inhalation 
d'aérosols de chlorure et d'oxyde de nickel. 

    Chez le rat, une exposition intense et prolongée à de l'oxyde 
de nickel a provoqué une pneumoconiose progressive.  Des réactions 
inflammatoires quelquefois accompagnées d'une légère fibrose ont 
été observées chez des lapins après exposition intense à la 
poussière de nickel et de graphite.  L'exposition de rats à du 
sous-sulfure de nickel a provoqué une fibrose pulmonaire. 

    Des sels de nickel, administrés par voie parentérale à des 
rats, des lapins et des poulets ont provoqué une hyperglycémie 
transitoire rapide.  Ce phénomène pourrait être lié aux effets qui 
ont été observés sur les cellules alpha et béta des ilots de 
Langerhans.  Le nickel réduit également la libération de 
prolactine.  L'administration par voie orale ou par inhalation de 
chlorure de nickel a réduit la fixation d'iode par la thyroïde. 

    Administrés par voie intraveineuse à des chiens, des sels de 
nickel ont entraîné une réduction du débit sanguin des artères 
coronaires; à forte concentration, le nickel diminue la 
contractilité du myocarde du chien  in vitro. 

    Le chlorure de nickel perturbe le système des cellules T et 
inhibe l'activité des cellules tueuses naturelles (cellules NK).  
On a observé que l'administration parentérale de chlorure et de 
sous-sulfure de nickel entraînait la mort intrautérine des foetus 
et réduisait le gain de poids chez le rat et la souris.  Chez des 
rats et des hamsters, l'inhalation de nickel carbonyle a provoqué 
la mort des foetus et une diminution de leur poids, avec en outre 
des effets tératogènes.  Les études en question ne donnaient aucune 
information sur la toxicité des composés du nickel pour les 
femelles gestantes.  On a fait état de mutations létales dominantes 
obtenues chez des rats par exposition au nickel carbonyle. 

    Un certain nombre de dérivés minéraux du nickel ont fait 
l'objet d'études de mutagénicité dans divers systèmes d'épreuve.  
En général les dérivés du nickel se révèlent inactifs chez les 
bactéries sauf dans le cas des tests de fluctuation.  On a observé 
des mutations chez plusieurs types de cellules mamaliennes en 
culture.  Les dérivés du nickel inhibent la synthèse de l'ADN chez 
un grand nombre d'organismes.  En outre, ces dérivés produisent des 
aberrations chromosomiques et des échanges entre chromatides soeurs 
tant dans les cellules mamaliennes que dans les cellules humaines 
en culture.  Chez des personnes exposées, de par leur profession, à 
des composés insolubles ou solubles du nickel on a effectivement 
observé des aberrations chromosomiques, mais pas d'échange entre 
chromatides soeurs (sauf dans le cas d'une étude portant sur des 
ouvriers travaillant dans des ateliers d'électrolyse).   In vitro, 
le nickel provoque la transformation des cellules. 

    Lors d'une étude d'inhalation, on a observé que du sous-sulfure 
de nickel provoquait l'apparition de tumeurs pulmonaires bénignes 
et malignes chez le rat.  Quelques tumeurs pulmonaires ont 
également été observées chez des rats soumis à une série d'études 
où on leur faisait inhaler du nickel carbonyle.  On n'a pas noté 
d'augmentation significative des tumeurs pulmonaires chez des rats 
soumis à l'inhalation de nickel métallique dans des conditions 
d'étude satisfaisantes.  L'inhalation d'oxyde noir n'a pas provoqué 
non plus l'apparition de tumeurs pulmonaires chez des hamsters 
dorés (espèce qui résiste à la cancérogénèse au niveau pulmonaire).  
On ne dispose pas de bonnes études de cancérogénicité basées sur 
l'exposition par inhalation à d'autres composés du nickel.  
Toutefois on a constaté qu'après l'instillation intratrachéenne 
réitérée de sous-sulfure de nickel, de poudre de nickel métallique 
et d'un oxyde non précisé, des tumeurs pulmonaires bénignes se 
formaient chez le rat. 

    Le nickel carbonyle, le nickelocène, ainsi qu'un grand nombre 
de composés légèrement solubles ou insolubles comme le sous-sulfure 
de nickel, le carbonate, le chromate, l'hydroxyde et divers 
sulfures, des seléniures, des arséniures, des téllurures, des 
antimoniures, différents oxydes non spécifiés, deux oxydes de 
nickel et de cuivre, du nickel métallique et divers alliages, ont 
provoqué l'apparition de tumeurs mésenchymateuses locales chez 
divers animaux d'ex-périence après administration intramusculaire, 
sous-cutanée, intrapéritonéale, intrapleurale, intraoculaire, 
intraosseuse, intrarénale, intra-articulaire, intratesticulaire et 

intra-adipeuse.  On n'a pas observé d'effet cancérogène local lors 
d'une étude portant sur des doses uniques de certains alliages de 
nickel, d'hydroxyde colloïdal de nickel et de deux échantillons 
d'oxyde, préparés spécialement en vue d'une étude de 
cancérogénicité par calcination à 735 et 1045 °C. 

    On a provoqué l'apparition de tumeurs de la cavité péritonéale 
chez des rats par administration intrapéritonéale réitérée de 
sulfate et d'acétate de nickel; toutefois aucun effet n'a été 
obtenu avec le chlorure de nickel. 

    On a étudié la cancérogénicité du nickel métallique et d'un 
grand nombre de dérivés du nickel par administration parentérale; à 
de rares exceptions près, toutes ces substances ont provoqué 
l'apparition de tumeurs locales. 

    C'est seulement dans le cas du sous-sulfure de nickel qu'on a 
des preuves convaincantes d'un pouvoir cancérogène après exposition 
par voie respiratoire.  Toutefois le nombre d'études de ce type qui 
sont vraiment satisfaisantes reste très limité. 

    Lors d'études au cours desquelles on a procédé à des 
instillations intratrachéennes répétées de poudre de nickel, 
d'oxyde et de sous-sulfure de nickel, on a observé l'apparition de 
tumeurs pulmonaires. 

    Trois sels solubles de nature différente qui n'avaient pas 
produit de tumeurs locales lors d'études antérieures ont été 
réétudiés en procédant cette fois à une administration 
intrapéritonéale réitérée: deux de ces sels ont alors manifesté des 
effets cancérogènes. 

8. Effets sur l'homme

    C'est le nickel carbonyle qui présente la toxicité aiguë la 
plus forte pour l'homme.  Elle se traduit par des céphalées 
frontales, des vertiges, de la nausée, des vomissements, de 
l'insomnie et de l'irritabilité, puis par des symptômes pulmonaires 
évoquant une pneumonie d'origine virale.  Parmi les lésions 
pulmonaires patho-logiques qui ont été observées on peut citer des 
hémorragies, de l'oedème et une désorganisation cellulaire.  Le 
foie, les reins, les surrénales, la rate et le cerveau sont 
également affectés.  On a aussi fait état d'intoxications par le 
nickel chez des malades sous dialyse après contamination du liquide 
de dialyse par des dérivés du nickel ainsi que chez des nickeleurs 
qui avaient bu accidentellement de l'eau contaminée par du sulfate 
et du chlorure de nickel. 

    On a signalé chez des nickeleurs et chez des ouvriers 
d'ateliers d'affinage du nickel des effets chroniques tels que 
rhinite, sinusite, perforation de la cloison nasale et asthme.  
Certains auteurs font état d'anomalies pulmonaires, notamment une 
fibrose, chez des ouvriers amenés à inhaler de la poussière de 
nickel. En outre, on a signalé des cas de dysplasie nasale chez des 
ouvriers travaillant dans des ateliers d'affinage du nickel.  

L'hypersensibilité de contact est très largement documentée tant 
dans la population générale que chez un certain nombre d'ouvriers 
exposés de par leur profession à des dérivés solubles du nickel.  
Dans plusieurs pays on indique que 10% de la population féminine et 
1% de la population masculine présentent une sensibilité au nickel.  
Parmi ces personnes, 40 à 50% présentent un eczéma vésiculeux des 
mains qui peut être très grave dans certains cas et entraîner une 
incapacité.  L'ingestion de nickel peut aggraver l'eczéma siégeant 
au niveau des mains ou d'autres régions du corps protégées de tout 
contact avec du nickel. 

    On a également signalé que les prothèses et autres implants 
chirurgicaux en alliage de nickel pouvaient produire une 
sensibilisation à ce métal ou aggraver une dermatite préexistante. 

    Des effets néphrotoxiques, comme un oedème rénal avec hyperémie 
et dégénérescence du parenchyme, ont été observés dans des cas 
d'exposition industrielle accidentelle à du nickel carbonyle.  Des 
effets néphrotoxiques passagers ont été enregistrés après ingestion 
accidentelle de sels de nickel. 

    On a fait état d'un risque très élevé de cancers pulmonaire et 
nasal chez des ouvriers travaillant dans des ateliers d'affinage du 
nickel où l'on effectue le grillage à mort des minerais sulfurés, 
opération qui entraîne une exposition importante au sous-sulfure, à 
l'oxyde et éventuellement au sulfate de nickel.  L'exposition à des 
dérivés solubles du nickel (électrolyse, extraction du sulfate de 
cuivre, hydrométallurgie), souvent associée à une exposition à 
l'oxyde de nickel mais sans exposition trop importante au sous-
sulfure, comporte des risques analogues.  Pour les mineurs et les 
ouvriers des ateliers d'affinage, le risque est beaucoup plus 
faible.  Chez les soudeurs d'acier inoxydable ou chez ceux qui 
travaillent dans des industries employant du nickel, les taux de 
cancer sont généralement proches de la normale, sauf dans le cas où 
il y a également exposition au chrome, en particulier dans des 
ateliers de galvanoplastie.  Il semblerait cependant que les 
ouvriers employés à la fabrication des accumulateurs au 
nickel/cadmium, qui sont exposés à de fortes concentrations de 
nickel et de cadmium, soient exposés à un risque légèrement plus 
important de cancer du poumon. 

    On a signalé occasionnellement un excès de divers cancers 
autres que ceux qui siègent au niveau des poumons ou du nez, par 
exemple des cancers rénaux, gastriques ou prostatiques, chez des 
travailleurs de l'industrie du nickel, mais cette surmorbidité n'a 
pas été systématiquement constatée. On peut s'appuyer sur les 
données épidémiologiques pour répondre à deux questions 
importantes: i) certains dérivés du nickel sont-ils effectivement 
cancérogènes, et ii) l'étude de cohortes faiblement exposées 
permet-elle d'établir la limite supérieure du risque pour des 
niveaux d'exposition donnés? 

 a) Dérivés solubles 

    On a mis en evidence un certain risque de cancer chez des 
ouvriers exposés à des concentrations en sels solubles de l'ordre 
de 1 à 2 mg/m3, qu'il s'agisse d'ouvriers d'ateliers d'électrolyse 
ou travaillant à la préparation de sels solubles.  Ces ouvriers 
étaient également exposés à d'autres dérivés du nickel mais souvent 
à des concentrations plus faibles que dans les processus à haut 
risque.  En l'absence d'une évaluation rétrospective de 
l'exposition, il est impossible de tirer des conclusions 
définitives de ces observations mais il existe certainement une 
forte présomption d'une cancérogénicité des dérivés solubles du 
nickel.  Les poussières des ateliers d'affinage contiennent 
quelques fois une proportion non négligeable de sulfate de nickel à 
côté du sous-sulfure.  Il se pourrait donc que le risque de cancer 
très important qui a été observé chez les ouvriers qui travaillent 
au grillage à mort des minerais sulfurés soit dû pour une part aux 
dérivés solubles du nickel. 

 b) Sous-sulfure de nickel (sulfure nickeleux) 

    Dans les ateliers d'affinage où le risque de cancer est élevé, 
on a constaté que l'exposition au sous-sulfure de nickel était 
toujours accompagnée d'une exposition à l'oxyde et peut-être même 
au sulfate (voir plus haut).  Il est donc difficile à partir des 
seules données épidémiologiques d'affirmer que le sous-sulfure est 
cancérogène, encore que ce soit probable. 

 c) Oxyde de nickel 

    Dans tous les cas où l'on a observé un risque élevé de cancer, 
il y avait présence d'oxyde de nickel accompagné d'une ou de 
plusieurs autres formes (sous-sulfure, sels solubles, nickel 
métallique).  Comme dans le cas du sous-sulfure, il est difficile 
d'affirmer ou d'écarter l'existence d'un pouvoir cancérogène sur la 
base des seules données épidémiologiques. 

 d) Nickel métallique 

    On n'a pas constaté d'accroissement du risque de cancer chez 
des ouvriers exposés uniquement à du nickel métallique.  L'ensemble 
des données relatives aux ouvriers qui travaillaient sur des 
alliages du nickel ou dans des ateliers de diffusion gazeuse et qui 
tous étaient exposés à des concentrations moyennes de l'ordre de 
0,5 mg/m3, ne font pas ressortir d'élévation du risque, encore que 
le nombre total de cancers du poumon parmi ces cohortes ait été 
trop faible pour qu'on puisse exclure un léger accroissement du 
risque à cette concentration. 

 e) Conclusion 

    Bien que quelques-uns, voire tous les dérivés du nickel 
puissent être cancérogènes, il n'existe que peu ou pas de risque 
décelable dans la plupart des secteurs de l'industrie du nickel aux 
niveaux d'exposition actuels; cette observation vaut aussi pour 

certains procédés dont on estimait jusqu'ici qu'ils comportaient un 
risque très élevé de cancers pulmonaire et nasal.  Une exposition 
prolongée à des dérivés solubles du nickel à des concentrations de 
l'ordre de 1 mg/m3 peut entraîner une augmentation sensible du 
risque relatif de cancer pulmonaire mais ce risque est à peu près 
égal à l'unité chez les ouvriers exposés à des concentrations en 
nickel métallique de l'ordre de 0,5 mg/m3 en moyenne.  Pour un 
niveau d'exposition donné, le risque de cancer est plus important 
dans le cas des composés solubles que dans le cas du nickel 
métallique et peut-être des autres dérivés du nickel.  L'absence 
d'un risque notable de cancer pulmonaire chez les nickeleurs n'est 
pas sur-prenante étant donné qu'en moyenne l'exposition aux dérivés 
solubles est beaucoup plus faible dans les ateliers de 
galvanoplastie que dans les ateliers d'affinage électrolytique ou 
de traitement des sels de nickel. 


1. Identidad, propiedades fisicas y químicas y métodos analíticos

    El níquel es un elemento metálico perteneciente al grupo VIIIb 
de la tabla periódica. Es resistente a los álcalis, pero en general 
se disuelve bien en ácidos oxidantes diluidos. El carbonato de 
níquel, el sulfuro de níquel y el óxido de níquel no son solubles 
en agua, mientras que sí lo son el cloruro de níquel, el sulfato de 
níquel y el nitrato de níquel. El carbonilo de níquel es un líquido 
incoloro y volátil que se descompone por encima de los 50 °C. La 
forma iónica predominante es la de níquel (II). En los sistemas 
biológicos, el níquel disuelto puede formar componentes complejos 
con diversos ligandos y unirse a materiales orgánicos. 

    Los métodos que más se utilizan en el análisis de materiales de 
origen biológico y medio ambiental son la espectroscopía de 
absorción atómica y la voltamperimetría. A fin de obtener 
resultados fidedignos, sobre todo en el orden de las ultratrazas, 
hay que adoptar procedimientos específicos para reducir al mínimo 
el riesgo de contaminación durante la recogida, el almacenamiento, 
el tratamiento y el análisis de muestras. En los materiales de 
origen biológico y en el agua se puede llegar límites de detección 
de 1-100 ng/litro, atendiendo a los procedimientos de tratamiento 
previo, extracción y enriquecimiento de la muestra. 

2. Fuentes de exposición humana y ambiental

    El níquel es un metal traza muy ampliamente distribuido, que se 
encuentra en el suelo, el agua, el aire y la biosfera. En la 
corteza terrestre hay un porcentaje medio del 0,008%. Los terrenos 
cultivables contienen entre 3 y 1000 mg de níquel/kg. En el agua 
natural los niveles oscilan entre 2 y 10 µg/litro (agua dulce) y de 
0,2 a 0,7 µg/litro (agua de mar). Las concentraciones atmosféricas 
de níquel en zonas remotas son de 0,1 a 3 ng/m3. 

    Los yacimientos metalíferos de níquel están formados por 
acumulaciones de minerales de sulfuro de níquel (principalmente 
pentlandita) y lateritas. El níquel se extrae de la mena mediante 
procesos de afinado piro e hidrometalúrgico. La mayor parte del 
níquel obtenido se destina a la producción de acero inoxidable y a 
otras aleaciones muy resistentes a la corrosión y a la temperatura. 
Las aleaciones de níquel y el niquelado se utilizan en vehículos, 
maquinaria industrial, armamento, herramientas, equipo eléctrico, 
utensilios domésticos y la acuñación de monedas. También se 
utilizan compuestos de níquel como catalizadores, pigmentos y en 
las baterías. En 1985, la producción minera mundial de níquel fue 
de unos 67 millones de kg. Las principales fuentes de emisión de 
níquel a la atmósfera son la combustión de carbón y petróleo para 
la obtención de calor o energía, la incineración de desechos y 
fangos cloacales, la extracción minera y la producción primaria de 
níquel, la fabricación de acero, la galvanoplastia y otras fuentes, 
como la producción de cemento. En el aire contaminado pre-dominan 
el sulfato, los óxidos y los sulfuros de níquel, y en menor 
cantidad el níquel metálico. 

    El níquel procedente de los distintos procesos industriales y 
de otras fuentes termina llegando a las aguas residuales. Los 
restos que se obtienen del tratamiento de esas aguas se eliminan 
mediante inyección en pozos profundos, vertido en los océanos, 
tratamiento en tierra e incineración. Los efluentes de las 
instalaciones de tratamiento de aguas residuales contienen, según 
los datos disponibles, hasta 0,2 mg de níquel/litro. 

3. Transporte, distribución y transformación en el medio ambiente

    El níquel se introduce en el medio ambiente a partir de fuentes 
tanto naturales como de origen humano y circula por todos sus 
compartimentos mediante procesos físicos y químicos, así como por 
el transporte biológico que efectúan los organismos vivos. 

    Se considera que en la atmosféra el níquel está principalmente 
en forma de aerosoles de partículas con distintas concentraciones 
del metal, en función de su procedencia. Las concentraciones más 
altas de níquel en el aire suelen aparecer en las partículas más 
pequeñas. El carbonilo de níquel es inestable en el aire y se 
descompone formando óxido de níquel. 

    El transporte y la distribución de las partículas de níquel a 
los diferentes compartimentos del medio ambiente o entre ellos 
depende en gran medida del tamaño de las partículas y de las 
condiciones meteorológicas. La distribución por tamaños de las 
partículas depende sobre todo de las fuentes de emisión. En 
general, las partículas de fuentes artificiales son más pequeñas 
que las que se encuentran en el polvo natural. 

    El níquel ingresa en la hidrosfera por eliminación desde la 
atmósfera, por la escorrentía superficial, por la descarga de 
residuos industriales y municipales, y también tras la erosión 
natural de los suelos y de las rocas. En los ríos, este elemento se 
transporta principalmente en forma de revestimiento precipitado 
sobre partículas y unido a materia orgánica; en los lagos, se 
transporta en forma iónica y de manera predominante unido a materia 
orgánica. La partículas de arcilla también lo pueden absorber, y a 
la biota pasa por ingestión o absorción. El proceso de absorción se 
puede invertir, lo que se traduce en una liberación del níquel del 
sedimento. Los ríos y arroyos transportan una parte hasta el mar. 
El aporte fluvial de partículas suspendidas se estima en 135 x 107 

    En función del tipo de suelo, el níquel puede presentar una 
gran movilidad dentro del perfil edáfico hasta alcanzar las aguas 
subterráneas y, con ello, los ríos y lagos. La lluvia ácida tiene 
una marcada tendencia a movilizar el níquel del suelo. Las plantas 
terrestres lo absorben principalmente por las raíces. La cantidad 
absorbida depende de diversos parámetros geoquímicos y físicos, 
entre los que figuran el tipo de suelo, su pH y humedad, su 
contenido en materia orgánica y la concentración de níquel 
extraíble. El caso más conocido de acumulación de níquel es el de 
algunas especies de plantas ("hiperacumuladoras"), que crecen en 

suelos serpentinosos relativamente poco fértiles y en las que se 
han encontrade niveles superiores a 1 mg/kg de peso seco. Los 
niveles de níquel superiores a 50 mg/kg de peso seco son tóxicos 
para la mayoria de las plantas. Se han observado casos de 
acumulación y efectos tóxicos en hortalizas cultivadas en suelos 
tratados con fangos residuales y en la vegetación próxima a las 
fuentes de emisión del metal. En plantas acuáticas se han detectado 
factores de concentración elevados. Los estudios de laboratorio han 
puesto de manifiesto que la capacidad de acumulación de níquel en 
los peces examinados es escasa. En aguas no contaminadas, las 
concentraciones halladas en los peces enteros (sobre la base del 
peso fresco) oscilaron entre 0,02 y 2 mg/kg. Estos valores pueden 
ser hasta diez veces superiores en los peces procedentes de aguas 
contaminadas. Sin embargo, no hay pruebas de que se produzca 
bioamplificación del níquel en la cadena de los alimentos. 

    El níquel se encuentra en muchos órganos y tejidos de animales 
silvestres, debido a su ingestión con los alimentos por los 
animales herbívoros y sus predadores carnívoros. 

4. Niveles medioambientales y exposición humana

    Los niveles de níquel en los organismos terrestres y acuáticos 
pueden diferir en varios ordenes de magnitud. La exposición humana 
a los valores habituales en la atmósfera, que oscilan entre 
alrededor de 5 y 35 ng/m3 en zonas rurales y urbanas, hace que la 
inhalación de este elemento sea de 0,1-0,7 µg/día. Aunque el agua 
potable contiene menos de 10 µg/litro, en ocasiones los empalmes de 
las tuberías pueden liberarlo, dando lugar a concentraciones de 
hasta 500 µg/litro. 

    Su concentración en los alimentos suele estar por debajo de 0,5 
mg/kg de peso fresco. El cacao, la soja, algunas legumbres secas, 
diversos frutos secos y la harina de avena contienen elevadas 
concentraciónes de níquel. Su ingestión diaria con los alimentos 
varía ampliamente en función de los diferentes hábitos 
alimentarios, y puede oscilar entre 100 y 800 µg/día; la ingestión 
media de níquel en la dieta es, en la mayoría de los países, de 
100-300 µg/día. Los utensilios de cocina liberan níquel, lo que 
contribuye de manera considerable a su ingestión. Fumando 40 
cigarrillos diarios pueden absorberse a través de los pulmones 2-23 

    La exposición cutánea en el medio ambiente general es 
importante, porque induce y mantiene la hipersensibilidad por 
contacto que produce en la piel el uso diario de objetos niquelados 
o con aleaciones de este metal (por ejemplo, joyería, monedas, 

    Puede haber exposición iatrogénica al níquel debida a las 
implantaciones y las prótesis hechas con aleaciones que lo 
contienen, a fluidos intravenosos o de diálisis y a los medios de 
contraste radiográfico. Se estima que la absorción media de níquel 
por vía intravenosa a partir de los fluidos de diálisis es de 100 
µg por tratamiento. 

    En el ámbito laboral, la concentración en el aire puede variar 
desde varios g/m3 a, en ocasiones, unos mg/m3, en función del 
proceso de que se trate y del contenido en níquel del material que 
se maneja. 

    Hay millones de trabajadores de todo el mundo expuestos a polvo 
y humo que contienen níquel durante las operaciones de soldadura, 
niquelado y pulimentado, la extracción minera, el afinado del 
níquel, y en las acerías, fundiciones y otras industrias 

    Hay una gran variedad de empleos en los que puede haber 
exposición cutánea al níquel, sea por contacto directo con el metal 
disuelto, como por ejemplo en las industrias de afinado, 
galvanoplastia y electroconformación, o bien por el manejo de 
herramientas que lo contienen. En los trabajos de limpieza con agua 
puede haber una exposición a este metal, a causa de las cantidades 
que lleva disueltas el agua de lavado. 

5. Cinetica y metabolismo en el hombre y en los animales

    El hombre y los animales pueden absorber níquel por inhalación, 
por ingestión o por vía cutánea. La absorción respiratoria, con 
asimilación gastrointestinal secundaria de níquel (soluble e 
insoluble), es la principal vía de penetración durante la 
exposición en el trabajo. Una cantidad importante del material 
inhalado se traga con el fluido mucociliar procedente del tracto 
respiratorio.  La mala higiene personal y las prácticas laborales 
deficientes pueden contribuir a la exposición gastrointestinal. La 
absorción percutánea es cuantitativamente insignificante, pero es 
importante en la patogenia de la hipersensibilidad por contacto. La 
absorción está relacionada con la solubilidad del compuesto, y 
sigue la relación general carbonilo de níquel > compuestos de 
níquel solubles > compuestos de níquel insolubles. El carbonilo de 
níquel es el compuesto de este metal que absorben de forma más 
rápida y completa el hombre y los animales. Hay pocos estudios en 
los que se haya administrado níquel por inhalación. En experimentos 
con hámsters y ratas tratados con óxido de níquel insoluble se 
observó una escasa absorción, con retención pulmonar de gran parte 
del material después de varias semanas. En cambio, la absorción de 
cloruro de níquel soluble o de sulfuro de níquel amorfo fue rápida. 
El níquel es transportado en la sangre, principalmente ligado a la 

    Su absorción gastrointestinal es variable y depende de la 
composición de la dieta. En un estudio reciente con un grupo de 
voluntarios se encontró que la absorción de níquel a partir del 
agua era del 27%, mientras que a partir de los alimentos era 
inferior al 1%. Todas las secreciones orgánicas, como la orina, la 
bilis, el sudor, las lágrimas, la leche y el fluido mucociliar, son 
posibles vías de eliminación. El níquel que no se absorbe se 
elimina con las heces. En roedores se ha demostrado que atraviesa 
la placenta. Tras la administración parenteral de sales de níquel, 
los niveles más altos de acumulación se producen en el riñon, las 
glándulas endocrinas y el hígado; si lo que se administra es 

carbonilo de níquel, también se observa una alta concentración en 
el cerebro. Los datos sobre excreción del níquel sugieren un modelo 
bicompartimental. Su concentración en el suero y la orina de 
adultos sanos no expuestos en el trabajo es de 0,2 µg/litro 
(oscilación: 0,05-1,1 µg/litro) y 1,5 µg/g de creatinina 
(oscilación: 0,5-4,0 µg/g de creatinina), respectivamente. Se ha 
observado que después de la exposición profesional, la 
concentración aumenta en ambos fluidos. La carga corporal de níquel 
en un adulto de 70 kg de peso no expuesto es de 0,5 µg. 

6. Efectos en los seres vivos del medio ambiente

    En los microorganismos, con concentraciones de 1-5 mg/litro de 
níquel en el medio se inhibía, en general, el crecimiento en 
actinomicetos, levaduras y eubacterias marinas y no marinas, y con 
niveles de 5-1000 mg/litro, en hongos filamentosos. En el caso de 
las algas, con una concentración aproximada de 0,05-5 mg de 
níquel/litro no se observó crecimiento. Ciertos factores abióticos, 
como el pH, la dureza, la temperatura y la salinidad del medio, así 
como la presencia de partículas orgánicas e inorgánicas, influyen 
en la toxicidad del níquel. 

    La toxicidad del níquel para los invertebrados acuáticos varía 
considerablemente en función de las especies y de los factores 
abióticos. En el género  Daphnia se ha encontrado una CL50 a las 96 
horas de 0,5 mg de níquel/litro, mientras que en moluscos los 
valores de la CL50 a las 96 horas fueron de unos 0,2 mg/litro en 
dos especies de caracol de agua dulce y de 1100 mg/litro en un 

    En los peces, los valores de la CL50 a las 96 horas suelen 
oscilar entre 4 y 20 mg de níquel/litro, pero pueden ser más altos 
en algunas especies. Los estudios a largo plazo realizados sobre 
los peces y su crecimiento en aguas blandas pusieron de manifiesto 
que niveles tan bajos como 0,05 mg de níquel/litro tenían algunos 
efectos en la trucha arco iris. En plantas terrestres se ha 
encontrado que los niveles superiores a 50 mg/kg de peso seco 
suelen ser tóxicos. Se ha observado que desde el punto de vista 
toxicologica el cobre tiene un efecto sinérgico con el níquel, 
mientras que el calcio reduce su toxicidad. Hay pocos datos acerca 
de los efectos del níquel en animales terrestres. 

    La lombriz de tierra parece ser relativamente insensible a este 
metal si el medio es rico en microorganismos y materia orgánica, 
que dejan menos níquel disponible para aquella. Aunque el níquel no 
se ha considerado un contaminante mundial en gran escala, en las 
cercanías de fuentes emisoras se han observado cambios ecológicos, 
como la disminución del número y la diversidad de especies. En 
estudios de microecosistemas se ha puesto de manifiesto que la 
adición de este elemento al suelo altera el ciclo del nitrógeno. 

7. Efectos en los animales de experimentación y en sistemas de
prueba  in vitro 

    El níquel es indispensable para la actividad catalítica de 
algunas enzimas vegetales y bacterianas. En algunas especies 
animales se ha señalado que una dieta carente de níquel provoca 
lentitud en la ganacia de peso, anemia y una disminución de la 
viabilidad de la descendencia. 

    El compuesto de toxicidad más aguda es el carbonilo de níquel, 
cuyo órgano destinatario es el pulmón; dentro de las cuatro horas 
siguientes a la exposición puede aparecer edema pulmonar. La 
toxicidad aguda de los demás compuestos del níquel es baja. 

    Aunque la alergia de contacto causada por este metal es muy 
frecuente en el hombre, en animales sólo se consigue inducir 
sensibilización experimental en determinadas condiciones. La 
exposición a un largo período de inhalación de níquel metálico, 
óxido de níquel o subsulfuro de níquel causó lesiones en las 
mucosas y una reacción inflamatoria del tracto respiratorio en 
ratas, ratones y cobayos. En ratas expuestas a la inhalación de 
aerosoles de cloruro de níquel u óxido de níquel se observó 
hiperplasia epitelial. 

    La exposición a altos niveles de óxido de níquel durante un 
período prolongado produjo una neumoconiosis progresiva en ratas. 
En conejos expuestos a un nivel elevado de polvo de níquel-grafito 
se observó una reacción inflamatoria, a veces acompañada de una 
ligera fibrosis. Las ratas expuestas a subsulfuro de níquel 
presentaron fibrosis pulmonar. 

    La administración de sales de níquel a ratas, conejos y pollos 
por vía parenteral indujo una hiperglucemia rápida transitoria. 
Estos cambios pueden estar relacionados con los efectos en las 
células alfa y beta de los islotes de Langerhans. El níquel también 
disminuyo la liberación de prolactina. Se ha informado de que la 
administración por vía oral o respiratoria de cloruro de níquel 
reduce la absorción de yodo por el tiroides. 

    La administración intravenosa de sales de níquel a perros hizo 
disminuir el flujo sanguíneo en las arterias coronarias; la 
concentración elevada de este metal redujo la contractibilidad del 
miocardio de perro  in vitro. 

    El cloruro de níquel afecta al sistema de células T y suprime 
la actividad de las células destructoras naturales. Se ha observado 
que la administración parenteral de cloruro de níquel y de 
subsulfuro de níquel a ratas y ratones causa mortalidad 
intrauterina y una disminución de la ganancia de peso. En ratas y 
hámsters expuestos a inhalaciones de carbonilo de níquel se produjo 
la muerte de fetos y una disminución de la ganancia de peso, y tuvo 
también un efecto teratógenico. En ninguno de esos estudios se 
informa acerca de la toxicidad materna. Se ha señalado que el 
carbonilo de níquel ocasiona mutaciones letales dominantes en la 

    Se han hecho pruebas con distintos sistemas para determinar la 
mutagenicidad de varios compuestos inorgánicos del níquel. Estos, 
en general, se mostraron inactivos en los ensayos de mutagénesis 
efectuados con bacterias, excepto en los casos en que se utilizaron 
pruebas de fluctuación. Se observaron mutaciones en varios tipos de 
células de mamíferos cultivadas. Los compuestos del níquel 
inhibieron la síntesis de ADN en una gran variedad de organismos. 
Además, produjeron aberraciones cromosómicas e intercambio de 
cromátidas hermanas en cultivos de células tanto de mamíferos como 
humanas. En personas profesionalmente expuestas a compuestos de 
níquel insolubles o solubles se observaron aberraciones 
cromosómicas, pero no intercambio de cromátidas hermanas (excepto 
en un estudio sobre personas que trabajan en electrólisis). El 
níquel indujo transformación celular  in vitro. 

    En un estudio de inhalación en ratas, el subsulfuro de níquel 
provocó la aparición de tumores pulmonares benignos y malignos. En 
una serie de estudios de inhalación de carbonilo de níquel en la 
rata, se observaron algunos tumores pulmonares. En un estudio de 
inhalación de níquel metálico efectuado en ratas no se apreció un 
aumento importante de tales tumores. La inhalación de óxido de 
níquel negro no indujo la aparición de tumores pulmonares en 
hámsters dorados sirios (especie resistente a la carcinogénesis 
pulmonar). No se conocen estudios adecuados sobre la carcinogénesis 
por inhalación de otros compuestos del níquel. Sin embargo, la 
instilación intratraqueal repetida de subsulfuro de níquel, de 
polvo de níquel metálico y de un óxido de níquel no especificado 
produjo en ratas tumores pulmonares benignos y malignos. 

    El carbonilo de níquel, el niqueloceno y gran número de 
compuestos del níquel ligeramente solubles o insolubles, entre 
ellos el subsulfuro, el carbonato, el cromato, el hidróxido, los 
sulfuros, los seleniuros, los arseniuros, el telururo, el 
antimoniuro, diversas preparaciones de óxidos no identificadas, dos 
óxidos de níquel y cobre, el níquel metálico y diversas aleaciones 
de níquel provocaron tumores mesenquimáticos locales en distintos 
animales de experimentación tras la administración por vía 
intramuscular, subcutánea, intraperitoneal, intrapleural, 
intraocular, intraósea, intrarrenal, intraarticular, 
intratesticular o intraadiposa. No se observó respuesta 
carcinogénica local en los estudios de dosis única con algunas 
aleaciones de níquel, hidróxido de níquel coloidal o dos muestras 
de óxido de níquel, especialmente preparados para pruebas de 
carcinogénesis mediante calcinación a 735 °C o bien a 1045 °C. 

    La administración repetida de sulfato y acetato de níquel a 
ratas por vía intraperitoneal indujo tumores en la cavidad 
peritoneal, pero no la de cloruro de níquel. 

    Se han realizado pruebas de carcinogénesis mediante la 
administración por vía parenteral de níquel metálico y de una gran 
variedad de compuestos; salvo algunas excepciones, se produjeron 
tumores locales. 

    Sólo en el caso del subsulfuro de níquel se ha demostrado de 
manera convincente que la inhalación produce cáncer. Sin embargo, 
hay muy pocos estudios adecuados sobre la exposición por vía 

    En los estudios de aplicación de instilaciones intratraqueales 
repetidas de polvo de níquel, óxido de níquel y subsulfuro de 
níquel aparecieron tumores pulmonares. 

    Cuando se realizaron pruebas con tres sales solubles de níquel 
distintas que en estudios anteriores no habían provocado la 
aparición de tumores locales, utilizando la administración 
intraperitoneal repetida, dos de las sales indujeron una respuesta 

8. Efectos en la especie humana

    En relación con la salud del ser humano, el carbonilo de níquel 
es el compuesto del metal con toxicidad más aguda. Entre los 
efectos de la intoxicación aguda que causa están dolor de cabeza 
frontal, vértigo, náuseas, vómitos, insomnio e irritabilidad, 
seguidos de trastornos pulmonares análogos a los producidos por una 
neumonía vírica. Entre las lesiones patológicas de los pulmones 
figuran hemorragias, edema y desorganización celular. También se 
ven afectados el hígado, los riñones, las cápsulas suprarrenales, 
el bazo y el cerebro. Ha habido asimismo casos de intoxicación en 
pacientes sometidos a diálisis con contaminación de níquel y en 
galvanizadores que accidentalmente han ingerido agua contaminada 
por sulfato y cloruro de níquel. 

    Se han notificado casos de efectos crónicos, como rinitis, 
sinusitis, perforación del tabique nasal y asma, entre trabajadores 
del afinado del níquel y del niquelado. Algunos autores han 
descrito alteraciones pulmonares con fibrosis en personas que en el 
trabajo respiraban polvo de níquel. Además, se ha informado de 
casos de displasia nasal en trabajadores del afinado del níquel. 
Hay abundante documentación acerca de la hipersensibilidad por 
contacto, tanto en la población en general como en algunos 
trabajadores profesionalmente expuestos a compuestos solubles de 
níquel. En varios países se ha comunicado que el 10% de la 
población femenina y el 1% de la masculina son sensibles al níquel. 
De ellos, el 40-50% tienen eccema vesicular en las manos; en 
algunos casos puede ser muy grave y causa de incapacidad laboral. 
La ingestión de níquel puede agravar la eccema vesicular de las 
manos y, posiblemente, inducir también su aparición en otras partes 
del cuerpo que no han tenido contacto cutáneo con este metal. 

    Se sabe que las prótesis y otras implantaciones quirúrgicas de 
aleaciones con níquel causan sensibilización a este elemento o 
agravan la dermatitis existente. 

    Se han descrito efectos nefrotóxicos, como edema renal con 
hiperemia y degeneración parenquimatosa, en casos de exposición 
industrial accidental a carbonilo de níquel. También se han 
registrado efectos nefrotóxicos pasajeros por ingestión accidental 
de sales de níquel. 

    Se ha informado de un elevadísimo riesgo de cáncer del pulmón y 
la nariz en los trabajadores del afinado del níquel que se ocupan 
de tostar a alta temperatura los minerales de sulfuro, lo que 
supone una gran exposición al subsulfuro, el óxido y quizás el 
sulfato de níquel. Se han señalado riesgos análogos en los procesos 
que entrañan exposición al níquel soluble (electrólisis, extracción 
de sulfato de cobre, hidrometalurgia), a menudo combinados con 
alguna exposición al óxido de níquel pero muy poca al subsulfuro. 
El riesgo de los mineros y otros trabajadores del afinado parece 
ser mucho menor. El índice de cáncer entre los soldadores de acero 
inoxidable y los trabajadores de industrias que usan níquel ha 
sido, en general, casi normal, salvo cuando hay exposición al 
cromo, particularmente en la galvanoplastia. Sin embargo, los 
trabajadores que hacen baterías de níquel/cadmio y están expuestos 
a altos niveles de ambos metales corren un riesgo ligeramente mayor 
de contraer cáncer de pulmón. 

    Ocasionalmente se ha notificado en trabajadores del níquel una 
frecuencia excesiva de otros tipos de cáncer distintos del de 
pulmón y el nasal, como por ejemplo renal, gástrico o de próstata, 
pero ninguno se ha encontrado de manera constante. 

    Se pueden utilizar los datos epidemiológicos para plantear dos 
importantes cuestiones: i) si se ha demostrado que ciertos 
compuestos de níquel que son carcinógenos; y ii) si las cohortes 
sometidas a bajas exposiciónes presentan límites superiores de 
riesgo a determinados niveles de exposición. 

 a) Níquel soluble 

    Se obtuiseron pruebas de que los trabajadores expuestos a 
concentraciones de níquel soluble del orden de 1-2 mg/m3, tanto en 
el sector de la electrólisis como en el de la preparación de sales 
solubles, corrían riesgo de cáncer. Esos trabajadores estaban 
expuestos también a otros compuestos de níquel, pero con frecuencia 
a niveles más bajos que en otros procesos de alto riesgo. En 
ausencia de mediciones anteriores de la exposición, es imposible 
llegar a conclusiones definitivas, pero las pruebas de que el 
níquel soluble es carcinógeno son ciertamente sólidas. El polvo del 
afinado contiene a veces una proporción importante de sulfato de 
níquel, además de subsulfuro. Esto plantea la posibilidad de que el 
altísimo riesgo de cáncer observado en los trabajadores que se 
ocupan de la oxidación de subsulfuro de níquel a alta temperatura 
pueda deberse en parte al níquel soluble. 

 b) Subsulfuro de níquel 

    En las zonas de afinado donde el riesgo de contraer cáncer era 
alto, la exposición al subsulfuro de níquel casi siempre iba 
acompañada de la exposición al óxido y, quizás, al sulfato (véase 
más arriba). Así pues, basándose solamente en los datos 
epidemiológicos, es dificil demonstrar que el subsulfuro de níquele 
sea carcinógeno, aunque parece probable. 

 c) Oxido de níquel 

    El óxido de níquel estaba presente en casi todas las 
circunstancias en que el riesgo de cáncer era elevado, acompañado 
de una o más formas del elemento (subsulfuro de níquel, níquel 
soluble, níquel metálico). Como en el caso del subsulfuro de 
níquel, es difícil afirmar o negar su carácter carcinogénico 
basándose exclusivamente en los datos epidemiológicos. 

 d) Níquel metálico 

    No se ha demostrado que los trabajadores expuestos 
exclusivamente al níquel metálico corran mayor riesgo de cáncer. 
Los datos combinados relativos a trabajadores que se ocupan de 
aleaciones de níquel y los dedicados a difusión gaseosa, todos 
ellos expuestos a concentraciones medias del orden de 0,5 mg de 
níquel/m3, no muestran un riesgo excesivo, aunque el número total 
de casos de cáncer de pulmón en estas cohortes era demasiado 
pequeño para excluir un pequeño aumento del riesgo a este nivel. 

 e) Conclusión 

    Aunque algunas, y quizás todas, las formas del níquel pueden 
ser carcinógenas, con los niveles normales de exposición en muchos 
sectores de la industria de este metal hay un riesgo pequeño o no 
detectable; entre ellos se encuentran algunos procesos que en el 
pasado estaban asociados con un riesgo muy alto de cáncer pulmonar 
y nasal. La exposición prolongada a concentraciones del orden de 1 
mg/m3 de níquel soluble puede ocasionar un importante aumento del 
riesgo relativo de cáncer de pulmón, pero este riesgo entre los 
trabajadores expuestos a un nivel medio de níquel metálico de 
alrededor de 0,5 mg/m3 es aproximadamente 1. El riesgo de cáncer 
con un determinado nivel de exposición puede ser más alto para los 
compuestos de níquel solubles que para el níquel metálico, y 
posiblemente, que para otras formas. No es extraña la ausencia de 
cualquier riesgo pronunciado de cáncer pulmonar entre los 
niqueladores, puesto que el promedio de exposición al níquel 
soluble es mucho más bajo que el que se produce en el afinado 
electrolítico o en el tratamiento de sales de níquel. 

    See Also:
       Toxicological Abbreviations
       Nickel (ICSC)
       Nickel (IARC Summary & Evaluation, Volume 49, 1990)