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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 61





    CHROMIUM









    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    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

    World Health Orgnization
    Geneva, 1988


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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR CHROMIUM

1. SUMMARY AND RECOMMENDATIONS

    1.1. Summary
         1.1.1. Analytical methods
         1.1.2. Sources of chromium, environmental levels and exposure
         1.1.3. Metabolism
         1.1.4. Effects on experimental animals
         1.1.5. Effects on human beings
                1.1.5.1  Clinical and epidemiological studies
         1.1.6. Evaluation of risks for human health
    1.2. Recommendations for further research
         1.2.1. Analytical methods
         1.2.2. Sources of chromium intake
         1.2.3. Studies on health effects
         1.2.4. Interaction with other environmental factors

2. PHYSICAL AND CHEMICAL PROPERTIES AND ANALYTICAL METHODS

    2.1. Physical and chemical properties
    2.2. Analytical methods
         2.2.1. Sampling
         2.2.2. Analytical methods

3. SOURCES IN THE ENVIRONMENT, ENVIRONMENTAL TRANSPORT AND DISTRIBUTION

    3.1. Natural occurrence
         3.1.1. Rocks
         3.1.2. Soils
         3.1.3. Water
         3.1.4. Air
         3.1.5. Plants and wildlife
         3.1.6. Environmental contamination from natural sources
    3.2. Production, consumption, and uses
    3.3. Waste disposal
    3.4. Miscellaneous sources of pollution
    3.5. Environmental transport and distribution

4. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    4.1. Environmental levels
         4.1.1. Air
         4.1.2. Water
         4.1.3. Food
    4.2. General population exposure
         4.2.1. Food and water
         4.2.2. Other exposures
    4.3. Occupational exposure
         4.3.1. Inhalation exposure
         4.3.2. Dermal exposure

5. KINETICS AND METABOLISM

    5.1. Absorption
         5.1.1. Absorption through inhalation
                5.1.1.1  Animal studies
                5.1.1.2  Human data
         5.1.2. Absorption from the gastrointestinal tract
                5.1.2.1  Animal studies
                5.1.2.2  Human data
    5.2. Distribution, retention, excretion
         5.2.1. Animal studies
         5.2.2. Human data
                5.2.2.1  Concentration in tissues, blood, urine,
                         and hair including possible biological
                         indicators of exposure
                5.2.2.2  Dynamic aspects of metabolism
                         and the influence of pathological states
    5.3. Influence of chemical form

6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    6.1. Microorganisms
    6.2. Plants
    6.3. Aquatic organisms

7. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    7.1. Nutritional effects of chromium
         7.1.1. Effects of deficiency on glucose metabolism
         7.1.2. Effects of deficiency on lipid  metabolism
         7.1.3. Effects of deficiency on life span, growth, and reproduction
         7.1.4. Other effects of deficiency
         7.1.5. Mechanism of action of chromium as an essential nutrient
                7.1.5.1  Enzymes, nucleic acids, and thyroid
                7.1.5.2  Interaction of chromium with insulin
         7.1.6. Chromium nutritional requirements of animals
     7.2. Toxicity studies
         7.2.1. Effects on experimental animals
                7.2.1.1  Carcinogenicity
                7.2.1.2  Genotoxicity
                7.2.1.3  Developmental toxicity and other
                         reproductive effects
                7.2.1.4  Cytotoxicity and micromolecular syntheses
                7.2.1.5  Fibrogenicity
         7.2.2. Observations in farm animals

8. EFFECTS ON MAN

    8.1. Nutritional role of chromium
         8.1.1. Biological measurements and their interpretation
         8.1.2. Chromium deficiency
                8.1.2.1  Adults
                8.1.2.2  Malnourished children
                8.1.2.3  Patients on total parenteral alimentation
                8.1.2.4  Epidemiological studies

         8.1.3. Mode of action
    8.2. Acute toxic effects
    8.3. Chronic toxic effects
         8.3.1. Effects on skin and mucous membranes
                8.3.1.1  Primary irritation of the skin
                         and mucous membranes
                8.3.1.2  Allergic contact dermatoses
         8.3.2. Effects on the lung
                8.3.2.1  Bronchial irritation and sensitization
         8.3.3. Effects on the kidney
         8.3.4. Effects on the liver
         8.3.5. Effects on the gastrointestinal tract
         8.3.6. Effects on the circulatory system
         8.3.7. Teratogenicity
         8.3.8. Mutagenicity and other short-term tests
         8.3.9. Carcinogenicity
                8.3.9.1  Lung cancer
                8.3.9.2  Cancer in organs other than lungs
                8.3.9.3  Relative risk between cancer risk
                         and chromium compound

9. EVALUATION OF HEALTH RISKS FOR MAN

    9.1. Occupational exposure
         9.1.1. Effects other than cancer
                9.1.1.1  Respiratory tract
                9.1.1.2  Skin
                9.1.1.3  Kidney
                9.1.1.4  Other organs and systems
         9.1.2. Teratogenicity
    9.2. General population

REFERENCES

WHO TASK GROUP ON CHROMIUM

 Members

Professor Chen Bingheng, Department of Environmental Health,
   Shanghai Medical University, Shanghai, China

Dr H.N.B. Gopalan, University of Nairobi, Department of Botany,
   Nairobi, Kenya

Professor C.R. Krishna Murti, Integrated Environmental 
   Programme on Heavy Metals, Department of Environment,
   Government of India, New Delhi, India  (Vice-Chairman)

Professor Aly Massoud, Department of Community, Environmental
   and Occupational Medicine, Faculty of Medicine, Ain Shams
   University, Cairo, Egypt

Dr W. Mertz, Human Nutrition Research Center, US Department of
   Agriculture, Beltsville, Maryland, USA  (Chairman)

Professor I.V. Sanotsky, Department of Toxicology, Institute
   of Industrial Hygiene and Occupational Diseases, Academy
   of Medical Sciences of the USSR, Moscow, USSR

Professor W. Stber, Fraunhofer Institute for Toxicology and
   Aerosol Research, Hanover, Federal Republic of Germany

 Secretariat

Dr J. Parizek, International Programme on Chemical Safety,
   World Health Organization, Geneva, Switzerland  (Secretary)

Dr R.F. Hertel, Fraunhofer Institute for Toxicology and
   Aerosol Research, Hanover, Federal Republic of Germany
    (Temporary Adviser) (Rapporteur)

Dr T. Ng, Office of Occupational Health, World Health
   Organization, Geneva, Switzerland

Mr J.D. Wilbourn, Unit of Carcinogen Identification and
   Evaluation, International Agency for Research on Cancer,
   Lyons, France


NOTE TO READERS OF THE CRITERIA DOCUMENTS

    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. 988400 - 
985850). 


ENVIRONMENTAL HEALTH CRITERIA FOR CHROMIUM

    A WHO Task Group on Environmental Health Criteria for Chromium 
met in Geneva from 24 to 27 March 1986. Dr J. Parizek opened the 
meeting on behalf of the Director-General.  The Task Group reviewed 
and revised the draft criteria document and made an evaluation of 
the health risks of exposure to chromium. 

    The initial draft was prepared by the INSTITUTE FOR GENERAL AND 
COMMUNITY HYGIENE, MOSCOW.  The second draft criteria document was 
prepared by DR W. MERTZ, HUMAN NUTRITION RESEARCH CENTER, US 
DEPARTMENT OF AGRICULTURE, USA, PROFESSOR ANNA BAETGER, JOHN 
HOPKINS UNIVERSITY, BALTIMORE, USA (deceased), and Dr R.F. HERTEL, 
FRAUNHOFER INSTITUTE OF TOXICOLOGY AND AEROSOL RESEARCH, Federal 
Republic of Germany. 

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


                         * * *


    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.  The United Kingdom Department of Health and Social 
Security generously supported the cost of printing. 



1.  SUMMARY AND RECOMMENDATIONS

1.1.  Summary

1.1.1.  Analytical methods

    Many analytical methods are available for the determination of 
chromium at trace levels, often in the 0.001 mg/kg range.  Among 
these are flameless atomic absorption spectrometry, atomic emission 
spectrometry with various excitation sources (the inductively-
coupled plasma torch is particularly advantageous), gas 
chromatography, destructive or non-destructive neutron activation 
analysis, and mass spectrometry using double-isotope dilution.  
Depending on the particular sample under examination as well as the 
analytical technique selected for the determination, wet or dry 
ashing procedures may be necessary to destroy the organic/inorganic 
matrix and minimize interelemental effects. 

    Determination of very low chromium concentrations in 
"unexposed" biological material (animal and human tissues, blood, 
urine, food, as well as water and air) is extremely difficult and 
many problems still have to be solved.  An accurate assessment of 
human exposure and nutritional chromium requirements depends on 
reliable analytical results. Chromium concentrations in blood, 
urine, and some low-chromium foods are close to or less than 1 
g/kg, which is near the detection limit of even the most sensitive 
analytical methods.  Thus, agreement as to "normal" levels of 
chromium among analytical investigators has been poor, and results 
of interlaboratory comparisons have differed widely, usually by one 
order of magnitude. Only in recent years has agreement been reached 
that "normal" chromium concentrations in unexposed blood and urine 
are in the range of 0.1 - 0.5 g/litre.  In this concentration 
range, it is not only the sensitivity of the final determination 
step that is limiting.  The preceding steps of sample collection, 
preparation, and digestion are equally important.  Contamination, 
easily introduced through cutting instruments and dust during 
collection, must be carefully controlled.  Digestion procedures are 
of the greatest importance.  Too rigorous treatment by heat or 
certain acids can cause a loss of chromium.  Few biological 
standard reference materials, certified for chromium, are available 
and almost all of the older, and most of the recent, published data 
were not checked using certified standards. For this reason, 
quantitative data concerning chromium concentrations in the range 
of < 1 - 100 g/kg in biological materials must be considered 
uncertain, and caution must be used in interpreting their health-
related significance. 

    Differential analysis for chromium species is of great 
scientific and public health concern, in view of the substantial 
differences in the biological availability and in the toxicity of 
hexavalent chromium (Cr VI) compared with trivalent (Cr III).  
Though methods based on solvent extraction, with or without prior 
oxidation, differentiate between these two oxidation states, few 
analytical data contain this important information. 

    The understanding of the chemical and physical principles of 
chromium determination is increasing, and existing methods are 
being improved and new methods developed.  However, at present, 
analysis for chromium is a sophisticated procedure requiring the 
full attention of a highly trained analytical chemist. 

1.1.2.  Sources of chromium, environmental levels and exposure

    Chromium occurs ubiquitously in nature (< 0.1 g/m3 in air).  
Natural levels in uncontaminated waters range from fractions of 1 
g to a few g/litre. 

    The concentration of chromium in rocks varies from an average 
of 5 mg/kg (granitic rocks) to 1800 mg/kg (ultramafic/basic and 
serpentine rocks).  The earth's most important deposits are either 
in the elemental or the trivalent oxidation state. 

    In most soils, chromium occurs in low concentrations (2 - 60 
mg/kg), but values of up to 4 g/kg have been reported in some 
uncontaminated soils.  Only a fraction of this chromium is 
available to plants.  It is not known whether chromium is an 
essential nutrient for plants, but all plants contain the element 
(up to 0.19 mg/kg on a  wet weight basis). 

    Almost all the hexavalent chromium in the environment arises 
from human activities.  It is derived from the industrial oxidation 
of mined chromium deposits and possibly from the combustion of 
fossil fuels, wood, paper, etc.  In this oxidation state, chromium 
is relatively stable in air and pure water, but it is reduced to 
the trivalent state, when it comes into contact with organic matter 
in biota, soil, and water.  There is an environmental cycle for 
chromium, from rocks and soils to water, biota, air, and back to 
the soil. However, a substantial amount (estimated at 6.7 x 106 kg 
per year) is diverted from this cycle by discharge into streams, 
and by runoff and dumping into the sea.  The ultimate repository is 
ocean sediment. 

    Chromium compounds are used in ferrochrome production, 
electroplating, pigment production, and tanning.  These industries, 
the burning of fossil fuels, and waste incineration are sources of 
chromium in air and water.  Most of the liquid effluent from the 
chromium industries is trapped and disposed of in land fills and 
sewage sludges, the chromium being in the form of the insoluble 
trivalent hydroxide. 

    In chromium ore mines, the concentration of chromium in dust 
ranges from 1.3 to 16.9 mg/m3.  During the production of refined 
ferrochromium, the air in the work-place may contain large amounts 
of dust (0.03 - 3.2 mg/m3).  In chromium plating factories, 
concentrations of 1 g/m3 up to 1.4 mg/m3 have been measured.  In 
Portland cement from 9 European countries, the contents of chromium 
(VI), extractable with sodium sulfate, varied from 1 to 83 g/kg 
cement. 

    Today, it is generally accepted that only the zero-, di-, tri-, 
and hexavalent oxidation states have biological importance.  The 
effects of the last 2 oxidation states are so fundamentally 
different that they must always be considered separately.  The 
trivalent form is an essential nutrient for man, in amounts of 50 - 
200 g/day. 

1.1.3.  Metabolism

    The kinetics of chromium depend on its oxidation state and the 
chemical and physical form within the oxidation state. Most of the 
daily chromium intake (50 - 200 g) is ingested with food and is in 
the trivalent form.  About 0.5 - 3% of the total intake of 
trivalent chromium is absorbed in the body. It is possible, but it 
has not yet been proved, that chromium in the form of some 
complexes, such as a dinicotinic-acid-complex, glucose tolerance 
factor, is better available for absorption.  The gastrointestinal 
absorption of 3 - 6% of the total intake of hexavalent chromium has 
been reported.  Once absorbed, chromium is almost entirely excreted 
with the urine; the daily urinary-chromium loss of 0.5 - 1.5 g is 
approximately equal to the amount absorbed from the average diet.  
However, dermal losses, losses by desquamation of intestinal cells 
and by perspiration have not been quantified.  Ingested or injected 
chromium leaves the blood rapidly.  Blood-chromium levels do not 
reflect the overall chromium content of tissues, except after a 
glucose load, which induces an immediate increase in the plasma- 
and urine-chromium levels of chromium-sufficient subjects. 
Trivalent chromium inhaled from the air is trapped in the lung 
tissues, if in the form of small particles within the respirable 
range.  The chromium concentrations in lungs increases with age.  
Larger particles (greater than 5 m), regardless of oxidation 
state, are moved to the larynx by ciliary action and become part of 
the dietary intake. 

    The intestinal absorption of hexavalent chromium is 3 - 5 times 
greater than that of trivalent forms; however, some of it is 
reduced by gastric juice.  Soluble chromates are rapidly absorbed 
through the epithelium of the alveoli and bronchi and cleared into 
the circulation, where part is preferentially accumulated by the 
red cells and part is excreted by the kidneys.  With the exception 
of the lungs, tissue levels of chromium decline with age. 

1.1.4.  Effects on experimental animal

    Doses of hexavalent chromium greater than 10 mg/kg diet affect 
mainly the gastrointestinal tract, kidneys, and probably the 
haematopoetic system.  When a similar dose is introduced 
parenterally, the principal effect is on the kidney, mainly in the 
proximal convoluted tubules, without evidence of glomerular damage.  
Toxic effects from trivalent chromium have been reported only 
following parenteral administration.  Dietary toxicity has not been 
reported, even in studies on cats administered amounts of up to 1 
g/day for 1 - 3 months.  When intravenously injected in mice, the 
LD50 of chromium carbonyl was 30 mg/kg body weight; this represents 
a 10 000-fold excess over the therapeutic dose required to cure 
signs of chromium deficiency. 

    Many studies on experimental animals have been conducted with 
chromium compounds in efforts to reproduce cancer similar to that 
found in man, when exposed to chromium. 

    Most tests have involved subcutaneous, intramuscular, or 
intrapleural injection.  In addition, several hexavalent chromium 
compounds have been administered to rats by intrabronchial 
implantation or intratracheal instillation. Relatively insoluble 
compounds, calcium chromate, strontium chromate, and certain forms 
of zinc chromate produced bronchogenic carcinomas; lead chromate, 
and barium chromate produced weak responses.  Intratracheal 
instillation of soluble sodium dichromate and dissolved calcium 
chromate produced bronchogenic tumours.  Injection of lead 
chromate, lead chromate oxide, and cobalt-chromium alloy resulted 
in the production of local sarcomas.  Thus, there is sufficient 
evidence that certain hexavalent chromium compounds are 
carcinogenic for experimental animals.  No increased tumour 
incidence was observed when trivalent compounds were given orally; 
however, the doses administered were low. 

    Hexavalent chromium has been reported to cause various forms of 
genetic damage in short-term mutagenicity tests, including damage 
to DNA, and misincoporation of nucleotides in DNA transcription.  
It was mutagenic in bacteria in the absence of an exogenous 
metabolic activation system, and in fungi.  Hexavalent chromium was 
also mutagenic in mammalian cells  in vitro and  in vivo.  
Hexavalent chromium caused chromosomal abererations and sister 
chromatid exchanges in mamalian cells  in vitro.  A few positive 
results in  in vitro assays for mammalian cell chromosomal 
aberrations and sister chromatid exchanges were obtained only with 
very high doses and could be explained by nonspecific toxic 
effects.  It induced formation of micronuclei in mice  in vivo.  
Potassium dichromate induced dominant lethal mutations in mice 
treated  in vivo. 

    Trivalent chromium is genetically active only in  in vitro
tests, where it can have a direct interaction with DNA, e.g., in 
experiments using purified DNA or tests to measure decreased 
fidelity of DNA synthesis  in vitro.  Reduction of chromium (VI) 
within the cell nucleus and the formation of chromium (III) 
complexes suggests that chromium (III) would be the ultimate 
mutagenic form of chromium.  Trivalent chromium was present in RNAs 
from all sources examined and probably contributes to the stability 
of the structure.  Injected chromium trichloride (CrCl3) 
accumulated in the cell nucleus (up to 20% of cellular chromium 
content).  It enhanced RNA synthesis in mice and in regenerating 
rat liver, suggesting that chromium (III) is involved directly in 
RNA synthesis.  On the other hand, chromium (VI) inhibited RNA 
synthesis and DNA replication in several systems. 

1.1.5.  Effects on human beings

    Studies on man and experimental animals have established the 
essential role of trivalent chromium for the maintenance of normal 
glucose metabolism.  Chromium deficiency has been demonstrated in 

malnourished children, in two patients on total parenteral 
nutrition, and in middle-aged subjects, the basic disturbance being 
an impairment of the action of circulating insulin. 

1.1.5.1.  Clinical and epidemiological studies

    In adult human subjects, the lethal oral dose is 50 - 70 mg 
soluble chromates/kg body weight.  The most important clinical 
features produced following this route of entry are liver and 
kidney necrosis and poisoning of blood-forming organs. 

    Hexavalent chromium causes marked irritation of the respiratory 
tract.  Ulceration and perforation of the nasal septum have 
occurred frequently in workers employed in the chromate producing 
and hexavalent chromium-using industries. In addition to 
inhalation, direct contact of the nasal septum with contaminated 
hands contributes to nasal exposure.  Cancer of the septum has not 
been reported.  Rhinitis, bronchospasm, and pneumonia may result 
from exposure to hexavalent compounds together with impairment of 
pneumodynamics during respiration. 

    Chromate compounds, mainly sodium and potassium chromate and 
dichromate, cause irritation of the skin and ulcers may develop at 
the site of skin damage.  Exposure to trivalent chromium does not 
produce such effects.  Certain persons manifest allergic skin 
reactions to hexavalent and possibly trivalent chromium.  Skin 
reactions through dermal exposure to chromium are often described, 
chromate being the most common contact allergen.  However, cancer 
of the skin due to chromium exposure has not been reported. 

    Chronic effects of exposure to chromium (excessive industrial 
exposure of the skin to hexavalent chromium, when associated with 
damaged skin or inhalation of airborne chromium (VI) or mixed dust) 
occur in the lung, liver, kidney, gastrointestinal tract, and 
ciculatory system.  Teratogenic risks from chromium exposure have 
not been reported for human subjects; a mutagenic potency is shown 
for potassium dichromate and therefore cannot be excluded for 
chromates in the chromate-using industries. 

    The results of epidemiological studies in various countries 
have demonstrated that men working in chromate-production plants 
before 1950 had a very high rate of bronchogenic carcinoma, 
compared with control populations. Because of the long period 
between initial exposure and the detection of cancer and the lack 
of data on the extent and type of exposure, the dose-response 
relationship has not been quantified.  However, the few data 
available indicate that, before the danger of cancer was 
recognized, the exposure levels in such plants were very high.  
Recent data show clearly that, though the risk of cancer in workers 
in modern plants has been greatly reduced, it still remains a 
problem. 

    Some epidemiological data suggest that an excess of lung cancer 
has also occurred in the chromate-pigment industry.  A few cases of 
cancer involving the upper respiratory tract have been reported, 
but cancer has not been convincingly demonstrated in other body 

tissues.  The specific compounds responsible for the cancers have 
not been identified.  Both hexavalent and trivalent compounds were 
present in the old plants.  However, on the basis of experimental 
animal studies, it is currently assumed that the slowly soluble, 
hexavalent chemicals, such as calcium and zinc chromate are 
responsible for the cancers.  This is based on the theory that 
these compounds remain in contact with the tissues for long periods 
of time (depot effect). 

    Trivalent chromium is not considered to be carcinogenic for the 
following reasons: (a) there was no evidence of excess cancer in 
studies in two industries where only trivalent compounds were 
present; (b) results of experimental animal and mutagenicity 
studies with trivalent chromium, were negative; and (c) because of 
the chemical and biological characteristics of the trivalent state, 
i.e., non-oxidizing, non-irritating, and probably unable to 
penetrate cell membranes. 

1.1.6.  Evaluation of risks for human health

    Chromium in the form of trivalent compounds is an essential 
nutrient.  The daily human intake of chromium varies considerably 
between regions.  Typical values range from 50 to 200 g/day.  Such 
intakes do not represent a toxicity problem, and they coincide with 
the calculated human requirements.  Not enough data are available 
for a quantitative assessment of the risk of chromium deficiency in 
different populations. 

    Evidence from studies on experimental animals shows that 
hexavalent chromium compounds, especially those of low solubility 
can induce lung cancer.  Mutagenicity and related studies have 
shown convincingly that hexavalent chromium is genetically active.  
On the other hand, trivalent chromium compounds are  inactive in 
most test systems, except in systems where they can directly 
interact with DNA. 

    Both oxidation states, when injected at high levels 
parenterally in animals, are teratogenic, with the hexavalent form 
accumulating in the embryos to a much greater extent than the 
trivalent. 

    A number of effects can result from occupational exposure to 
airborne chromium, including irritative lesions of the skin and 
upper respiratory tract, allergic reactions, and cancers of the 
respiratory tract.  The data on other effects in, e.g., the 
gastrointestinal, cardiovascular, and urogenital systems are 
insufficient for evaluation. 

    Epidemiological studies have shown that workers engaged in the 
production of chromate salts and chromate pigments are at increased 
risk of developing bronchial carcinoma.  No detailed data on dose-
response relationships are available.  Although a suspicion of 
increased lung cancer risks in chromium-plating workers has been 
raised, the available data are inconclusive and so are data for 
other industrial processes where chromium compounds are used rather 

than produced.  There is insufficient evidence to implicate 
chromium as a causative agent of cancer in any organ other than the 
lung.  The frequency of sister chromatid exchanges in the 
lymphocytes of workers in chromium-plating factories was higher 
than in control groups. 

    The general population living in the vicinity of ferro-alloy 
plants and exposed to ambient air concentrations of up to 1 g/m3 
did not show increased lung cancer mortality. 

    The results of many studies suggest that exposure to chromium 
through inhalation and skin contact can pose health problems for 
the general population, but no data on dose-response relationships 
are available.  Thus, there is no reason, at present, to be 
concerned that chromium in the air presents a health problem, 
except under conditions of industrial exposure. 

1.2.  Recommendations for Further Research

1.2.1.  Analytical methods

    Data from the determination of chromium should not be accepted 
unless proper quality assurance procedures have been used, 
including the analysis of a certified reference material of similar 
composition.  There is a great need for the preparation and 
certification of additional standards, especially of blood, serum, 
or plasma, urine containing only physiological chromium 
concentrations, hair, and foods. 

    All analyses related to the environmental role of chromium 
should differentiate between hexavalent and trivalent forms and 
these values should be reported separately.  While the 
differentiation between hexavalent and trivalent chromium can be 
accomplished by established methods, the definition of the exact 
chemical species of the trivalent and hexavalent forms in air, 
water, food, and tissues will require much further research. 

    Further development of analytical instrumentation and 
preanalytical processing techniques to extend the detection limit 
by one order of magnitude is recommended.  The need for 
interlaboratory comparison persists to improve existing methods and 
to validate new procedures. 

1.2.2.  Sources of chromium intake

    More data are needed on the chemical and physical properties of 
airborne chromium, such as the oxidation state, particle size, and 
solubility.  These are important determinants of biological and 
toxic action.  Existing information on the chromium contents of 
foodstuffs is unreliable and incomplete and more composition data 
are needed for a valid assessment of the human chromium requirement 
and the supplies available in different regions of the world to 
meet these requirements.  Diagnostic procedures to detect marginal 
deficiency and marginal overexposure in man must be developed and 
the long-term effects of both these imbalances must be defined.  

Finally, not enough is known about the fate of chromium in 
landfills, sewage sludges, and aquatic environments.  Further 
studies are needed to investigate environmental factors that 
influence the mobilization, migration, and bioavailability of 
chromium in the biosphere. 

1.2.3.  Studies on health effects

    Prospective studies on the health of industrial workers, 
combined with the determination of the composition and 
environmental levels of the chromium compounds to which they were 
exposed, are needed to determine the specific chemical or chemicals 
responsible for cancer, and the dose-response relationship between 
hexavalent chromium and bronchogenic carcinoma.  Smoking histories 
should be recorded and, when possible, information on exposure to 
ionizing radiation and other chemical carcinogens should be 
obtained in order to evaluate possible synergistic relationships.  
More studies should be carried out on the chrome-using industries. 
Preventive measures include searching for more specific biochemical 
indicators of chromium exposure and early effects. 

    Epidemiological studies are needed to assess the incidence and 
severity of chromium deficiency.  The relation of chromium status 
to cardiovascular diseases needs further investigation, 
particularly in areas with protein-energy malnutrition. 

1.2.4.  Interaction with other environmental factors

    The interaction of other pollutants in the atmosphere with 
chromium, particularly with respect to particle size, adsorption at 
the particle surface, etc., require further studies. 

    Interactions between trivalent chromium in the diet and other 
dietary constituents are poorly understood and should be 
investigated. 

2.  PHYSICAL AND CHEMICAL PROPERTIES AND ANALYTICAL METHODS

2.1.  Physical and Chemical Properties

    Chromium (atomic number 24, relative atomic mass 51.996) occurs 
in each of the oxidation states from -2 to +6, but only the 0 
(elemental), +2, +3, and +6 states are common.  Divalent chromium 
is unstable in most compounds, as it is easily oxidized to the 
trivalent form by air.  Only the trivalent and hexavalent oxidation 
states are important for human health. In the context of this 
publication, it is of great importance to realize that these two 
oxidation states have very different properties and biological 
effects on living organisms, including man.  Therefore, they must 
always be examined separately: a valid generalization of the 
biological effects of chromium as an element cannot be made. 

    This discussion will concentrate only on the aspects of 
chromium chemistry that are of concern for health. 

    The relation between the hexavalent and trivalent states of 
chromium is described by the equation: 

    Cr2O72- + 14H+ + 6e  ->  2 Cr(III) + 7H2O + 1.33v.

The difference electric potential between these 2 states reflects 
the strong oxidizing properties of hexavalent chromium and the 
substantial energy needed to oxidize the trivalent to the 
hexavalent form.  For practical purposes, it can be stated that 
this oxidation never occurs in biological systems.  The reduction 
of hexavalent chromium occurs spontaneously in the organism, unless 
present in an insoluble form.  A gradual reduction of hexavalent 
chromium to the trivalent state is demonstrated by the colour 
change of the conventional chromate cleaning solution in the 
laboratory from bright orange to green, in the presence of organic 
matter.  In blood, chromate is reduced to the trivalent state, once 
it has penetrated the red cell membrane and becomes bound to the 
haemoglobin and other constituents of the cell and therefore unable 
to leave the cell again.  The rapid reduction of injected 
51chromium-labelled chromate in the rat has been demonstrated by 
Feldman (1968).  Although a compound CrF6 is well known, the stable 
forms of hexavalent chromium are almost always bound to oxygen 
(e.g., CrO4-2, Cr2O7-2).  The trivalent form exists in coordination 
compounds, but never as the free ion.  As a rule, its coordination 
number is 6, the complexes being generally octahedral. 

    A large number of complexes and chelates of chromium have been 
investigated, ranging from simple hexa- or tetra-aquo complexes to 
those with organic acids, vitamins, amino acids and others.  The 
rate of ligand exchange of chromium complexes is slow in comparison 
with other transition elements, with the exception of the even 
slower rate of cobalt complexes; most of the Cr(III)-complexes are 
kinetically stable in solutions.  This property adds to the relative 
inertness of trivalent compounds, in addition to the 
electrochemical stability of the trivalent state.  However, at near 
neutral or alkaline pH, the milieu of the animal organism, the 

simple chromium compounds to which the organism is exposed in the 
environment or through supplementation, rapidly become insoluble, 
because hydroxyl ions replace the coordinated water molecules from 
the metal and form bridges, linking the chromium atoms into very 
large, insoluble complexes.  Coordination of trivalent chromium to 
biological ligands is the prerequisite for its solubility at 
physiological pH and therefore for its biological function and for 
its availability for intestinal absorption.  The coordination 
chemistry and the specific biochemical reactions have been reviewed 
by Cotton & Wilkinson (1966) and Mertz (1969), respectively.  The 
physical and chemical properties of chromium and some chromium-
compounds are summarized in Table 1. 

Common chromium compounds

    Poorly soluble "sandwich complexes" of metallic chromium 
(oxidation state = O) are known, e.g., Cr(C6H6)2; these have little 
practical application.  Divalent compounds, such as chromium (II) 
chloride (CrCl2) are used as strong reducing agents in the 
laboratory, but have little industrial use.  Of the many hundreds 
of trivalent chromium compounds known, chromic oxide (Cr2O3 x 
nH2O), is used as a pigment in paints and as a faecal marker in 
digestive studies.  It dissolves in acids and forms the hexa-aquo 
or tetra-aquo complex, e.g., 

    Cr2O3 x 9H2O + 6HCl  ->  2 [Cr(H2O)6] Cl3
                    (colour: violet)
or
           2 [Cr(H2O)4Cl2] Cl + 4H2O
                  (colour: dark green).

Chromium chloride ([Cr(H2O)6]Cl3 or [Cr(H2O)4Cl2]Cl) is used in 
basic solution for leather tanning.  The fluoride is used 
industrially in printing and dyeing, and chromium sulfates and 
nitrates are used as colouring and printing dyes. 

    One of the numerous organic complexes of chromium, a 
dinicotinatoglutathionato-chromium complex has been isolated from 
yeast.  It is postulated as the physiologically active form in the 
animal organism, but its exact structure is not known (Toepfer et 
al., 1977). 


Table 1.  Physical and chemical properties of chromium and some selected chromium compounds
--------------------------------------------------------------------------------------------------------
Name             Chemical  Relative   Specific  Melting    Boiling   Colour   Solubility  CAS registry
                 symbol    molecular  gravity   point      point              in water    number
                           mass       (g/cm3)   (C)       (C)               (weight %)
--------------------------------------------------------------------------------------------------------
Chromium         Cr        51.996     7.19      1857       2672      steel-   insoluble   7440-47-3
                                                                     grey

Chromium (III)-  Cr2O3     151.99     5.21      2266       4000      green    insoluble   1308-38-9
oxide

Chromium (VI)-   CrO3      99.99      2.70      196       decompo-  red      62.41       1333-82-0
oxide                                                      sition

Potassium-       K2CrO4    194.20     2.732     968.3     decompo-  yellow   39.96       7789-00-6
chromate (VI)                                              sition

Potassium-       K2Cr2O7   294.19     2.676     398       decompo-  red      11.7        7778-50-9
dichromate (VI)                                            sition

Calcium-         CaCrO4    192.09     1025                 decompo-  yellow   3.5         13765-19-0
chromate (VI)    x 2H2O                                    sition
dihydrate

Calcium-         CaCr2O4   208.07     4.8       2090         -       olive-   insoluble
chromium (III)-                                                      green
oxide
--------------------------------------------------------------------------------------------------------
For vapour pressure at 20C, no data.
    The earth's most important deposits of chromium are in either 
the elemental or the trivalent oxidation state. Hexavalent 
compounds of chromium in the biosphere are predominantly man-made, 
and experience with hexavalent chromium is relatively short.  
Chromates and dichromates are produced from chromite ore by 
roasting in the presence of soda ash. From these, chromium (VI) 
oxide, (CrO3), is precipitated out by the addition of sulfuric 
acid.  Sodium and potassium dichromates are widely used 
industrially as sources of other chromium compounds, particularly 
of chromium (VI) oxide, and these processes are a major source of 
hexavalent chromium pollution (US EPA, 1978). 

2.2.  Analytical Methods

    Methods for the determination of chromium in biological and 
environmental samples are developing rapidly, as shown by the fact 
that chromium concentrations in the blood and urine of unexposed 
subjects, reported as normal, have been revised downwards by 2 
orders of magnitude, in only 15 years (Versieck et al., 1978).  
This development is not only due to the increasing powers of 
detection and specificity of more recent methods, but also to the 
better methods of contamination control that have become available.  
For these reasons, all data concerning chromium levels in blood and 
urine (particularly the early results), should be interpreted with 
caution following scrutiny of all experimental details.  On the 
other hand, analytical results concerning the much higher chromium 
levels in foodstuffs and human tissue have not changed as much and 
can be accepted with more confidence. However, all interpretations 
of chromium data should take into account the need for caution 
expressed in section 2.2.2. 

2.2.1.  Sampling

    As chromium is present in biological materials in very low 
concentrations, care must be taken to avoid contamination. The 
collection of dust from air samples may introduce contamination 
from the chromium in the filters; blood or tissue samples may 
become highly contaminated by the chromium in needles, knives, 
blenders, and other instruments (Behne & Brtter, 1979).  Water 
samples may extract chromium from containers.  Finally, reagents 
used in sample dissolution, separation, chelation, acid digestion, 
and other reactions, may contribute significant amounts of 
chromium.  Thus, it is necessary to control for these influences by 
simultaneously performing a blank analysis, i.e., by carrying out 
the whole analysis, including sampling, preparation, and digestion, 
using all reagents, excluding a sample (Davis & Grossman, 1971). 

    Conversely, chromium in low concentrations may be adsorbed on 
the surface of containers during long periods of storage. This 
aspect has not yet been sufficiently investigated (Shendrikar & 
West, 1974).  Procedures for the sampling of different materials 
for chromium determination have been reviewed by Beyermann (1962), 
Brown et al. (1970), Murrman et al. (1971), Versieck & Speecke 
(1972), Skogerboe (1974), Johnson (1974), and US DHEW (1975).  All 
suggest strictest contamination control (clean rooms or laminar 
flow facilities). 

2.2.2.  Analytical methods

    The voluminous literature on analysis for chromium was reviewed 
by US EPA (1978).  A discussion on analytical methods must 
distinguish between two categories: (a) methods for measuring 
large, potentially toxic concentrations of chromium as a 
contaminant, and (b) methods of analysis for chromium as an 
essential nutrient.  The first category requires reliable 
determinations of chromium at the g/kg level; the second requires 
greater sensitivity, e.g., to determine accurately the chromium 
level in urine at several hundred ng/litre. 

    The sensitivity of instrumental analysis for the determination 
of chromium does not present any problems for concentrations in the 
mg/kg range, and a number of techniques can furnish satisfactory 
precision and accuracy (Table 2).  On the other hand, the 
sensitivity of instrumentation for the determination of chromium in 
the ng or g/kg range is severely limited, and no one method is 
entirely satisfactory, at present (Seeling et al., 1979).  The 
biologically active concentrations are near the detection limits of 
the most sensitive methods, such as neutron activation analysis or 
flameless atomic absorption spectrometry.  In an inter-laboratory 
comparison, there was poor agreement between the analytical results 
obtained by well-established, experienced analytical laboratories 
in several countries (Parr, 1977). Some of the results are 
presented in the Table 3.  It is of paramount importance for the 
interpretation of all published analytical data on chromium to 
realize the great variation in reported results, even for high 
concentrations.  These results indicate the following conclusions: 


1.  No one analytical method can be expected to produce
    "true" results of absolute chromium concentrations, unless
    the analyses are controlled by the use of a certified
    reference material with a matrix composition similar to
    that of the material to be analysed.

2.  No valid comparisons can be made on the basis of
    analytical results obtained by different laboratories,
    unless the same reference materials have been used by
    both, or samples have been exchanged.

3.  There is a great need for certified Standard
    Reference Materials with many different matrix
    compositions.  Six such standards of biological materials
    have been certified for chromium content (tomato leaves,
    pine needles, citrus leaves, oyster tissue, unexposed
    bovine serum, and brewer's yeast).  In addition, seven
    standard reference materials of environmental samples are
    available (coal, fly ash, water, sediment, urban
    particulate, etc.) and more than 180 industrial samples of
    various steels and metal alloys.  These are available from
    the National Bureau of Standards, Washington DC, USA.  New
    reference specimens of blood and urine have been produced

    for the quality control of heavy metals in industrial
    medicine and toxicology (Mller-Wiegand et al., 1983).
    The assigned values were determined by reference
    laboratories of the "Deutsche Gesellschaft fr
    Arbeitsmedizin; the control blood and urine preparations
    are offered by Behringwerke AG, D-3550 Marburg, Federal
    Republic of Germany.

4.  In inter-laboratory quality assurance studies, it is
    preferable to use the methodology developed in the
    WHO/UNEP project on biological monitoring for lead and
    cadmium (Vahter, 1982).

    In 1983, the German DIN-Committee AAS adopted a method for the
determination of the chromium content of water and sewage (by means
of the flame AAS) (Kempf & Sonneborn, 1976); inductively coupled
plasma emission spectrometry is recommended with regard to serial
analyses (Kempf & Sonneborn, 1981).

    Two special problems in the analysis for chromium may add to, 
or subtract from, the true concentrations, i.e., contamination and 
possible loss through volatilization or formation of refractory 
compounds during sample preparation. Contamination is a serious 
problem when low concentrations in blood or urine are measured.  
Dust in laboratories may contain a chromium level of 700 mg/kg 
(Mertz, 1969), approximately 6 orders of magnitude higher than the 
concentration in urine of 0.2 - 0.7 g/litre (Guthrie et al., 
1979).  In other words, contamination of a one-ml urine sample by 
only 1 g of dust will increase the apparent chromium concentration 
two-fold. Special precautions, such as those proposed by Tlg 
(1974), must be taken to control this problem.  The second problem, 
that of potential loss during sample preparation, has been 
discussed by Wolf & Greene (1976).  There is evidence from several 
studies that certain methods of sample preparation, such as heating 
or acid digestion in open systems, may lead to the loss of 
detectable amounts of chromium (Kotz et al., 1972).  A typical 
example, in which identical samples were determined by the 
identical method, by the same analyst, in the same laboratory is 
presented in Table 4. 


Table 2.  Instrumental methods for the determination of chromiuma
--------------------------------------------------------------------------------------------------------
Analytical          Relevant             Detection    Interfering substance    Selectivity
method              applications         limit
--------------------------------------------------------------------------------------------------------
Atomic              fresh and saline     2 g/litreb  interfering substances   all of the extracted 
absorption          water, industrial                 present in the original  chromium is measured, 
spectroscopy        waste fluids,                     sample are usually not   but only hexavalent 
(flame)             dust, and sediments               extracted into the       chromium is extracted 
                    biological solids                 organic solvent          from the original sample,
                    and liquids, alloys                                        unless oxidative 
                                                                               pretreatment is used
                                       

Atomic              biological solids    0.005 g/    no interfering sub-      total chromium is 
absorption          and fluids; tissue,  litreb       substances reported      determined
(electrothermal)    blood, urine;                     for samples of urinen,
                    industrial waste                  and bloodo; less than 
                    waters                            10% interference ob-  
                                                      served for Na+, K+,   
                                                      Ca2+, Mg3+, Cl-,      
                                                      F-, SO4-3, and PO4-3  
                                                      in certain industrial 
                                                      waste watersp         

Emission            a wide variety of    4 g/litrel  no interfering           total chromium is 
spectroscopy        biological and                    substances reported      determined
(inductively-       environmental
coupled plasma      samples      
source)                            
              

Emission            a wide variety of    0.5 ngc                               total chromium is 
spectroscopy        environmental                                              determined
(arc)               samples


--------------------------------------------------------------------------------------------------------

Table 2.  (contd.)
--------------------------------------------------------------------------------------------------------
Analytical          Relevant             Detection    Interfering substance    Selectivity
method              applications         limit
--------------------------------------------------------------------------------------------------------

Spectrophotometry   natural water and    3 g/litred  iron, vanadium, and      after chelation, only 
                    industrial waste                  mercury may interfere    the hexavalent chromium 
                    solutions having                                           in solution is determined
                    5 - 400 mg hexa-
                    valent chromium/
                    litre can be 
                    analysed; higher 
                    concentrations 
                    must be reduced 
                    by dilution 

X-ray fluorescence  atmospheric          2 - 10 g/g  the particle size of     total chromium is 
                    particulates,        (liver)e;    the sample and the       determined
                    geological           1.5 g/g     matrix may influence
                    materials            (coal)f      the observed measure-
                                                      ments

Neutron activation  air pollution        depends on   interference may arise   total chromium is 
analysis            particulates,        activation   from gamma ray activity  measured
                    fresh and saline     procedure;   from other elements,
                    waters, biological   typical      especially Na-24, Cl-38,
                    liquids and solids,  limit:       K-42, and Mn-56; P-32
                    sediments, metals,   10 ngm       may also cause inter-
                    foods                             ference

Gas chromatography  blood, serum,        0.03 pgg     excess chelating agent   only chromium that is 
(electron capture   natural water                     or other electron-       chelated and extracted
detection)          samples                           capturing constituents   is measured; other 
                                                      in the sample may lead   electro-negative substances  
                                                      to erroneous results     may elute from the column
                                                                               and be detected at the
                                                                               same time as the chromium    
                                                                               chelate
                                                                                                     
Stable isotope      all biological                    not expected             high precision and accuracy
dilution mass       materialsk,q                                               (1%) complete sample  
spectrometry                                                                   digestion and exchange of
                                                                               endogenous chromium with
                                                                               added stable isotope
--------------------------------------------------------------------------------------------------------

Table 2.  (contd.)
--------------------------------------------------------------------------------------------------------
Analytical          Relevant             Detection    Interfering substance    Selectivity
method              applications         limit
--------------------------------------------------------------------------------------------------------
Gas chromatography  blood, serum,        ~1 ngh       no interference          only chromium that is  
(atomic             biological material               reported                 chelated and extracted is
spectroscopic                                                                  detected; atomic 
detection)                                                                     spectroscopic methods   
                                                                               of detection are 
                                                                               inherently more selective
                                                                               for chromium in complex
                                                                               samples

Gas chromatography  blood, plasma,       0.5 pgi      no interference          only chromium that is 
(mass               serum                             reported                 chelated and extracted 
spectrometric                                                                  can be detected
detection)

Chemiluminescence   fresh, natural       30 ng/       Co(II), Fe(II), and      only trivalent chromium 
                    waters; dissolved    litrek       Fe(III) interfere but    ion is measured
                    biological material               may be compensated for
                                                      by running a blankc
--------------------------------------------------------------------------------------------------------
a   Modified from: US EPA (1978).
b   From: Welz (1983).
c   From: Seeley & Skogerboe (1974).
d   From: American Public Health Association, American Water Works Association,
    and Water Pollution Control Federation  (1971).
e   From: Kemp et al. (1974).
f   From: Kuhn (1973).
g   From: Savory et al. (1969).
h   From: Wolf (1976).
i   From: Wolf et al. (1972).
k   From: Seitz et al. (1972).
l   From: Welz (1980).
m   From: Keller (1980).
n   From: Schaller et al. (1973).
o   From: Environmental Instrumentation Group (1973).
p   From: Morrow & McElhaney (1974).
q   From: Veillon et al. (1979).
Table 3.  Results for 3 IAEA intercomparison studiesa
-----------------------------------------------------------
Laboratory  Method     Number of       Laboratory   SD (%)
code        codeb      determinations  mean
-----------------------------------------------------------
A.  Simulated air filter
   (true chromium concentration: 1.85 g/filter)

a           7          2               1.3          3
b           3          1               1.6          7
c           2          4               1.78         5
d           2          10              1.85         6
e           2          6               1.86         52
f           2          2               2.00         30
g           2          3               2.07         10
h           2          6               2.07         9
i           2          6               2.07         6
j           7          10              2.16         10
k           5          6               2.83         40
l           7          2               3.00         -c
m           3          5               3.17         4
n           7          1               4.20         8
o           2          5               6.14         6
p           2          1               7.50         22

B.  Water
   (true chromium concentration: 11.1 g/kg)

a           3          4               1.85         18
b           3          5               3.80         12
c           7          6               4.16         15
d           7          1               4.50         11
e           7          6               4.77         6
f           7          2               5.25         -
g           2          5               5.51         3
h           2          5               5.84         4
i           7          1               6.00         -
j           2          3               6.08         4
k           7          2               6.50         -
l           7          2               6.85         17
m           2          2               7.00         -
n           7          2               7.30         -
o           7          3               8.67         3
p           7          2               8.90         20
q           3          1               9.00         20
r           7          5               9.60         12
s           7          6               9.92         10
t           2          5               10.8         11
u           2          4               11.3         11
v           7          3               11.5         45
w           5          2               18.0         30
x           7          1               73.0         14
-----------------------------------------------------------

Table 3.  (contd.)
-----------------------------------------------------------
Laboratory  Method     Number of       Laboratory   SD (%)
code        codeb      determinations  mean
-----------------------------------------------------------
C.  Bovine liver (SRM 1577)
   (certified chromium concentration: 88  12 g/kg)

a           2          -c              5            -c
b           1          -c              51           13
c           1          -c              140          -c
d           2          -c              150          13
e           1          -c              150          33
f           1          -c              160          24
g           1          -c              240          53
h           2          -c              490          39
i           1          -c              540          64
j           2          -c              1300         -c
k           2          -c              1600         25
-----------------------------------------------------------
a   From: Parr (1977).
b   Method code:
    1. Destructive activation analysis.
    2. Nondestructive activation analysis.
    3. Emission spectroscopy.
    5. Spark source mass spectrometry.
    7. Atomic absorption, unspecified.
c   Information not given.


    At present, there is no explanation of the reason why "losses" 
of almost 90% were associated with the direct graphite furnace 
ashing, compared with oxygen plasma ashing in the case of molasses, 
but not of refined sugar.  Canfield & Doisy (1976) and Tuman et al. 
(1978) suggested that the loss of chromium in biological samples, 
such as urine, yeast extracts, or synthetic glucose tolerance 
factor (GTF) preparations represented the biologically active GTF 
fraction of the chromium.  They correlated this "volatile" fraction 
in yeast extracts with the antidiabetic activity of the extract in 
genetically diabetic mice, and the amount of "volatile" chromium in 
the urine of human subjects with the efficiency of the glucose 
metabolism of these subjects.  This hypothesis of "volatile" 
chromium has been confirmed by some investigators (Behne et al., 
1976; Koirtyohann & Hopkins, 1976; Shapcott et al., 1977; 
McClendon, 1978), and contradicted by others (Jones et al., 1975; 
Rook & Wolf, 1977).  While the question of the "volatility" of 
chromium, under various conditions, remains unanswered, it is 
obvious that chromium determination presents many problems, the 
most pressing of which is the selection and control of sample 
digestion (Wolf & Greene, 1976). 

Table 4.  Apparent chromium content depending on the method of 
ashinga
-----------------------------------------------------------------
Type of sugar      Number     Chromium content + SEM (g/kg)   
                   of       Oxygen     Muffle    Graphite 
                   samples  plasma     furnace   furnace ashing
                            ashing     ashing    (1000 C)
                            (150 C)   (450 C)  (direct
                                                 analysis)
-----------------------------------------------------------------
molasses           3        266  50   129  54  29   5
sugar (unrefined)  8        162  36   88  20   37  13
sugar (brown)      5        64  5     53  8    31   2
sugar (refined)    7        20  3     25  3    < 10
-----------------------------------------------------------------
a   From: Wolf et al. (1974).

    Finally, it is important in any study of the environmental 
effects of chromium, to distinguish analytically between the 
trivalent and hexavalent forms.  This can be accomplished by 
dithiocarbamate chelation and solvent extraction (for example, with 
methyl isobutylketone) prior to oxidation.  Only the hexavalent 
chromium remains after this process, and thus it is possible to 
differentiate between the oxidation states (Feldman et al., 1967; 
Cresser & Hargitt, 1976; Bergmann & Hardt, 1979; Joschi & Neeb, 
1980).  When determining chromium in biomaterial, the samples are 
usually ashed with strong acids to destroy the organic components.  
The relationship between the acids used and the behaviour of 
chromium were investigated by Hara (1982) who showed that the 
oxidation state of chromium was apt to change (hexavalent to 
trivalent), because of the reducing action of each acid and the 
conditions under which they were used. 

3.  SOURCES IN THE ENVIRONMENT, ENVIRONMENTAL TRANSPORT AND DISTRIBUTION

3.1.  Natural Occurrence

    Chromium is ubiquitous in nature; it can be detected in all 
matter in concentrations ranging from less than 0.1 g/m3 in air to 
4 g/kg in soils.  Naturally occurring chromium is almost always 
present in the trivalent state: hexavalent chromium in the 
environment is almost totally derived from human activities. 

    Merian (1984) has compiled the global sources of chromium in 
the environment.  Total input (100%) consists of inputs by: 
volcanic emissions (less than 1%); the biological cycle (30%) 
including extraction from soil by plants (15%) and weathering of 
rocks and soils (15%); and man-made emissions (70%) including those 
from general ore and metal production (3%), from metal use (60%), 
and from coal burning and other combustion processes (7%). 

3.1.1.  Rocks

    Almost all the sources of chromium in the earth's crust are in 
the trivalent state, the most important mineral deposit being in 
the form of chromite (FeOCr2O3) which, however, is rarely pure.  
Living matter does not produce the energy necessary to oxidize 
trivalent to hexavalent chromium in the organism, therefore, it can 
be stated that nearly all hexavalent chromium in the environment is 
produced by human activities.  The industrial use of chromium and 
the oxidation to the hexavalent state on an industrial scale did 
not begin until 1816.  Thus, man's experience with this form is 
very short. 

    The concentration of chromium in rocks varies from an average 
of 5 mg/kg (range of 2 - 60 mg/kg) in granitic rocks, to an average 
1800 mg/kg (range, 1100 - 3400 mg/kg) in ultrabasic and serpentine 
rocks (US NAS, 1974b). 

    Chromium deposits in the hexavalent oxidation state (crocoite 
PbCrO4), were described by Lomonossow, in the year 1763 (Hintze, 
1930), who found it in the Ural Mountains. Being a rare mineral, 
chromium is found in the oxidized zones of lead deposits in regions 
in which lead veins have traversed rocks containing chromite.  It 
may be associated with pyromorphite, cerussite, and wulfenite.  
Notable localities are: Dundas, Tasmania; Beresovsk near 
Sverdlovsk, Ural Mountains (Aleksandrov & Kainov, 1975), and 
Rezbanya, Rumania.  It is found in small quantities in the Vulture 
district, Arizona, USA (Dana, 1971) and in the German Democratic 
Republic in Callenberg, Saxony (Rohde et al., 1978). 

    Chromium concentrations in igneous rocks are positively 
correlated with concentrations of silica, magnesium, and nickel.  
Of agricultural importance, is the high chromium concentration in 
sedimentary rocks, where the element is present in phosphorites.  
This material is used as a phosphate fertilizer in agriculture and 
is a significant source of chromium for agricultural soils. 

    Chromium-containing rocks and ores are found in all regions of 
the world, but the major sources of the world's chromium supplies 
are the ultra basic rocks of South Africa, Turkey, the USSR and 
Zimbabwe (US NAS, 1974b).  While underlying undisturbed rocks 
contribute little chromium to the vegetation directly, the chromium 
content is strongly correlated with that of the overlying soils. 

    Chromium can also be found in coal (5 - 10 mg/kg) (Merian, 
1984). 

3.1.2.  Soils

    The weathering of rocks produces chromium complexes that are 
almost exclusively in the trivalent state.  In most soils, chromium 
occurs in low concentrations; an average of 863 soil samples from 
the USA contained 53 mg/kg (Shacklette et al., 1970).  The highest 
concentrations, as high as 3.5 g/kg (Swaine & Mitchell, 1960), are 
always found in serpentine soils.  In a small area in Maryland, 
USA, with soil infertility, the chromium concentration (as Cr2O3) 
was as high as 27.4 g/kg (Robinson & Edington, 1935).  Conversely, 
low chromium concentrations (10 - 40 mg/kg) have been detected in 
soils derived from granite or sandstone (Swaine & Mitchell, 1960).  
Only a fraction of the chromium in soil is available to the plant; 
thus, it is important to determine "available" soil-chromium.  A 
rough approximation of this available chromium fraction can be made 
by extracting soil with acids or chelating agents and by measuring 
the chromium in the extract.  Though the amount of extractable 
chromium is not identical with that truly available to the plant, 
it is a much better measure of availability than the total 
chromium.  In the study of Swaine & Mitchell (1960), the amount of 
chromium extracted from the soil with acetic acid varied much less 
than the total soil content, and was not correlated with the latter 
(Table 5). 

    The comparisons in this Table indicate that the amount of 
chromium available to the plant is relatively independent of the 
total concentration.  The complex principles determining the 
availability of chromium for plants are poorly understood. 

Table 5.  Total versus extractable chromium in different 
Scottish soilsa
----------------------------------------------------------
Soil             Total chromium      Extractable chromium
derived from:    (mg/kg)             (mg/kg)
----------------------------------------------------------
Granite          20, 40, 20          0.15, 0.1, 0.11

Serpentine,      3500, 2000, 3000    0.31, 0.24, 0.63
ultrabasic
----------------------------------------------------------
a   From: Swaine & Mitchell (1960).

3.1.3.  Water

    It is now generally agreed that, except in areas with 
substantial chromium deposits, high chromium levels in water arise 
from industrial sources (US NAS, 1974b). 

    With the exception of areas bearing chromium deposits or in 
highly industrialized areas, most surface waters contain very low 
levels of chromium.  The chromium content in surface water in the 
Tia-ding county, Shanghai, ranged from 0 to 80 g/litre (256 
samples).  According to the Yang-Pu water works, which is the 
biggest water works in Shanghai, the chromium levels in well water 
are below 50 g/litre.  Between 1980 and 1982, chromium was not 
detectable in the Yellow River.  There is no information concerning 
the analytical methods used (Chen Bingheng, personal communication 
to the Task Group, 1986).  Kopp & Kroner (1968) detected chromium 
in only 25% of surface water samples from sources in the USA, with 
a range of 1 - 112 g/litre, and a mean concentration of 9.7 
g/litre.  The remaining 75% contained less than 1 g/litre, the 
detection limit.  Another survey of 15 rivers in the USA revealed 
levels ranging from 0.7 to 84 g/litre, the majority of samples 
containing between 1 and 10 g/litre (Durum & Haffty, 1963).  On 
the other hand, chromium contents in natural water of up to 215 
g/litre were reported by Novakova et al. (1974).  Although modern 
methods of water treatment remove much of the naturally present 
chromium, it should be noted that chlorinated drinking-water 
usually contains traces of hexavalent chromium.  The mean level in 
the drinking-water supplies in 100 cities in the USA was only 0.43 
g/litre, with a range from barely detectable to 35 g/litre 
(Durfor & Becker, 1964). 

    Sea water contains less than 1 g chromium/litre (US NAS, 
1974b), but the exact chemical forms in which chromium is present 
in the ocean, and surface water are not known. Theoretically, 
chromium can persist in the hexavalent state in water with a low 
organic matter content.  In the trivalent form, chromium will form 
insoluble compounds at the natural pH of water, unless protected by 
complex formation.  The exact distribution between the trivalent 
and hexavalent state is unknown. 

3.1.4.  Air

    Chromium occurs in the air of non-industrialized areas in 
concentrations of less than 0.1 g/m3.  The natural sources of air-
chromium are forest fires and, perhaps, volcanic eruptions (section 
3.5).  Man-made sources include all types of combustion and 
emissions by the chromium industry (section 4.1.1).  The chemical 
forms of chromium in the air are not known, but it should be 
assumed that part of the air-chromium exists in the hexavalent 
form, especially that derived from high-temperature combustion.  
Chromium trioxide (CrO3) may be the most important compound in the 
air (Sullivan, 1969). 

3.1.5.  Plants and wildlife

    It is not known whether chromium is an essential nutrient for 
plants, but all plants contain the element in concentrations 
detectable by modern methods. 

    Chromium concentrations in food plants growing on normal soils 
range from not detectable to 0.19 mg/kg wet weight (Schoeder et 
al., 1962).  In addition, chromium of vegetable origin has a 
relatively low biological activity (Toepfer et al., 1973). 

    Much higher concentrations have been reported in plants growing 
on chromium deposits.  For example, ash analysis showed a chromium 
level of 0.34% in New Zealand lichen and 0.3% in Yugoslav  Allysium 
 markgrafi (US NAS, 1974b).  Growing on a serpentine soil (chromium 
concentration 62 000 mg/kg in old mine tailings), the plant 
chromium concentrations (on the basis of ash analysis) ranged from 
700 mg/kg in  Phormium colensoi and  Liliacae to 5400 mg/kg in 
 Gentiana corymbifera (Lyon et al., 1970).  Not all plants tolerate 
high concentrations of available soil-chromium; chlorosis of citrus 
trees has been observed in high-chromium areas and in laboratory 
experiments.  Plants grown in the vicinity of chromium-emitting 
industries or those fertilized by sewage sludge are exposed to 
substantial amounts of chromium.  The chromium contents of plants 
growing were determined by Taylor et al. (1975) near cooling 
towers, where chromates were present as corrosion inhibitors.  It 
was shown that chromium levels in grasses, trees, and litter, 
decreased with increasing distance from the towers.  No information 
was given as to whether the variations in chromium concentrations 
were the result of surface contamination or of true absorption by 
the roots of the plant. 

    The atmospheric deposition of metals and their retention in 
ecosystems were studied by Mayer (1983).  He measured mean annual 
deposition rates in a beech and spruce forest ecosystem in the 
Solling (Federal Republic of Germany) in 1974-78 and found that 
chromium deposition in the forest canopy was in the range of 13.5 - 
15.1 mg/m2 per year; the deposition on the soil below the forest 
canopy ranged from 1.6 to 2.3 mg/m2 per year.  Thus, up to 80% of 
the metals from the atmosphere were retained in the canopy, and 30 
- 50% of chromium remained in the noncycling parts of forest 
biomass (bark and wood). 

    Sewage sludge can contain chromium levels as high as 9000 
mg/kg.  Application of sewage sludge to soils, which increased the 
chromium levels from 36.1 to 61 mg/kg on a dry weight basis, 
increased the contents of chromium in plants growing in the soil 
from, e.g., 2.6 to 4.1 mg/kg in fodder rape (Andersson & Nilsson, 
1972).  However, most of the increased uptake in plants is retained 
in the roots, and only a small fraction appears in the edible part 
(Cary et al., 1977).  Other elements within the sludge, e.g., 
cadmium or nickel, pose a greater problem for human health (Chaney, 
1973). 

    Of particular importance is the chromium concentration in the 
forage of meat animals.  Kirchgessner et al. (1960) found strong 
seasonal variations in the chromium levels in 3 different kinds of 
grasses; the highest level found was 590 g/kg dry weight in hay. 

    Higher levels of chromium in vegetation not used for human 
consumption may account for the generally higher chromium contents 
in the organs of wild animals, compared with man (Schroeder, 1966). 

    Schroeder (1970) determined the chromium concentrations in 
different organs and muscles of wild animals and found that they 
ranged from 0.04 to 0.48 mg/kg on a wet weight basis. Chromium 
concentrations in the hair of several wild-animal species, 
collected by Huckabee et al. (1972), ranged from 640 mg/kg in a 
pronghorn antelope living in Lemhi Range, Idaho, USA, to about 0.6 
mg/kg in a coyote, sampled in Jackson Hole, Wyoming, USA. 

3.1.6.  Environmental contamination from natural sources

    No data have been found that indicate any significant 
contamination of the environment from natural sources, though major 
catastrophic events, such as large forest fires or volcanic 
eruptions, could conceivably contribute to the concentration of 
chromium in air.  Water supplies originating in areas with chromium 
deposits may contain elevated chromium concentrations (section 
4.1.2).  However, none of these natural sources contributes enough 
chromium to pose a hazard for human or animal health. 

3.2.  Production, Consumption, and Uses

    The world's mining production of chromium ore was approximately 
9.73 million tonnes (gross weight) in 1980; it fell to 9 million 
during 1981 (Thomson, 1982), but rose again to 11 million tonnes in 
1985.  Exact data on the yield of elemental chromium are not 
available, but may range around half of the gross weight of the 
mined ore. 

    The major uses and amounts of chromium used in the USA in 1968 
in thousands of tonnes were: transportation, 77; construction 
products, 105; machinery and equipment, 72; home appliances and 
equipment, 25; refractory products, 68; plating of metals, 20; 
pigment and paints, 15; leather goods, 10; and other uses, 66; 
giving a total of 458 thousand tonnes. 

    The principal uses of chromium are in the metallurgical 
processing of ferrochromium and other metallurgical products, 
chiefly stainless steel, and, to a much lesser extent, in the 
refractory processing of chrome bricks and chemical processing to 
make chromic acid and chromates. 

    Chromates are used for the oxidation of various organic 
materials, in the purification of chemicals, in inorganic 
oxidation, and in the production of pigments.  A large percentage 
of chromic acid is used for plating.  Dichromate is converted to 
chromic sulfate for tanning.  Fungicides and wood preservatives 
consume an estimated 1.3 million kg of chromium annually.  
Chromates are used as rust and corrosion inhibitors, for example, 
in diesel engines.  Because chromite has a high melting point and 
is chemically inert, it is used in the manufacture of bricks for 
lining metallurgical furnaces. 

    In 1981, the demand for chromium was at its lowest level since 
1975.  However, on the basis of 1978 figures, the demand for 
chromium is expected to increase at an annual rate of about 3.2%, 
up to 1990.  While the level of stainless steel production will 
continue to be the principal influence affecting markets for 
chromite and ferrochrome, other factors could have a significant 
impact on future trends, e.g., purchases for government stockpiles 
(in 1981, the USA had a stockpile of 1.48 million tonnes, and 
France and Japan announced the build up of stockpiles) or the 
development of new alloys and steels (Thomson, 1982). 

3.3.  Waste Disposal

    Substantial amounts of chromium enter sewage-treatment plants 
in major cities.  Klein et al. (1974) estimated a total daily 
chromium burden for New York city treatment plants of 676 kg, of 
which 43% came from electroplating, 9% from other industries, 9% 
from runoff, 11% from unknown sources, and 28% from residential 
homes.  This waste from one city alone (amounting to 2.4 x 105 
kg/year), if untreated, would add a significant burden to the 
ocean, in comparison with the estimated global natural chromium 
mobilization by weathering of 3.6 x 107 kg/year (Bertine & 
Goldberg, 1971).  The high chromium discharge from homes is 
difficult to explain; it has been suggested that this could arise 
from the corrosion of stainless steel or the use of waste disposal 
units in domestic sinks.  The contribution from excreta, estimated 
at 100 g chromium/day per person, should not exceed 1 kg/day for 
the 10 million people in the New York area. 

    The concentration of chromium in the waste-water received at 
the New York treatment plants varied between 40 and 500 g/litre; 
this range is probably representative of the chromium discharge in 
major cities.  The removal of chromium from the waste-water was 
studied by Brown et al. (1973). Primary sewage treatment removed 
only 27%, secondary treatment using a trickling-filter method 
removed 38%; the most effective secondary treatment method 
(activated sludge) removed 78%.  In another study of a treatment 

plant (Chen et al., 1974), the primary effluent contained 300 
g/litre and the secondary effluent, after the activated sewage 
sludge and sedimentation process, 60 g/litre (80% removal).  The 
final discharge from the plant, a mixture of primary and secondary 
effluent and digested sludge had quite a high chromium content of 
200 g/litre.  This level is substantially higher than the natural 
chromium content of surface water and represents a significant 
source of contamination. 

    Waste-waters from chromium industries contain very high levels 
of chromium, ranging from 40 mg/litre (leather industry) to 50 000 
mg/litre (chromium plating) (Cheremisinoff & Habib, 1972).  These 
levels must be reduced by precipitation before the waste-water can 
be discharged.  The steps include reduction of hexavalent to 
trivalent chromium at an acidic pH, followed by precipitation of 
the hydroxides at pH 9.5 (Ottinger et al., 1973).  The precipitates 
containing chromium and other metals are then collected in settling 
ponds and disposed of by landfill, incineration, or dumping in the 
ocean (US EPA, 1980).  If the last procedure is used, the waste-
water treatment itself will contribute to the contamination of the 
oceans. 

    Landfill and sewage sludge operations are, in turn, potential 
sources of contamination of soil and groundwater by chromium.  
However, at alkaline pH values, chromium hydroxides are insoluble 
and leaching by any but very acidic water should be minimal.  
Pohland (1975) did not detect any measurable concentrations of 
chromium in the leachate from a simulated landfill. 

    Similary, the chromium in sewage sludge is very poorly soluble.  
Berrow & Webber (1972) found a mean concentration of only 22 
mg/litre (range, < 0.9 - 170 mg/litre) in samples of 42 sludges 
extracted with 2.5% acetic acid.  This represented 0.7 - 8.5% of 
the chromium concentration in the original sludge.  As acetic acid 
is a good complexing and extracting agent for chromium, the 
reported levels of extractable chromium are probably much greater 
than those resulting from extraction with water at near neutral pH.  
However, sludge application to land does increase the chromium 
content of the soil (LeRiche, 1968).  The application of 66 
tonnes/hectare each year, for 19 years, resulted in an increase in 
the acetic acid-soluble chromium in the soil from 0.9 to 2.6 mg/kg, 
7 years after sludge application was discontinued.  This 
extractable chromium is presumably available to the plant. The 
final link in the cycle of the soil-chromium derived from sewage 
sludge is not well known.  Undoubtedly, some will be removed by the 
growth of vegetation (section 3.1.5).  The rate of migration into 
ground water depends on the properties of the soil and climatic 
conditions.  Thus, it is not surprising that, in one study 
(LeRiche, 1968), a very slow rate of disappearance was reported 
(reduction of extractable chromium from 2.8 to 2.6 mg/kg in 8 
years), whereas in another, there was a very rapid rate of 
disappearance (reduction of total chromium from 118 to 30 mg/kg, in 
3 years) (Page, 1974). 

3.4.  Miscellaneous Sources of Pollution

    As discussed earlier, waste-waters from residential areas in 
New York carried approximately 200 kg of chromium daily to the 
treatment plants.  Of this amount, only 1 kg can be accounted for 
by the human excreta of 10 million persons.  If a water use of 200 
litres per person and a (high) chromium content of 10 g/litre is 
assumed, this concentration would account only for an additional 20 
kg.  The origin of the rest is unknown (section 3.3).  It should be 
pointed out that analytical accuracy is difficult to achieve in 
chromium analysis (section 2.2.2) and will affect the results of 
all "balance" calculations. 

    It is evident that the chief source of air pollution with 
chromium is ferrochromium refining.  Appreciable, but far smaller 
emissions, come from refractory operations and inadvertent sources.  
The lowest emissions come from the chemical processes in the 
production of dichromate and other chrome chemicals.  Combustion of 
coal and oil, and cement production, large-scale, spray-painting 
operations (e.g., ships and planes) and glass plants constitute 
other major sources of chromium emissions. 

3.5.  Environmental Transport and Distribution

    Industrial effluents containing chromium, some of which is in 
the hexavalent form, are emitted into streams and the air. Whether 
the chromium remains hexavalent until it reaches the ocean depends 
on the amount of organic matter present in the water.  If it is 
present in large quantities, the hexavalent chromium may be reduced 
by, and the trivalent chromium adsorbed on, the particulate matter.  
If it is not adsorbed, the trivalent chromium will form large, 
polynucleate complexes that are no longer soluble.  These may 
remain in colloidal suspension and be transported to the ocean as 
such, or they may precipitate and become part of the stream 
sediment. Similar processes occur in the oceans: hexavalent 
chromium is reduced and settles on the ocean bed.  It is replaced 
by an estimated 6.7 x 106 kg of chromium from rivers (Bowen, 1966). 
In a study of the oxidation state of chromium in ocean water, Fukai 
(1967) detected an increased proportion of the trivalent form with 
increasing depth. 

    Chromium is emitted into the air, not only by the chromium 
industries, but also by every combustion process, including forest 
fires.  The oxidation state of chromium emissions is not well 
defined quantitatively, but it can be assumed that the heat of 
combustion may oxidize an unknown proportion of the element to the 
hexavalent state.  While suspended in the air, this state is 
probably stable, until it settles down and comes into contact with 
organic matter, which will eventually reduce it to the trivalent 
form.  Living plants and animals absorb the hexavalent form in 
preference to the trivalent, but once absorbed, it is reduced to 
the stable, trivalent state. 

    The transport of chromium in the environment is summarized in 
Fig. 1.  It should be noted that there is a complete cycle from 
rocks or soil to plants, animals, and man, and back to soil.  Only 
part of the chromium is diverted to a second pathway leading to the 
repository, the ocean floor.  This part consists of chromium from 
rocks and soil carried by water (concentrations, a few g/litre) 
and animal and human excreta, a small part of which may find their 
way into water (e.g., runoff from sewage sludge).  Another cycle 
consists of airborne chromium from natural sources, such as fires, 
and from the chromate industry.  This cycle also contains some 
hexavalent chromium, with byproducts going into the water and air.  
Part of the air-chromium completes the cycle by settling  on the 
land, but a very significant portion goes into the repository, the 
ocean, where it ends up as sediment on the ocean floor. 

FIGURE 1

4.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

4.1.  Environmental Levels

4.1.1.  Air

    Chromium concentrations in air vary with location. Background 
levels determined at the South Pole ranged from 2.5 to 10 pg/m3 and 
are believed to be due to the weathering of crustal material (US 
NAS, 1974a).  Data collected by the US National Air Sampling 
Network in 1964 gave the national average concentration for 
chromium in the ambient air as 0.015 g/m3, varying from non-
measurable levels to a maximum of 0.35 g/m3.  Chromium 
concentrations in most non-urban areas and even in many urban areas 
were below detection levels.  Yearly average concentrations for 
cities in the USA varied from 0.009 to 0.102 g/m3.  Concentrations 
ranging from 0.017 to 0.087 g/m3 have been reported for Osaka, 
Japan (US EPA, 1978).  The chromium content of the air in the 
vicinity of industrial plants may be higher.  In 1973, the reported 
chromium concentrations ranged from 1 to 100 mg/m3 for coal-fired 
power plants, from 100 to 1000 mg/m3 for cement plants, from 10 to 
100 mg/m3 for iron and steel industries, and from 100 to 1000 mg/m3 
for municipal incinerators (US EPA, 1978).  Ferrochromium plants 
have the highest emission rates (Radian Corporation, 1983).  
However, modern chromium chemical plants contribute very little to 
pollution today, because of the installation of collecting 
equipment that returns the material for reuse.  Drift from cooling-
towers contributes to atmospheric pollution, when chromium is used 
as a corrosion inhibitor (section 3.1.5).  Little information 
exists on the particle size distribution of chromium in the air.  
The mass median diameter in a study in the United Kingdom was 
1.5 m (Cawse, 1974). 

    The chemical form of chromium in air depends on the source.  
Chromium from metallurgical production is usually in the trivalent 
or zero state.  During chromate production, chromate dusts can be 
emitted.  Aerosols containing chromic acid can be produced during 
the chrome-plating process; chromate is also the form found in air 
contaminated by cooling-tower drift. 

4.1.2.  Water

    Except for regions with substantial chromium deposits, the 
natural content of chromium in surface waters and drinking-water is 
very low, most of the samples containing between 1 and 10 g/litre 
(US NAS, 1974a).  Substantially higher concentrations are almost 
always the result of human activities, reflecting pollution from 
industrial activities or sewage waste (Perlmutter & Lieber, 1970).  
Thus, the chromium concentration in untreated surface water 
supplies reflects the extent of the industrial activity in an area 
(Table 6). 


Table 6.  Chromium in water supplies
-----------------------------------------------------------------------
Country                Chromium       Range       Reference
                       concentration  (g/litre)
                       (g/litre)
-----------------------------------------------------------------------
 Bulgaria
   flat district       -a             7 - 8       Novakova et al. 
   hilly district      -              60 - 215    (1974)

 Canada
   Great Lakes         1              0.2 - 19    Weiler & Chawla 
                                                  (1969)
   Ottawa River        0.01           -           Durum & Haffty 
                                                  (1963);
                                                  Merrit (1971)
                                                  
 China
   Yellow River        undetectable   -           Chen Bingheng 
   Tia-Ding country    -              0 - 80      (personal 
   surface water                                  communication, 1986)

 Germany, Federal                                                     
 Republic of                                                         
   Rhine River         18                         DeGroot & Allersma
                                                  (1973)            
 Poland
   Wisla               -              31 - 112    Pasternak (1973)

 USA
   Illinois River      21             5 - 38      Mathis & Cummings 
                                                  (1973)
   Lake Tahoe          < 0.07         -           Bond et al. (1973)
   Mississipi River                   3 - 20      Bond et al. (1973)
   New York area,      1250           -           Lieber et al. (1964)
   contaminated stream
-----------------------------------------------------------------------
a   No data available.
    Drinking-water from 100 public water supplies in the USA had a 
median chromium content of 0.43 g/litre, ranging from non-
detectable concentrations to 35 g/litre.  In the Federal Republic 
of Germany, levels in about 90% of drinking-water samples from 1062 
public water supplies were below 0.5 g/litre; in 1.4% of the water 
samples, levels exceeded the prescribed limit value of 50 g/litre 
(Kempf & Sonneborn, 1981). 

    Both trivalent and hexavalent forms of chromium occur in water.  
National and international drinking-water standards reject 
drinking-water containing hexavalent chromium concentrations of 
more than 50 g/litre.  Such high concentrations occur naturally, 
only in areas with substantial chromium deposits (Novakova et al., 
1974); in all other regions they would be caused by industrial 
wastes. 

4.1.3.  Food

    The available food data (Schroeder et al., 1962; Schlettwein-
Gsell & Mommsen-Straub, 1971; Toepfer et al., 1973; Kumpulainen et 
al., 1979) indicate a range of the chromium concentrations in 
different foodstuffs of 5 -250 mg/kg (Table 7).  Highly refined 
foods, such as sugar and flour of low extraction, contain the 
lowest levels.  Very high concentrations have been reported in 
pepper (Schroeder et al., 1962) and brewer's yeast. 

Table 7.  Ranges of chromium concentrations in some 
food groupsa
---------------------------------------------------
Food                        Chromium content
                            (g/kg of wet weight)  
                            Mean      Range
---------------------------------------------------
Flour, refined              < 20

Bran                        50

Meat (beef, pork, chicken)            10 - 60

Fish, fresh                           < 10 - 10

Vegetables                            5 - 30

Nuts                        140

Whole Milk                  10

Cheeses                               10 - 130

Sugar, refined              < 20

Egg yolk                    200
---------------------------------------------------
a   From: Koivistoinen (1980).

4.2.  General Population Exposure

4.2.1.  Food and water

    The chromium intake from diet and water varies considerably 
between regions (Table 8).  However, these variations should be 
interpreted with caution because not all the analyses have been 
controlled by the use of standard reference material or proper 
quality assurance procedures, and discrepancies in methods cannot 
be completely discounted. 

Table 8.  Chromium intake from diet and water
--------------------------------------------------------------------
Region            Chromium    Remarks           Reference
                  intake
                  (g/day)
                  (range)
--------------------------------------------------------------------
Canada            189         -                 Canada, National
                  (136 -                        Health and Welfare
                  282)                          (1980)

Germany, Federal  62          DAa; 4 subjects,  Schelenz (1977)
Republic of       (11 -       1 week
                  195)

Japan             723         urban adults      Murakami et al.
                  (202 -                        (1965)
                  1710)

                  943         rural adultsb     Murakami et al.
                  (> 180 -                     (1965)
                  1190)

New Zealand       81  32     DAa; 11 women,    Guthrie (1973)
                  (39 - 190)  self-selected 
                              diets

United Kingdom    (80 - 100)                    Facer, J.L.
                                                (1983)c

USA               52          DAa               Levine et al.
                  (5 - 115)                     (1968)

USA               78  42     DA; 28 diets,     Kumpulainen 
                  (25 - 224)  complete          et al.
                              (controlled       (1979)
                              by SRM)

USSR
  Tatar           (88 - 126)  childrend         Goncharov (1968)
--------------------------------------------------------------------
a   DA = Direct analysis of composite diets as consumed.
b   Analysis of composite of cooked servings for one complete day
    collected from 10 families in different localities.
c   Personal communication to Dr M. Mercier, IPCS (United Kingdom 
    Ministry of Agriculture, Fisheries and Food, London).
d   Analysis of diets in kindergartens.

    Most reported chromium intakes range from 50 to 200 g/day.  
However, a comparison of the chromium levels reported by different 
investigators reveals substantial differences, some of which may be 
due to the influence of the location where the foods were grown.  
Only one study (Kumpulainen et al., 1979) was controlled by the use 
of standard reference materials.  The data should therefore be 
treated as preliminary.  Furthermore, data concerning total 
chromium concentrations do not include information on the species 

of chromium in the food and their biological availability.  In an 
attempt to estimate the biologically available chromium in food, 
Toepfer et al. (1973) measured the effects of extracts from foods 
on the potentiation of insulin action in epididymal fat tissue  in 
 vitro.  No correlation was found between the insulin potentiation 
and the total chromium extracted from the foods by acid hydrolysis, 
but a significant correlation ( P = 0.01) appeared between the 
ethanol-extractable amount of chromium and biological activity.  
The highest concentrations of ethanol-extractable chromium were 
found in brewer's yeast, black pepper, calf liver, cheese, and 
wheatgerm. 

4.2.2.  Other exposures

    Since chromium compounds are increasingly present in products 
used in daily life, chromium eczemas are often observed in the 
general population.  Polak et al. (1973) surveyed the most 
important chromium-containing materials or objects: chromium ore, 
baths, colours, lubricating oils, anti-corrosive agents, wood 
preservation salts, cement, cleaning materials, textiles, and 
leather tanned with chromium.  According to Polak et al. (1973), 
people who work with material containing mere traces of chromium 
salts are more at risk than workers who come into contact with high 
concentrations of chromium salts.  Some less frequently occurring 
cases include sensitization by tattooing (especially green and 
light-blue)( Tazelaar, 1970), artificial dentures made of chromium-
containing steel, metal pins used for internal fixation of broken 
bones, and bullets retained in the body (Langard & Hensten-
Pettersen, 1981). 

4.3.  Occupational Exposure

4.3.1.  Inhalation exposure

    In chromium ore mines, the concentration of dust in the air in 
different work-places ranged from 1.3 to 16.9 mg/m3. In the 
crushing and sorting factory, it varied from 6.1 to 148 mg/m3.  The 
chromium content in settled dust (calculated as Cr2O3) varied from 
3.6 to 48%.  During the period 1955-69, levels of trivalent 
chromium in the dust in different work-places in ferro-alloy 
factories ranged from 16 to 42%, while the concentrations of dust 
in the air varied from 14 to 38 mg/m3 (Pokrovskaja & Shabynina, 
1974). 

    In the past, the production of refined ferrochromium led to 
high concentrations of dust in the air of the work-place (10 - 30 
mg/m3) (Velichkovsky & Pokrovskaja, 1973).  The concentrations of 
hexavalent chromium after implementation of a number of sanitation 
and hygienic measures were 0.03 - 0.06 mg/m3 (Velichkovsky & 
Pokrovskaja, 1973). 

    In the manufacture of chromates, the oxidation state, 
solubility, and composition of air-borne material varied in 
different areas of the plant.  Exposure in the ore-crushing area 
was to trivalent, insoluble particulates; in the leaching area, 

exposure was to tri- and hexavalent, soluble and insoluble 
particulates and droplets; at the dry end of the process, the 
workers were exposed to the very soluble hexavalent chromates in 
particulate form, and to the insoluble residue after leaching 
(Velichkovsky & Pokrovskaja, 1973).  In plants using calcium in the 
roasting process, the residue that is recycled contains, among 
other products, calcium chromate, currently believed, on the basis 
of animal studies, to be at least partly responsible for the 
carcinogenicity of chromium. 

    Chromium plating of metal surfaces was accompanied by the 
release of hexavalent chromium into the air in work premises, in 
concentrations ranging from 0.04 to 0.4 mg/m3 (Yunisova & 
Pavlovskaja, 1975).  In one electroplating factory, the 
concentration of chromic acid vapours in the air varied from 0.1 to 
1.4 mg/m3 (Gomes, 1972).  In the vicinity of 3 different baths in a 
Swedish chromium plating factory, chromium concentrations ranged 
from 20 to 46 g chromium (VI)/m3, while, at another factory, the 
exposure levels near all baths were below 1 g/m3 (Lindberg et al., 
1985). 

    Occupational exposure to chromium during welding has been 
analysed and the results published by several authors (Stern, 
1981).  Welding of metals using chromium and nickel electrodes 
require high temperatures that melt both the material welded and 
the electrode, producing a complex mixture of gases, oxides, and 
other compounds, the chemistry of which is determined by the 
technology, materials, and welding parameters used in each case 
(Lautner et al., 1978). Hexavalent chromium compounds were found in 
the respiratory zone of the welder at concentrations ranging from 
3.8 to 6.6 g/m3 (Migai, 1975).  For the welding industry as a 
whole, the average exposure arising from welding is not homogeneous 
but depends on the type and conditions of the welding process 
(Stern, 1982). 

    In a cement-producing factory, the concentration of hexavalent 
chromium in the air in the work-place varied from 0.0047 to 0.008 
mg/m3.  The presence of chromium was explained by the fact that the 
lining of the kilns was composed of chrome-magnesium bricks 
containing 17 - 28% chromium compounds (Retnev, 1960).  Forty-two 
types of American cement were analysed for total chromium content 
and particularly for hexavalent chromium.  It was found that 
hexavalent chromium was present in 18 out of 42 samples in 
concentrations varying from 0.1 to 5.4 g/kg cement, while the total 
chromium content ranged from 5 to 124 g/kg (Perone et al., 1974).  
Analysis of 59 samples of Portland cement from 9 European countries 
showed that the contents of hexavalent chromium extractable with 
sodium sulfate varied from 1 to 83 g/kg of cement, while the total 
chromium contents ranged from 35 to 173 g/kg (Fregert & Gruvberger, 
1972). 

4.3.2.  Dermal exposure

    Occupational dermal exposure can result in percutaneous 
absorption and in harmful effects on the skin (section 8.3.1), 
though the percutaneous absorption of chromium (III) sulfate has 
been questioned by Aitio et al. (1984). 

    Chromium, especially chromate, is the most common contact 
allergen and of great importance in occupational contact dermatitis 
(Thormann et al., 1979). 

    Chromium eczema occurred most frequently in building labourers 
followed by painters, galvanizers, machine drillers, metal-workers, 
graphic artists, and workers in the timber, chemical, leather, and 
textile industries (Polak et al., 1973).  This is likely to reflect 
the exposure to chromium compounds from a large number of every-day 
products (section 4.2.2).  The skin exposure to cement may be of 
particular importance as building labourers belong to the most 
affected group. 

5.  KINETICS AND METABOLISM

5.1.  Absorption

5.1.1.  Absorption through inhalation

5.1.1.1.  Animal studies

    Few animal studies have been performed to determine the 
absorption of chromium compounds via inhalation.  In one early 
study, mice and rats were exposed to chromium particulates in an 
inhalation chamber for various periods of time.  The concentrations 
of soluble chromium (CrO3) in air were between 1 and 2 mg/m3 for 
the mice and 2 and 3 mg/m3 for the rats.  The concentrations of 
soluble versus insoluble chromium in the lung tissue of the mice 
varied greatly.  The soluble chromium concentrations ranged from 
4.3 to 10.7 g/kg dry tissue, after 100 weeks of exposure (Baetjer 
et al., 1959a). 

    The amount of chromium that is absorbed through inhalation 
depends on the size of the particles and droplets, on their 
solubility in body fluids, and on their reaction with the 
respiratory mucosa.  Particles greater than 5 m in diameter 
(aerodynamic size) are deposited on the mucosal surface of the 
nasal membrane, trachea, and bronchi and are carried by the action 
of the cilia to the pharynx, where they are swallowed. Smaller 
particles and droplets, especially those below 2 mm in size, 
penetrate to the alveoli.  Particles and droplets of soluble 
compounds, such as hexavalent chromium compounds, are rapidly 
absorbed in the blood.  Insoluble particles, such as chromite, are 
taken up by macrophages and slowly cleared. Soluble materials that 
react with the constituents of the lung tissue, such as soluble 
trivalent compounds, are also cleared slowly.  Baetjer et al. 
(1959b) were the first to describe the differences in the clearance 
rates of soluble chromates and chromic chloride, when injected 
intratracheally into the lungs of animals.  The hexavalent chromate 
was more rapidly transported from the lungs to other tissues than 
the trivalent chromic chloride.  Ten minutes after injection, only 
15% chromium (IV) remained in the lung compared with 70% chromium 
(III).  After 60 days, the corresponding figures were 1.7% and 13% 
(Baetjer et al., 1959b).  Hexavalent chromium is taken up by the 
red blood cells in much larger quantities than trivalent chromium.  
This finding has been confirmed by Wiegand et al. (1984b) 
performing intratracheal instillation (Na251CrO4) studies on 
anaesthetized rabbits, as shown in Fig. 2.  Confirmation of the 
macrophage uptake of insoluble chromate was obtained by exposing 
hamsters to 0.5 - 1 mg chromic oxide dust/m3 for 4 h.  The median 
diameter of the particles was 0.17 m.  Over 90% of the oxide was 
found in the macrophages (Sanders et al., 1971). 

FIGURE 2

5.1.1.2.  Human data

    A mean chromium concentration of 0.22 mg/kg wet weight was 
found in the lung tissue of subjects from various locations in the 
USA, but there was no correlation between chromium levels in the 
lungs and those in the air (Schroeder et al., 1962). 

    A Committee of the National Research Council (US NAS, 1974a) 
concluded: "It is unlikely that the intake from air under ordinary 
conditions contributes significantly to the total intake of 
available chromium; the intake from the air is calculated to be 
less than 1 g/day; but excessive exposure to airborne chromium 
does result in some increased intake". 

5.1.2.  Absorption from the gastrointestinal tract

    The absorption of ingested chromium compounds can be estimated 
by measuring the amount of chromium excreted in the urine, as 
almost all of intravenously injected chromium is excreted via the 
urine and only 2% is found in the faeces. Although a potential loss 
of endogenous chromium via the skin and its annexa has not yet been 
measured and quantified, it can be stated that this organ, as well 
as the gastrointestinal tract are of minor importance in the 
excretion of endogenous chromium.  The gastrointestinal tract is, 
of course, the major organ for the excretion of exogenous chromium. 

    When considering the gastrointestinal absorption of chromium, 
it is essential to recognize the substantial differences in the 
efficiency of absorption of trivalent and hexavalent compounds.  
These differences exist in both man and animals.  Many trivalent 
chromium compounds are so poorly absorbed that they have been used 
as faecal markers in man and animals.  The absorption of hexavalent 
chromium, administered orally, was higher in all species examined, 
but did not exceed 5% of the dose (Donaldson & Barreras, 1966).  No 
physiological regulation has yet been established for chromium 
absorption. 

5.1.2.1.  Animal studies

    The gastrointestinal absorption of chromate in rats has been 
reported to be between 3 and 6% of a tracer dose (MacKenzie et al., 
1958; Byerrum, 1961).  As in man, trivalent chromium compounds are 
less well absorbed in the rat, with reported efficiencies ranging 
from less than 0.5% (Visek et al., 1953) to 3% (Mertz et al., 
1965a).  Within the category of trivalent compounds, there are 
moderate differences in absorption, depending on the chemical form.  
Binding of the chromium ion to suitable ligands, such as certain 
organic acids, stabilizes the metal against precipitation in the 
alkaline milieu of the intestines and increases absorption 
efficiency by a factor of 3 - 5 times, compared with that for 
chromium chloride.  This has been shown for certain chelating 
agents (Chen et al., 1973), a yet unidentified small peptide 
complex isolated from yeast (Votava et al., 1973), and synthetic 
glucose tolerance factor (GTF), a dinicotinic-acid-glutathione-
chromium complex (Mertz et al., 1974).  Nothing is known about the 
interaction of chromium with the flora of the gastrointestinal 
tract.  Absorption of chromium chloride by ruminant species is 
similar to that in rats, with a mean efficiency of 0.76% (Anke et 
al., 1971); laying hens have been found to absorb almost 15% of a 
tracer dose of the element (Hennig et al., 1971). 

5.1.2.2.  Human studies

    Donaldson & Barreras (1966) studied the gastrointestinal 
absorption of hexavalent chromium by administering trace doses of 
Na251CrO4 orally to 6 volunteer patients, who were hospitalized, 
and by measuring the amount of radioactivity in the faeces and 
urine.  The mean urinary excretion, expressing the absorption 
efficiency, was 2.1  1.5% of the dose given. Administration by 
jejunal infusion in 4 volunteers increased these values, suggesting 
reduction of the chromate to trivalent compounds by the acid 
content of the gastric juice. The same authors reported a mean 
absorption efficiency of only 0.5  0.3% for trivalent chromium, 
administered as CrCl3 x 6H2O, with a range of 0.1 - 1.2%. 

    On the basis of the chromium content in diets (60 g) and 
chromium excretion (0.22 g) in healthy subjects, Anderson et al. 
(1983) calculated a minimum chromium absorption of about 0.4%. 
Increasing intake by supplementation with chromium (chromic 
chloride tablets, furnishing 200 g chromium/day) led to an 
excretion of 0.99 g, equivalent to 0.4% of the intake. 

    Aitio et al. (1984) investigated the intake and urinary 
excretion of chromium (III) in leather tanning workers.  The 
environmental concentrations were recorded as low, but chromium was 
present in air in the form of large droplets that were not 
collected by the standard air measurement technique. It was assumed 
that the large droplets were cleared by the upper respiratory tract 
and swallowed, and that the chromium in the droplets was absorbed 
from the gastrointestinal tract. A calculation showed that this 
would explain the urinary excretion levels.  No absorption of 
chromium through the skin was detected. 

    In a recent study, the minimum chromium absorption calculated 
on the basis of urinary-chromium excretion was about 0.4%.  
Increasing intake 5-fold, by chromium supplementation, led to a 
nearly 5-fold increase in chromium excretion, suggesting that the 
extent of absorption of supplemental inorganic chromium was similar 
to that from normal dietary sources (Anderson et al., 1983a). 

    A similar absorption for trivalent chromium of 0.69% was 
reported by Doisy et al. (1968) in healthy human subjects, 
regardless of age.  However, a group of 14 insulin-requiring 
diabetic patients absorbed 4 times as much of the chromium dose as 
the non-diabetic or maturity-onset diabetic subjects, as shown by 
elevated levels of 51chromium in blood plasma and urine (Doisy et 
al., 1971). 

5.2.  Distribution, Retention, Excretion

5.2.1.  Animal studies

    Most animal studies on chromium metabolism have been performed 
on rats.  From the site of intestinal absorption, chromium is taken 
up by plasma-protein fractions.  Small, physiological doses of 
51chromium have been shown to bind almost entirely to the iron-
binding protein, transferrin (Hopkins & Schwarz, 1964).  On the 
other hand, inhaled chromium (Glaser et al., 1984) was bound to 
albumin rather than to transferrin.  With larger quantities of 
trivalent chromium, non-specific binding to other proteins also 
occurred, but not to the red blood cells.  Visek et al. (1953) 
measured the effects of the different chemical forms of chromium on 
tissue distribution and found that soluble, chelated forms, such as 
acetate or citrate complexes, were cleared quite rapidly, in 
contrast with colloidal or protein-binding forms (chromite, chromic 
chloride), which have a great affinity for the reticulo-endothelial 
system (bone marrow, liver, spleen), and clear more slowly.  The 
blood clearance of hexavalent chromium, such as chromate, was slow, 
because of irreversible binding within the red blood cells.  Tissue 
distribution of 51chromium, administered in nanogram doses to rats 
was studied by Hopkins (1965).  As in the preceeding studies, the 
element accumulated in bone, spleen, testes, and epididymis; much 
less was retained in the lungs, brain, heart, and pancreas. This 
obvious difference in chromium distribution between man and rats is 
unexplained. 

    As in man, trivalent 51chromium in the rat was rapidly cleared 
from the blood, after absorption, and was retained by the tissues 
(Mertz et al., 1965a).  These tissue stores, labelled with 
51chromium chloride, administered orally or intravenously, were not 
immediately available for specific physiological functions.  For 
example, 51chromium, administered as CrCl3 x 6H2O to pregnant rats, 
was not transported into the embryos (Mertz et al., 1969), nor did 
any 51chromium appear in the blood in response to glucose or 
insulin injections (Mertz & Roginski, 1971).  The fact that fetal 
chromium concentrations are low, when the pregnant rats are fed a 
low-chromium Torula yeast diet, and increase when a high-chromium 
natural stock ration is fed, indicates that placental transport and 
possibly, the acute chromium response depend on a special form of 
chromium, which is different from chromium chloride.  It is 
possible, but has not yet been proved, that this form is the 
dinicotinic acid-glutathione-chromium complex, known as glucose 
tolerance factor.  Yeast extracts containing this factor labelled 
with 51chromium have been shown to cross the placenta (Mertz et 
al., 1969) and, in preliminary studies, to furnish chromium for the 
acute chromium response (Mertz & Roginski, 1971). 

    With reference to interactions between chromium and other trace 
elements, competition with iron by way of their common carrier 
(transferrin) has been suggested in rats (Hopkins & Schwarz, 1964) 
and in human beings (Sargent et al., 1979). Goncharov (1968) 
reported a close interaction between chromium and dietary iodine.  
In iodine-deficient white rats, addition of chromium to the diets 
in amounts supplying from 0.6 to 600 g/animal per day stimulated 
thyroid function, as indicated by morphological and functional 
changes. Conversely, chromium, in all but the lowest dose, 
decreased thyroid function in animals receiving adequate iodine 
levels. This relation is in agreement with epidemiological data 
from the USSR (Goncharov, 1968). 

5.2.2.  Human data

5.2.2.1.  Concentration in tissues, blood, urine, and hair
including possible biological indicators of exposure

    (a)   Tissues

    The most comprehensive survey of tissue-chromium concentrations 
is that of Schroeder et al. (1962), who carried out a 
spectrographic analyses on 20 - 39 samples for each autopsy tissue, 
all of which had been carefully collected to avoid extraneous 
contamination.  The following results were obtained (mean values in 
mg/kg ash) for a group of subjects who had died between the ages of 
30 and 40 years: lung, 15.6; aorta, 9.1; pancreas, 6.5; heart, 3.8; 
testes, 3.1; kidney, 2.1; liver, 1.8; spleen, 1.7.  In all tissues, 
except for the lungs there was a rapid decline in chromium 
concentrations from time of birth to the age of 10 years, followed 
by a more gradual decrease to the age of 80 years.  It cannot be 
stated with certainty whether the decline is an expression of a 
physiological mechanism or of a dietary deficiency.  The lungs lost 
their initially high chromium levels (85.2 mg/kg ash) up to the age 
of 20 years (6.8 mg/kg); subsequently, the concentrations increased 

to between 20 and 38 mg/kg.  This discrepancy demonstrates that the 
chromium in lungs is not in equilibrium with the general pool.  The 
decline of chromium in the aorta, quite pronounced in subjects in 
the USA, was much less dramatic in the aortas from subjects of 
other countries (Schroeder et al., 1970). 

    Mancuso & Hueper (1951), as well as Baetjer et al. (1959b), 
found concentrations of chromium in the lungs of former chromate 
workers that were several orders of magnitude higher than those in 
control subjects.  In a study on 16 chromate workers, including 11 
with lung cancer, Baetjer et al. (1959b), using a colorimetric 
method, observed a median concentration of water- and acid-soluble 
chromium in the lung of 70 mg/kg dry weight and a median 
concentration of acid-insoluble chromium of 17 mg/kg.  The chromium 
concentration did not differ between cancer cases and non-cancer 
cases.  The tissue specimens were obtained 0 - 23 years after the 
termination of occupational exposure, which had lasted 1.5 - 42 
years.  With the use of emission spectrometry and atomic absorption 
spectrophotometry, Hyodo et al.  (1980) found a chromium content of 
3.6 mg/kg wet weight in the lung in a male smoker with lung cancer, 
who died 10 years after employment for 30 years in a chromate-
producing plant.  The concentration in other tissues ranged from 
0.05 (bone marrow) to 1.5 mg/kg (suprarenal gland).  In five 
unexposed controls, lung concentrations ranged from 0.09 to 0.88 
mg/kg; concentrations in other tissues ranged from 0.003 (kidney) 
to 0.156 mg/kg (suprarenal gland).  The ratio of hexavalent to 
total chromium in the lungs was 29% in the worker and 22.7  10.6% 
(mean  SD) in the controls. 

    Brune et al. (1980) gave tissue concentrations for chromium and 
other metals in the lung, liver, and kidney of 20 deceased copper 
smelter workers, who had retired 0 - 19 years prior to death, and 
of a control group (8 subjects).  Tissue analysis was carried out 
using neutron activation analysis as well as atomic absorption 
spectrophotometry, and included a comparison with certified 
reference samples (National Bureau Standards, bovine liver).  In 
the controls, the concentrations ranged from below detection (0.003 
mg/kg wet weight) to 0.07 mg/kg in kidneys and 0.11 mg/kg in liver.  
There was no marked difference between the chromium contents of 
these 2 tissues and those in the exposed workers.  On the other 
hand, the lung concentrations were between 3 and 4 times higher in 
the workers than in the controls (median levels, 0.29 and 0.08 
mg/kg, respectively). 

    Chromium determinations were carried out on lung and kidney 
samples of 45 autopsies from the Northern Bavaria area (Federal 
Republic of Germany) (Zober et al., 1984).  The analyses were 
carried out using electrothermal AAS after wet oxidative digestion.  
Median values of 0.097 mg/kg wet weight (range, 0.0006 - 1.230 
mg/kg) in lung tissue and 0.0096 mg/kg wet weight (range, 0.0002 - 
0.690 mg/kg) in kidney were found. 

    Very limited data are available on chromium levels in tissues 
other than those referred to above.  Shmitova (1978) estimated 
chromium levels in fetal and placental tissues (abortive material), 

derived on the 12th week of pregnancy, and found 92.8 and 30 g 
Cr/kg tissue, respectively. 

    It can be concluded that chromium may be retained in the lungs, 
several years after the termination of occupational exposure.  
However, it is not known whether this observation has any 
biological relevance to the appearance of lung cancer.  In this 
context, it is of interest to note that chromium is retained in the 
human lung for a relatively long period, even without occupational 
exposure. 

    (b)   Blood

    The values reported by various investigators for chromium 
concentrations in the blood of unexposed human beings range from 
0.2 to 70 g/litre in serum and plasma and 5 to 54 g/litre in red 
blood cells (US EPA, 1978).  Insufficient evidence is available to 
state whether the blood values in the normal population are 
influenced by concentrations in the ambient air.  The most 
extensive determination of blood-chromium levels in chromate 
workers was made by Mancuso (1951).  Blood values during exposure 
varied from 5 to 170 g/litre and from 10 to 140 g/litre, 74 days 
after work ended.  No decrease in blood-chromium levels was found, 
even after 74 days without exposure. 

    Because of a selective affinity of hexavalent chromium for the 
erythrocyte, substantially increased environmental exposure to 
chromates is reflected in an increased ratio of the hexavalent 
chromium level in red blood cells to that in plasma.  Baetjer et 
al. (1959a) found the following concentrations in 3 exposed 
chromate workers: blood cells, 30, 54, and 140 g/litre; plasma, 0, 
20, and 17 g/litre, respectively.  In the absence of exposure to 
chromate, the chromium concentrations in erythrocytes and plasma, 
as serum, were nearly identical (Paixao & Yoe, 1959).  Chromium 
(VI) is incorporated into human red blood cells and remains there 
over a long period of time (Wiegand et al., 1985), since the 
approximate lifetime of human red cells is about 100 days. Exposure 
to 2 mg trivalent chromium/day, for 3 months, resulted in an 
increased concentration  (0.2 mg/kg) in the red cells of 5 human 
males, compared with 0.11 mg/kg in 5 controls without supplement 
(Schroeder et al., 1962).  However, later studies did not show any 
increase in chromium concentrations in red cells, following 
exposure to trivalent chromium (Beyersmann et al., 1984; Wiegand et 
al., 1985).  Monitoring of red blood cell-chromium may be a useful 
indicator of exposure to hexavalent, but not to trivalent, 
chromium. 

    Most of the later studies show that the true chromium 
concentration in the plasma or serum of healthy subjects is of the 
order of 1 g/litre or less (Guthrie et al., 1978; Versieck et al., 
1978).  Seeling et al. (1979) determined chromium in serum and 
plasma using flameless AAS.  This study was supported by measuring 
a standard reference material (National Bureau of Standards, 1569 
brewer's yeast, reference data: 2.12  0.05 mg/kg, measured data: 
2.3  0.2 mg/kg).  The chromium levels in serum ranged from 0.7 to 
2.2 g/litre and in plasma from 1 to 1.5 g/litre (central 
parameters of a long normal distribution). 

    Pooled serum samples of 6 healthy Finnish volunteers were 
studied by Kumpulainen et al. (1983).  A mean value of 0.11  0.05 
g chromium/litre (range, 0.06 - 0.20) was found. Nomiyama et al. 
(1980b) analysed 20 blood samples of Japanese subjects, using 
direct flameless ASS, and reported a value of 2.9  1.7 g 
chromium/litre whole blood. 

    Zober et al. (1984) analysed the blood of 45 autopsied subjects 
from the Northern Bavaria area (Federal Republic of Germany).  A 
median chromium concentration of 2.8 g/litre of postmortem blood 
(range, 0.20 - 24 g/litre) was found, the value was not influenced 
by age or sex. 

    A reference material for chromium, bovine serum (RM 8419) is 
available from the National Bureau of Standards, Washington DC, 
USA. 

    (c)   Urine

    Chromium concentrations in the urine of non-occupationally 
exposed subjects have been reported to range from 1.8 to 11 
g/litre (Imbus et al., 1963).  Except for exposed persons and 
juvenile diabetic patients, the reported values for daily chromium 
excretion in urine (Table 9) do not differ as much as those for 
blood.  In later studies, such as that of Guthrie et al. (1979), a 
method of flameless atomic absorption was used in which it was 
possible to correct for spectral interference (Zander et al., 
1977).  Such interference was difficult to eliminate with earlier 
methods (Guthrie et al., 1978).  Urine samples from 189 Japanese 
volunteers, aged 10 - 80 years, in 4 pollution-free areas, were 
analysed for chromium by Nomiyama et al. (1980a), using direct 
flameless AAS.  The average level was 0.4  0.37 g/litre (X  SE) 
or 0.47 0.42 mg/kg creatinine.  Urinary chromium tended to be 
higher in males than in females and to decrease with age, but the 
differences were not significant.  Using electrothermal AAS, the 
urinary excretion of various metals in non-occupationally exposed 
adults was measured by Schaller & Zober (1982).  For smokers, a 
median value of 1.6 g chromium/litre was found (non-smoker: 1.4 g 
chromium/litre).  Commercially available urine samples were used 
for quality control (Angerer et al., 1981).  Although a "normal" 
level of chromium excretion for healthy, unexposed persons cannot 
yet be established with certainty, such a level may be less than 1 
g/day. 

    Several investigators have measured urinary-chromium excretion 
in exposed workers.  In a study on chromate workers, the urine 
values ranged from 5 to 380 g chromium/litre during exposure and 
from 10 to 54 g chromium/litre, 74 days after the end of exposure 
(Mancuso, 1951).  No relationship was evident between the urine 
levels and the weighted average number of years of exposure.  In 
every case where urine values were recorded, both during, and 74 
days after the end of, exposure, the chromium concentrations 
decreased with time away from exposure. 

    A study of 12 workers in a galvanizing plant in the Federal 
Republic of Germany showed an average concentration of chromium in 
urine of 9.5 g/litre (range, 1.4 - 24.6 g/litre) compared with a 
value of 1.8  1.1 g/litre in 60 unexposed workers (Schaller et 
al., 1972).  Gylseth et al. (1977) investigated a group of 14 
welders exposed to about 0.05 mg chromium/m3 air, and reported a 
urinary chromium concentration of approximately 40 mg/litre.  At 
the same exposure level, Tola et al. (1977) found a concentration 
of 30 mg chromium/kg of creatinine in the urine.  In both of these 
studies, there was a correlation between recent exposure to 
airborne chromium and chromium concentrations in urine.  In the 
study by Tola et al. (1977), it was shown that the water-soluble 
fraction of airborne chromium was better correlated with the 
concentration excreted in the urine than with total chromium.  It 
was also shown that the water-soluble fraction consisted mainly of 
hexavalent chromium. 

Table 9.  Daily chromium excretion in urine
---------------------------------------------------------------------------
Subjects           Number  Excretion      Range        Reference
                           (g/day)       (g/day)
                           (mean  SD)
---------------------------------------------------------------------------
Adult males        2       0.72a          0.58 - 0.86  Schroeder et al.
                                                       (1962)

Adult males, fed   3       31.0a          20.8 - 46.5  Schroeder et al.
2 mg trivalent,                                        (1962)
chromium/day for         
3 months                 
                         
Normal adults      16      13  6         4 - 24       Voelkl (1971)
Chromate workerb           16 000
                         
Normal adults      60      1.6  1.1                   Schaller et al.
                                                       (1972)
                         
Galvano-technical  12      9.7  6.6      1.4 - 24.6   Schaller et al.
workers                                                (1972)
                         
Normal young       20      8.4  5.2                   Hambidge (1974)
adults                   
                         
Normal children,   18      5.5  2.9                   Hambidge (1974)
8 years old

Insulin-dependent  7       19.2  18.9                 Hambidge (1974)
diabetic children,       
11 years old             
                         
Young women        9       7.2  1.2      5.9 - 10.0   Mitman et al.
                                                       (1975)

Adult males        12      0.8  0.4      0.4 - 1.8    Guthrie et al.
                                                       (1979)
---------------------------------------------------------------------------

Table 9.  (contd.)
---------------------------------------------------------------------------
Subjects           Number  Excretion      Range        Reference
                           (g/day)       (g/day)
                           (mean  SD)
---------------------------------------------------------------------------
Adult males        91      0.48  0.41a   0.42 - 0.53  Nomiyama et al.
                                                       (1980b)

Adult females      98      0.34  0.31a   0.22 - 0.43  Nomiyama et al.
                                                       (1980b)

Adult males        48      0.20  0.01a   0.05 - 0.58  Anderson et al.
                                                       (1982b)

Adult females      28

Adult males        27      0.17  0.10                 Anderson et al.
                                                       (1983a)

Adult females      15      0.20  0.12                 Anderson et al.
                                                       (1983a)

Adult males and    299     0.80  0.6a    0.4 - 2.1    Fang (1983)
females

Normal adults      10      0.11  0.05a   0.06 - 0.20  Kumpulainen et al.
                                                       (1983)

Normal adultsc     10      4.9            0.10 - 14.2  Zober et al.
                                                       (1984)
---------------------------------------------------------------------------
a   Data calculated as g/litre urine.
b   Tanner, suffering from an acute ulceric gasteroenterocolitis.
c   Samples taken post-mortem from autopsies. Original values are related
    to mass (kg) instead of volume (litre).
    Lindberg & Vesterberg (1983a) measured airborne, and urinary-
chromium levels among platers.  Concentrations of chromium in urine 
of < 5 g/litre occurred when the time-weighted average values of 
exposure were about or below 2 g/m3 air.  Severe damage to the 
nasal septum and effects on lung function have not been found at
levels lower than this. It was shown that post-shift urinary-
chromium determinations could be used to monitor exposure in this 
occupational group. 

    The urinary-chromium excretion and chromium clearance in 22 
welders, who had been exposed to airborne hexavalent chromium (5 - 
150 g/m3) during 2 - 40 years (mean working time, 18.9 years) were 
measured by Mutti et al. (1979).  The method used was flameless 
atomic absorption spectrometry.  A highly significant correlation 
was detected between the ratio of urinary-chromium to creatinine 
and the airborne chromium concentration in the workplace, with 
excretions ranging from 5.3  3.7 to 33.3  6.9 mg chromium/kg 
creatinine in slightly exposed and heavily exposed welders, 

respectively.  The authors also reported an increase in chromium 
clearance with increasing body burden of chromium, which indicates 
that high urinary-chromium excretion may be caused by previous high 
exposure as well as by current exposure. 

    Baseline data for chromium excretion in unexposed subjects in 
the report by Mutti et al. (1979) are approximately 10 times higher 
than the values recently proposed and generally accepted as normal.  
However, there is reason (section 2.2.2) to accept relative 
differences in analytical results in studies by one author using 
one method, even if the absolute values reported may be questioned. 

    To test whether chromium excretion is also associated with 
exercise-induced increases in glucose utilization, the urinary 
chromium excretion, serum glucose, insulin, and glucagon of 9 male 
runners (23 - 46 years old) were evaluated by Anderson et al. 
(1982a).  The mean urinary-chromium concentration was increased 
nearly 5-fold, 2 h after running; excretion of sodium, potassium, 
and calcium was unchanged.  These data demonstrate an increase in 
chromium excretion with exercise-induced increase in glucose 
utilization. 

    (d)   Milk

    The chromium concentration was determined in 261 samples of 
breast milk collected by manual expression from 45 American women.  
Chromium levels were measured in whole, liquid milk by graphite-
furnace AAS, using the method of standard additions. The mean 
chromium content of the breast milk samples was 0.30 g/litre.  The 
range of individual values was 0.06 - 1.56 g/litre and did not 
change significantly with duration of lactation (Casey & Hambidge, 
1984).  Kumpulainen et al. (1983) analysed frozen samples of pooled 
breast milk taken from women in different stages of lactation and 
obtained from the Milk Bank of the Children's Hospital of Helsinki.  
The mean chromium content  SD was 0.49  0.067 g/litre (range, 
0.37 - 0.57 g/litre). 

  (e)   Hair

    Hair-chromium concentrations in children during the first 6 
months of life were significantly higher than at any other age 
(Hambidge & Baum, 1972); they declined from an initial value of 
1493 g/kg to an average of 412 g/kg at 2 - 3 years.  Hambidge 
(1971) compared the chromium concentration in the hair of 15 
newborn babies and that of their mothers: in only one case was the 
chromium level in the mother's hair higher than that in the newborn 
baby.  Chromium levels were significantly lower than those 
mentioned above in 50 Turkish women and their newborn babies (203 
and 119 g/kg, respectively) and only 12 newborn babies were found 
to have higher concentrations than their mothers, suggesting 
suboptimal chromium status (Grson, 1977).  Hair appears to reflect 
the nutritional chromium status of groups.  The hair-chromium level 
is significantly lower in parous women than in nulliparae (Hambidge 
& Rodgerson, 1969; Mahalko & Bennion, 1976) and in diabetic 
children compared with normal controls (Hambidge et al., 1968).  It 
is low in adult-onset diabetic adults (Benjanuratra & Bennion, 

1975).  These findings are in agreement with the expected changes 
in chromium balance during pregnancy and in diabetes. 

5.2.2.2.  Dynamic aspects of metabolism and the influence of
pathological states

    Once chromium is absorbed into the organism, it clears rapidly 
from the blood stream and is excreted or taken up by the tissues.  
In a clinical study, Sargent et al. (1979) detected a 4-
compartment-type clearance from blood, with mean half-times of 13 
min, 6.3 h, 1.9 days, and 8.3 days.  However, the disappearance 
from 3 tissue compartments was much slower, with half-times of 
0.56, 12.7, and 192 days.  The half-times for blood 3-compartment 
clearance in rats (Hopkins, 1965) were calculated to be 0.56, 5.33, 
and 57 h (Withey, 1983). 

    Whether any organ is specifically responsible for the storage 
and release of the "metabolically responsive" chromium is not 
known.  The "metabolically responsive" chromium in blood is defined 
as the fraction that increases acutely in response to an elevation 
of blood-glucose or blood-insulin levels.  It is believed that this 
chromium increment interacts with the increased insulin secreted in 
response to a glucose load, to facilitate the action of the hormone 
on the insulin receptors of the insulin-sensitive cells. 

    In young, healthy subjects, but not in elderly subjects and 
diabetic patients, an oral glucose load or the injection of insulin 
results in a sudden increase in serum- or plasma-chromium 
(Glinsmann et al., 1966; Levine et al., 1968; Hambidge, 1971; Behne 
& Diel, 1972; Liu & Morris, 1978).  This increase may appear 30 
min, or as late as 120 min, after the challenge; much of the 
chromium responsible for the increase is subsequently lost in the 
urine.  Lack of this increase, also termed "relative chromium 
response", is often associated with impaired glucose tolerance, 
indicative of chromium deficiency.  It should be noted that, when 
the glucose load was given intravenously (Pekarek et al., 1975) to 
healthy volunteers, the serum-chromium level decreased rapidly, 
while the blood-glucose level increased.  Supplementation with 
chromium chloride or high-chromium yeast extracts for several weeks 
resulted in the reappearance of the relative chromium response and 
improvement of glucose tolerance (Glinsmann et al., 1966; Liu & 
Morris, 1978).  These findings support the conclusion that the 
"relative chromium response" measured during a glucose or insulin 
tolerance test may serve as an indicator of the adequacy of 
metabolically responsive chromium. 

    Much of the chromium increment secreted into the blood stream 
in response to glucose or insulin is subsequently lost in the 
urine.  Hambidge (1971) observed greatly increased urinary-chromium 
excretion in 2 diabetic children after insulin therapy had begun, 
compared with the excretion in the same children before insulin 
treatment.  It is not known whether the increased urinary loss of 
chromium is compensated for by an increase in absorption efficiency 
from the intestines.  Hambidge et al. (1968) reported significantly 
lower chromium concentrations in the hair of diabetic children 
compared with normal children, and Morgan (1972) found that 

the chromium contents in the livers of 31 diabetic adults at 
autopsy were lower than those in 24 control livers from non-
diabetic persons (8.57 versus 12.7 mg/kg ash;  P = 0.05). 

    On the other hand, Doisy et al. (1971) demonstrated greatly 
increased intestinal absorption, together with elevated chromium 
excretion, in 14 insulin-dependent diabetic patients administered 
51CrCl3 x 6H2O, orally.  It is not known whether the greater 
absorption efficiency is adequate to compensate for the increased 
urinary losses; the decreased chromium concentrations in hair and 
liver, discussed above, suggest that a negative balance may prevail. 

    Several other pathological conditions affect chromium 
metabolism.  Sargent et al. (1979) detected significantly less 
retention of intravenously administered 51chromium in 11 patients 
with haemochromatosis compared with 5 normal controls.  This may be 
related to the high saturation with iron of transferrin, which is 
also the carrier protein for newly absorbed chromium. 

    Chronic ischaemic heart disease also affects chromium 
metabolism.  Neiko & Del'va (1978) observed a significantly 
increased urinary-chromium loss, greater by a factor of 1.5 - 1.6 
than that of normal controls, in 65 heart patients.  The urinary-, 
and to a lesser extent, the faecal-chromium loss increased 
progressively with increasing severity of signs and symptoms and 
resulted in a negative chromium balance in the post-infarct state.  
The balance became positive again on discharge from the hospital 
after medical treatment. 

    Acute infections also appear to influence chromium metabolism.  
Pekarek et al. (1975) measured glucose tolerance, and insulin and 
chromium levels in human volunteers, before and after infection 
with the benign sandfly fever virus. Impaired glucose tolerance and 
a significantly increased insulin response to a glucose load, 
observed at the height of the infection, were accompanied by very 
significantly depressed serum-chromium levels (0.5 g/litre, 
compared with 1.4 g/litre before infection;  P < 0.05)  In 
contrast with the sharp decline in serum-chromium following the 
intravenous injection of glucose in the healthy state observed by 
these authors, the depressed serum-chromium levels declined very 
little during the glucose tolerance test at the height of 
infection.  The mechanism of the changes in chromium metabolism in 
heart disease and sandfly fever is not clear. Of great potential 
importance is the unanswered question of whether the observations 
described here reflect an increased chromium requirement in the 
patients or a normal reaction to various forms of stress. 

    The information on the dynamic aspects of chromium metabolism 
in animals is limited and should be considered in connexion with 
the more detailed studies on human subjects. Diabetes, induced in 
rats by the injection of streptozotocin, affected the tissue 
distribution of injected 51CrCl3.  Sixteen days after injection of 
streptozotocin, 51CrCl3 was injected into 5 diabetic rats and 6 
normal controls and the 51Cr content measured 5 days later.  The 
serum of the diabetic rats contained more than 3 times the 51Cr 
activity found in the controls (0.24 versus 0.07% of the injected 

dose  P < 0.01). Significant differences were also detected in the 
distribution of 51Cr in the subcellular fractions of the liver;  in 
the diabetic tissue, 51Cr activity was higher in the nuclear and 
supernatant fractions ( P < 0.01) and lower in mitochondria and 
microsomes ( P < 0.05).  The mechanism responsible for these 
changes is not known (Mathur & Doisy, 1972). 

5.3.  Influence of Chemical Form

    The diverse biological effects of chromium on living organisms 
cannot be understood without knowledge of the chemical and physical 
forms in which the element is present. As stated earlier, the 
metallic state (zero valence) is biologically inert, the trivalent 
state represents the essential element chromium, and the hexavalent 
state is of concern to the toxicologist.  Compounds of trivalent 
chromium are poorly absorbed, whereas those of the hexavalent state 
easily penetrate physiological barriers, such as cell membranes.  
Hexavalent chromium compounds are easily reduced by living matter, 
but oxidation of trivalent to hexavalent chromium does not occur in 
the organism. 

    The physical form of hexavalent compounds (such as particle 
size) and chemical properties (such as solubility) determine 
metabolic pathways after inhalation and, therefore, health effects.  
There is an equally strong influence of the chemical form of 
trivalent chromium on metabolism and health effects.  When chromium 
is bound to water or small anions (e.g., CrCl3 x 6H20), it 
precipitates in the neutral or alkaline milieu of the body fluids.  
When it is bound to ligands, such as organic acids, the element is 
light in solution and is available for intestinal absorption.  The 
forms in which trivalent chromium occurs in nature are not really 
known.  Plants probably contain chromium complexes with organic 
acids. 

    The biological availability of chromium compounds in foods is 
of great nutritional importance, but is poorly defined. One 
compound or a group of closely related compounds, glucose tolerance 
factor, has been isolated from yeast and shown to be more active 
than chromium chloride in genetically diabetic mice and in the  in 
 vitro potentiation of the action of insulin on rat epididymal fat 
tissue (section 7.1.5.2).  It has been identified as a dinicotinic-
acid glutathione complex, but the exact stereochemical structure is 
not yet known (Toepfer et al., 1977).  It has been postulated, but 
not proved, that this factor is the active form of chromium within 
the organism. 

6.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    The environmental effects of chromium as a pollutant have been 
reviewed by US EPA (1978), Anderson (1982), and EIFAC (1983).  
Various effects have been reported, but, because of the presence of 
other chemicals, it remains doubtful whether chromium alone is 
responsible for the effects observed.  Data are available on 
microorganisms, plants, and aquatic organisms. 

6.1.  Microorganisms

    Most microorganisms (protozoa, protophyta, fungi, algae, 
bacteria) are able to absorb chromium.  The active uptake of 
chromate by the sulfate transport system has been shown in 
 Neurospora crassa  (Roberts & Marzluf, 1971).  No distinction has 
been made between ab- and adsorption in other studies (e.g., algae) 
(Calow & Fletcher, 1972), and it has not yet been shown that 
chromium is an essential element for microorganisms.  In general, 
toxicity for most microorganisms occurs in the range of 0.05 - 5 mg 
chromium/kg of medium.  The internal concentration of chromium 
depends on the species.  In most groups of microorganisms, it 
ranges between the levels of 0.6 mg dry weight present in one litre 
of sample of microplankton from Monterey Bay, California, USA, and 
21.4 mg/litre phytoplankton collected in the Pacific Ocean (Martin 
& Knauer, 1973). 

    Trivalent chromium is less toxic than hexavalent.  The main 
features are inhibition of growth (at concentrations greater than 
0.5 mg/litre in  Chlorella cultures) (Nollendorf et al., 1972) and 
inhibition of various metabolic processes, such as photosynthesis 
or protein synthesis (US EPA, 1978). 

    The toxicity of chromium for soil bacterial isolates was 
studied by measuring the turbidity of liquid cultures supplemented 
with hexavalent chromium and trivalent chromium. Gram-negative 
bacteria were more affected by hexavalent chromium (1 - 12 mg/kg) 
than gram-positive bacteria.  Toxicity due to trivalent chromium 
was not observed at similar levels. The toxicity of low levels of 
hexavalent chromium (1 mg/kg) indicates that soil microbial 
transformations, such as nitrification, may be affected (Ross et 
al., 1981). 

6.2.  Plants

    Although chromium is present in all plants, it has not been 
proved to be an essential element for plants.  Most substances, 
including chromium, can be absorbed through either the root or the 
leaf surface.  Several factors affect the availability of chromium 
for the plant (Black, 1968), including the pH of the soil, 
interactions with other minerals or organic chelating compounds, 
and carbon dioxide and oxygen concentrations. 

    Little chromium is translocated from the site of absorption; 
however, the chelated form is transported throughout the plant 
(Verfaillie, 1974). 

    Chromium in high concentrations can be toxic for plants, but 
Yopp et al. (1974) stated that there was no specific pattern of 
chromium intoxication. 

    During the smelting of chromite, considerable quantities of 
waste are produced, which contain soluble chromates.  When combined 
with a high pH, Gemmell (1973) showed an inhibition of germination 
and growth in white mustard plants  (Sinapis alba)  growing on waste 
heaps.  Covering the waste with a 25-to 30-cm layer of granular-
free-draining subsoil followed with layers of soil, peat, or sewage 
sludge was shown to be the best revegetation technique (Gemmell, 
1974). 

    The main feature of chromium intoxication is chlorosis, which 
is similar to iron deficiency (Hewitt, 1953). 

    Soybeans, treated in nutrient culture containing 0 - 5 mg 
hexavalent chromium/litre showed decreased uptake of calcium, 
potassium, phosphorus, iron, and manganese (Turner & Rust, 1971).  
Death of plants occurred within 3 days of treatment with 30 or 60 
mg chromium/litre. 

    A reduction in leaf dry weight occurred after treatment with 
0.01 mg hexavalent chromium/litre (Rediske et al., 1955).  Chromium 
affects the carbohydrate metabolism, and the leaf chlorophyll 
concentration decreased with increasing hexavalent chromium 
concentration (0.01 - 1 mg hexavalent chromium/litre) (Rediske, 
1956).  Hexavalent chromium appears to be more toxic than trivalent 
chromium (Hewitt, 1953; Stanley, 1974; Verfaillie, 1974).  At 
present, no data are available concerning the mechanism of action 
or the dose-dependent pattern of chromium intoxication. 

6.3.  Aquatic Organisms

    More studies have been performed with aquatic species than with 
free-living (non-parasitic) animals.  Depending on the species, 
chromium can be less toxic for fish in warm water, but marked 
decreases in toxicity are found with increasing pH or water 
hardness; changes in salinity have little if any effect on its 
toxicity.  Chromium can make fish more susceptible to infection; 
high concentrations can damage and/or accumulate in various fish 
tissues and in invertebrates such as snails and worms.  
Reproduction of  Daphnia was affected by exposure to 0.01 mg 
hexavalent chromium/litre (EIFAC, 1983).  Numerous other factors 
influence the availability of chromium and, therefore, its 
toxicity.  These include the presence of other minerals and organic 
pollutants, and the temperature of the environment; this has been 
shown in mice (Nomiyama et al., 1980a). 

    Hexavalent chromium is accumulated by aquatic species by 
passive diffusion (US EPA, 1978).  Ecological factors, in the 
abiotic and living environment, are involved in this process, which 
varies according to the sensitivity of different species.  The 
physiological state and activity of the fish also affect 
accumulation (Reichenbach-Klinke, 1977, 1980). Kittelberger (1973) 
analysed the organs and tissues of the roach  (Leuciscus rutilus)

from the river Rhine and found that concentrations of chromium in 
the spleen, bronchi, and intestine (between 30 and 37.5 mg/kg) were 
10 - 30 times higher than those in the heart, skin, muscle, and 
scales. 

    LC50s are listed in Table 10 for hexavalent and trivalent 
chromium compounds in the aquatic environment. 

Table 10.  The toxicity of chromium for fresh-water organisms 
(expressed as 50% mortality)a
-----------------------------------------------------------------------
Compound    Category      Exposure      Toxicity range  Most
                                        (mg/litre)      sensitive
                                                        species
-----------------------------------------------------------------------
hexavalent  invertebrate  acute         0.067 - 59.9    scud
chromium                  long-termb    -               -

            vertebrate    acute         17.6 - 249      fathead minnow
                          long-term     0.265 - 2.0     rainbow trout

trivalent   invertebrate  acute         2.0 - 64.0      cladoceran
chromium                  long-term     0.066           cladoceran
            
            vertebrate    acute         33.0 - 71.9     guppy
                          long-term     1.0             fathead minnow
-----------------------------------------------------------------------
a  From: US EPA (1980).
b  No data available.

    In general, invertebrate species, such as polychaete worms, 
insects, and crustaceans are more sensitive to the toxic effects of 
chromium than vertebrates, such as some fish (Mathis & Cummings, 
1973).  The lethal chromium level for several aquatic and 
nonaquatic invertebrates has been reported to be 0.05 mg/litre (US 
NAS/NAE, 1972). 

    EIFAC (1983) reviewed the literature on the occurrence and 
effects of chromium in fresh water and proposed tentative water-
quality criteria that distinguish between salmonid and non-salmonid 
waters.  To protect salmonid waters, the mean aqueous concentration 
of "soluble" chromium should not exceed 0.025 mg chromium/litre, 
and the 95 percentile should not exceed 0.1 mg chromium/litre.  
However, more stringent values may be necessary in very soft, acid 
waters, and less stringent values in alkaline waters. 

7.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

7.1.  Nutritional Effects of Chromium

    The criteria for an essential nutrient have been defined in 
different ways by different authors, but all definitions postulate 
that a reduction in the total daily intake of the nutrient below a 
certain level must consistently induce signs of deficiency, and 
that the supplementation of the daily intake above this level must 
prevent and cure the deficiency signs.  Chromium deficiency has 
been produced experimentally in mice, rats, and squirrel monkeys, 
and the full reversal of the deficiency signs by the oral 
administration of chromium has been demonstrated in rats (Mertz, 
1969).  For these reasons, chromium must be considered an essential 
micro-nutrient.  It is physiologically active in the trivalent 
oxidation state at concentrations of approximately 100 g/kg diet. 

7.1.1.  Effects of deficiency on glucose metabolism

    Semipurified rations, containing Torula yeast as the source of 
protein, were fed to groups of 10 male Sprague Dawley rats at 
weaning, and intravenous glucose tolerance tests were performed by 
injecting 1250 mg glucose/kg body weight and measuring the 
subsequent decline in blood-glucose levels.  The rate of glucose 
disappearance can be calculated from the straight line plot of log 
increment glucose (excess of glucose at any time (t) over fasting 
glucose), versus time.  The disappearance constant k is expressed 
as % decline of the increment glucose per min; it is a measure of 
the efficiency of glucose utilization.  In weaning rats, the rate 
constant was found to decline, within 3 weeks or less, from an 
average of 4%/min to 2.6%/min in animals fed the Torula yeast diet, 
but not in animals administered a diet in which 4 or 8% of Torula 
yeast was replaced by an equal amount of brewer's yeast.  This 
observation suggested that brewer's yeast, but not Torula yeast, 
contained an unknown substance necessary for the maintenance of 
normal glucose tolerance.  Because the only known effect of the 
substance was that on glucose tolerance, it was named "Glucose 
Tolerance Factor" (GTF) (Mertz & Schwarz, 1959).  GTF was extracted 
from brewer's yeast and pork kidney powder, concentrated and 
purified, and its active ingredient was identified as trivalent 
chromium (Schwarz & Mertz, 1959).  Chromium in the form of most 
common complexes (except for very stable ones) cured the impairment 
of glucose tolerance in deficient rats, either as one oral dose of 
200 g/kg body weight, or as an intravenous (iv) injection of 2.5 
g/kg body weight.  Chromium in the diet also prevented the 
impairment of glucose tolerance. 

    In order to produce more pronounced deficiencies of chromium 
and other trace elements, Schroeder et al. (1963) constructed a 
special animal house on a mountain top in Vermont, USA, far removed 
from traffic and industry.  The interior was specially coated with 
organic resins to reduce any metallic exposure.  Air was introduced 
through special filters, and strict practices were enforced to 
avoid the introduction of dust and dirt.  This will be referred to 
as the "controlled environment".  Under these conditions, a more 

severe chromium deficiency resulted in very low glucose removal 
rates of 1.12%/min in 6 rats and of 0.18%/min in 4 female breeder 
rats (482 days old), after 11 days on a chromium-deficient diet.  
The removal rate in 4 control rats receiving the same diet with a 
chromium supplement improved from 0.51 to 1.39% during the same 
period (Mertz et al., 1965b).  This strong impairment of glucose 
tolerance in rats kept in the "controlled environment" was 
reflected in their fasting blood-glucose levels, compared with 
those of chromium-supplemented controls: 1370  68 versus 1170  17 
mg/litre in males and 1390  68 versus 960  65 mg/litre in 
females.  More than half of 185 deficient rats excreted more than 
0.25% glucose in the urine, whereas glycosuria was found in only 9 
of the chromium-supplemented controls (Schroeder, 1966).  A 
significant reduction in the intravenous glucose removal rate was 
also observed in 8 rats in plastic cages, fed an EDTA-washed low-
protein diet (7% casein), compared with 8 controls receiving 50 g 
chromium as the chloride, by stomach tube, daily for 2 weeks (2.1 
versus 3.6%/min;  P < 0.01).  However, chromium supplements did not 
improve the near-normal removal rates in rats receiving a 20% 
casein diet (Mickail et al., 1976).  Significantly lower plasma-
glucose levels, due to supplementation with chromium, were reported 
in rats fed the chromium-deficient Torula yeast diet (Whanger & 
Weswig, 1975).  In another series of studies, only a slight 
reduction in blood-glucose (from 1240 to 1180 g/litre) was found 
in 10 rats receiving a diet supplemented with chromium (10 g/kg) 
(Djahanshiri, 1976). 

    Impaired glucose tolerance in squirrel monkeys, fed a 
commercial laboratory chow, was shown to respond to chromium 
supplementation.  Of 9 monkeys with an impaired glucose removal 
rate (1.38%/min), 8 responded after 22 weeks of supplementation of 
their drinking-water (chromium acetate, 10 mg/litre) with a 
normalization of their glucose tolerance (average removal rate, N = 
9, 2.33  0.3%/min) (Davidson & Blackwell, 1968).  There was no 
effect on food consumption, growth rate, or serum-insulin 
concentrations.  The chromium content of the commercial chow was 
stated to be 3.3 mg/kg, a very high concentration.  In view of the 
uncertainties of methods of analysis for chromium (section 2.2), it 
is not possible to interpret the results as indicative of a very 
high chromium requirement of the squirrel monkey or of an unusually 
poor bioavailability of the chromium in that particular ration.  A 
marginal chromium deficiency may have existed in mice fed a bread 
and milk diet, as daily administration of 10 g chromium for 16 
days to 8 months produced a 10 - 30% decline in blood-glucose 
levels (Vakhrusheva, 1960).  However, this effect was not specific 
for chromium, as it was also observed when manganese was 
administered. 

    The glucose tolerance of guinea-pigs did not differ 
significantly between groups fed diets containing chromium at 
0.125, 0.625, or 50 mg/kg, even though the animals fed the 2 higher 
levels exhibited a lower mortality rate during pregnancy (Preston 
et al., 1976). 

    Although the administration of synthetic glucose tolerance 
factor (a chromium-dinicotinic acid-glutathione complex) to 6 pigs 
did not affect glucose tolerance tests, it resulted in a 
significant increase in the hypoglycaemic effect of insulin 
injected at 0.1 U/kg body weight (Steele et al., 1977a). 

    Turkey poults, fed a practical ration containing chromium 
levels of 5 mg/kg, responded to chromium supplementation (20 mg/kg 
diet) with a significant increase in liver glycogen and in glycogen 
formation, following a fast, and with a significant increase in 
glycogen synthetase (EC 2.4.1.11) activity in the liver (Rosebrough 
& Steele, 1981). 

    It can be concluded that the impairment of glucose tolerance in 
rats fed a low-chromium Torula yeast diet is due to chromium 
deficiency.  The effects of chromium in squirrel monkeys, pigs, and 
turkeys, though statistically significant, are somewhat difficult 
to interpret, because of the reported high chromium content of the 
basal diet.  No evidence for chromium deficiency has yet been 
obtained through glucose tolerance tests on other animal species. 

7.1.2.  Effects of deficiency on lipid metabolism

    Though trivalent chromium in high doses (2.5 mg/kg body weight) 
has been shown to increase the synthesis of fatty acids and 
cholesterol in the liver (Curran, 1954), lower, physiological doses 
appear to decrease serum-cholesterol concentrations in rats.  
Schroeder & Balassa (1965) found an average level of 927 mg 
cholesterol/litre serum in 24- to 26-month-old male rats, kept in a 
controlled environment and administered chromium in the drinking-
water at a concentration of 5 mg/litre, compared with an average of 
1229 mg/litre in controls not receiving chromium ( P < 0.01).  The 
effects in female rats were ambigous, one study producing the 
expected reduction in cholesterol due to chromium, another showing 
an elevation in the supplemented female rats.  Schroeder's 
observations of a cholesterol-reducing effect of chromium in male 
rats were confirmed by Staub et al. (1969) and by Whanger & Weswig 
(1975) but were contradicted by results of a third study in which 
there were not any significant effects of chromium on sucrose-
induced triglyceridaemia and cholesterolaemia (Bruckdorfer et al., 
1971).  Perhaps more significant than the effect on circulating 
cholesterol is the direct effect of chromium on the occurrence of 
aortic plaques. Schroeder & Balassa (1965) observed 6 plaques in 54 
male and female chromium-deficient rats, but only one plaque in 48 
animals receiving 5 mg chromium/litre in drinking-water. These 
results are in agreement with those from a subsequent report of the 
protective effect of the natural chromium content of water (60 - 
215 g/litre) against atherosclerosis in cholesterol-fed rabbits 
(Novakova et al., 1974).  Abraham et al. (1980) extended these 
observations by demonstrating that daily chromium injections (20 g 
K2CrO4) reversed the established atherosclerosis in the aorta of 11 
cholesterol-fed rabbits, compared with 12 controls.  The mean 
plaque area was reduced from 95% to 63%, the total aortic 
cholesterol from 729 mg to 458 mg, and the atheromatous lesions, as 

measured by technetium incorporation from 285 000 cpm to 114 000 
cpm, all differences being statistically significant.  These 
results are reinforced by observations in man discussed in section 
8.1. 

7.1.3.  Effects of deficiency on life span, growth, and 
reproduction

    The mortality of male, but not of female mice, raised in a 
"controlled environment" (section 7.1.1) was reduced by trivalent 
chromium administered as acetate in the drinking-water at a 
concentration of 5 mg/litre (Schroeder et al., 1964).  The survival 
rates at 12 months were 92.6% and 68.8% ( P < 0.0001) in 
supplemented and deficient animals, respectively.  Similary, male, 
but not female, rats receiving a chromium concentration of 5 
mg/litre in the drinking-water had longer life spans than deficient 
controls.  The mean age of the last surviving 10% of animals was 
1249 days, compared with 1141 days in the deficient animals ( P < 
0.01). Survival of male rats fed a low-chromium (< 100 g/kg), 
low-protein ration and subjected to a controlled acute haemorrhage 
was significantly less than that of chromium-supplemented rats, in 
2 studies (67 versus 92%;  P < 0.05 and 27 versus 60%;  P < 0.01, 
respectively) (Mertz & Roginski, 1969). 

    In Schroeder's study, growth rates in treated mice and rats of 
both sexes raised in a "controlled environment", were higher after 
6 and 12 months, with highly significant differences in body weight 
ranging from 9 to 17% ( P < 0.005) compared with the controls.  
Again, the effects of chromium supplementation were greater in 
males than in females (Schroeder et al., 1964, 1965). 

    Similar results were reported by Djahanschiri (1976), who 
studied a total of 2750 rats of a special inbred strain (Hk51) fed 
a basal diet (0.15 mg chromium/kg diet) and chromium supplements 
ranging from 10 to 500 mg/kg diet.  At 12 weeks, the average 
weights of the chromium-supplemented animals, regardless of dose 
level, were significantly higher (by 6% in the males and 3% in the 
females) than those of the animals on the basal diet.  The same 
author reported a progressive diminution in both the milk 
production of lactating rats and weight gain in 3 consecutive 
generations fed the low-chromium diet, compared with rats receiving 
chromium supplementation. Increased mortality was reported in 
pregnant guinea-pigs fed a low-chromium diet (125 g/kg diet) 
compared with animals receiving a chromium supplement of either 625 
g/kg or 50 mg/kg (Preston et al., 1976). 

    When rats raised on a low-chromium Torula yeast diet (< 100 
g/kg) mated with those on a normal diet, they were able to 
impregnate the females at a 100% conception rate only up to the age 
of 4 months.  After this age, the conception rate declined to 25%, 
25%, and 0%, at the age of 7, 8, and 9 months, respectively.  This 
decline was accompanied by a significant ( P < 0.01) decrease in 
the sperm count in the chromium-deficient males to approximately 
half of the count in supplemented controls at the age of 8 months 
(Anderson & Polansky, 1981). 

7.1.4.  Other effects of deficiency

    Male weanling rats, fed a 10% soya protein ration with a 
chromium content of less than 100 g/kg, developed a visible 
opacity of the cornea in one or both eyes. In several studies, the 
incidence of this effect ranged from 10 to 15% in deficient rats.  
No opacities developed in control animals receiving 2 mg 
chromium/kg diet (Roginski & Mertz, 1967). 

    Chromium deficiency has been shown to reduce the physical 
performance of rats under stress.  Ten male rats raised on a 
chromium-deficient diet (150 g/kg diet) swam for an average of 250 
min, until exhaustion, in contrast with 10 rats receiving a 
supplement of 10 mg chromium/kg diet, which were exhausted only 
after 320 min (Djahanschiri, 1976). 

7.1.5.  Mechanism of action of chromium as an essential nutrient

7.1.5.1.  Enzymes, nucleic acids, and thyroid

    Chromium is present in nucleic acids in very high 
concentrations, but the function of these is not clear at present 
(Mertz, 1969).  However, recent work suggests a biological function 
of chromium in nucleic acid metabolism (Okada et al., 1984).  
Ribonucleic acid synthesis in mouse liver was significantly 
increased by as little as 1 mol trivalent chromium, in the 
presence of DNA or chromatin (Okada et al., 1981).  These effects 
were also present when the DNA or chromatin were first complexed 
with chromium prior to incubation.  However, prior complexation of 
RNA polymerase with chromium depressed activity.  These effects 
were obtained  in vitro with a concentration (52 g/litre) that is 
similar to physiological levels.  Goncharov (1968) presented data 
suggesting that chromium is involved in the function of the thyroid 
gland.  These findings have been supported by Lifschitz et al. 
(1980). 

    An oligopeptide with a relative molecular mass of 1480, which 
was crystallized from liver tissue, had a specific affinity for 
chromium (Wu, 1981). 

7.1.5.2.  Interaction of chromium with insulin

    The interaction of chromium with insulin has been extensively 
studied and can therefore be presented in some detail, but this 
does not imply that this is the only, or the most important, 
function of chromium. 

    The effects of chromium  in vitro, and probably  in vivo, depend 
on the presence of endogenous or exogenous insulin, no effects 
having been demonstrated in  in vitro systems that did not either 
depend on, or contain, insulin. Chromium deficiency causes an 
impaired response to added insulin in rat epididymal fat tissue, 
and, when glucose uptake or glucose oxidation or utilization for 
lipid synthesis is measured, the dose-effect curve is flat.  
Addition of suitable chromium compounds significantly increases the 

slope of the curve (Fig. 3).  This demonstrates the true 
potentiation of the insulin action and indicates that chromium 
alone does not act as an insulin-like substance (Mertz et al., 
1961; Mertz & Roginski, 1971; Mertz, 1981).  Chromium was also 
shown to stimulate the transport of D-galactose into epididymal fat 
cells.  This suggests cell transport, the first step of sugar 
metabolism, as a major site of action for chromium (Mertz & 
Roginski, 1963).  Insulin-potentiating effects have also been 
observed on the swelling of liver mitochondria (Campbell & Mertz, 
1963) and on glucose utilization in isolated rat lens (Farkas & 
Roberson, 1965). 

FIGURE 3

    Stimulation of the effects of insulin has been observed in a 
glucose-independent, but insulin-responsive, system.  Significantly 
more alpha-amino isobutyric acid (a non-metabolizable amino acid 
analogue) was incorporated into the heart and liver tissue of 
chromium-supplemented male rats than in the tissues of chromium-
deficient controls, in response to the  in vivo injection of the 
labelled analogue and insulin (Roginski & Mertz, 1969). 

    These observations suggest a peripheral action of chromium to 
facilitate the action of insulin; no evidence has been produced 
indicating that chromium plays any role in the production, storage, 
or release of insulin by the pancreas. Thus, the primary result of 
chromium deficiency is a diminution in the effectiveness of 
insulin.  The resulting metabolic impairment may be compensated for 
by increased insulin production in some cases, resulting in 
elevated concentrations of the hormone, but not enough data exist 

from experimental animal studies to assess the action of the 
element on insulin metabolism.  More information is available for 
human subjects and this is discussed in section 8.1.  The 
interaction between chromium, insulin, and receptor sites of liver 
mitochondrial membranes was studied using polarographic techniques.  
The results formed the basis for the hypothesis that chromium may 
facilitate bond formation between the intra-chain disulfide of 
insulin and sulfur-containing groups of the receptors, by 
participating in a ternary complex (Christian et al., 1963). 

    This hypothesis is consistent with results of studies on rats 
fed, either a low-chromium Torula yeast diet or a brewer's yeast 
diet known to be adequate in chromium.  While the insulin-binding 
capacity of hepatocytes was not significantly different, the 
insulin affinity of the cells was significantly greater ( P < 0.01) 
for the chromium-adequate rats than for the deficient Torula yeast 
rats (Steele et al., 1977b). 

7.1.6.  Chromium nutritional requirements of animals

    In the preceding sections, studies were evaluated in which the 
effects of chromium supplementation were determined in animals that 
were at least marginally chromium deficient.  In other studies, the 
effects of chromium were investigated in animal systems in which 
the existence of chromium deficiency was either not ascertained or 
not investigated.  Before these studies are described and 
interpreted for the determination of chromium nutritional 
requirements of animals, it is helpful to consider them against the 
background of Venchikov's (1974) model.  This model is generally 
applicable to trace element effects defining 3 zones of action, the 
zone of biological action, that of pharmacodynamic action, and that 
of toxicity (Fig. 4).  The biological zone, in response to 
supplements with low amounts of an element, represents the 
correction of a deficiency and the resulting level of biological 
activity is that of optimal function.  Increasing the amount of 
supplement further may lead to a certain depression, followed by a 
zone of new, increased activity, in which the element no longer 
acts as an essential nutrient, but as a drug.  Still greater 
supplements, beyond the homeostatic control capability of the 
organism produce toxic effects and death.  Because all the studies 
described subsequently involved amounts of chromium supplements 
that were higher than the levels normally needed to correct a 
deficiency, it is possible, according to Venchikov's definition, 
that the observed effects might be pharmacological. 

FIGURE 4

    Tuman & Doisy (1977) studied the effects of yeast concentrates 
of high chromium (glucose tolerance factor) content and of 
synthetic chromium complexes with GTF activity (Tuman et al., 1978) 
in mice, raised on a presumably complete commercial stock diet.  
Six animals were used for each test, either genetically diabetic 
mice or their control litter mates of the C57Bl-KSI strain.  
Injections of either 5 mg of the GTF-containing yeast extracts or 
0.1 mg of the synthetic chromium complex, acutely reduced the 
elevated plasma-glucose levels in the diabetic and the non-fasting 
normal mice by 10 - 38% of the initial values ( P < 0.01) and the 
plasma-triglycerides by 26 - 56% ( P < 0.01), compared with control 
mice injected with saline.  Injection of insulin into diabetic mice 
produced only an 11 - 18% decrease in plasma-glucose levels, 
whereas injection of the GTF-containing extract together with 
insulin reduced plasma-glucose levels by 39 - 51% and plasma-
triglyceride levels by 76% (Table 11). 

    The results suggest either a much higher increase in the 
chromium requirement of the genetically diabetic mice or their 
inability to use chromium in the diet. 

Table 11.  Acute effects of GTF and exogenous insulin on non-
fasting plasma-glucose and plasma-triglyceride (TG) concentrations 
in 19-week-old genetically diabetic micea
------------------------------------------------------------------
Treatment  Plasma-      deltaGlucose   Plasma-         deltaTG
           glucoseb                    triglyceridesb
           (mg/litre)                  (mg/litre)
------------------------------------------------------------------
saline     11 120                     3960  160(5)c
           490(5)c

GTF        9320        -180 (16%)     2790  170(5)d  -117 (30%)
           280(5)d

insulin    9840        -128 (12%)     3020  400(5)   - 94 (24%)
           410(5)

insulin    7060        -406 (37%)     940  220(5)e   -302 (76%)
and GTF    840(5)e
------------------------------------------------------------------
a   Modified from: Tuman & Doisy (1977).
b   Glucose and triglyceride values represent mean  SEM for 6 mice in
    each treatment group. Dose of GTF was 5 mg (WL-10-AT) administered
    intraperitoneally, 12 h prior to collection of blood. Lente insulin
    (0.1 U per mouse) was administered subcutaneously, 12 h prior to
    collection of blood. Data were treated by analysis of variance to
    detect differences between the various treatment groups; independent
    orthogonal comparisons were performed in the following groups ( P value
    indicates level of significance for each comparison).
c   Saline versus all other treatments,  P < 0.005.
d   GTF versus insulin,  P < 0.05.
e   GTF and insulin alone versus combined GTF and insulin,  P < 0.005.
    Thus, GTF and insulin > GTF = insulin > saline.

    Steele & Rosebrough (1979) reported a significant stimulation 
of the growth rate of one-week-old turkey poults (both sexes) by 
supplementation of a practical ration with 20 mg chromium (as 
chloride)/kg.  The weight gains within the 2-week study were 235 g 
and 267 g for the 60 controls and 60 supplemented turkeys, 
respectively ( P < 0.001).  As the practical ration contained 
ground yellow corn and soybean meal, limestone, and dicalcium 
phosphate, chromium deficiency would appear unlikely.  The amount 
of the chromium supplement (20 mg/kg diet) is quite high, and 
further studies are needed to decide whether the observed effects 
were of a pharmaco-dynamic nature or truly nutritional, i.e., 
correcting a deficiency.  A similar interpretation should be 
applied to a report of improved egg quality in the laying hen 
(Jensen et al., 1978). 

    The quantitative aspects of the effects of chromium on animals 
can be summarized as follows: normal rats fed semi-purified, semi-
synthetic rations, with Torula yeast or individual proteins and 
sucrose or starch as the source of carbohydrates, develop mild 
signs of deficiency at a dietary level of 100 - 150 g chromium/kg.  
To prevent deficiency, most authors used very high supplements of 
several mg/kg diet and did not determine the biological 
availability of the chromium complexes used for the 
supplementation.  Diets containing raw ingredients and supplying 
chromium levels between 0.5 and 1 mg/kg do not induce signs of 
deficiency and probably meet the requirement of the rat.  A very 
tentative estimate of the dietary chromium need of the rat and 
probably the mouse would be approximately 0.5 mg/kg diet.  This 
estimate should be interpreted with caution, because of the lack of 
knowledge concerning the biological availability of chromium and of 
its interaction with dietary constituents. 

7.2.  Toxicity Studies

    The toxicology of chromium compounds has been reviewed by the 
US National Academy of Science (US NAS, 1974a), Langard & Norseth 
(1979), the International Agency for Research on Cancer (IARC, 
1980), Langard (1980a, 1982), and Burrows (1983). 

    In discussing toxicological problems, it is important to 
differentiate between the various oxidation states of chromium and 
its compounds.  Trivalent chromium, when administered to animals in 
food or water, does not appear to induce any harmful effects, even 
when given in large doses (US NAS, 1974a) (section 7.2.1).  Acute 
and chronic toxic effects of chromium are mainly caused by 
hexavalent compounds.  Since it has been shown that both industrial 
trivalent chromium compounds as well as reagent-grade trivalent 
chromium compounds can be contaminated by hexavalent chromium 
(Petrilli & DeFlora, 1978a; Levis & Majone, 1979), the evaluation 
of experimental studies becomes difficult, especially when the 
purity of the chemical compounds used is not known. 

    Discrimination between the biological effects, caused by 
hexavalent chromium and trivalent chromium is difficult, because, 
after penetration of membranes in tissues, hexavalent chromium is 
immediately reduced to trivalent chromium (Gray & Sterling, 1950; 

US NAS, 1974a), and it is not evident whether the observed 
phenomena are caused by this reduction or even by the trapping of 
trivalent chromium by ligands after uptake in the cells.  Another 
problem in evaluating the data is associated with the route of 
administration.  Hexavalent chromium, introduced by the oral route, 
is partly reduced to trivalent chromium by acidic gastric juice 
(Donaldson & Barreras, 1966; DeFlora & Boido, 1980); thus, the 
effects or lack of effects observed may be caused mainly by 
trivalent chromium and not by the hexavalent chromium, actually 
administered. 

7.2.1.  Effects on experimental animals

    Many local effects on human beings have been reported (section 
8.3), but only a few studies have verified these effects in 
experimental animals.  A comprehensive survey of hexavalent 
chromium-induced effects is given in Table 12 (US NAS, 1974a).  For 
most studies, details were not given of the length of exposure, 
number of treated animals and controls, etc.  Diagnoses were stated 
without presenting all the original data.  Thus, in this section, 
some papers will be discussed that refer to the most prominent 
local and systemic effects to support and clarify the effects shown 
in human beings. 

    It is evident that the toxicity of hexavalent chromium in 
animals varies with the route of entry into the body.  Low 
concentrations of hexavalent chromium may be tolerated, when 
administered in the feed or drinking-water, the extent of 
absorption being a factor of importance.  For example, rats 
tolerated hexavalent chromium in drinking-water at 25 mg/litre, for 
1 year, and dogs did not show any effects from chromium 
administered as potassium chromate at 0.45 - 11.2 mg/litre over a 
4-year period (US NAS, 1974a).  However, oral exposure of both male 
and female rabbits to sodium dichromate (0.1% solution, 0.2 - 5 
mg/kg body weight, for up to 545 days) resulted in significant 
morphological changes in the gonads, including atrophy of the 
epithelium and dystrophic alterations of the Sertoli and Leydig 
cells in the testes, and sclerotic and atrophic changes in ovaries 
(Kucher, 1966). 

    Larger doses of hexavalent chromium are highly toxic and may 
cause death, especially when injected iv, subcutaneously (sc), or 
intragastrically.  The LD50 of chromium compounds was determined 
for several experimental animal species.  The LD50 of potassium 
dichromate (hexavalent chromium), administered orally (stomach 
tube) to rats, was 177 mg/kg body weight in males and 149 mg/kg 
body weight in females (Hertel, 1982). When injected iv in mice 
(sex not given), the LD50 of chromium carbonyl was 30 mg/kg body 
weight (IARC, 1980). 

    Performing a life-time inhalation study on the rat, Glaser et 
al. (1984) found an LC50 for Na2Cr2O7 of 28.1 mg/m3 (range, 16.7 - 
47.3 mg/m3).  Assuming a deposition rate in the lung of 30% of the 
dose administered, the LC50 dose was 1 mg/kg body weight in male 
and 1.2 mg/kg in female rats. 


Table 12.  Effects of hexavalent chromium in animalsa
---------------------------------------------------------------------------------------------------------
Animal    Route       Compound(s)     Average dose      Duration       Effect            Reference
                                      or concentration
---------------------------------------------------------------------------------------------------------
Rabbit,   inhalation  chromates       1 - 50 mg/m3      14 h/day for   pathological      Lukanin (1930)
cat                                                     1 - 8 months   changes     
                                                                       in the lungs

Rabbit    inhalation  dichromates     11 - 23 mg/m3     2 - 3 h/day    none              Lehmann (1914)
                      as dichromate                     for 5 days

Cat       inhalation  dichromates     11 - 23 mg/m3     2 - 3 h/day    bronchitis,       Lehmann (1914)
                      as dichromate                     for 5 days     pneumonia           
                                                                       perforation of
                                                                       nasal septum  

Mouse     inhalation  mixed dust      1.5 mg/m3         4 h/day,       no tumours        Baetjer et al.
                      containing      as CrO3           5 days/week,                     (1959a);
                      chromates                         for 1 year                       Steffee &
                                                                                         Baetjer (1965)

Mouse     inhalation  mixed dust      16 - 27 mg/m3     1/2 h/day      tumours in        Baetjer et al.
                      containing      as CrO3           intermit-      some strains      (1959a);
                      chromates                         tently                           Steffee &
                                                                                         Baetjer (1965)

Mouse     inhalation  mixed dust      7 mg/m3           37 h over      increased         Baetjer et al.
                      containing      as CrO3           10 days        tumour rate       (1959a);
                      chromates                                                          Steffee &
                                                                                         Baetjer (1965)

Rat       inhalation  mixed dust      7 mg/m3           37 h over      barely            Baetjer et al.
                      containing      as CrO3           10 days        toleratedb        (1959a);
                      chromates                                                          Steffee &
                                                                                         Baetjer (1965)

Rabbit,   inhalation  mixed dust      5 mg/m3           4 h/day,       none marked       Baetjer et al.
guinea-               containing      as CrO3           5 days/week,                     (1959a);
pig                   chromates                         for 1 year                       Steffee &
                                                                                         Baetjer (1965)
---------------------------------------------------------------------------------------------------------

Table 12.  (contd.)
---------------------------------------------------------------------------------------------------------
Animal    Route       Compound(s)     Average dose      Duration       Effect            Reference
                                      or concentration
---------------------------------------------------------------------------------------------------------
Rat,      inhalation  hexacarbonyl    1.6 mg/m3         4 months,      anaemia; lipid    Roschina (1976)
rabbit                                                  4 h, 5 days    and/or protein      
                                                        a week         dystrophia  
                                                                       in liver          
                                                                       and kidneys       

Rat,      inhalation  hexacarbonyl    0.16 mg/m3        4 months,      anaemia; no       Roschina (1976)
rabbit                                                  4 h, 5 days    biochemical             
                                                        a week         or morphological
                                                                       effects         
                                                                                       
Rat       inhalation  hexacarbonyl    35 mg/m3          30 min         100% death        Roschina (1976)

Rat       inhalation  dichromates     0.006 - 0.2       28 days/       increase in       Glaser et al.
                                      mg/m3             90 days        lung-macrophages  (1985)
                                                        23 h/day                  
                                                        7 days/week    lymphocytes
                                                                       immunoglobulin,
                                                                       reduced Fe2O3
                                                                       lung clearance

Rat       intratra-   dichromates     5 per week        up to 30       toleratedc        Steinhoff
          cheal in-                   0.01 - 0.25       months                           et al. (1983)
          stillation                  mg/kg

Rat       intratra-   dichromates     1 per week        up to 30       tolerated;        Steinhoff
          cheal in-                   0.05 - 1.25       months         1.25 mg/kg        et al. (1983)
          stillation                  mg/kg                            harmful

Rat       oral        potassium       500 mg/litre      daily          maximal           Gross & Heller
                      chromate in                                      non-toxic         (1946)
                      drinking-water                                   concentration

Rat,      oral        zinc chromate   10 g/kg           daily          maximal           Gross & Heller
mouse                 in feed                                          non-toxic         (1946)
(mature)                                                               concentration
---------------------------------------------------------------------------------------------------------

Table 12.  (contd.)
---------------------------------------------------------------------------------------------------------
Animal    Route       Compound(s)     Average dose      Duration       Effect            Reference
                                      or concentration
---------------------------------------------------------------------------------------------------------

Rabbit    oral        sodium di-      0.2 - 5.0 mg/kg   545 days       morphological     Kucher (1966)
                      chromate                                         changes in               
                                                                       gonads (testes:          
                                                                       atrophy of               
                                                                       epithelium,              
                                                                       dystrophic               
                                                                       alterations of           
                                                                       Sertoli &                
                                                                       Leydiz alls.             
                                                                       Ovaries:                 
                                                                       sclerotic and            
                                                                       atrophic   
                                                                       changes)                 
                                                                       
Rat       oral        zinc chromate   1.2 g/kg          daily          maximal           Gross & Heller
(young)               in feed                                          non-toxic         (1946)
                                                                       concentration

Rat       oral        potassium       1.2 g/kg          daily          maximal           Gross & Heller
(young)               chromate                                         non-toxic         (1946)
                      in feed                                          concentration

Dog,      oral        monochromate    1.9 - 5.5 mg      29 - 685       none harmful      Lehmann (1914)
cat,                  or dichromates  chromium/kg       days
rabbit                                body weight per
                                      day 1 mg chrom-
                                      ium equivalent
                                      to 2.83 mg
                                      K2Cr2O7
                                      or 3.8 mg
                                      K2CrO4
---------------------------------------------------------------------------------------------------------

Table 12.  (contd.)
---------------------------------------------------------------------------------------------------------
Animal    Route       Compound(s)     Average dose      Duration       Effect            Reference
                                      or concentration
---------------------------------------------------------------------------------------------------------
Dog       oral        potassium       1 - 2 g as        daily          fatal in 3        Brard (1935)
                      dichromate      chromium                         months anaemia

Dog       stomach     potassium       1 - 10 g as       -              rapidly fatald    Brard (1935)
          tube        dichromate      chromium

Monkey    subcutan-   potassium       0.02 - 0.7 g in   -              fatald            Hunter & Roberts
          eous        dichromate      2% solution                                        (1933)

Dog       subcutan-   potassium       210 mg as         -              rapidly fatal     Brard (1935)
          eous        dichromate      chromium

Guinea-   subcutan-   potassium       10 mg             -              lethald           Ophls (1911a)
pig       eous        dichromate                                                         Ophls (1911b)

Rabbit    subcutan-   potassium       1.5 cc of 1%      -              80% fatald        Hasegawa (1938)
          eous        dichromate      solution/kg body
                                      weight

Rabbit    subcutan-   potassium       20 mg             -              lethald           Ohta (1940)
          eous        dichromate

Rabbit    subcutan-   potassium       0.5 - 1 cc of     -              nephritisd        Ohta (1940)
          eous        dichromate      0.5% solution/kg
                                      body weight

Rabbit,   subcutan-   sodium          0.1 - 0.3 g as    -              rapid deathd      Priestley
guinea-   eous or     chromate        CrO3                             fall in blood     (1877)
pig       intravenous                                                  pressure

Rabbit    intra-      potassium       0.7 cc of 2%      -              lethald           Mazgon (1932)
          venous                      solution/kg                      8-10 days after
                                      body weight                      injection

Dog       intra-      potassium       10 grains         -              instant death     Gmelin (1826)
          venous      chromate
---------------------------------------------------------------------------------------------------------

Table 12.  (contd.)
---------------------------------------------------------------------------------------------------------
Animal    Route       Compound(s)     Average dose      Duration       Effect            Reference
                                      or concentration
---------------------------------------------------------------------------------------------------------

Dog       intra-      potassium       1 grain           -              none marked       Gmelin (1826)
          venous      chromate

Dog       intra-      potassium       210 mg as         -              rapidly fatal     Brard (1935)
          venous      dichromate      chromium

Dog       intra-      potassium       3 mg/100 cc       2 doses        marked renal      Hepler & Simonds
          venous      dichromate      blood per dose                   damage            (1946); Simonds
                                                                                         & Hepler (1945)
---------------------------------------------------------------------------------------------------------
a  Modifed from: US NAS (1974a).
b  Pathological changes in experimental and control rats, 101 weeks after exposure.
c  The same weekly dose distributed over 5 days was clearly better tolerated than a single weekly 
   administration.
d  Renal damage.
    A local corrosive action of hexavalent chromium on the skin, 
similar to that seen in man, was described by Samitz & Epstein 
(1962), who induced chrome ulcers in guinea-pigs at 4 trauma sites, 
with daily exposure to 0.34 MK2Cr2O7 solution for 3 days.  Mosinger 
& Fiorentini (1954) showed the same effects using potassium 
chromates. 

    Following parenteral administration, the most common systemic 
effects of chromium were parenchymatous changes in the liver and 
kidney (Mosinger & Fiorentini, 1954).  Later studies showed 
selective damage in the renal proximal convoluted tubules, without 
evidence of glomerular damage, as demonstrated after one single sc 
injection of potassium dichromate of 10 mg/kg body weight (Schubert 
et al., 1970) or after one single intraperitoneal (ip) injection of 
sodium chromate of 10 or 20 mg/kg body weight (Evan & Dail, 1974). 
Effects have also been found in fish (Strik et al., 1975). After 32 
days of continuous exposure to 0.1, 1, or 10 mg hexavalent chromium 
(as potassium dichromate)/litre, the fish  Rutilus rutilus developed 
lysis of the intestinal epithelium with haemorrhages as well as 
hypertrophy and hyperplasia of the gill epithelium. 

    Franchini et al. (1978) found an increase in urinary protein, 
lysozyme, glucose, and beta-glucuronidase in rats after a single sc 
injection of potassium dichromate at 15 mg/kg body weight.  After 
sc injection (3 mg/kg body weight), every other day for 2 - 8 
weeks, the authors observed a correlation between the chromium 
contents of the renal cortex and chromium clearance. 

    Five-week-old male Wistar rats of the strain TNO-W-74 were 
continuously exposed in inhalation chambers to submicron aerosols 
of sodium dichromate at concentrations ranging from 25 (low level) 
to 200 g chromium/m3 (high level) (Glaser et al., 1985).  Exposure 
for 28 days to 25 or 50 g chromium/m3 resulted in "activated" 
alveolar macrophages with stimulated phagocytic activity, and 
significantly elevated antibody responses to injected sheep red 
blood cells.  After 90 days of low-level exposure, there was a more 
pronounced effect on the activation of the alveolar macrophages, 
with increased phagocytic activity. However, inhibited phagocytic 
function of the alveolar macrophages was seen at the high 
hexavalent chromium exposure level (200 g/m3).  In rats exposed to 
this chromium aerosol concentration for 42 days, the lung clearance 
of inert iron oxide was significantly reduced.  The humoral immune 
system was still stimulated at a low chromium aerosol concentration 
of 100 g/m3, but significantly depressed at 200 g chromium/m3. 

    Exposure of rats, through inhalation, to chromium carbide or 
chromium boride dust at very high levels (300 - 350 mg/m3 for each 
substance) for 3 months (2 h/day) resulted in effects on the 
vascular system of the lungs, e.g., endothelial hyperplasia.  
Bronchitis and a decrease in the blood-haemoglobin concentration 
were also observed (Roschina, 1964). The effects of chromium boride 
were more pronounced than those of chromium carbide. 

    Steinhoff et al. (1983) performed an intracheal injection study 
on rats (930 rats, 30 months, 0.05 - 1.25 mg Na2Cr2O7/kg body 
weight per week; 1.25 mg CaCrO4/kg body weight per week).  Half of 
the rats were intratracheally injected once a week and the other 
half received the same weekly dose distributed over 5 injections 
per week.  In rats receiving doses 5 times a week, there were some 
significant changes in levels of total plasma-protein and 
-cholesterol, in some haematological variables, in organ weights, 
and in survival times in females.  Only male rats receiving 1.25 mg 

sodium dichromate/kg body weight, once a week, showed a sharp 
reduction in body weight, female rats being less affected. Rats 
receiving calcium chromate in the same dose showed reduced body 
weight but to a lesser extent.  The weight of lung and trachea was 
increased by both substances in all doses. 

    Marked histopathological changes (congestion, fairly large 
areas of focal necrosis, bile duct proliferation) described after 
long-term exposure of rabbits to hexavalent chromium (ip injection 
of 2 mg chromium/kg body weight per day for 6 weeks) (Tandon et 
al., 1978), as well as the increase in hepatic metallothionein and 
decrease in cytochrome P-450 levels after ip injection of 400 mol 
chromium/kg per day (type of chromium compound not mentioned) 
(Eaton et al., 1980) need further confirmation.  The finding of an 
accumulation of hexavalent chromium in the reticuloendothelial 
system including bone marrow (Baetjer et al., 1959b; Langard, 1977) 
may be of importance for a disturbed blood picture. 

    Merkurieva et al. (1980a,b) studied the effects of potassium 
dichromate in the drinking-water on the activities of different 
enzymes in rats.  Exposure included daily doses of 0.0005, 0.005, 
0.05, or 0.5 mg/kg body weight for up to 6 months.  After 20 days 
of exposure at the highest dose level, enzyme activities increased 
by 15 - 28% in liver microsomes (inosine-5-diphosphatase), 
lysosomes (beta-D-galactosidase), and cytosol (lactate dehydrogenase 
(EC 1.1.1.27)).  For some of these enzymes, as well as for 
acetylesterase (EC 3.1.1.6), increases in activity of up to 54% 
were found in the gonads, kidneys, seminal fluid, and serum.  At a 
dose of 0.05 mg/kg, the only statistically significant finding was 
a 54% increase in the activity of acetylesterase in the gonads.  
After a 6-month exposure at this dose level, there was a 70% 
increase in lactate dehydrogenase activity in the seminal fluid as 
well as a 50% increase in free beta-galactosidase in the liver.  There 
were no changes in enzyme activities at the two lowest dose levels. 

    Painting of rat skin with an aqueous solution of potassium 
dichromate (0.5%), daily, for 20 days, resulted in a local 
inflammatory reaction, an increased level of hexose glyco-proteins 
in the skin and serum, and an elevated concentration of serotonin 
in the skin and liver (Merkurieva et al., 1982). Most of these 
effects were also seen earlier in the exposure period, though they 
were not as pronounced.  Ten days after the start of exposure, a 
nearly 3-fold increase in the serum-acetylcholine concentration 
occurred together with decreased acetylcholinesterase activity.  
Thus, the data of Merkurieva et al. show systemic effects following 
both oral and dermal exposure to hexavalent chromium. 

    Cats fed chromic phosphate or oxydicarbonate at 50 - 1000 mg/day 
for 80 days did not exhibit signs of illness or tissue damage.  
Similarly, toxic reactions were not observed in rats administered 
drinking-water containing 25 mg trivalent chromium/litre, for 1 
year, or 5 mg trivalent chromium/litre throughout their lifetime 
(US NAS, 1974a).  The toxicity of trivalent chromium is so low that 
even by parenteral administration, a chromic acetate level of 2.29 
g/kg body weight or a chromic chloride level of 0.8 g/kg body 

weight is required to kill mice.  Even very large doses given 
intragastrically were not fatal for dogs.  Brard (1935) reported 
that 10 or 15 g of chromium as chromic chloride proved fatal in one 
dog (US NAS, 1974a).  Some fatal doses of trivalent chromium 
compounds reported in the literature are listed in Table 13. 

    Rats exposed through inhalation to chromic oxide (trivalent 
chromium) at 42 mg/m3 or to chromic phosphate at 43 mg/m3 (5 h/day 
for 5 days/week) for 4 months developed chronic irritation of the 
bronchus and lung parenchyma, and dystrophic changes in the liver 
and kidney (Blokin & Trop, 1977). 

    Inhalation exposure of rats (number not given) to dusts 
containing 36 or 50% chromite for 4 months (2 h/day), at 
concentrations of 375 - 400 mg/m3, resulted in thickening of the 
walls of pulmonary vessels and bronchi (Roschina, 1959). The high 
exposure levels in these studies make it difficult to evaluate the 
effects. 

    Inhalation studies have also been performed with chromium 
carbonyl, where chromium is in the 0 oxidation state (Roschina, 
1976).  Twelve rabbits and 48 rats were exposed for 4 months (4 
h/day, 6 days/week) at a concentration of 1.6 or 0.16 mg/m3.  At 
both exposure levels, there was loss of body weight (25 and 12%, 
respectively) as well as anaemia and leukocytosis.  In the higher 
exposure group, the animals showed an elevated gamma-globulin level 
in serum and an increased transaminase activity.  The contents of 
cholesterol and SH-groups were reduced, and there was a decrease in 
cholinesterase (EC 3.1.1.7) activity.  Lipid and/or protein 
dystrophy were noted in several organs, e.g., in the liver and 
kidneys.  No such effects were detected in the animals in the low-
exposure group. 
Table 13.  Fatal doses of trivalent chromium in animalsa
---------------------------------------------------------------------------------------------
Animal  Number of  Routeb  Compound             Chromium       Effect  Reference
        animals            dose (g/kg)
---------------------------------------------------------------------------------------------
Dog     2          sc      chromic chloride     0.8            fatal   Brard (1935)
Rabbit  1          sc      chromic chloride     0.52           fatal   Brard (1935)
Rat     38         iv      chrome alum          0.01 - 0.018   LD50    Mertz et al.
                           chromium-hexaurea                           (1965a)
                           chloride
Mouse   -c         iv      chromic chloride     0.8            MLDd    Windholz et al. (1960)
Mouse   -c         iv      chromic acetate      2.29           MLD     Windholz et al. (1960)
Mouse   -c         iv      chromic chloride     0.4            MLD     Schroeder (1970)
Mouse   -c         iv      trivalent chromium ? 0.25 - 2.3     MLD     Windholz et al. (1960)
Mouse   -c         iv      chromic sulfate      0.247          MLD     Windholz et al. (1976)
Mouse   -c         iv      chromic sulfate      0.085          MLD     Schroeder (1970)
Mouse   -c         iv      chromium carbonyl    0.03           LD50    Schroeder (1970)
---------------------------------------------------------------------------------------------
a Modified from: US NAS (1974a).
b sc = subcutaneous; iv = intravenous.
c No figures given.
d Minimum lethal dose.
7.2.1.1.  Carcinogenicity

    Various types of chromium chemicals, methods of administration, 
and species of animals have been studied (IARC, 1980a). 

    Ideally, carcinogenicity should be tested with the methods 
recommended by IARC (1980b), but, in many of the early studies, 
this was not done.  Carcinomas of the lung have been reported in 
animals as a result of the administration of chromium chemicals.  
Hueper (1958) found 2 squamous cell carcinomas and one 
carcinosarcoma in 25 rats following intra-pleural injection of 
chromite ore roast.  After intrapleural implantation of strontium 
chromate lasting 27 months, Hueper (1961) found tumours (type 
unspecified) in 17/28 rats.  Laskin et al. (1970) and Levy & Venitt 
(1975) produced a number of bronchogenic carcinomas by implanting 
pellets of cholesterol mixed with various chromium compounds 
encased in a wire mesh cage in the bronchi of rats.  Calcium and 
zinc potassium chromate produced a number of bronchogenic 
carcinomas, but soluble chromates and trivalent chromium chemicals 
failed to produce cancer. 

    Using the same technique, Levy & Martin (1983) tested 21
different chromium-containing materials (pigments, intermediates, 
and residues from the bichromate-producing industry, relatively 
pure crystalline compounds) in 2250 random-bred rats and found that 
chromates, described as sparingly soluble, were carcinogenic in the 
rat lung.  These materials included strontium and calcium chromate 
and, to a far lesser extent, certain forms of zinc chromate.  
Barium and lead chromate evoked only a very weak carcinogenic 
response compared with strontium and calcium chromate.  In the 
study of Laskin et al. (1970), it was shown that chromium trioxide 
produced hepatocellular carcinomas in 2/100 rats (controls, 0/24). 

    After inhalation of 13 mg calcium chromate/m3 (5 h/day, 5
days/week, for lifetime), Nettesheim et al. (1971) found 14 lung 
adenomas in 136 treated mice and 5 in 136 untreated controls, but 
no carcinomas.  Steffee & Baetjer (1965), performing inhalation 
studies on rats, mice, guinea-pigs, and rabbits (inhalation of 
mixed chromate dust, corresponding to 3 - 4 mg CrO3/m3, 4 - 5 
h/day, 4 days/week, for lifetime, or 50 months, respectively) could 
only find 3 alveologenic adenomas in 50 treated guinea-pigs.  
Laskin (1972) and Laskin et al. (1970) found 1 squamous cell 
carcinoma of the lung, 1 of the larynx and 1 "peritruncal tumor" in 
rats (inhalation of calcium chromate, 2 mg/m3, 589 exposures of 5 h 
over 891 days) and 1 squamous cell carcinoma and 1 papilloma of the 
larynx in hamsters.  The number of treated animals was not 
specified in either paper.  Steinhoff et al. (1983) performed 
intratracheal instillations of chromates in rats for 30 months with 
one treatment/week and the same weekly dose distributed over 5 
treatments/week (Table 14).  In 880 exposed rats, 28 adenomas of 
alveolar-bronchiolar origin (benign) and 12 malignant tumours (3 
adenocarcinomas and 9 squamous cell carcinomas) were found.  All 
lung tumours developed very late and were only detected at the end 
of the lifetime study, often in lungs with callosities.  The 
tumours were tiny and none of them caused the animal to die.  

Sodium dichromate was not carcinogenic after exposure on 5 
days/week.  With calcium chromate, the carcinogenic effect was more 
pronounced after treatment once per week, than after treatment 5 
times per week. 

Table 14.  Incidence of benign and malignant lung tumours among 
880 rats intracheally injected with Na dichromate and Ca chromatea
----------------------------------------------------------------
                  Dose     Number of   Incidence of lung tumours
                  (mg/kg)  injections  benign   malignant
                           per week
----------------------------------------------------------------
Na2Cr2O7 x 2H20   0.25     5           none     none

Na2Cr2O7 x 2H20   1.25     1           12       8

CaCrO4            0.25     5           5        1

CaCrO4            1.25     1           11       3
----------------------------------------------------------------
a  From: Steinhoff et al. (1983).

    Hueper (1961) reported unspecified tumours at implantation 
sites in 12/34 rats, following intramuscular (im) implantation of 
sintered calcium chromate (25 mg). No tumours were observed in 32 
control animals. The same author found implantation-site tumours in 
15/33 animals treated with strontium chromate compared with no 
tumours in 32 control animals.  Single sc injections of 30 mg lead 
chromate (Maltoni 1974, 1976) resulted in injection-site sarcomas 
in 26/40 treated rats. After administration of the same amount of 
lead chromate oxide, injection-site sarcomas were found in 27/40 
rats; no sarcomas were found in 60 vehicle controls.  Following 9 
im injections of 8 mg lead chromate, Furst et al.  (1976) found 
injection-site sarcomas in 31/47 treated rats, and renal carcinomas 
in 3/24 treated rats; no sarcomas were found in 0/22 vehicle 
controls.  Heath et al. (1971) found injection-site sarcomas and 
other tumours in 7/74 treated rats after im injection of 28 mg 
cobalt-chromium alloy. 

    Administration of low levels of trivalent chromium acetate (5 
mg/litre in the drinking-water) to mice and rats for the lifetime 
did not result in increased tumour incidences compared with 
controls (Schroeder et al., 1964, 1965). 

    Trivalent chromium oxide incorporated in bread at 
concentrations of 10, 20, or 50 g/kg and fed to BD rats did not 
increase tumour incidence compared with controls (Ivankovic & 
Preussmann, 1975).  Hexavalent chromium compounds have not been 
tested by oral administration. 

    IARC (1980a) summarized the data of all available references 
and concluded as follows: "There is sufficient evidence for the 
carcinogenicity of calcium chromate and some relatively insoluble 
chromium (VI) compounds (sintered calcium chromate, lead chromate, 

strontium chromate, sintered chromium trioxide and zinc chromate) 
in rats. There is limited evidence for the carcinogenicity of lead 
chromate (VI) oxide and cobalt-chromium alloy in rats.  The data 
were inadequate for the evaluation of the carcinogenicity of other 
chromium  (VI) compounds and of chromium (III) compounds". 

    (a)   Interaction with other factors

    The possibility that chromium may act synergistically with 
other agents in the production of cancer has been tested in several 
studies.  Nettesheim et al. (1970) pretreated one group of mice 
with 100 R whole-body radiation and infected another group with PR8 
influenza virus.  These mice and control mice were exposed through 
inhalation to chromium oxide dust for 6 - 18 months.  No measurable 
effects of either of the pretreatments were found on the incidence 
of tumours.  In a similar study with inhalation of calcium chromate 
(CaCrO4, 5 h/day, 5 days per week for the lifetime), pre-exposure 
to X-rays did not affect the tumour rate, but PR8 influenza 
infection reduced tumour incidence (Nettesheim et al., 1971). 
Steffee & Baetjer (1965) also found that the infection of rats with 
PR8 influenza virus associated with intratracheal injection of 
chromates did not lead to the production of tumours.  Chromite ore 
injected iv did not affect the development of tumours induced by iv 
injection of 20-methyl-cholanthrene (Shimkin & Leiter, 1940).  
Thus, at present, there are not sufficient data to suggest that 
chromium acts synergistically with virus infections, ionizing 
radiation, or other chemical carcinogens to produce cancers. 

7.2.1.2.  Genotoxicity

    The mutagenicity of chromium compounds was reviewed by IARC 
(1980a), Petrilli & DeFlora (1980), Levis & Bianchi (1982), and 
Baker (1984).  Present knowledge, in the light of recent findings, 
is summarized in Table 15 (hexavalent chromium) and Table 16 
(trivalent chromium). 

    When evaluating the results of chromium mutagenicity tests, it 
is necessary to take into consideration several properties of the 
tested compound (oxidation state, solubility, ability to penetrate 
cell membranes, intracellular stability, and reactivity with 
cellular components).  Most of the  in vitro mutagenicity 
experiments have been performed with chromium chemicals, following 
the introduction of the reverse mutation test by Ames (1973).  
Bacterial strains of  Salmonella typhimurium (Petrilli & DeFlora, 
1977) containing mutants that require histidine for growth, and 
 Escherichia coli (Venitt & Levy, 1974) with mutants requiring 
tryptophan for growth have been used.  In each case, the bacterial 
cultures have been incubated with the test chromium compounds and 
the number of revertant colonies scored.  The chromium compounds 
studied included both hexavalent and trivalent compounds; a survey 
of the results is given in Table 17 (DeFlora, 1981).  Zhurkov 
(1981) performed an Ames test to study the mutagenic activity of 
potassium dichromate (K2Cr2O7) with  S. typhimurium TA 1535 and TA 
1538.  A medium degree of mutagenic activity without metabolic 
activation was shown by the strain TA 1535. 

    Only hexavalent chromium compounds have shown mutagenic 
effects.  Using the  Salmonella /mammalian microsome tests of Ames 
et al. (1973), DeFlora (1978) and Lfroth (1978) both showed a 
decrease in the mutagenicity of hexavalent chromium in the presence 
of an NADPH-generating system, suggesting reduction of mutagenic 
hexavalent chromium to trivalent chromium.  In this chromate 
metabolism, cytochrome P-450 functions as the reductase (Garcia & 
Wetterhahn Jennette, 1981).  In recent  in vitro studies, Wiegand et 
al. (1984b) showed that glutathione could reduce hexavalent 
chromium to trivalent chromium, without any further cofactors or 
metabolizing enzymes.  In rats, the most efficient tissue in 
decreasing hexavalent chromium mutagenicity was the liver, followed 
by the suprarenal glands, kidney, stomach, and lung (Petrilli & 
DeFlora, 1980).  These studies suggest a possible way of 
intracellular detoxification of hexavalent chromium in low doses. 

    Schoental (1975) suggested that hexavalent chromium caused the 
formation of epoxyaldehydes having mutagenic potential. Venitt & 
Levy (1974) assumed that chromates belong to the transition-
inducing class of mutagens.  They cause both frameshift and base-
pair substitutions (Petrilli & DeFlora, 1980).  The hypothesis of 
Kazantzis & Lilly (1979), that chromates cause guanine-cytosine to 
adenine-thymine transitions in the subsequent round of DNA-
replication, needs further confirmation. 
    
Table 15.  Genotoxic activity of chromium (VI) compoundsa
---------------------------------------------------------------------
Assay               Compounds       Activity  Reference
---------------------------------------------------------------------
DNA degradation     CaCrO4          -         Casto et al. (1976)
                    K2Cr2O7         -         Bianchi et al. (1983)
                    PbCrO4          -         Douglas et al. (1980)
                    K2CrO4          +         Whiting et al. (1979)

Decreased fidelity  PbCrO4,         + (1)     Levis & Majone (1981)
of DNA synthesis    K2Cr2O7
                    CrO3            +         Sirover & Loeb (1976)
                    K2Cr2O7         +         Bianchi et al. (1983)

Microbial DNA       K2CrO4,         +         Yagi & NishioKa (1977)
repair              K2Cr2O7
                    CrO3, K2CrO4,   +         Kanematsu et al. (1980)
                    K2Cr2O7
                    K2CrO4,         +         Nishioka (1975)
                    K2Cr2O7
                    K2CrO4,         +         Nakamuro et al. (1978)
                    K2Cr2O7
                    CrO3,           +         Gentile et al. (1981)
                    K2Cr2O7,
                    Na2Cr2O7,       +         Gentile et al. (1981)
                    (NH4)2Cr2O7
---------------------------------------------------------------------

Table 15.  (contd.)
---------------------------------------------------------------------
Assay               Compounds       Activity  Reference
---------------------------------------------------------------------
Microbial gene      K2Cr2O7         +  (2)    Bonatti et al. (1976)
mutation            CrO3            +  (2)    Fukunaga et al. (1982)
                    Na2Cr2O7,       +/-(3)    Petrilli & De Flora
                    CrO3,           +/-(3)    (1978a,b)
                    ZnCrO4xZn(OH)2  +/-(3)
                    K2Cr2O7         +         Zhurkov (1981)
                    Na2Cr2O7        +/-(3)    DeFlora (1978)
                    chromate (4)    +/-(3)    Lfroth (1978)
                    dichromate      +/-(3)
                    K2Cr2O7         -         Kanematsu et al. (1980)
                    K2CrO4,         +         Lfroth & Ames (1978)
                    K2Cr2O7         +
                    K2Cr2O7         +         Nishioka (1975)
                    K2CrO4, CaCrO4  +         DeFlora (1981)
                    (NH4)2CrO4,
                    CrO3,
                    Na2CrO4,        +         Venitt & Levy (1974)
                    K2CrO4
                    CaCrO4
                    K2Cr2O7         +         Bianchi et al. (1983)
                    Na2Cr2O7,
                    ZnCrO4
                    K2CrO4,         +         Nakamuro et al. (1978)
                    K2Cr2O7            
                    K2CrO4, CaCrO4  +         Petrilli & DeFlora
                    CrO3                      (1977)
                    Na2Cr2O7
                    K2CrO4          +         Green et al. (1976)
                    PbCrO4, CrO3    +         Nestmann et al. (1979)

Mammalian cell      K2Cr2O7         +         Bianchi et al. (1983)
gene mutation       K2Cr2O7,        +         Newbold et al. (1979)
                    ZnCrO4          +
                    PbCrO4          -
                    K2Cr2O7         + (5)     Bonatti et al. (1976)
                    K2Cr2O7         +         Pashin et al. (1982)
                    NaeCr2O         +         Pashin & Kozachenko
                    (NHy)2Cr2O7     +         (1981)

---------------------------------------------------------------------

Table 15.  (contd.)
---------------------------------------------------------------------
Assay               Compounds       Activity  Reference
---------------------------------------------------------------------
Mammalian cell      K2CrO4,         +         Umeda & Nishimura (1979)
chromosomal         K2Cr2O7         +
mutation            K2Cr2O7         +         Bigaliev et al. (1978)
                    K2CrO4,         +         Nakamuro et al. (1978)
                    K2Cr2O7         +
                    Na2CrO4,        +         Majone & Levis (1979)
                    K2CrO4          +
                    Na2Cr2O7,                 Levis & Majone (1979)
                    K2Cr2O7
                    CrO3, CaCrO4
                    PbCrO4          +         Douglas et al. (1980)
                    K2Cr2O7         +         Imreh & Radulescu (1982)
                    CrO3            +         Kaneko (1976)
                    Na2Cr2O7        +         Sarto et al. (1980)
                    K2Cr2O7         +
                    CrCl3           +
                    CrO3            +         Tsuda & Kato (1977)
                    K2Cr2O7         +         Raffetto (1977)
                    K2Cr2O7         +         Stella et al. (1982)
                    Na2Cr2O7,       +         Majone & Levis (1979)
                    K2Cr2O7         +
                    K2CrO4          +         Wild (1978)
                    Na2Cr2O7        + (7)     Krishnaja & Rige (1982)

Mammalian cell      CrO3, K2CrO4,   +         Ohno et al. (1982)
SCE                 K2Cr2O7         +
                    K2Cr2O7         +         Bianchi et al. (1983)
                    K2CrO4,
                    Na2CrO4         +         Levis & Majone (1979)
                    CrO3,           +
                    K2Cr2O7,        +         Majone & Levis (1979)
                    Na2Cr2O7        +
                    PbCrO4          +         Douglas et al. (1980)
                    K2Cr2O7         +         Imreh & Radulescu (1982)
                    CaCrO4, CrO3,   +         Gomez-Arroyo et al.
                    K2Cr2O7         +         (1981)
                    K2Cr2O7         +         Majone & Rensi (1979)
                    CrO3            + (6)     Stella et al. (1982)
                    K2Cr2O4,        +         Elias et al. (1983)
                    Na2CrO4,        +
                    Na2Cr2O7        +
                    K2Cr2O7,
                    K2CrO4          +         McRae et al. (1979)

---------------------------------------------------------------------

Table 15.  (contd.)
---------------------------------------------------------------------
Assay               Compounds       Activity  Reference
---------------------------------------------------------------------
Mammalian cell      CaCrO4, K2CrO4  + (8)     Casto et al. (1979)
transformation      ZnCrO4          + (9)
                    Na2CrO4,        
                    CaCrO4          +         Casto et al. (1976)
                                    +         Di Paolo & Casto (1979)
                    K2Cr2O7         +         Bianchi et al. (1983)
                    K2Cr2O7         +         Tsuda & Kato (1977)
                    CaCrO4          +         Fradkin et al. (1975)
                    K2Cr2O7         +         Raffetto (1977)
---------------------------------------------------------------------
a   Modified from: Baker (1984).

Note:

(1) As industrial pigments (Cr-yellow-orange; Zn-yellow; Mo-orange).
(2) Gene conversion.
(3) No mutagenicity in the presence of mammalian microsomal activation
    system (S-9 mix).
(4) No compounds given.
(5) Forward mutation was observed in 7/480 054 colonies (controls 0/84
    546).  A significant increase can be stated if comparison is made
    with the historical spontaneous mutation rate, i.e., no mutants in
    106 colonies.
(6) Occupatinal exposure.
(7) Induction of chromosomal aberrations in gill cells of the fish
     Boleophthalmus dussumieri (Goby).
(8) 2 times control levels.
(9) 4 times control levels.

    The results summarized in Table 17 show that the chromate ion 
(hexavalent chromium) induces different kinds of genetic damage, 
even at low doses, whereas the chromosome-damaging capacity of 
trivalent chromium was only observed when it was tested in very 
high doses. 

    In assays with whole-cell systems, trivalent chromium is 
inactive, unless there is a direct interaction with DNA, e.g., in 
studies in which purified DNA was exposed to trivalent chromium, 
where modifications of the physical and chemical properties, as 
well as decreased fidelity of DNA synthesis, were produced (Levis & 
Bianchi, 1982).  According to Warren et al. (1981), it appeared 
that trivalent chromium in a proper ligand environment could have 
considerable genetic toxicity. However, in recent studies, Bianchi 
et al. (1984) found that trivalent chromium (CrCl3, 10-3 to 10-5 M) 
was neither cytotoxic nor mutagenic in permeabilized hamster 
fibroblasts (BHK were incubated for 30 min in Ea or BSS made 
hypertonic with 4.2% NaCl). 


Table 16.  Genotoxic activity of chromium (III) compoundsa
---------------------------------------------------------------------------
Assay               Compounds            Activity  Reference
---------------------------------------------------------------------------
DNA degradation     CrCl3                +         Bianchi et al.
                                                   (1983)

Decreased fidelity  Cr2O3                +         Levis & Majone
of DNA synthesis                                   (1981)

Microbial DNA       cis-[Cr(bipy)2ox]    +         Warren et al. (1981)
repair              I x 4H2O

                    cis-[Cr(bipy)2Cl2]   +         Warren et al. (1981)
                    Cl x 2H2O

                    cis-[Cr(phen)2Cl2]   +         Warren et al. (1981)
                    Cl x 2,5H2O

                    [Cr(urea)6]          +         Warren et al. (1981)
                    Cl3 x 3H2O

                    [Cr(H2O)6]Cl3        -         Warren et al. (1981)

                    [Cr(en)3](SCN)3      +         Warren et al. (1981)

                    [Cr(en)3]Cl3 x 3H2O  +         Warren et al. (1981)

                    [Cr(pn)3]Cl3 x 3H2O  +         Warren et al. (1981)

                    trans-[Cr(en)2       +         Warren et al. (1981)
                    (SCN)2]SCN

                    CrCl3, Cr2O3,        -         Yagi & Nishioka
                    Cr(OH)3                        (1977)

                    K2Cr2(SO4)4          -         Yagi & Nishioka
                                                   (1977)
                    K2Cr2(SO4)4          -         Kanematsu et al.
                                                   (1980)

                    Cr2(SO4)3            -         Kanematsu et al.
                                                   (1980)
                    CrCl3                -         Nishioka (1975)

                    Cr(NO3)3,            +         De Flora (1981)
                    Cr(CH3COO)3

                    CrCl3                -         Nakamuro et al.
                                                   (1978)
                    CrCl3                +         Gentile et al.
                                                   (1981)
                    CrCl3, KCr(SO4)2,    -         Gentile et al.
                                                   (1981)
                    Cr2(SO4)3            -         Gentile et al.
                                                   (1981)
---------------------------------------------------------------------------

Table 16.  (contd.)
---------------------------------------------------------------------------
Assay               Compounds            Activity  Reference
---------------------------------------------------------------------------
Microbial gene      CrCl3, Cr(NO3)3      -         Lfroth & Ames
mutation                                           (1978)

                    Cr(CIO4)3            -         Lfroth & Ames
                                                   (1978)

                    CrCl3, Cr(NO3)3      -         Venitt & Levy (1974)

                    Cr2SO4,              -         Venitt & Levy (1974)
                    K2SO4 x 2H2O

                    Cr(CH3COO)3          +         Nakamuro et al.
                                                   (1978)

                    Cr(NO3)3             +         Nakamuro et al.
                                                   (1978)

                    CrCl3                -         Nakamuro et al.
                                                   (1978)

                    CrK(SO4)2 x 12H2O    -         Petrilli & De Flora
                                                   (1977)

                    CrCl3 x 6H2O         -         Petrilli & De Flora
                                                   (1978a)

                    Cr(NO3)3 x 9H2O      -         Petrilli & De Flora
                                                   (1978b)

Microbial gene      cis-[Cr(bipy)2ox]    +         Warren et al. (1981)
mutation            I x 4H2O

                    cis-[Cr(bipy)2Cl2]   +         Warren et al. (1981)
                    Cl x 2H2O

                    cis-[Cr(phen)2Cl2]   +         Warren et al. (1981)
                    Cl x 2,5H2O

                    [Cr(urea)6]          +         Warren et al. (1981)
                    Cl3 x 3H2O

                    [Cr(H2O)6]Cl3        -         Warren et al. (1981)

                    [Cr(en)3](SCN)3      -         Warren et al. (1981)

                    [Cr(en)3]Cl3 x 3H2O  -         Warren et al. (1981)

                    [Cr(pn)3]Cl3 x 3H2O  -         Warren et al. (1981)

                    trans-[Cr(en)2       -         Warren et al. (1981)
                    (SCN)2]SCN 
---------------------------------------------------------------------------

Table 16.  (contd.)
---------------------------------------------------------------------------
Assay               Compounds            Activity  Reference
---------------------------------------------------------------------------
Mammalian cell      CrCl3                -         Bianchi et al.
gene mutation                                      (1983)
  
                    Cr(CH3COO)3          -         Newbold et al.
                                                   (1979)

Mammalian cell      Cr2(SO4)3            -         Umeda & Nishimura
chromosomal                                        (1979)
mutation
                    Cr(CH3COO)3          +         Nakamuro et al.
                                                   (1978)

                    CrCl3, Cr(NO3)3      -         Nakamuro et al.
                                                   (1978)

                    Cr(NO3)3,            +         Levis & Majone
                                                   (1979)

                    KCr(SO4)2,           +         Levis & Majone
                                                   (1979)

                    Cr(CH3COO)3          +         Levis & Majone
                                                   (1979)

                    CrCl3                +         Kaneko (1976)

                    CrCl3                -         Sarto et al. (1980)

                    Cr2(SO4)3, CrCl3     -         Tsuda & Kato (1977)

                    CrCl3                +         Raffetto (1977)

                    CrCl3                -         Stella et al. (1982)

                    CrCl3                - (1)     Bianchi et al.
                                                   (1984)

Mammalian cell      CrCl3, Cr2O3         +         Elias et al. (1983)
SCE
                    Cr2O3                +         Levis & Majone
                                                   (1981)

                    Cr(NO3)3,            -         Levis & Majone
                    KCr(SO4)2                      (1979)

                    CrCl3, Cr(CH3COO)3   -         Levis & Majone
                                                   (1979)

                    CrCl3                + (2)     Ohno et al. (1982)

                    Cr2(SO4)3            -         Ohno et al. (1982)

---------------------------------------------------------------------------

Table 16.  (contd.)
---------------------------------------------------------------------------
Assay               Compounds            Activity  Reference
---------------------------------------------------------------------------

Mammalian cell      CrCl3                -         Bianchi et al.
SCE (contd).                                       (1983)

                    CrCl3                -         Majone & Rensi
                                                   (1979)

Mammalian cell      CrCl3                -         Bianchi et al.
transformation                                     (1983)
---------------------------------------------------------------------------
a   Modified from: Baker (1984).

Note:

(1)  Thymidine uptake, DNA replication, damage and repair and SCE were
     tested in permeabilized hamster fibroblasts.
(2)  Weakly positive.

    Levis & Buttignol (1977) and Levis et al. (1978) raised the 
question of whether trivalent chromium could be an active mutagenic 
agent within a cell.  Others, such as Bianchi et al. (1980), 
supported this theory, suggesting that trivalent chromium is bound 
to genetic material after reduction of the hexavalent form by an 
NADPH-dependent microsomal enzyme system (Norseth, 1978; Jennette, 
1979).  The studies of Sirover & Loeb (1976), showing a 30% error 
in DNA synthesis after application of 0.64 mM trivalent chromium 
compared with 16 mM of hexavalent chromium, support this theory. 

    Pashin et al. (1982) demonstrated the induction of dominant 
lethal mutations in mice.  They treated male mice with a single 
injection of potassium dichromate (0.5 - 20 mg/kg body weight, ip) 
or with daily injections (1 and 2 mg/kg, ip, for 21 days).  The 
single injections (0.5 - 2 mg/kg) did not induce any effects; 
repeated or higher dosages of potassium dichromate induced a 
statistically significant decrease in the survival of embryos from 
cells treated at the early spermatid and late spermatocyte stages. 

    Karyological alterations in mammalian cells were induced after 
exposure to concentrations of hexavalent chromium that were more 
than 100 times lower than the concentration of trivalent chromium 
causing the same changes (Majone & Rensi, 1979). 

    Analysing the effects of fume particles from stainless steel 
welding on sister chromatid exchanges and chromosome aberrations in 
cultured Chinese hamster cells, Koshi (1979) found an increase in 
cytogenic effects with increasing fume doses, due to the dissolved 
hexavalent chromium.  Hexavalent chromium and stainless steel 
welding fume particles containing chromium compounds produced 
positive results in the "mammalian spot test", a somatic tissue 
assay (Knudsen, 1980). 


Table 17.  Mutagenicity of chromium compoundsa
---------------------------------------------------------------------------------------------------------
Compound (source)               Reverted strains  Range of  Mutagenic  Effect of   Remarks
                                                  activity  potency    S9 mix
                                                  (nmoles/  (revs/     (rat
                                                  plate)    nmol)      liver
                                                                       Aroclor(R))
---------------------------------------------------------------------------------------------------------
L.  Hexavalent chromium compounds

1)  Sodium dichromate (Merck)   -  +w  +w  +w  +  50 - 250  4.4        decrease    toxic and mutagenic 
    Na2Cr2O7 x 2H2O                                                                Cr6+ was converted  
                                                                                   into inactive Cr3+  
2)  Potassium chromate (BDH)    -  +w  +w  +w  +  80 - 410  2.9        decrease    by reducing         
    K2CrO4                                                                         chemicals (ascorbic 
                                                                                   acid, sodium        
3)  Calcium chromate (BDH)      -  +w  +w  +w  +  60 - 290  3.2        decrease    sulfite) or         
    CaCrO4                                                                         metabolites (NADH, 
                                                                                   NADPH, GSH), by     
4)  Ammonium chromate           -  +w  +w  +w  +  50 - 320  3.7        decrease    human gastric juice 
    (Carlo Erba)                                                                   and erythrocyte     
    (NH4)2CrO4                                                                     lysates, by S9 mix  
                                                                                   containing human    
                                                                                   liver S9 fractions  
5)  Chromium trioxide or        -  +w  +w  +w  +  40 - 220  5.1        decrease    or rat tissue S9    
    chromic acid (Merck)                                                           fractions (in order 
    CrO3                                                                           of efficiency:      
                                                                                   liver>suprarenal   
                                                                                   glands>kidney>   
                                                                                   stomach>lung);     
                                                                                   pretreatment of    
                                                                                   rats (Aroclor(R)    
                                                                                   1254), ether,       
                                                                                   ethanol) influenced 
                                                                                   the efficiency of   
                                                                                   metabolic systems;  
                                                                                   conversely, Cr6+    
                                                                                   mutagenicity was not
                                                                                   affected by human   
                                                                                   serum or plasma nor
                                                                                   by S9 mix containing
                                                                                   other rat (spleen,  
                                                                                   colon, bladder, 
                                                                                   striated muscle) S9 
                                                                                   fractions
---------------------------------------------------------------------------------------------------------

Table 17.  (contd.)
---------------------------------------------------------------------------------------------------------
Compound (source)               Reverted strains  Range of  Mutagenic  Effect of   Remarks
                                                  activity  potency    S9 mix
                                                  (nmoles/  (revs/     (rat
                                                  plate)    nmol)      liver
                                                                       Aroclor(R))
---------------------------------------------------------------------------------------------------------
                                   
6)  Zinc yellow (Montedison)    -  +w  +w  +w  +  90 - 590  1.4        decrease    the mutagenic effects 
    ZnCrO4 x Zn(OH)2 +                                                             of Cr6+ compounds and
    10% CrO3                                                                       benzo( a)pyrene were
                                                                                   less than additive

7)  Chromyl chloride (BDH)      -  +w  +w  +w  +  100 - 430 1.8        decrease    liquid volatile 
    Cl2CrO2                                                                        compound; vapours
                                                                                   were also toxic and 
                                                                                   mutagenic

8)  Chromium orange or basic    -  -   -   -   +b 2 mg                             the three pigments 
    lead                                          (spot test)                      containing PbCrO4
    PbCrO4 x PbO                                                                   were scarcely  (L8), 
    chromate (Montedison)                                                          very scarcely  (L9), 
                                                                                   or totally  (L10) 
                                                                                   insoluble in water; 
                                                                                   they were assayed
                                                                                   by directly spotting 
                                                                                   these compounds at 
                                                                                   the centre of plates  
9)  Molybdenum orange or        -  -   -   -   +b 2 mg
    lead solfomolybdo-                            (spot test)
    chromat (Montedison)      
    PbCrO4      72-77%
    PbSO4       4-6%  
    Al2O3       2%    
    PbMoO4      12-14% 

---------------------------------------------------------------------------------------------------------

Table 17.  (contd.)
---------------------------------------------------------------------------------------------------------
Compound (source)               Reverted strains  Range of  Mutagenic  Effect of   Remarks
                                                  activity  potency    S9 mix
                                                  (nmoles/  (revs/     (rat
                                                  plate)    nmol)      liver
                                                                       Aroclor(R))
---------------------------------------------------------------------------------------------------------

10) Chromium yellow or          -  -   -   -   -b
    lead solfochromate        
    (Montedison)              
    PbCrO4      41-85%            
    PbSO4       4-45% 
    SiO2        0.1-3%
    Al2O3       2-6%  
                
11) Chromium                    -  -   -   -   -  -2.3x103  -          -           hexacoordinated 
    hexacarbonyl (BDH)                                                             compound; formally, 
    Cr(CO)6                                                                        its oxidation state 
                                                                                   is 0; insoluble in 
                                                                                   water, dissolved in 
                                                                                   ether

M.  Trivalent chromium compounds

1)  Chromic chloride            -  -   -   -   -  -3x104    -          -           inactive Cr3+ 
    (BDH) CrCl3 x 6H2O                                                             compounds could be 
                                                                                   converted into toxic 
                                                                                   and mutagenic Cr6+ 
                                                                                   only in the presence 
                                                                                   of oxidizing chemicals 
                                                                                   (potassium 
                                                                                   permanganate), while a 
                                                                                   variety of metabolic 
                                                                                   systems were 
                                                                                   ineffective 

2)  Chromic nitrate (Riedel-    -  -   -   -   -  -2x104    -          - 
    de Haen)
    Cr(NO3)3 x 9H2O

---------------------------------------------------------------------------------------------------------

Table 17.  (contd.)
---------------------------------------------------------------------------------------------------------
Compound (source)               Reverted strains  Range of  Mutagenic  Effect of   Remarks
                                                  activity  potency    S9 mix
                                                  (nmoles/  (revs/     (rat
                                                  plate)    nmol)      liver
                                                                       Aroclor(R))
---------------------------------------------------------------------------------------------------------

3)  Chromic potassium           -  -   -   -   -  -1.6x104  -
    sulfate (BDH)
    CrK(SO4)2 x 12H2O
                                                     
4)  Chromic acetate (BDH)       -  -   -   -   -  -7x104    -          -
    Cr(CH3COO)3
                                                                  
5)  Neochromium (Montedison)    -  -   -   -   -  -5x104    -          -
    Cr(OH)SO4   56-58%
    Na2SO4      23-24%
    H2O         18-21%

6)  Chromium alum (Montedison)  -  -   -   -   -  -4.3x104  -          -
    Cr2(SO4)3  37-39%
    K2SO4      16-18%
    H2O        43-37%

7)  Chromite (Montedison)       -  -   -   -   +  2 mg      -                      Contaminated with Cr6+ 
    Cr2O3      44-46%                             (spot test)                      traces ( sim-diphenyl-
    Fe2O3      29-30%                                                              carbazide reagent); 
    Al2O3      15-16%                                                              scarcely soluble in 
    SiO3       0.5-3%                                                              water; assayed by 
    CoO        0.5-2%                                                              directly spotting the 
                                                                                   powder at the centre 
                                                                                   of plates 
--------------------------------------------------------------------------------------------------------

Table 17 (contd.)

Note:

Sensitivity of  Salmonella strains:                   Range of activity:                       
                               
In the assays carried out in this study,             This column indicates the lower and      
the numbers of spontaneous revertants of             the upper limits (in nmol per plate)     
 Salmonella tester strains fell within the            of the mutagenic response, as in-    
following ranges:                                    ferred from dose-response curves           
TA 1535: 10-25, both with and without S9 mix;        with the most sensitive bacterial          
TA 1537: 3-18, both with and without S9 mix;         strain and under the most favourable       
TA 1538: 10-25 without S9 mix; 15-35 with S9 mix;    metabolic situation (i.e., with or         
TA 98: 20-35 without S9 mix; 25-40 with S9 mix;      without S9 mix) for each positive          
TA 100: 150-200 without S9 mix; 140-180 with S9 mix  compound; for negative compounds,          
                                                     the maximum dose tested is indicated       
The key for the interpretation of symbols in the                                                
column "Reverted strains" is the following:          Mutagenic potency:                         
+  clearly positive result indicated by a dose-                                                 
   related and reproducible increase of his+         the values presented have                  
   revertants over controls (at least a 3-fold       been calculated by dividing the number     
   increase);                                        of revertants in excess of controls        
+w weak positivity indicated by an increase of       by the corresponding amount of compounds   
   revertants 2 - 3 times in controls;               (in nmoles); the number of net revertants  
  reproducible but less than 2-fold increase        was determinated at the top level of the   
   of revertants;                                    linear part of dose-response curves, which 
No symbol: no conclusive experiment carried out      were drawn as indicated under the previous 
   with the corresponding strain.                    sub-heading.                               
                                                                                                
                                                     Effects of S9 mix                          
                                                                                                
                                                     The effect of S9 mix containing            
                                                     liver S9 fractions from        
                                                     Arochlor(R) pretreated rats on             
                                                     the mutagenicity of test                   
                                                     compounds is reported          
--------------------------------------------------------------------------------------------------------
a   From: DeFlora (1981).
b    L8, L9, and  L10, as well as PbCrO4, were positive in the plate test when 
    dissolved in 0.5 N NAOH.
    Embryonic fibroblast cell cultures showed significant 
chromosome aberrations, when potassium dichromate was added to the 
medium (Tsuda & Kato, 1976). When the potassium dichromate was 
reduced with sodium disulfite (Na2SO3), no significant aberrations 
occurred, even with 100 times the chromium concentrations. 

    At present, it is widely accepted that hexavalent chromium is 
genetically active, because of its ability to cross the membranes 
and enter the cells.  If reduction of hexavalent chromium takes 
place outside the cell (or even outside the cell nucleus, e.g., in 
mitochondria or microsomes) its genetic activity is suppressed; if 
the reduction takes place inside the nucleus (near, or at, the 
target DNA molecules) alterations in DNA can occur, depending on 
the oxidation power of hexavalent chromium or the formation of 
trivalent chromium complexes with nucleophilic sites of the DNA; 
thus, trivalent chromium could be the ultimate mutagenic form of 
chromium (Levis & Bianchi, 1982).  More recent investigations 
(Wiegand et al., 1984) have shown that hexavalent chromium may 
enter the body unreduced via the lung and be partly deposited in 
erythrocytes over a prolonged period of time.  From a DNA-repair 
test in bacteria, DeFlora et al. (1984) concluded that hexavalent 
chromium causes irritation in nucleotide pools and, due to its 
oxidizing power, induces single-strand breaks in DNA, while 
trivalent chromium induces DNA-protein and DNA-DNA cross-links and 
decreases the fidelity of DNA replication. 

7.2.1.3.  Developmental toxicity and other reproductive effects

    The teratogenicity of hexavalent chromium as chromium trioxide 
was tested in golden hamsters (Gale, 1974, 1978, 1982; Gale & 
Bunch, 1979) and that of trivalent chromium as chromic-chloride in 
ICR mice (Iijima et al., 1975; Matsumoto et al., 1976).  Injections 
of hexavalent chromium into the fertilized chick egg increased 
embryolethality and produced malformations in the survivors (Gilani 
& Marano, 1979). 

    The golden hamsters were treated with a single iv injection of 
chromium trioxide (5, 7.5, 10, or 15 mg/kg body weight) on the 8th 
day of gestation (Gale, 1978). 

    Dose-response relationships were demonstrated between the rate 
of absorption and the rate of malformations including delayed 
ossification of the skeletal system.  At 5 mg/kg body weight, 4% of 
the fetuses showed external abnormalities (oedema, exencephaly), 
and 34% showed cleft palate (controls: 2%), which increased to 85% 
with the higher doses of 7.5 or 10 mg/kg body weight.  Thirty-one 
percent of fetuses were retarded following treatment with 7.5 mg/kg 
body weight and 49% following 10 mg/kg body weight.  The dose of 15 
mg/kg body weight was lethal for 75% of the dams.  Gale & Bunch 
(1979) injected a single dose of 8 mg CrO3/kg body weight on day 7, 
8, 9, 10, or 11 of gestation in female golden hamsters (Table 18).  
The treated females were adversely affected (body weight loss, 
tubular necrosis of the kidneys).  In a later study, Gale (1982) 
injected 8 mg CrO3/kg iv in hamsters on day 8 of gestation.  An 
increased incidence of cleft palate was seen in strains LVG, LSH, 
and MHA, but no effects were reported in strains CB, LHC, and PD4. 

    ICR mice were injected sc with chromic chloride (Iijima et al., 
1975; Matsumoto et al., 1976).  In the first series (animals 
administered 9.8 or 19.5 mg/kg body weight, every other day, from 
the 0th to 16th day of gestation), according to the authors, a 
slight increase in the rate of malformations could not be excluded.  
In the second series, with ip injections of 9.8 - 24.4 mg/kg body 
weight, on the 8th day of gestation, the authors reported a dose-
dependent increase in the frequency of exencephaly, anencephaly, 
and the occurrence of rib fusion. 

    Danielsson et al. (1982) studied the rate of embryonic or fetal 
uptake of trivalent chromium and hexavalent chromium in early and 
late gestational mice (Table 19) and found placental passage of 
chromium.  Hexavalent chromium appeared in the fetus in high enough 
concentrations for a direct effect on embryonic structures to be 
likely, trivalent chromium may act on placental structures. 

    Gilani & Marano (1979) injected chromium trioxide into 840 
embryonating chicken eggs (air sack) at doses ranging from 0.002 to 
0.05 mg per egg, on days 0, 1, 2, 3, and 4 of incubation (0.1 ml 
physiol. saline injections per control egg).  All embryos were 
examined on day 8.  The following malformations were observed in 
the 720 eggs affected: short and twisted limbs, microphthalamia, 
exencephaly, short and twisted neck, everted viscera, oedema, and 
reduced body size. However, the incidence of abnormalities in the 
120 controls was reported to be "low". 

    Inhalation studies were conducted by Glaser et al. (1984) on 
Wistar rats (TNO-W-74 SPF) to study the effects of sodium 
dichromate on reproduction and teratogenicity in 3 generations.  
Whole-body exposures to sodium dichromate aerosols (0.2 mg 
chromium/m3) were performed with an exposure time of 130 days per 
generation.  No effects on reproduction were found.  All 
teratogenicity tests were negative, and there was no increase in 
fetal chromium content.  However, from generation to generation, 
there was an increase in immunosuppression and hyperplasia of 
organs (especially in the lungs) and changes in haematological 
variables. 


Table 18.  Embryotoxicity following maternal exposure to CrO3 on different days
of gestation in hamstersa
-------------------------------------------------------------------------------------
                                                          Findings in live fetuses
Day of     No. of   No. of        No. of   Frequency    External   Internal  Cleft
gestation  females  implantation  living   resorptions  defects    defects   palate
           treated  sites         fetuses  No.   %b     No.  %b    No.  %b   No.  %b
-------------------------------------------------------------------------------------
                                  Treated CrO3 8 mg/kg

7          6        64            10       54    84     1    10    1c   10   5    50
8          6        88            54       14    20     8d   15    4e   7    17   31
9          6        77            67       10    13     18f  27    0    0    25   37
10         6        77            77       0     0      0    0     0    0    0    0
11         6        68            67       1     1      0    0     0    0    0    0

                                  Controls H2O 5 ml/kg

7          3        35            33       2     6      0    0     0    0    0    0
8          3        44            41       3     7      0    0     0    0    0    0
9          3        37            36       1     3      0    0     0    0    0    0
10         2        20            19       1     5      0    0     0    0    0    0
11         3        34            33       1     3      0    0     0    0    0    0
-------------------------------------------------------------------------------------
a From: Gale & Bunch (1979).
b Underlined %, significantly different statistically from controls.
b Right hindlimb with two digits.
c Right kidney absent.
d Oedema (7), tail short (1).
e Small kidneys (3), right kidney absent (1).
f Oedema (17), omphalocele (1).

Table 19.  Comparison of concentrations of trivalent and hexavalent
chromium in fetuses, placentas, and maternal organsa,b
------------------------------------------------------------------
                 Day 13                       Day 16           
          Hexavalent   Trivalent       Hexavalent    Trivalent
          chromium     chromium        chromium      chromium
------------------------------------------------------------------
Fetus     0.3  0.01   0.03  0.002    0.5  0.04    0.1  0.01
Placenta  -            -               3.0  0.2     2.4  0.2
Liver     29.4  2.2   30.8  6.5      33.9  3.9    27.7  3.5
Kidney    38.1  1.9   5.3  0.7       36.0  4.3    8.7  2.3
Serum     2.6  0.2    9.3  0.9       2.8  0.4     11.0  1.6
------------------------------------------------------------------
a   From: Danielsson et al. (1982).
b   Trivalent chromium (51CrCl3) and hexavalent chromium 
    (Na251Cr2O7) were injected iv on day 13 and day 16 of gestation 
    at doses of 10 mg chromium/kg body weight. The pregnant animals 
    were autopsied after 1 h. Concentrations are expressed in 
    mg/litre or g  SEM (N = 4). 

7.2.1.4.  Cytotoxicity and micromolecular syntheses

    Wacker & Vallee (1959) reported that trivalent chromium was 
present in RNA from all sources examined; they hypothesized that 
chromium might contribute to the stabilization of the structure. 

    Administration of trivalent chromium to mice (ip injection of 
CrCl3 at 5 or 0.5 mg chromium/kg body weight;  P < 0.01) caused 
accumulation of chromium in the cell nucleus, which amounted to 
about 20% of the accumulated chromium content of the liver cell, 
and also enhanced RNA synthesis.  Hexavalent chromium inhibited RNA 
synthesis (K2CrO4 at 5 or 0.5 mg chromium/kg body weight; 
 P < 0.01) (Okada et al., 1983).  In further studies, Okada et al. 
(1984) pretreated rats with CrCl3 (ip injection of 5 mg chromium/kg 
body weight) and then partially hepatectomized the rats.  Chromium 
accumulated in the regenerating liver, and hepatic RNA synthesis 
was accelerated compared with that of partially hepatectomiced 
controls.  These findings suggest a direct participation of 
chromium in RNA synthesis. 

    Potassium dichromate enhanced the passive uptake of ribo-and 
desoxyribonucleosides (Levis et al., 1978; Bianchi et al., 1979), 
caused an inhibition of DNA replication to BHK fibroblasts, and 
reduced the colony-forming ability of BHK cells (doses: 10-4 - 20-7
mol).  Hexavalent chromium (potassium dichromate with a 
concentration of 5 x 10-7 mol/litre) reduced by half the 
proliferation of NHIK 3025 cells originating from a human cervix 
carcinoma (White et al., 1979). 

    The addition of calcium chromate to BHK21 cell cultures altered 
their growth characteristics.  Whereas these cells normally grow as 
elongated fibroblast cells in parallel orientation, the chromium-
exposed cells grew as shortened fibroblasts with enlarged nuclei 
and granular cytoplasm, randomly orientated.  When grown in 
carboxymethyl cellulose, the chromate-exposed cells underwent many 
divisions in contrast to the 1 or 2 divisions of normal cells.  
These alterations in growth properties persisted, even after 
transfer to a normal medium (Fradkin et al., 1975). 

    Cultures of HeLa and rat embryonic cells were incubated with 
various hexavalent and trivalent chromium compounds for 3 days and 
the 50% inhibitory dose (ID50) for cell growth was determined.  The 
ID50 for sodium and potassium chromate and dichromate and calcium 
chromate varied from 0.34 to 0.78 g/ml of the medium.  The ID50 
for the trivalent compounds varied over a wider range: chromic 
oxalate, 4; acetate, 52; nitrate, 720; chloride, 1030; and bromide, 
1500 mg/litre.  Similar results were found in rat embryonic cell 
cultures (Susa et al., 1977). 

7.2.1.5.  Fibrogenicity

    Because of the well-known fibrogenic effects of silica and 
asbestos minerals, studies were initiated to determine whether 
chromite and various other dusts exhibited similar properties. A 
single intratracheal injection in rats of 40 mg chromite particles 

(33% chromium, 0.7% SiO2, 99.9% of the particles being smaller than 
5 m) suspended in 1 ml Ringer's solution caused a moderate 
cellular reaction that reached a peak after 2 months and then 
decreased.  After 8 months (end of observation), the lung weight 
was within normal limits.  Only an increase in fibrils that was not 
significant was observed. The tissue reaction in regional lymph 
nodes was minimal (Swensson, 1977). 

    Chromite FeO(CrAl)2O3 (10 mg), ground to an average particle 
diameter of 1 m, was injected into the pleural cavities of 25 
mice.  The animals were killed at intervals ranging from 2 weeks to 
18 months after injection.  Chromite produced the least reaction of 
all the 15 dusts tested.  This material attracted very few cells 
and the eventual production of collagen was minimal (Davies, 1972). 

7.2.2.  Observations in farm animals

    Systemic poisoning of farm animals with chromates is rare and 
is mainly suspected to be a consequence of accidental industrial 
contamination of drinking-water.  The acute lethal dose for mature 
cattle is approximately 600 - 800 mg/kg body weight; chronic 
poisoning in young calves was produced by a daily dose of 30 - 40 
mg/kg body weight for one month (NZ Department of Agriculture, 
1954) with a clinical picture of profuse scouring, severe 
dehydration, low blood pressure, changes in the alimentary tract, 
including congestion and inflammation, and the rumen and abomasum 
showing ulceration near perforation. 

    High chromium levels were found in the blood and liver of 
calves that had died from poisoning.  The minimum tissue levels 
causing poisoning were 30 mg/kg in the liver and 4 mg/litre in 
whole blood (Harrison & Staples, 1955). According to Romoser et al. 
(1961), a level of 100 mg hexavalent chromium (as sodium 
chromate)/kg did not affect growing chicks. 

8.  EFFECTS ON MAN

8.1.  Nutritional Role of Chromium

    The physiological role of chromium and the need for small 
amounts of dietary chromium are indicated by: 

    (a) chromium-responsive cases of impaired glucose
        metabolism in malnourished children and middle-aged
        persons;

    (b) 2 cases of proved chromium deficiency in patients fed
        exclusively by parenteral alimentation; and

    (c) epidemiological studies suggesting a link between
        chromium deficiency and risk factors for cardiovascular 
        diseases.

8.1.1.  Biological measurements and their interpretation

    Biochemical methods for the diagnosis of the human nutritional 
chromium status are still at the developmental stage.  Blood- or 
urine-chromium concentrations are not indicative of chromium 
status.  Several studies suggest the validity of the "relative 
chromium response" in plasma or serum to the ingestion of 50 - 100 
g of glucose within 30 - 120 min; the response also appears in the 
urine.  Lack of this response suggests chromium deficiency, 
especially when combined with impaired glucose tolerance in the 
presence of normal or elevated plasma-insulin levels. 

8.1.2.  Chromium deficiency

8.1.2.1.  Adults

    Chromium deficiency is diagnosed mainly through therapeutic 
trials in which an impaired function is restored by supplementation 
of the diet with small amounts of chromium close to the estimated 
human requirement.  Glinsmann & Mertz (1966) studied 4 male 
diabetic patients for several months to 1 year, under the strictly 
controlled conditions of a metabolic ward.  The subjects, who were 
fed identical portions of a diet prepared before the start of the 
study, were allowed a measured amount of physical activity and were 
stabilized under these conditions before the beginning of the 
control periods. Three of the 4 patients responded to a chromium 
level of 180 - 1000 g/day as CrCl3 x 6H2O with a significant 
improvement in oral glucose tolerance; the fourth showed a very 
slight lowering of the glycaemic curve, which was not statistically 
significant.  A representative example is given in Table 20. 


Table 20.  Effect of chromium on mean glucose tolerancea,b
------------------------------------------------------------------------
Supplementation     Days       Number  Mean blood glucose concentration
                               of      ---------------------------------
                               tests   Fast-  Min after glucose load
                                       ing    30    60     90    120
------------------------------------------------------------------------
None                0 - 32     10      840    2170  2290   1950  1560
60 g, 3 x per day  33 - 74    12      850    2240  2380   2090  1620
60 g, 3 x per day  75 - 119   13      840    2100  2130   1860  1410
60 g, 3 x per day  120 - 140  5       840    2030  2010c  1750  1120c

None                180 - 194  1       960    2070  2900   2930  2370
60 g, 3 x per day  195 - 211  5       830    1960  1930c  1750  1180c

None                256 - 313  10      870    2200  2450   2240  1660
1 mg, 3 x per day   337 - 340  1       680    1480  1620   1510  960
------------------------------------------------------------------------
a   Modified from: Glinsmann & Mertz (1966).
b   A 46-year-old man with maturity-onset diabetes, controlled on diet;
    oral glucose tolerance test consisted of constant noon meal and 100 g
    glucose.
c   Mean values significantly different from control ( P < 0.025).

    The condition of one of 2 diabetic out-patients, observed over 
several months, was improved by chromium supplementation, the 
condition of the other was not.  Short-term treatment of 7 diabetic 
patients for 1 - 7 days with 1 mg chromium did not affect any 
variables of glucose metabolism, nor did chromium supplementation 
change the normal glucose tolerance tests of 10 healthy, young 
volunteers. 

    Glinsmann's positive results were not confirmed in a double-
blind crossover study on 4 normal volunteers and 10 diabetic 
persons, with a crossover after 16 weeks.  No effects of chromium 
were detected on glucose tolerance or on fasting or postprandial 
blood-glucose levels (Sherman et al., 1968). Schroeder et al. 
(1970), while reporting that 2 - 10 mg chromium/day "almost always" 
restored the impaired glucose tolerance in older, non-diabetic 
subjects to normal, found only erratic and mild improvement in 4 
out of 12 diabetic out-patients.  On the basis of these 
observations, Mertz (1969) concluded that chromium should not be 
considered a therapeutic agent for diabetic patients. 

    On the other hand, it was reported in a later study on chromium 
metabolism that chromium administration (500 g/day, for 2 weeks) 
produced a marked improvement in glucose utilization in both 
juvenile and maturity-onset diabetic patients.  Five of the 
patients were followed for more than 1 year after exposure and were 
found to maintain their improved glucose metabolism (Nath, 1976). 

    Of 10 non-diabetic elderly subjects with impaired glucose 
tolerance, 4 responded to 150 g chromium/day with complete 
normalization of oral glucose tolerance tests.  The remaining 6 

subjects were not affected by the supplements (Levine et al., 
1968).  Significant effects of a GTF-chromium-containing yeast 
preparation were reported by Doisy et al. (1976) in 6 out of 12 
elderly subjects with impaired glucose tolerance 
Table 21.  Effect of GTF supplementation on glucose tolerance tests in
elderly subjects with impaired tolerancea,b
-------------------------------------------------------------------------
              Mean plasma-glucose levels       Cholesterol  Triglyceride
                       (mg/litre)              (mg/litre)   (mg/litre)
             0 h         1 h        2 h
-------------------------------------------------------------------------
Before GTF   1060  40c  2010  70  1780  80  2450  90    1210  80
11 tests

After GTF    990  40    1620  110 1320  50  2050  100   1120  120
9 tests

Signifi-     NS          < 0.01     < 0.001     < 0.01      NS
canced
-------------------------------------------------------------------------
                 Mean serum-insulin levels
                      (microunits/ml)        
                0 h         1 h        2 h

Before GTF      24  6      78  17    118  17

after  GTF      26  12     70  8     83  8
-------------------------------------------------------------------------
a  From: Doisy et al. (1976).
b  Supplement: 4 g yeast per min/day (Yeastamin Powder 95, Staley Co.,
   Chicago, Illinois, USA). GTT: 100 g oral load.
c  Mean  SEM.
d  Using paired t test, difference is significant.

    In addition to the improvement in glucose tolerance in the 
presence of a reduced insulin response, plasma-cholesterol 
concentrations were significantly reduced.  Several other 
individual cases are reported in the publication of Doisy et al. 
(1976), all of whom showed a lower serum-insulin response to a 
glucose tolerance test during chromium supplementation. 

    Liu & Morris (1978) performed a similar study on the effects of 
a yeast-chromium supplementation in 27 women, 40 - 75 years old, of 
whom 15 had a normal and 12 an abnormal glucose tolerance test.  In 
11 of the normal subjects (73%), the integrated insulin response 
was significantly reduced from 436 to 335 U/ml ( P < 0.025) during 
supplementation, without a statistically significant change in 
glucose tolerance test. Significant reductions in the total glucose 
response (10 650 - 9820 mg/litre;  P < 0.001) and in the total 
insulin response to glucose were observed in the subjects with 
impaired glucose tolerance (1288 - 831 U/ml;  P < 0.001).  The 
glucose tolerance improved in 7 out of 12 women, but all 12 showed 
a reduction in plasma-insulin. 

    The effects of supplementation of the diet with 200 g 
chromium/day (as chloride) on the glucose tolerance of 76 normal 
adult volunteers was investigated in a double-blind cross over 
study, with each period lasting 3 months.  All 18 subjects entering 
the study with impaired glucose tolerance (serum-glucose equal to 
or greater than 1 g/litre, 90 min after a glucose load), showed 
significant improvement during chromium supplements, but not with a 
placebo, with an average decline in the 90-min serum-glucose levels 
of 180 mg/litre ( P < 0.01) (Anderson et al., 1983b). 

    In another placebo-controlled study, 24 elderly volunteers were 
given a daily supplement of either chromium-rich brewer's yeast or 
chromium-deficient Torula yeast (9 g/day, for 8 weeks).  The 
glucose tolerance of the subjects given brewer's yeast 
significantly improved with a concomitant decrease in plasma-
insulin levels, and a significant decline in plasma-cholesterol as 
well as total plasma-lipids.  No significant changes were observed 
in the control group given the chromium-poor Torula yeast 
(Offenbacher & Pi-Sunyer, 1980). 

    Additional, preliminary studies suggest a specific effect of 
brewer's yeast on individual lipoprotein cholesterol fractions.  
Twenty normal human subjects responded to daily supplementation 
with 18 g of brewer's yeast over a 8-week period with a significant 
reduction in low-density lipoprotein-cholesterol ( P < 0.01) and 
with a simultaneous increase of 14% in the high-density lipoprotein 
( P < 0.01) (Nash et al., 1979). 

    Similar results were observed in a 6-week supplementation trial 
involving 8 physician volunteers, each of whom received 7 g/day of 
brewer's yeast. Low-density lipoprotein-cholesterol declined by 
nearly 18% ( P < 0.01), whereas the high-density cholesterol 
fraction increased by 17.6%, resulting in a significant 
( P < 0.001) decrease in the LDL/HDL ratio of 28% (Riales, 1979). 

    These studies suggest that the primary effect of the 
supplementation must have been an increase in the effectiveness of 
the insulin, because glucose tolerance was maintained or improved 
in spite of lower insulin responses.  It is important to note that 
while the reduction in insulin levels occurred in all cases, an 
improvement in glucose tolerance occurred in only a fraction.  This 
suggests two possible interpretations of all the results discussed 
here, including those showing improvement in glucose tolerance in 
only some of the subjects or no improvement at all.  Lack of a 
response to chromium could suggest that the subjects were not 
chromium deficient and that their impaired glucose metabolism was 
the result of other causes.  Second, they may have responded with a 
reduction in circulating insulin levels, as did all the subjects 
with impaired glucose tolerance in whom the insulin response was 
measured.  Unfortunately, these measurements were not performed in 
the earlier studies. 

8.1.2.2.  Malnourished children

    Chromium deficiency has been implicated as a factor 
contributing to the impairment of glucose tolerance in children 

with protein calorie malnutrition in 3 countries, Jordan, Nigeria, 
and Turkey.  Hopkins et al. (1968) measured intravenous glucose 
tolerance in 10 malnourished infants from the mountainous area of 
Jordan and 9 equally malnourished infants from the valley area.  
They found a severely depressed glucose removal rate of 0.7%/min in 
the first group and a normal rate in the second, 3.8%/min (Table 
22).  The protein intake of both groups prior to hospitalization 
had been identical; it was supplied in the form of a milk powder 
with a chromium content of 18 g/litre, when reconstituted.  
However, analysis of 10 water samples revealed 3 times as much 
chromium in the samples from the valley as in those from the 
mountainous area (0.5 versus 1.6 g/litre).  This suggested the 
possibility of chromium being a major determinant in the glucose 
metabolism of these children, and the effects of supplementation 
were measured in 6 children from the hills, with a severely 
impaired tolerance test.  The morning after oral administration of 
250 g chromium, as CrCl3 x 6H2O, the glucose removal rate had 
markedly improved to 2.9%/min from a pretreatment level of 
0.6%/min.  Similar results were obtained in Nigeria (Table 22); 
these tests also included control children who did not receive 
chromium. 

    The immediate effects of chromium on these children were 
remarkable and different from the lag phase always present in the 
studies on adults.  Equally important, was the short duration of 
the effect of one dose demonstrated in a Jordanian child observed 
for a longer period of time. These observations suggest that a 
marked depletion in chromium stores must have existed in the 
children. 
Table 22.  Significance of the effect of chromium on the impaired glucose
tolerances of malnourished infantsa
---------------------------------------------------------------------------
Subjects                                 Number    Glucose   Significance
                                         of        removal   of
                                         infants   rate      difference
                                                   (%/min)
---------------------------------------------------------------------------
Jordanian infants from hill area with
0.5 g chromium/litre in drinking-water  10        0.7

Jordanian infants from valley with
1.6 g chromium/litre in drinking-water  9         3.8        P < 0.001

Jordanian infants;
initial glucose tolerance test           6         0.6        P < 0.001
after chromium treatment                 6         2.9

Nigerian infants;
initial glucose tolerance test           6         1.2
after chromium treatment                 6         2.9        P < 0.05

Non-treated infants:
Initial glucose tolerance test           5         1.9       not signi-
Repeated glucose tolerance test          5         2.1       ficant
---------------------------------------------------------------------------
a From: Hopkins et al. (1968).
    Similar results were reported from a study in the Istanbul area 
of Turkey (Grson & Saner, 1971).  Fourteen malnourished children 
with an impaired glucose removal rate of 1.71%/min were given 250 
g of chromium (CrCl3 x 6H2O), and a second test was performed 
after 15 h.  The removal rate increased to 3.91%/min ( P < 0.001).  
This average increase was due to a pronounced increase in 9 of the 
children; no change was observed in the remaining 5.  No 
improvement in glucose tolerance occurred in 5 control children 
receiving identical hospital treatment, except for the 
administration of the chromium.  The children receiving the 
chromium supplementation grew significantly more than the control 
children during the following 30 days, with the greatest growth 
rates found in the 9 children who had responded to administration 
of chromium with an improvement in glucose tolerance. 

    The fact that chromium deficiency interacts with protein-
calorie malnutrition only in certain geographical areas was 
confirmed by Carter et al. (1968), who gave chromium 
supplementation (250 g/day as CrCl3 x 6H2O) without effects on 
glucose tolerance in 9 Egyptian children tested. Plasma-chromium 
levels were in the normal range, and chromium levels in 
representative foods were high, ranging from 200 to 390 g/kg.  
These findings suggest that the chromium status of these subjects 
was normal, which would explain the lack of an effect. 

8.1.2.3.  Patients on total parenteral alimentation

    A female patient, maintained on total parenteral alimentation 
since the age of 35 years, developed an unexpected weight loss of 
15% after 5 years combined with peripheral neuropathy, impaired 
intravenous glucose tolerance, in spite of normal insulin response, 
and a decreased respiratory quotient of 0.66.  Insulin treatment 
(45 U/day) was ineffective.  A strongly negative chromium balance 
and low plasma- and hair-chromium levels suggested that the daily 
estimated chromium intake from the infusion fluids of 5.3 g had 
not met the patient's requirement and resulted in chromium 
deficiency. The insulin infusions were stopped and replaced by the 
daily infusion of 250 g chromium (as CrCl3 x 6H2O) for 2 weeks. 
The result was normalization of glucose tolerance and respiratory 
quotient, disappearance of signs and symptoms of neuropathy, return 
to the previous normal body weight, in spite of reduced caloric 
intake, disappearance of the requirement for exogenous insulin, and 
a positive chromium balance.  The nitrogen balance, which had been 
erratic and often negative, became consistently positive following 
chromium supplementation.  Reduction of the daily supplement to 20 
g chromium proved to be sufficient to maintain the patient in a 
state of well-being (Jeejeebhoy et al., 1977). 

    This case is the best demonstrated example of chromium 
deficiency in a human subject.  In addition to confirming the well-
known signs of chromium deficiency reported earlier, such as 
insulin resistance and its consequences, it was the first case to 
demonstrate the occurrence of peripheral neuropathy and disturbance 
of nitrogen balance as a result of deficiency. These disturbances 
require further study.  A second case of chromium deficiency as a 

consequence of long-term total parenteral alimentation was reported 
by Freund et al. (1979). Signs and symptoms were similar to those 
of the first case, except that central encephalopathy was present 
instead of peripheral neural disorder.  Supplementation with 150 g 
of chromium/day resulted in normalization of the deficiency signs.  
Chromium at that time was not routinely added to intravenous 
solutions, therefore it is possible that more cases of deficiency 
may exist in patients on long-term infusion treatment.  As an 
outcome of this study, an Expert Panel of the American Medical 
Association (AMA, 1979) suggested that the stable adult patient on 
total parenteral alimentation should receive 10 - 15 g chromium 
daily. 

8.1.2.4.  Epidemiological studies

    Two epidemiological studies suggest a link between chromium 
status and cardiovascular diseases (Schroeder et al., 1970; Punsar 
et al., 1975).  Lack of chromium is associated with impaired 
glucose tolerance, elevation of circulating cholesterol, and aortic 
plaques.  All of these variables are recognized risk factors for 
cardiovascular disease.  It has also been suggested that the 
elevated insulin levels, often present in chromium-deficient human 
subjects (Liu & Morris, 1978) represent a substantial risk for the 
development of cardiovascular disease (Strout, 1977). 

    Schroeder et al. (1970) have summarized their studies of 
chromium concentrations in normal and diseased tissues, 
particularly in aortas (Table 23).  The total body burden of 
chromium, excluding the lungs, was lower in the USA, where there is 
a higher incidence of cardiovascular disease, compared with other 
regions, 1.72 - 1.86 mg/kg ash weight in the USA compared with 7.7, 
9.6, and 2.7 mg in Africa, the Far East, and the Near East, 
respectively.  The only significant difference in tissue-chromium 
concentrations in deaths from heart disease compared with deaths 
from accidental causes was in the aorta (Table 23).  Concentrations 
in aortas from Africa, the Far and Near East were generally higher 
and did not show such a difference. 

Table 23.  Chromium in aortasa
----------------------------------------------------------
Location                   Chromium (mg/kg dry weight)    
                     Accident       P       Heart disease
----------------------------------------------------------
Africa               0.072 (5)b    NS      0.116 (2)

Far East             0.97  (8)     NS      0.246 (5)

Middle East          0.36  (8)     NS      0.216 (3)

USA (Nine cities)    0.26  (103)   0.005   0.052 (13)

USA (San Francisco)  0.228 (10)    0.005   0.048 (15)
----------------------------------------------------------
a   From: Schroeder et al. (1970).
b   The number in parenthesis denotes the number of cases 
    observed.

    The second epidemiological study was part of a cohort study 
conducted in Finland beginning in 1959 (Punsar et al., 1975). A 
total of 327 drinking-water samples were analysed for 22 
characteristics including pH, anions, bulk minerals, and several 
trace elements including chromium.  The study included 504 and 622 
men in the Western and Eastern areas of Finland, respectively, 
whose domicile had not changed since 1959. 

    The coronary heart disease mortality rate is much higher in the 
east of Finland than in the west.  As seen in Table 24, the 
chromium levels in drinking-water were much lower in the east than 
in the west, whereas the opposite was true for copper.  The metal 
concentrations in the drinking-water of those with heart disease 
and others only differed slightly (Table 24), but, according to the 
authors, the data suggest that low chromium levels may play a role 
in the high heart disease death rate of eastern Finland. 


Table 24.  Concentrations of copper and chromium in the 
drinking-water of men who died between 1969 and 1973, and 
of those who were alive in 1973a
-------------------------------------------------------------
                                           Alive
                    Deaths        (Clinical status in 1969)  
                 CHDb    Other    CHDb     Other    No
                                           heart    heart
                                           disease  disease
-------------------------------------------------------------
  West           N = 19  N = 23   N = 63   N = 31   N = 288

Copper       X   22.15c  20.17    20.05    20.94    20.15
(g/litre)   SD  3.92    4.69     4.69     5.12     4.74

Chromium     X   7.52    9.38     9.45     9.74     8.45
(g/litre)   SD  2.06    3.42     4.01     4.44     3.31


  East           N = 23  N = 26   N = 129  N = 44   N = 279

Copper       X   41.59   41.24    42.67    39.50    36.32
(g/litre)   SD  29.91   30.43    33.65    28.74    28.66

Chromium     X   2.20    2.09     2.04d    2.49     3.01
(g/litre)   SD  2.17    2.41     2.08     2.17     2.37
-------------------------------------------------------------
a From: Punsar et al. (1975).
b CHD = coronary heart disease.
c  P < 0.05.
d  P < 0.001.

 Note: Levels of significance refer to differences observed 
when the concentrations were compared with those in the 
"no heart disease" category. 

    Newman et al. (1978) measured serum-chromium concentrations in 
32 patients, 18 male and 14 female, aged 25 - 65 years, in whom 
coronary artery cine-arteriography was performed for medical 
reasons.  Serum-chromium was significantly lower in the 15 subjects 
with coronary artery disease than in the 17 subjects without 
involvement (2.51 versus 6.09 g/litre;  P < 0.01), whereas serum-
cholesterol, weight index, and systolic or diastolic blood pressure 
did not differ among the groups.  Serum triglycerides were higher 
in the group with coronary artery disease (1.84 versus 1.12 
g/litre;  P < 0.05). No subject with a serum-chromium  
concentration of more than 6 g/litre exhibited coronary artery 
involve- ment, and by regression analysis, serum-chromium was 
judged to explain 17% of the total variance of the disease. 

    These results were independently confirmed in a second study in 
which plasma chromium concentrations of 23 healthy persons were 
more than 8 times greater than those of 67 patients with coronary 
artery disease, as confirmed by cine-angiography (Simonoff et al., 
1984). 

8.1.3.  Mode of Action

    As in experimental animals, the best known action of chromium 
is the potentiation of insulin.  This is shown by the 
supplementation studies of Doisy et al. (1976) and Liu & Morris 
(1978) in which a reduction in insulin levels in response to 
glucose was observed, together with an improvement in glucose 
tolerance.  Direct proof, for example from  in vitro studies with 
human biopsy tissue, has not yet been obtained. Furthermore, it is 
not known whether the potentiation of insulin is responsible for 
all the effects observed during chromium supplementation, including 
the reduction of circulating cholesterol and the growth stimulation 
observed in malnourished children and during parenteral nutrition. 

    In the healthy, chromium-sufficient human subject, chromium 
levels in the bloodstream increases acutely following a glucose 
load or an injection of insulin.  Glinsmann et al. (1966) observed 
acute increases in 5 young, healthy volunteers during a glucose 
tolerance test, but not when the same subjects were given an 
equivalent volume of water.  Maturity-onset diabetic patients did 
not exhibit this chromium response initially, but did show a rise 
in plasma-chromium, after several weeks of chromium 
supplementation.  These observations were confirmed by Levine et 
al. (1968), Hambidge (1971), Behne & Diel (1972), and Liu & Morris 
(1978), who saw the acute chromium rise in some, but not all, 
subjects.  In the study of Liu & Morris (1978), which was the most 
detailed, the relative chromium response (CrR) was measured by 
neutron activation analysis in 15 women with normal glucose balance 
and in 12 with impaired tolerance. 

              (1-h serum-chromium)
       CrR = ------------------------  x 100
             (fasting serum-chromium)

Initially, the normal group had a mild positive response (CrR = 
107), compared with a negative response (CrR = 81) in the impaired 

subjects.  Following three months of supplementation with a 
chromium-rich yeast extract, the CrR of the normal subjects 
increased to 140, and that of the impaired group became positive 
with CrR = 149.  As discussed in section 8.1.2, these changes were 
accompanied by a significant decrease in the insulin response to 
glucose and an improvement in glucose tolerance.  The results of 
these studies are in apparent contrast with those of Davidson & 
Burt (1973), who found a significant decline in plasma-chromium 
levels following a glucose load in normal, non-pregnant women (mean 
age 26 years), but a mild to moderate increase in all but 1 of 10 
pregnant women (mean age 20 years).  As the time of the acute rise 
varied between women, statistical analysis at any one time did not 
produce any significant results.  Hambidge (1971) and Behne & Diel 
(1972) demonstrated an acute plasma-chromium response following 
injection of insulin; it can therefore be assumed that the effect 
of glucose on the chromium response is associated with 
hyperinsulinaemia.  The acute "relative chromium response" is 
believed to reflect the chromium status of human subjects.  It does 
not appear when stores from which the chromium increment must come 
are depleted.  Depleted stores can be replenished by 
supplementation, with a resulting reappearance of the response 
shown in the two previously discussed studies.  As it has been 
shown that chromium levels in urine increase following a glucose 
load (Wolf et al.  1974; Grson & Saner, 1978), it is likely that a 
fraction or all of the chromium increment is subsequently excreted. 

8.2.  Acute Toxic Effects

    In adults, the lethal oral dose of soluble chromates is 
considered to be between 50 mg/kg body weight (RTECS, 1978) and 70 
mg/kg body weight (Deichmann & Gerarde, 1969).  The clinical 
features of toxicity are vomiting, diarrhoea, haemorrhagic 
diathesis, and blood loss into the gastrointestinal tract causing 
cardiovascular shock.  If the patient survives about 8 days, the 
outstanding effects are liver necrosis (Brieger, 1920), tubular 
necrosis of kidneys, and poisoning of blood-forming organs 
(Langard, 1980).  A 14-year-old boy, who had ingested about 1.5 g 
of potassium dichromate, died 8 days later.  Kaufmann et al. (1970) 
also reported enlargement and oedema in the boy's brain. 

8.3.  Chronic Toxic Effects

    The chronic effects of trivalent and hexavalent chromium have 
been reviewed by Langard & Norseth (1979).  The most important 
features are changes in the skin and mucous membranes, and allergic 
dermal and broncho-pulmonary effects. Important systemic effects 
occur in the kidneys, liver, gastrointestinal tract, and 
circulatory system. 

    Mancuso (1951) studied several biological variables in persons 
occupationally exposed to chromate and related them to clinical 
signs and symptoms.  He found occasional leukocytosis or 
leukopenia, monocytosis, eosinophilia, reduced haemoglobin 
concentrations and prolonged bleeding times, but none of them were 
consistent enough to serve as reliable diagnostic tests. 

    Mild normochronic anaemia was reported by Myslyaeva (1965) in 
94 subjects exposed to chromium compounds with 68 of them showing 
signs of chronic toxicity.  Though the report of Baetjer et al. 
(1959b) was based only on 3 cases, it indicated that chromate 
attached preferentially to red blood cells. Koutras et al. (1964) 
reported the inhibition of the red blood cell enzyme gluthathione 
reductase by chromate concentrations of 5 - 25 mg/kg body weight.  
However, the lowest effective dose is far in excess of levels 
found, even in heavily exposed persons. Thus, all attempts made so 
far have failed to identify a specific sensitive biochemical test 
for the assessment of chronic chromium toxicity. 

    Long-term surveillance of pregnant women working at a plant 
producing dichromates and those living in its immediate vicinity 
(Shmitova, 1980) revealed increased chromium levels in the blood 
and urine, compared with those in the control group.  At 32 weeks 
of pregnancy, the blood concentrations of chromium were, 
respectively, 2.5 mg/litre in the women workers, 1.2 mg/litre in 
the women living near the plant, and 0.19 mg/litre in the controls; 
the levels in the urine were 1, 0.47, and 0.045 mg/litre, 
respectively.  Umbilical venous blood contained 1.8, 0.66, and 0.37 
mg chromium/litre, respectively.  The placental chromium contents 
in the surveyed women were 162, 179, and 40 g/kg, respectively, 
and the breast-milk levels were 119, 20, and 31 g/litre, which 
means that chromium is capable of transplacental entry into breast 
milk and into the fetal and infant organism.  Women working at the 
bichromate plant exhibited a high incidence of obstetric pathology 
and geotoses.  Chromium levels were estimated in fetal and 
placental tissues (abortive material) derived on the 12th week of 
pregnancy from women workers of the dichromate facility and those 
not exposed to chromium.  In the test group, chromium levels were 
1140 g/kg in the fetal tissues and 135 g/kg in the placental 
tissue, whereas, in the controls, they were 928 and 30 g/kg, 
respectively.  No teratogenic effects have been revealed (Shmitova, 
1980). 

8.3.1.  Effects on skin and mucous membranes

    Several different types of effects on skin and mucous membranes 
may result from exposure to chromium chemicals, and the main 
features are: 

    (a) primary irritation: ulcers (corrosive reactions),
        scarred and non-ulcerative contact dermatitis;

    (b) allergic contact dermatitis: eczematous and
        noneczematous.

    A general survey of the nature and cause of contact dermatitis 
is given by Fregert (1981). 

8.3.1.1.  Primary irritation of the skin and mucous membranes

    (a)   Skin

    Skin irritation, manifested by a sharp hyperaemia as well as by 
vesicular, papular, and rash pattern, may result from contact with 
chromates.  However, the major problems in the primary irritation 
dermatoses are ulcers, often called chrome holes or chrome sores.  
Ulceration is likely to occur among workers who have contact with 
high concentrations of chromic acid, sodium or potassium dichromate 
or chromate, or ammonium dichromate.  It does not result from 
contact with trivalent chromium compounds.  An ulcer may develop if 
the chromium compound, either a dust or a liquid, comes into 
contact with any break in the skin such as an abrasion, scratch, 
puncture, or a laceration.  Favoured sites for ulcer development 
are the nailroot areas, the creases over the knuckles, finger webs, 
the backs of the hands, and the forearms (Bloomfield & Blum, 1928). 

    Primary irritation by chromium can be attributed to hexavalent 
chromium, as the salts of trivalent chromium are not considered 
capable of producing such effects (Fregert, 1981).  However, 
prolonged exposure to trivalent chromium salts has been reported to 
cause skin lesions, less marked than those following exposure to 
hexavalent chromium salts (Domaseva, 1971).  Findings in 164 
patients with eczema showed that skin tests on people who had 
contact with trivalent chromium did not give positive results with 
dichromate (Valer & Racz, 1971). 

    Ordinarily, a chrome sore, if not deep, persists for about 3 
weeks after exposure is discontinued.  There is no evidence that 
the ulcers undergo malignant transformation. Furthermore, the 
presence of chromium ulcers did not influence the development of 
sensitization to chromates (Edmundson, 1951), evidenced by patch 
testing with a 0.5% solution of K2Cr2O7. 

    (b)   Nasal septal mucosa

    Perforation of the nasal septum was one of the main chronic 
effects in workers who had contact with chromates and chromic acid 
(Bloomfield & Blum, 1928; Langard & Norseth, 1979).  In a group of 
100 persons constantly in contact with chromium compounds, 44 had 
superficial ulceration of the anterior nasal septal mucosa.  
Twenty-one people had profound ulcers and 5 had perforations of 
various sizes in the cartilaginous part of the nasal septum.  
Perforation of the nasal septum and cicatricial alterations were 
observed in people with 3 or more years of service, whereas 
ulcerous lesions arose in 2 years of work with chromium compounds.  
An additional consequence of the effect on the nasal mucous 
membranes is a loss of the senses of smell and taste (Seeber et 
al., 1976).  In workers with profound ulcerous lesions of the nasal 
septal mucosa, strains of white staphylococcus with elevated 
resistance to chromium are sometimes isolated (Cherevaty et al., 
1965). 

    Pokrovskaya et al. (1976) studied 561 workers engaged in the 
open excavation of chromium ores (chromium content was 62% in the 
form of a complex compound of magnesium chromite and other chromium 
ores).  Almost half of the workers had worked there for more than 5 
years, and about 40% had been working there for 6 - 15 years.  
Changes in the nasal septal mucosa, typical of the effect of 
chromium compounds, were found in 8.2% of the workers.  The longer 
the service record, the greater the prevalence of these lesions.  
After 5, 11, and 15 years of work, the prevalence was 2.3%, 8.3%, 
and 11.2%, respectively. 

    The prevalence of nasal septum perforation in chromium plating 
workers was very high (24%) in the early 1950s in China (Yang, 
1956).  With the introduction of control measures, the prevalence 
dropped so that, in 1982, only 2 cases of nasal septum perforations 
were found among 393 chromium-exposed workers (Peng, 1982). 

    One hundred and four subjects (85 male, 19 female) exposed to 
chrome plating and 19 unexposed controls were studied by Lindberg & 
Hedenstierna (1983) with regard to changes in the nasal septum.  
Exposed subjects were employed at 13 different companies and 
included all who were working on the day of study at the particular 
company.  The median exposure time was 4.5 years (range, 0.1 - 36 
years).  Forty-three subjects were exposed almost exclusively to 
chromic acid and constituted both a "low exposure" group (8-h mean 
below 2 g/m3, N = 22) and a "high exposure" group (2 g/m3 or 
more, N = 21).  Their median exposure time was 2.5 years (range, 
0.2 - 23.6 years). The other 61 subjects were exposed to a mixture 
of chromic acid (0.2 - 1.7 g/m3) and other pollutants, such as 
nitric, hydrochloric, and boric acids, as well as caustic soda, 
nickel, and copper salts.  The last group was included to disclose 
any additive or synergistic effects of chromic acid and other 
pollutants and was studied with regard to lung function only.  The 
breakdown of subjects into various groups is shown in Table 25.  
Nasal septal ulceration and perforation were seen in 10 out of 14 
subjects exposed to peak levels of 20 - 46 g chromic acid/m3 or 
more; no one in the control group showed signs of atrophy, 
ulcerations, or perforations. 

8.3.1.2.  Allergic contact dermatoses

    Chromium is a very important skin sensitizer.  Sensitization 
is reported to require about 6 - 9 months, but can occur in less 
than 3 months (Piril & Kilpio, 1949).  Genetic factors appear to 
contribute to the appearance of chrome sensitivity within the 
Jewish population (Wahba & Cohen, 1979). 

    Apart from the primary irritation and ulceration effects, 
direct contact with small amounts of the chromates may cause 
allergic dermatosis (dermatitis and eczema).  As this allergic 
reaction is cell-mediated, i.e., antibody formation is intra-
cellular and not humoral, delayed allergic reactions are rarely 
observed. 

    Fregert et al. (1969) reported that the skin-patch test for 
chromium was positive in 8 - 15% of all patients suffering from 
eczema.  The dermatitis caused by chromium is described as a 
diffuse erythematous type with severe cases progressing to an 
exudative stage.  Persons sensitive to chromium react to patch and 
intracutaneous tests with nonirritant concentrations of potassium 
dichromate (K2Cr2O7).  Opinion is divided about the role of the 
oxidation state of chromium as a causal agent in allergic contact 
dermatoses (Morris, 1958; Fregert & Rorsman, 1964; Kogan, 1971).  
In a review, Polak et al. (1973) showed that hexavalent chromium, 
which penetrates the skin by a direct effect of a hapten, is 
reduced to the trivalent state, chiefly by sulfhydryl groups of 
aminoacids.  It then conjugates with proteins thus forming the full 
antigen that initiates sensitization. 

    Guinea-pigs sensitized with either trivalent chromium chloride 
or hexavalent potassium dichromate are capable of reacting  in vivo 
and  in vitro to challenges with both chromium salts.  This double 
reactivity is also found after repeated stimulation with only one 
of these chromium compounds.  Since it is not possible to select 
lymphocytes directed specifically against a chromium determinant of 
a particular valence, it is concluded that, by sensitization with 
chromium salts of different valences, a common determinant or 
closely related determinants are formed.  It is suggested that this 
determinant is formed by chromium in the trivalent form 
(Siegenthaler et al., 1983). 

    Two to three years after medical treatment, a follow-up study 
on 555 patients with contact dermatitis was completed by means of 
questionnaires (Fregert, 1975).  The eczema had healed in one-
quarter of the patients, one-half had periodic symptoms, and one-
quarter had permanent symptoms.  The prognosis for persons who 
changed their work or stopped working was the same as that for 
those who continued eczema-inducing work. 

    From 48 positively tested patients (0.5% potassium dichromate), 
38 persons, i.e., 79%, still had a positive patch test after 4 - 7 
years.  In 72% of the cases, a history of occupational exposure to 
chromates could be proved (Thormann et al., 1979). 

    A fairly rapid transformation of dermatitis into eczema is a 
characteristic feature of chromium-induced skin lesions. Kogan 
(1971) recognized the following important properties: (a) absence 
of adaptation, which makes it necessary to discontinue chromium 
handling until the slightest clinical manifestations have 
disappeared; (b) a persistent chronic development of an eczematous 
process; (c) a long-term latent period; and (d) absence of a direct 
correlation between the incidence of sensibilization in the exposed 
workers and the chromium concentration to which they have been 
exposed.


Table 25.  Series of exposed subjects and referencesa
--------------------------------------------------------------------------------------------------------
                                  Exposed subjects                            
                                                        Mixed exposure to
               Low exposure to    High exposure to        chromic acid
                chromic acid        chromic acid      (< 2 g/m3) and other
             (< 2 g Cr6+/m3)    (> 2 g Cr6+/m3)     acids and metallic salts   References
             -----------------   ------------------   -----------------------    -----------------
             Nb   Age (years)c   N    Age (years)     N     Age (years)          N    Age (years)
--------------------------------------------------------------------------------------------------
Men
Non-smokers  10   35.8  16.7    6    33.4  14.1     12    33.6  12.2          52   34.2  13.2
Smokers      6    30.8  9.7     16   30.2  11.8     36    42.8  13.1          67   30.5  8.9

Women
Non-smokers  3    30.7(17-46)    0                    9     48.3  13.0
Smokers      2    44.5(29-60)    1    51.2            4     31.0(19-43)
--------------------------------------------------------------------------------------------------
a  From: Lindberg & Hedenstierna (1983).
b  When N < 5, the range is given instead of SD.
c  X  SD.


    Patients suffering from chromium-induced allergic skin 
dermatoses had a tendency to develop cross-correlated hyper-
sensitivity to other metals, in particular, to cobalt and nickel 
(Rostenberg & Perkins, 1951; Geiser et al., 1960; Clark & Kunitsch, 
1972; Kogan et al., 1972). 

    Increased sensitivity to chromium is proved by skin reaction 
tests.  In a number of cases, additional immuno-haematological 
bioassays are made to confirm the specificity of these tests.  A 
method for studying the basophil (mast-cells) degranulation  in vivo, 
at the site of positive compress skin tests, was suggested by Kogan 
(1968).  The method was used as a basis for proving the specificity 
of cutaneous tests for chromium and other sensitising metals of the 
chromium group (cobalt and nickel) (Kogan, 1968; Kogan et al., 
1972). 

    Photosensitivity is sometimes observed in patients with chronic 
dermatitis.  Wahlberg & Wennerstein (1977) investigated patients 
allergic to chromium, with or without clinically observed light 
sensitivity, by a standardized photopatch test procedure.  A 
significantly more intense reaction was observed in 48% of the 
cases in the UV-irradiated sites (4/5 minimal erythema dose) 
compared with the non-irradiated control sites. 

    No cases of cancer of the skin have been reported to result 
from exposure to any form of chromium (Fregert, 1981). 

8.3.2.  Effects on the lung

    Airborne chromium trioxide is rapidly absorbed in the broncho-
pulmonary tract causing corrosive reactions (Borghetti et al., 
1977).  The absorption of chromium aerosols may depend on the 
physical and chemical properties of the particles (Taylor et al., 
1965), as well as on the  activity of alveolar macrophages, and the 
lymphatic drainage (Sanders et al.  1971). 

    Both Jindrichova (1978) and Keskinen et al. (1980) reported 
that welders using chromium-containing electrodes suffered from 
bronchitis.  Zober (1982) studied arc welders who had used filler 
metals containing chromium and nickel for some years.  Compared 
with controls, the welders reported more previous ailments of the 
respiratory system, mainly in the form of acute bronchitis.  In 
X-rays of welders, more roundish shadows were found, probably 
indicative of benign accumulations of ferrous dust.  The greater 
incidence of significant findings was clearly apparent in welders 
who smoked (probably a combined effect of tobacco smoke and welding 
fumes). Reggiani et al. (1973) studied 101 electroplaters by means 
of spirometric tests and found an obstructive disease pattern in 
13% of them.  After inhalation of acetylcholine, a bronchospastic 
reaction occurred in 23% of the workers.  In another spirometry 
study (Bovet et al., 1977) on 44 chromium electroplaters, an 
obstructive respiratory syndrome was found among the workers with a 
high urinary-chromium content.  The authors concluded that the 
influence of tobacco smoking on the spirometric tests was much less 
than the influence of chromium. 

    Studying lung function and generalized obstructive lung 
diseases in electrofurnace workers in a ferrochromium and 
ferrosilicon-producing plant, Langard (1980b) found a reduced 
forced vital capacity (FVC) and an increased prevalence of 
obstructive lung diseases.  Unable to document a connection between 
the presence of chromates and increased lung diseases, the author 
suggested that the effects were due to high levels of total dust, 
especially amorphous silica dust. 

    Lindberg & Hedenstierna (1983) studied lung function in more 
than 100 subjects exposed to chrome plating and in 119 car 
mechanics as controls (no car painters or welders).  In the exposed 
subjects, FVC and the forced expired volume in one second (FEV1) 
were both reduced by 0.2 litre, and the forced mid-expiratory flow 
was reduced by 0.4 litre/second.  The authors concluded that an 8-h 
mean exposure level of more than 2 g/m3 might cause a transient 
decrease in lung function. 

    Pneumoconiosis was diagnosed in Germany (Letterer et al., 1944) 
and again in chromite miners in South Africa (Sluis-Cremer & du 
Toit, 1968).  However, American medical officers could not confirm 
this feature when examining 897 workers in chromate-producing 
plants in the USA (US PHS, 1953).  It should be noted that chromium 
dusts had a poor fibrogenic potency in experimental animal studies 
(section 7.2.1.5). Davies (1974) X-rayed workers employed in the 
manufacture of ferro-chrome and found results similar to miliary 
lung tuberculosis.  The workers were in the immediate area of the 
furnace and were exposed to dust-particles, 90% of which were less 
than 2 m in diameter.  The dust deposited on girders consisted of 
95% SiO2 and 2.4% Cr2O3.  The author did not find any symptoms or 
signs of tuberculosis, but there was sufficient evidence to 
indicate an inhalation hazard in the ferro-chrome industry, thus 
underlining earlier observations of Princi et al. (1962). 

8.3.2.1.  Bronchial irritation and sensitization

    Chromium irritates mucous membranes, as has been seen with 
exposure to airborne chromium trioxide fume (Meyers, 1950) or mixed 
dust (Card, 1935; Broch, 1949; Williams, 1969).  The first symptom 
was an irritating cough, 4 - 8 h after exposure. Chromium causes 
sensitization that can result in asthmatic attacks.  These can last 
for 24 - 36 h, without treatment (Langard & Norseth, 1979).  An 
attack may recur on later exposure, even when this exposure is to a 
much lower concentration (US NAS, 1974a). 

    A double-blind experimental exposure study on an asthmatic 
patient, who had been exposed to chromium and nickel, showed that 
chromium was the main cause of the asthma (Novey et al., 1983).  
Keskinen et al. (1980) pretreated their patients, stainless steel 
welders, with both disodium cromoglycate and betamethasone and 
found an inhibition of this reaction. Placebo medication failed to 
produce this inhibition. 

8.3.3.  Effects on the kidney

    In the early part of this century, chromates and chromic acid 
were occasionally used as therapeutic chemicals for some skin 
lesions.  Fatal cases of acute nephritis occurred with albumin, 
hyaline, and granular casts and red cells appearing in the urine, 
accompanied by oliguria.  Autopsies revealed tubular necrosis, but 
not glomerular damage (Kaufman et al., 1970).  Acute toxic 
gastroenteritis developed, followed by arterial hypotonia, in 
suicide cases a few hours after swallowing 1.5 - 10 g potassium 
dichromate.  Within 2 - 4 days, all patients developed signs of 
acute renal insufficiency with oliguria, anuria, and hyperhydration 
and also evidence of acute toxic hepatitis (Luzhnikov et al., 
1976). Kidney damage has also occurred in industry, as a result of 
accidental exposure of the skin to large amounts of chromate, 
especially when associated with extensive skin damage (Luzhnikov et 
al., 1976). 

    The mortality from kidney diseases among workers in the 
chromium industry does not appear to have increased.  In one study, 
no deaths from nephritis and uraemia were found in 4 chromate-
producing plants; in only 1 plant was the mortality rate above that 
for the controls (Machle & Gregorius, 1948). Hayes et al. (1979) 
reported that 4 deaths from nephritis and nephrosis had occurred 
between 1945 and 1977 in workers in a chromate-producing plant, 
compared with 4.95 cases in the control population.  Satoh et al.  
(1981) found one case of nephritis and nephrosis in a group of 
chromate workers compared with an expected number of 2.18. 

    Some authors (Franchini et al., 1975; Borghetti et al., 1977; 
Gylseth et al., 1977; Tola et al., 1977) have concluded that 
urinary excretion and renal clearance of diffusible chromium can be 
used as biological indicators for evaluating the extent of exposure 
to airborne chromium and the body burden.  However, a dose-effect 
relationship could not be established between duration of exposure 
and either the level of chromium excretion (Tandon et al., 1977) or 
early nephrotoxic indicators (Mutti et al., 1979).  A dose-
response relationship for hexavalent chromium effects on the kidney 
was described by Mutti et al. (1979), measuring beta-glucuronidase, 
protein, and lysozyme in the urine.  Abnormal patterns were not 
observed in 39 stainless-steel welders during 4.5  3.2 years of 
exposure.  In another group of workers employed in welding armoured 
steel with special electrodes for 1  0.4 years, 22% showed an 
increase in beta-glucoronidase and 10% in protein in the urine.  In a 
study on 24 workers in the chromium-plating industry who were 
exposed for 8.9  7.3 years, the authors found increased urinary 
levels of beta-glucoronidase in 37% of the workers, an increase in 
protein in 17%, and an elevated level of lysozyme in 4%.  Urinary 
beta2-microglobulin was also studied by Lindberg & Vesterberg (1983b) 
in chromeplaters (24 males, mean age 36 years, working in 4 
different factories).  The exposure was measured using personal air 
samplers.  The 8-h mean value ranged between 2 and 20 g hexavalent 
chromium/m3 and averaged 6 g/m3.  Most of the workers showed 
symptoms of airway irritation, 2 of them had ulcerated nasal septum 
and another 2, complete perforation.  Significantly higher urine 

beta2-microglobulin levels (0.23 mg/litre; range, 0.04 - 1.24 mg/litre; 
SD, 0.27) were found in this group of workers in comparison with a 
reference group of workers of a comparable age (mean age, 38 years; 
mean urinary beta2-microglobulin level, 0.15 mg/litre; range, 0.06 - 
0.19 mg/litre; SD, 0.08).  A relationship was observed (Table 26) 
between the range of exposure and prevalence of urinary beta2-micro- 
globulin levels exceeding 0.3 mg/litre.  The 2 workers with 
perforated nasal septum were in the highest exposure group.  A 
difference in urinary beta2-microglobulin levels was not found between 
a group of workers employed several years earlier in an old 
chromeplating plant (mean, 0.25 mg/litre) and a group of workers of 
comparable age (mean, 0.29 mg/litre), but it should be noted that 
the mean age of both these groups exceeded 52 years. 

Table 26.  beta2-microglobulin U-beta2 levels in urine of workers
related to present exposure levelsa
-------------------------------------------------------------------------
Plant  Exposure  Number  Age     Persons with an "elevated"  U-beta2
No.    range     of      (mean)  (U-beta2 > 0.30 mg/litre)   range
       (g/m3)   workers         concentration               (mg/litre)
                                 No.    Ages
-------------------------------------------------------------------------
1      11 - 20   5       39      3      21, 37, 58           0.23 - 1.30
2 - 3  14 - 8    13      37      2      20, 21               0.04 - 0.44
4      2 - 3     6       6       -      -                    0.06 - 0.18
-------------------------------------------------------------------------
a From: Lindberg & Vesterberg (1983b).

8.3.4.  Effects on the liver

    Statistics on diseases of the liver are seldom published 
separately; they are usually included in the group of diseases of 
the digestive system.  The chromate industry was reported to have 
the same rate in this group of diseases as many other industries 
(US PHS, 1953).  The Federal Security Agency in the USA 
investigated 14 chromate workers reported to have "enlarged livers" 
but found that these cases were not related to the time spent in 
the industry.  Acute hepatitis with jaundice was described in one 
worker employed in a chromium-plating plant. 

    In an epidemiological study, Satoh et al. (1981) reported a low 
rate of cirrhosis of the liver in chromium workers and liver 
function test results that did not differ significantly from those 
of the controls. 

    However, following ingestion of high doses of potassium 
dichromate, liver necrosis (Brieger, 1920) and congested liver 
(Kaufman et al., 1970) with loss of its architecture have been 
described.  There are also case studies of liver function and 
histology in electroplaters (Pascale et al., 1952) and chromate 
chemical plant workers (Etmanova, 1965), but the results are 
difficult to interpret. 

8.3.5.  Effects on the gastrointestinal tract

    The following symptoms and signs were reported in workers 
engaged in the production of chromium salts (Sterekhova et al., 
1978): hyperchlorhydria, elevated pepsin and pepsinogen level, 
oedema, hyperaemia and erosion of the mucosa, polyposis, 
dyskinesia, and gastritis.  However, Satoh et al. (1981) reported 
that the incidence of peptic ulcer in chromate workers was below 
the expected rate, and another study showed that the mortality rate 
for diseases of the digestive system was lower in chromate workers 
than in the control population (Hayes et al., 1979). 

    The gastric juice has been shown to play a role in the 
detoxification of ingested hexavalent chromium by reducing it to 
trivalent chromium, which is poorly absorbed and eliminated with 
the faeces (Donaldson & Barreras, 1966; DeFlora & Boido, 1980). 

8.3.6.  Effects on the circulatory system

    A clinical study was performed by Kleiner et al. (1970) on 
myocardial function in more than 200 workers in the potassium 
chromate industry, suffering from pulmonary or gastrointestinal 
diseases, attributed by the authors to chromium poisoning.  A 
control group of 70 healthy individuals was included.  Pathological 
changes in the ECG and in other tests of heart function indicated 
disturbance of right heart function, which the authors considered 
secondary to the pulmonary pathology.  The full paper was not 
available and, consequently, the data could not be evaluated in 
detail.  It should be noted that no unexpected findings in 
cardiovascular mortality were cited in the epidemiological studies 
described in section 7.3.9. 

8.3.7.  Teratogenicity

    The only human data available concerning this topic were 
reported in an abstract (Morton & Elwood, 1974).  The authors did 
not find any correlation between frequency of malformations in the 
central nervous system and the chromium content in water samples 
collected in South Wales.  Furthermore, Suzuki et al. (1979) did 
not find any indication of accumulation of chromium in fetal 
tissues. 

8.3.8.  Mutagenicity and other short-term tests

    Few reports exist dealing with chromium-induced mutagenicity in 
human subjects, and only hexavalent chromium causes any effects. 

    Bigaliev et al. (1978) found a 3 - 8% increase in chromosomal 
aberrations of peripheral blood leukocytes in workers handling 
chromium-compounds, compared with 2% in unexposed controls. 

    When classified according to the Papanicolaou system, 
cytological samples of the sputum of 116 workers in the chromate-
production industry did not show any stages of tumour development 

(Maltoni, 1976).  However, intermediate stage lesions found in 30 
workers were described as atypical adenomatous proliferation, 
squamous-cell, and basal-cell dysplasia. 

    Studying cultured lymphocytes obtained from workers 
occupationally exposed to CrO3, Sarto et al. (1982) found an 
increased frequency of sister chromatid exchanges compared with 
controls, which was correlated with urinary-chromium levels and 
enhanced by smoking habits. 

8.3.9.  Carcinogenicity

8.3.9.1.  Lung cancer

    (a)   Epidemiological studies in chromate-producing plants

    The first recognition that cancer of the respiratory tract 
might be related to chromium exposures resulted from the reporting 
in 1932 of 2 cases of bronchogenic carcinoma that had occurred in 
an old German chromate chemical plant (Lehmann, 1932).  Gross & 
Klsch (1943) reported 10 deaths from lung cancer in small plants 
producing the chromates of lead and zinc.  By 1947, 52 such cases 
had been reported from this industry and 10 cases from a chrome 
pigment plant, also in the Federal Republic of Germany (Baetjer, 
1950a). 

    The first epidemiological study was reported in the USA in 
1948.  The mortality data were based on the records of the group 
life insurance policies of 6 chromate-producing plants in the USA 
compared with similar data from a non-chromium industry or from a 
life insurance company.  The study reported that 21.8% of all 
deaths between 1938 and 1947 in the chromate plants were due to 
cancer of the respiratory tract compared with 1.4% in the control 
group.  The crude death rate for cancer of the bronchi and lungs 
was 28 times that for the control groups (Machle & Gregorius, 
1948).  In one of these plants (Mancuso & Hueper, 1951), the cancer 
death rate was 15 times that of the general population in the 
county where the plant was located.  The US PHS (1953) also studied 
the respiratory cancer risk in these 6 plants and estimated a 
relative risk of 28.9 using the average cancer mortality rates for 
US males between 1940 and 1948 as a comparison. 

    In addition to these studies, where the cause of death was 
taken from insurance or death certificate records, a case-control 
study, using only cases diagnosed by autopsy or biopsy, was 
conducted by Baetjer (1950b).  Two hospitals near the largest 
chromate plant in the USA were asked to supply the histories of all 
cases diagnosed in 1924-46 as cancer of the lung bronchi, and to 
confirm histopathologically.  A group of non-cancer cases matched 
individually by age, sex, and date of admission was selected as 
controls.  Of the 290 confirmed cancer cases, 3.26% had been 
employed in the chromate plant, whereas none of the 900 control 
cases was found to have had chromate exposure.  The percentage of 
chromate workers in the lung cancer series was 28.6 times the 

percentage of chromate workers among the employed male population 
of the city.  The plant involved in this study was rebuilt in 1950, 
following the discovery of the cancer problems.  A new study of 
this plant was made by Hayes et al. (1979) to determine whether the 
risk of cancer had been eliminated.  The investigation covered 438 
deaths among 2101 males, who were initially employed between 1945 
and 1974 for more than 90 days, and who died between 1945 and 1977.  
The SMRa for malignant neoplasms of the trachea bronchi and lungs 
was 202.  Cancer deaths in the city in which the plant was located 
were used to calculate the expected number of cases.  No cases of 
respiratory cancer occurred in the plant between 1960 and 1977 
among workers employed only in the new plant.  Because of the long 
latent period, further follow-up is necessary. 

    Increased lung cancer rates among chromate workers in the USA 
have been confirmed by Taylor (1966), Enterline (1974), and Mancuso 
(1975), who also showed that the risks were especially high during 
the early years of the study of the cohorts, e.g., before 1950.  
Studies conducted in other countries have shown similar results.  
In a 1956 study on workers in chromium-producing plants in the 
United Kingdom, the rate of lung cancer mortality was 3.6 times the 
rate for England and Wales (Bidstrup & Case, 1956).  In a follow-up 
study on 2715 men who had worked at the 3 chromate-producing 
factories in the United Kingdom from 1948 to 1977, Alderson et al. 
(1981) found 116 deaths from lung cancer (expected, 48). Since 
modification of the one plant that is still in operation, the 
relative risk of lung cancer has decreased from over 3 to about 
1.8. 

    Two epidemiological studies have been conducted in the Japanese 
chromate industry.  In one plant, 5 lung cancer deaths occurred 
between 1960 and 1973 in 136 workers who had been exposed for more 
than 9 years; the SMR was 1510 (Watanabe & Fukuchi, 1975).  In 
another plant, the mortality rate for respiratory cancer was 
determined for 896 males who worked in the plant from 1918 to 1975 
and were followed to 1978; the SMR was 920 (expected deaths based 
on 1975 age-cause-specific mortality rates for Japanese males) 
(Satoh et al., 1981). 

    In the Federal Republic of Germany, a study was conducted in 2 
chromate-producing plants (Korallus et al., 1982). Comparing the 
SMR for lung cancer during the period 1948-79 for these 2 groups, a 
clearly decreasing tendency was observed.  In the first plant, for 
1948-52, the SMR was 512 and, for 1978-79, it was 98; for the other 
plant, the corresponding figures were 1905 and 150, respectively. 

    The newest data indicate a decreasing risk approaching the 
frequency in unexposed people (Korallus & Loenhoff, 1981). This is 
a result of occupational hygienic and technological measures, 
especially of a change in manufacture namely the "on line" 
--------------------------------------------------------------------
a   The SMR (standardized mortality ratio) is the ratio of
    observed to expected deaths times 100.

processing of the chrome ore, which has minimized the contents of 
the carcinogenic hexavalent chromium compounds within the process 
(Korallus et al., 1982). 

    Bittersohl (1972) described the results of a study on 30 000 
employees of a large chemical unit for the period 1921-70 in the 
German Democratic Republic.  In particular, 588 malignancies in men 
and 170 in women were evaluated for the period 1957-70.  In 1971, 
108 new malignancies in men and 29 in women came to light.  In a 
chromate factory, the rate of all cancers was far above average.  
The factory manufactured catalysts through the reaction of chromic 
acid and iron (III) oxide and nitric acid. The airborne 
concentrations of chromium were not reported in detail, but it was 
stated that short-term exposures above 400 g/m3 occurred.  The 
incidence of malignant neoplasms in employees in the chromate 
factory was 852 per 10 000 employees.  In "unexposed" personnel, 
the incidence of malignant neoplasms was 84 per 10 000 employees. 
Approximately 86% of all those with malignant neoplasms were 
smokers, and 78% of those without malignant neoplasms were also 
smokers, indicating that smoking is not likely to be a confounding 
factor. 

    In the USSR, a high incidence of cancer of the lungs was 
reported for men engaged in the production of chrome salts. The 
ratio of lung cancer in the plant to that in the control population 
was 6.4 for ages 50 - 59 (748 observed, 116 expected) and 15.7 for 
ages 60 - 69 (2657 observed, 170 expected) (Tyushnyakova et al., 
1974). 

    A survey was conducted in China in 1982 to investigate the 
problem of lung cancer among chromate-producing workers.  It 
covered 7 cities and included 2184 male and 798 female workers who 
had worked for at least one year in the industry.  The preliminary 
report revealed that 11 of the 101 deaths among male workers were 
due to lung cancer, but none of the 13 deaths among female workers 
was due to this cause.a

    (b)   Epidemiological studies - chrome pigment industry

    The first epidemiological study, conducted in 1973, covered 3 
small chrome pigment-manufacturing plants in the USA.  The 
percentage of lung cancer deaths was tentatively reported to be 
about 3 times that in unexposed workers (Equitable Environmental 
Health Inc., 1976). 

    Lung cancer mortality was studied among 1152 men working at 3 
chromate pigment factories in the United Kingom from the 1930s or 
1940s until 1981 (Davies, 1979, 1984).  Among workers at factory A, 
which produced both zinc and lead chromates, entrants to the 
factory between 1932-45 with high and medium exposures had excess 

---------------------------------------------------------------------------
a   Report of an Investigation Team for Cancer in Chromate
    Workers (1983).

risks of lung cancer (SMR = 223).  A similar excess was seen in 
1946-54 entrants, but the excess risk fell just short of 
statistical significance.  Highly significant excess risks of lung 
cancer were seen among 1947-64 entrants that had high or medium 
exposures at factory B, which also produced lead and zinc 
chromates.  Excesses were more severe in workers employed for more 
than 10 years.  In factory C, which produced only lead chromate, no 
excess of lung cancer was found.  However, the number of workers 
and the power of the study were small. 

    Twenty-four male workers, who had been employed in a small 
Norwegian company for more than 3 years between 1948 and 1972, were 
identified and followed up by Langard & Norseth (1975), because 
their principal exposure was to zinc chromate dust (measured 
routinely with readings occasionally up to 0.5 mg hexavalent 
chromium/m3).  By December 1980, 6 cases of lung cancer had been 
diagnosed, giving a relative risk of 44 compared with that of the 
general population in the country. The authors stated that 5 out of 
the 6 patients were smokers and only one had been exposed to 
chromates other than zinc chromates (Langard & Vigander, 1983). 

    Sheffet et al. (1982) undertook a detailed mortality study on 
workers employed in a pigment plant in Newark, where lead and zinc 
chromates were used.  Observed deaths from each cause among 1296 
white and 650 non-white males employed between 1940 and 1969, were 
compared with expected deaths, as computed from cause-, age-, and 
time-specific standard death rates for the USA.  A  statistically-
significant  relative risk  of  1.6  for lung cancer among white 
males, employed for 10 years or more, was found.  A relative risk 
of 1.9 was noted for individuals employed for at least 2 years, who 
were at least moderately exposed to chromates. 

    An epidemiological study covering several centres in Europe was 
conducted by Frentzel-Beyme (1983).  This study was designed to 
quantify the mortality from cancer and other diseases among workers 
in European factories producing chromate pigments (3 German, 2 
Dutch factories).  Observed deaths in factories were compared with 
expected deaths calculated on the basis of mortality figures for 
the region in which a given factory was located.  The overall 
mortality did not deviate from the expected rates.  Lung cancer 
rates were always in excess of expected numbers, but only in one 
cohort was the excess statistically significant.  The pattern of 
duration of exposure indicates that the lung-cancer risk was not 
clearly correlated with length of employment. 

    A slight excess of lung cancer risk in chrome pigment (zinc 
chromate) spray painters from 2 maintenance bases in the USA was 
reported by Dalager et al. (1980).  Among the 202 deaths 
identified, 21 were due to respiratory cancer (11.4 expected; 
comparison population: proportionate mortality, US males).  No 
statistically significant excess of lung cancer was found in a 
group of automobile painters in which 226 deaths, including 22 
cancer cases, were analysed using proportionate mortality for areas 
in which the plants were located as a comparison (Chiazze et al., 
1980). 

    (c)   Epidemiological studies - ferro-chrome industry

    Langard et al. (1980) reported that 7 cases of bronchogenic 
carcinoma occurred among 976 workers, who started work before 
January 1, 1960.  The expected number was 3.1 using national rates, 
1.8 using local rates, and < 1 when using an international 
reference rate for comparison.  The difference was not significant 
for the national and local rates, but was significant for the 
international rate. 

    A study in Sweden did not reveal any significant excess of 
respiratory cancer in ferro-chrome workers (Axelsson et al., 1980).  
The incidence of cancer among 1932 workers employed for at least 
one year between 1930 and 1975 was compared with the expected 
number based on the National Cancer Registry data for the county in 
which the plant was located.  Five cases of respiratory cancer were 
found against an expected 7.2 cases. 

    An excessive rate of lung cancer was reported for a ferro-
chrome plant in Russia (Pokrovskaya & Shabynina, 1973). The number 
of deaths from cancer between 1955 and 1969 was higher than that in 
the town in which the plant was located. The authors considered 
that both hexavalent and trivalent chromium exposures were 
responsible for the excess, since similar excessive rates were 
found in a nearby ore-crushing plant, where only trivalent chromium 
was present. The number of cases and the rates involved in these 
studies were not given. 

    Hexavalent chromium is produced in some types of welding. In 
section 7.2.1.2, it was mentioned that welding fume particles were 
positive in the mammalian spot test, indicating a mutagenic and 
possible carcinogenic potential. The incidence of lung cancer was 
determined by Sjgren (1980), in a cohort of 234 welders, who had 
welded stainless steel for more than 5 years between 1950 and 1965, 
and were followed to 1977.  Three welders died from lung cancer in 
comparison with an expected number of 0.68 in the general 
population ( P = 0.03). 

    Comparing lung cancer mortality in 2 parishes with ferro-alloy 
industries to mortality in other parishes of similar size without 
such industries from the same county, Axelson & Rylander (1980) 
were unable to detect an increased incidence of death due to lung 
cancer mortality.  The concentration of chromium in the ambient air 
of the most polluted areas ranged from 0.1 to 0.4 g/m3.  It should 
be noted that several possible confounding factors were not under 
control, e.g., migration, occupational exposure, and smoking 
habits. 

    (d)   Epidemiological studies - chromium-plating workers

    Epidemiological studies on workers in the chromium-plating and 
related industries were reviewed by Hayes (1982).  The relevant 
data from these studies are presented in Table 27. According to 
Hayes, the epidemiological evidence is not sufficient to determine 
the risk of cancer associated with industrial exposure to chromic 

acid and, if an excess risk exists, it is probably lower than that 
typically described for employment in the chromium-chemical 
producing industry. 

    In a more recent paper, Franchini et al. (1983) conducted a 
retrospective cohort study in 9 chromium-plating plants to examine 
the mortality of workers employed for at least one year during the 
period January 1951 to December 1981.  The study group totalled 178 
individuals; vital status ascertainment was 97% complete.  The 
total number of deaths was close to the expected figure (15 
observed, 15.2 expected), whereas death from lung cancer exceeded 
the expected number (3 observed, 0.7 expected;  P = 0.03).  The 
increased mortality from lung cancer among chromium-platers seemed 
to be related to exposure intensity. 

8.3.9.2.  Cancer in organs other than lungs

    A few cancers of the upper respiratory tract and oral region, 
but no excessive rates have been reported to occur in the chromate-
producing industry.  The cancers have involved the buccal cavity, 
pharynx, and oesophagus.  Cancers of the nasal septum have not been 
documented, with the exception of one case in Italy (Vigliani & 
Zurlo, 1955). 

    In a joint Danish-Finnish-Swedish case-reference investigation, 
initiated in 1977, the connection between nasal and sinonasal 
cancer and various occupational exposures was studied.  All new 
cases of nasal and sinonasal cancer were collected from the 
national cancer registers (Finland and Sweden) or from the hospitals 
(Denmark).  The results showed associations between nasal and 
sinonasal cancer and exposure to chromium, welding, flame-cutting, 
and soldering, hardwood or mixed wood dust, and softwood dust alone 
(13.4) (Hernberg et al., 1983). 

    In 5 plants in the USA, during the early years of extremely 
high exposures, the rate of cancer of the digestive tract varied 
from 0 to 3.04/1000 compared with a rate of 0.59/1000 for the 
controls (Machle & Gregorius, 1948).  The mortality rates from 
stomach cancer have been reported for chromate-producing plants in 
Japan (SMR = 90) (Satoh et al., 1981) the USA (SMR = 40) (Hayes et 
al., 1979).  No significant differences were reported between the 
incidence of stomach cancer in a Russian plant (Pokrovskaya & 
Shabynina, 1973) and the incidence in the surrounding area. 

    Studying cancer mortality in a pigment plant using lead and 
zinc chromates, Sheffet et al.  (1982) found an increased (but not 
statistically risk of stomach (SMR = 170) and pancreas (SMR = 200) 
cancer among the total cohort (1946 employees). 


Table 27.  Summary of epidemiological studies on respiratory cancer in 
workers employed in the chromium plating and related industriesa
------------------------------------------------------------------------------------------------
Study population            Follow-up                 Respiratory cancer  Comparison population
                                                      Number   Estimated
                                                        relative risk
------------------------------------------------------------------------------------------------
Chromium plating

1056 workers employed       Deaths in former and      24       1.8b       Unexposed workers in
> 3 months in 54 plants     current (followed 2                           plants and in 2 non-
in the United Kingdom       years) workers,                               plating industries
                            about 80% traced

About 5000 workers                                    49       1.4c       Mortality analysis,
employed since 1945 in                                                    method not specified
1 plating factory in
the United Kingdom

889 workers exposed > 6     Reports from management   0        < 1b        Tokyo mortality
months in Tokyo chromium    of plating firms and                          rates
plating plants, 1970-76     follow-up of retired
                            workers; 19 total deaths
                            reported

Related industries

1292 deaths among US        Union death benefit       62       1.1b       Proportionate
metal polishers and         claims                                        mortality, US males
platers, union members,
1951-69

238 deaths among employees  Pension, insurance and    39       2.1c       Proportionate
for 10 years in one US      benefit records                               mortality, US
plant for metal die
casting, finishing, and
electroplating, 1974-78.
------------------------------------------------------------------------------------------------
a   Adapted from: Hayes (1982).
b   Not statistically significant.
c    P  < 0.05, calculated using an assumption that the observed number is distributed as a 
    Poisson random variable.
8.3.9.3.  Relationship between cancer risk and type of chromium 
compound

    As the exposures are often poorly defined, it is sometimes not 
certain whether workers have been exposed to hexavalent chromium, 
trivalent chromium, or a combination of the two. Some authors have 
concluded that there is no increased risk of cancer mortality due 
to trivalent chromium compounds (Korallus et al., 1974 a,b,c; 
Axelsson et al., 1980; Langard et al., 1980; Norseth, 1980), 
whereas others do not exclude that trivalent chromium compounds 
have a carcinogenic capacity (Essing et al., 1971; Mancuso, 1975; 
Zober 1979). 

    Summing up the data from case reports as well as 
epidemiological studies in chromate-producing, chromate-pigment, 
chromium-plating, and ferrochromium industries, the IARC Working 
Group on the Evaluation of the Carcinogenic Risk of Chemicals to 
Humans (IARC, 1980) came to the conclusion that "there is 
sufficient evidence of respiratory carcinogenicity in men 
occupationally exposed during chromate production.  Data on lung 
cancer risk in other chromium-associated occupations and for cancer 
at other sites are insufficient.  The epidemiological data do not 
allow an evaluation of the relative contributions to carcinogenic 
risk of metallic chromium, trivalent chromium and hexavalent 
chromium or of soluble versus insoluble chromium compounds". 

9.  EVALUATION OF HEALTH RISKS FOR MAN

    Low levels of chromium are omnipresent in the environment. 
Under normal conditions, human exposure to chromium does not 
represent a toxicological risk, but it should be pointed out that 
too low an intake of chromium may lead to deficiency. Airborne 
concentrations of chromium, predominantly as trivalent chromium, 
are usually below 0.1 g/m3 and there are many places where the 
concentration is below the detection limit.  Concentrations in 
river water are typically in the range of 1 - 10 g/litre and do 
not constitute a health threat.  Drinking-water from municipal 
water supplies does not contribute more than a few micrograms of 
chromium to the daily human intake, but untreated water in certain 
areas may be contaminated by runoff or effluents from industrial 
sources and may contribute significant amounts of chromium.  The 
oceans contain less than 1 g/litre.  The daily human intake 
through food varies considerably between regions.  Typical values 
range from 50 to 200 g/day.  They do not represent a toxicity 
problem. 

    However, significant exposures exist in the occupational field.  
In the past, chromium-ore mining generated chromium-containing 
dusts, levels of which ranged up to 20 mg/m3 in different work-
places.  Other exposures ranged up to 150 mg/m3 and consisted of 
dust containing as much as 48% chromium (Cr2O3).  In production 
plants, hexavalent chromium can occur in the airborne state.  
However, implementation of protective measures at ferrochromium 
production sites reduced the airborne hexavalent chromium to levels 
of 30 - 60 g/m3. 

    The health effects of the two common oxidation states of 
chromium are so fundamentally different that they must be 
considered separately.  In the form of trivalent compounds, 
chromium is an essential nutrient and is relatively non-toxic for 
man and other mammalian species.  The hexavalent form is man-made 
by oxidation of naturally-occurring trivalent chromium minerals and 
is widely used.  Compounds of hexavalent chromium penetrate 
biological membranes easily and can thus interact with essential 
constituents of the cells, including genetic material which they 
can damage through oxidation and complexation with resulting 
trivalent species.  On the other hand, oxidation of trivalent 
chromium has not been demonstrated in the living organism, and for 
practical purposes, the reduction of hexavalent chromium to 
trivalent chromium in lungs and other animal tissues is 
irreversible. 

9.1.  Occupational Exposure

    A number of effects can result from occupational exposure to 
airborne chromium including irritative lesions of the skin and 
upper respiratory tract, allergic reactions, and cancers of the 
respiratory tract.  The data on other effects, e.g., in the 
gastrointestinal, cardiovascular, and urogenital systems are 
insufficient for evaluation. 

    Epidemiological studies have shown that workers engaged in the 
production of chromate salts and chromate pigments experience an 
increased risk of developing bronchial carcinoma.  No detailed data 
on dose-response relationships are available from epidemiological 
studies.  Although a suspicion of increased lung cancer risks in 
chromium plating workers has been raised, the available data are 
inconclusive as are data for other industrial processes where 
exposure to chromium occurs.  There is insufficient evidence on the 
role of chromium as a cause of cancer in any organ other than the 
lung.  Evidence from studies on laboratory animals shows that 
hexavalent chromium compounds, especially those of low solubility, 
can induce lung cancer. 

    In the lymphocytes of workers in chromium-plating factories, 
the frequency of sister chromatid exchanges was higher in exposed 
than in control groups. 

    Mutagenicity and related studies have convincingly shown that 
hexavalent chromium is genetically active.  Hexavalent chromium can 
cross cellular membranes and is then reduced to trivalent chromium, 
which can cause DNA cross-links and increase the infertility of DNA 
implication.  Trivalent chromium compounds have been shown to be 
genetically inactive in most test systems, except in systems where 
they can directly interact with DNA. 

9.1.1.  Effects other than cancer

9.1.1.1.  Respiratory tract

    It has been reported that the threshold for acute irritative 
effects in the upper respiratory tract is 25 g/m3 for the most 
sensitive individuals.  Long-term exposure to doses over 1 g 
chromic acid/m3 can cause nasal irritation, atrophy of the nasal 
mucosa, and ulceration of perforation of the nasal septum. 

    Bronchial asthma was previously attributed to exposure to 
chromium compounds, but scientific data are too scarce to draw 
conclusions. 

9.1.1.2.  Skin

    Skin rashes, ulcers, sores, and eczema have been reported among 
occupationally exposed workers.  Both trivalent and hexavalent 
chromium compounds can give rise to sensitization of skin, 
especially under certain environmental conditions, such as those 
encountered in the cement industry, where the high incidence of 
chromium-induced skin lesions can be attributed to the alkaline 
exposure conditions. 

    Eczematous dermatitis, which manifests first as a diffuse
erythematous type, progresses in severe cases to an exudative
stage and is associated in 8 - 15% of patients with sensitivity to 
chromium, as revealed by skin-patch tests.  Although opinion is 
divided on the oxidation state of chromium responsible for inducing 
sensitization, there is evidence of hexavalent chromium penetrating 

the skin as a hapten to be reduced to the trivalent state and 
conjugated with proteins and transformed into the full antigen 
that initiates the sensitization reaction, involving presumably 
only a cell-mediated immune response. It should be noted that 
patients suffering from chromium-induced skin allergy tend to 
become hypersensitive to cobalt and nickel.  Furthermore, 48% of 
cases of skin allergy induced by chromium, with or without 
clinically observed light sensitivity, showed a significantly more 
intense reaction by a standardized photopatch test procedure, when 
they were exposed to a 4/5 minimal erythema dose of irradiation. 

9.1.1.3.  Kidney

    After high-dose, short-term oral ingestion of chromium, acute 
nephritis and tubular necrosis were observed.  A few 
epidemiological studies on workers in chrome-plating industries 
include data on diseases of the kidney, most of them without giving 
exact exposure levels.  A recent study related increased urinary-beta2 
microglobulin levels to exposure ranges between 2 and 20 g/m3. 
The dose-response relationship observed in this study needs 
confirmation on a larger number of exposed workers. 

9.1.1.4  Other organs and systems

    There are no conclusive data to evaluate the effects of 
chromium compounds on the liver or gastrointestinal and circulatory 
systems. 

9.1.2.  Teratogenicity

    Both oxidation states, when injected at high levels 
parenterally into animals, are teratogenic, with the hexavalent 
form accumulating in the embryos to much higher concentrations than 
the trivalent.  The Task Group was not aware of any report 
indicating teratogenicity in human populations. 

9.2.  General Population

    Persons living in the vicinity of ferro-alloy plants, exposed 
to an ambient air concentration of up to 1 g/m3, did not show 
increased lung cancer mortality. 

    The results of many studies suggest that exposure to chromium 
through inhalation and skin contact can pose health problems for 
the general population.  Very little information is available on 
the health effects of chromium ingested through untreated drinking-
water, though, in a single study, a correlation was observed 
between frequency of malformation in the central nervous system and 
the chromium content of water samples (Morton & Elwood, 1974).  In 
order to assess the nature of the magnitude of these problems, 
there appears to be a need for more general population studies on 
the effects of inhaled, absorbed, or ingested chromium on 
respiratory, cardiovascular, and renal functions, and on the skin. 

    Studies on animals and man have established trivalent chromium 
as an essential micronutrient that interacts with insulin and 
enhances the physiological effects of the hormone. Supplementation 
trials in a number of countries including Finland, Jordan, Nigeria, 
Sweden, Turkey, and the USA have shown that segments of the 
population could improve their glucose metabolism and, in some 
instances, fat metabolism, by ingesting trivalent chromium 
compounds.  These observations suggest that some populations are at 
risk of chromium deficiency.  Children suffering from protein-
energy malnutrition may be at special risk. 

    As chromium concentrations in the body fluids of unexposed 
persons are generally less than 1 g/litre, analysis for chromium 
requires the strictest quality control, including measures to 
exclude sample contamination.  Even with adequate analytical 
methods, it is not possible, as yet, to diagnose chromium 
deficiency in individuals by chemical or biochemical methods alone.  
Therefore, a quantitative assessment of the prevalence of chromium 
deficiency in human populations is not yet possible. 

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1969).  For these reasons, chromium must be considered an essential 
micro-nutrient.  It is physiologically active in the trivalent 
oxidation state at concentrations of approximately 100 g/kg diet. 

7.1.1.  Effects of deficiency on glucose metabolism

    Semipurified rations, containing Torula yeast as the source of 
protein, were fed to groups of 10 male Sprague Dawley rats at 
weaning, and intravenous glucose tolerance tests were performed by 
injecting 1250 mg glucose/kg body weight and measuring the 
subsequent decline in blood-glucose levels.  The rate of glucose 
disappearance can be calculated from the straight line plot of log 
increment glucose (excess of glucose at any time (t) over fasting 
glucose), versus time.  The disappearance constant k is expressed 
as % decline of the increment glucose per min; it is a measure of 
the efficiency of glucose utilization.  In weaning rats, the rate 
constant was found to decline, within 3 weeks or less, from an 
average of 4%/min to 2.6%/min in animals fed the Torula yeast diet, 
but not in animals administered a diet in which 4 or 8% of Torula 
yeast was replaced by an equal amount of brewer's yeast.  This 
observation suggested that brewer's yeast, but not Torula yeast, 
contained an unknown substance necessary for the maintenance of 
normal glucose tolerance.  Because the only known effect of the 
substance was that on glucose tolerance, it was named "Glucose 
Tolerance Factor" (GTF) (Mertz & Schwarz, 1959).  GTF was extracted 
from brewer's yeast and pork kidney powder, concentrated and 
purified, and its active ingredient was identified as trivalent 
chromium (Schwarz & Mertz, 1959).  Chromium in the form of most 
common complexes (except for very stable ones) cured the impairment 
of glucose tolerance in deficient rats, either as one oral dose of 
200 g/kg body weight, or as an intravenous (iv) injection of 2.5 
g/kg body weight.  Chromium in the diet also prevented the 
impairment of glucose tolerance. 

    In order to produce more pronounced deficiencies of chromium 
and other trace elements, Schroeder et al. (1963) constructed a 
special animal house on a mountain top in Vermont, USA, far removed 
from traffic and industry.  The interior was specially coated with 
organic resins to reduce any metallic exposure.  Air was introduced 
through special filters, and strict practices were enforced to 
avoid the introduction of dust and dirt.  This will be referred to 
as the "controlled environment".  Under these conditions, a more 

severe chromium deficiency resulted in very low glucose removal 
rates of 1.12%/min in 6 rats and of 0.18%/min in 4 female breeder 
rats (482 days old), after 11 days on a chromium-deficient diet.  
The removal rate in 4 control rats receiving the same diet with a 
chromium supplement improved from 0.51 to 1.39% during the same 
period (Mertz et al., 1965b).  This strong impairment of glucose 
tolerance in rats kept in the "controlled environment" was 
reflected in their fasting blood-glucose levels, compared with 
those of chromium-supplemented controls: 1370  68 versus 1170  17 
mg/litre in males and 1390  68 versus 960  65 mg/litre in 
females.  More than half of 185 deficient rats excreted more than 
0.25% glucose in the urine, whereas glycosuria was found in only 9 
of the chromium-supplemented controls (Schroeder, 1966).  A 
significant reduction in the intravenous glucose removal rate was 
also observed in 8 rats in plastic cages, fed an EDTA-washed low-
protein diet (7% casein), compared with 8 controls receiving 50 g 
chromium as the chloride, by stomach tube, daily for 2 weeks (2.1 
versus 3.6%/min;  P < 0.01).  However, chromium supplements did not 
improve the near-normal removal rates in rats receiving a 20% 
casein diet (Mickail et al., 1976).  Significantly lower plasma-
glucose levels, due to supplementation with chromium, were reported 
in rats fed the chromium-deficient Torula yeast diet (Whanger & 
Weswig, 1975).  In another series of studies, only a slight 
reduction in blood-glucose (from 1240 to 1180 g/litre) was found 
in 10 rats receiving a diet supplemented with chromium (10 g/kg) 
(Djahanshiri, 1976). 

    Impaired glucose tolerance in squirrel monkeys, fed a 
commercial laboratory chow, was shown to respond to chromium 
supplementation.  Of 9 monkeys with an impaired glucose removal 
rate (1.38%/min), 8 responded after 22 weeks of supplementation of 
their drinking-water (chromium acetate, 10 mg/litre) with a 
normalization of their glucose tolerance (average removal rate, N = 
9, 2.33  0.3%/min) (Davidson & Blackwell, 1968).  There was no 
effect on food consumption, growth rate, or serum-insulin 
concentrations.  The chromium content of the commercial chow was 
stated to be 3.3 mg/kg, a very high concentration.  In view of the 
uncertainties of methods of analysis for chromium (section 2.2), it 
is not possible to interpret the results as indicative of a very 
high chromium requirement of the squirrel monkey or of an unusually 
poor bioavailability of the chromium in that particular ration.  A 
marginal chromium deficiency may have existed in mice fed a bread 
and milk diet, as daily administration of 10 g chromium for 16 
days to 8 months produced a 10 - 30% decline in blood-glucose 
levels (Vakhrusheva, 1960).  However, this effect was not specific 
for chromium, as it was also observed when manganese was 
administered. 

    The glucose tolerance of guinea-pigs did not differ 
significantly between groups fed diets containing chromium at 
0.125, 0.625, or 50 mg/kg, even though the animals fed the 2 higher 
levels exhibited a lower mortality rate during pregnancy (Preston 
et al., 1976). 

    Although the administration of synthetic glucose tolerance 
factor (a chromium-dinicotinic acid-glutathione complex) to 6 pigs 
did not affect glucose tolerance tests, it resulted in a 
significant increase in the hypoglycaemic effect of insulin 
injected at 0.1 U/kg body weight (Steele et al., 1977a). 

    Turkey poults, fed a practical ration containing chromium 
levels of 5 mg/kg, responded to chromium supplementation (20 mg/kg 
diet) with a significant increase in liver glycogen and in glycogen 
formation, following a fast, and with a significant increase in 
glycogen synthetase (EC 2.4.1.11) activity in the liver (Rosebrough 
& Steele, 1981). 

    It can be concluded that the impairment of glucose tolerance in 
rats fed a low-chromium Torula yeast diet is due to chromium 
deficiency.  The effects of chromium in squirrel monkeys, pigs, and 
turkeys, though statistically significant, are somewhat difficult 
to interpret, because of the reported high chromium content of the 
basal diet.  No evidence for chromium deficiency has yet been 
obtained through glucose tolerance tests on other animal species. 

7.1.2.  Effects of deficiency on lipid metabolism

    Though trivalent chromium in high doses (2.5 mg/kg body weight) 
has been shown to increase the synthesis of fatty acids and 
cholesterol in the liver (Curran, 1954), lower, physiological doses 
appear to decrease serum-cholesterol concentrations in rats.  
Schroeder & Balassa (1965) found an average level of 927 mg 
cholesterol/litre serum in 24- to 26-month-old male rats, kept in a 
controlled environment and administered chromium in the drinking-
water at a concentration of 5 mg/litre, compared with an average of 
1229 mg/litre in controls not receiving chromium ( P < 0.01).  The 
effects in female rats were ambigous, one study producing the 
expected reduction in cholesterol due to chromium, another showing 
an elevation in the supplemented female rats.  Schroeder's 
observations of a cholesterol-reducing effect of chromium in male 
rats were confirmed by Staub et al. (1969) and by Whanger & Weswig 
(1975) but were contradicted by results of a third study in which 
there were not any significant effects of chromium on sucrose-
induced triglyceridaemia and cholesterolaemia (Bruckdorfer et al., 
1971).  Perhaps more significant than the effect on circulating 
cholesterol is the direct effect of chromium on the occurrence of 
aortic plaques. Schroeder & Balassa (1965) observed 6 plaques in 54 
male and female chromium-deficient rats, but only one plaque in 48 
animals receiving 5 mg chromium/litre in drinking-water. These 
results are in agreement with those from a subsequent report of the 
protective effect of the natural chromium content of water (60 - 
215 g/litre) against atherosclerosis in cholesterol-fed rabbits 
(Novakova et al., 1974).  Abraham et al. (1980) extended these 
observations by demonstrating that daily chromium injections (20 g 
K2CrO4) reversed the established atherosclerosis in the aorta of 11 
cholesterol-fed rabbits, compared with 12 controls.  The mean 
plaque area was reduced from 95% to 63%, the total aortic 
cholesterol from 729 mg to 458 mg, and the atheromatous lesions, as 

measured by technetium incorporation from 285 000 cpm to 114 000 
cpm, all differences being statistically significant.  These 
results are reinforced by observations in man discussed in section 
8.1. 

7.1.3.  Effects of deficiency on life span, growth, and 
reproduction

    The mortality of male, but not of female mice, raised in a 
"controlled environment" (section 7.1.1) was reduced by trivalent 
chromium administered as acetate in the drinking-water at a 
concentration of 5 mg/litre (Schroeder et al., 1964).  The survival 
rates at 12 months were 92.6% and 68.8% ( P < 0.0001) in 
supplemented and deficient animals, respectively.  Similary, male, 
but not female, rats receiving a chromium concentration of 5 
mg/litre in the drinking-water had longer life spans than deficient 
controls.  The mean age of the last surviving 10% of animals was 
1249 days, compared with 1141 days in the deficient animals ( P < 
0.01). Survival of male rats fed a low-chromium (< 100 g/kg), 
low-protein ration and subjected to a controlled acute haemorrhage 
was significantly less than that of chromium-supplemented rats, in 
2 studies (67 versus 92%;  P < 0.05 and 27 versus 60%;  P < 0.01, 
respectively) (Mertz & Roginski, 1969). 

    In Schroeder's study, growth rates in treated mice and rats of 
both sexes raised in a "controlled environment", were higher after 
6 and 12 months, with highly significant differences in body weight 
ranging from 9 to 17% ( P < 0.005) compared with the controls.  
Again, the effects of chromium supplementation were greater in 
males than in females (Schroeder et al., 1964, 1965). 

    Similar results were reported by Djahanschiri (1976), who 
studied a total of 2750 rats of a special inbred strain (Hk51) fed 
a basal diet (0.15 mg chromium/kg diet) and chromium supplements 
ranging from 10 to 500 mg/kg diet.  At 12 weeks, the average 
weights of the chromium-supplemented animals, regardless of dose 
level, were significantly higher (by 6% in the males and 3% in the 
females) than those of the animals on the basal diet.  The same 
author reported a progressive diminution in both the milk 
production of lactating rats and weight gain in 3 consecutive 
generations fed the low-chromium diet, compared with rats receiving 
chromium supplementation. Increased mortality was reported in 
pregnant guinea-pigs fed a low-chromium diet (125 g/kg diet) 
compared with animals receiving a chromium supplement of either 625 
g/kg or 50 mg/kg (Preston et al., 1976). 

    When rats raised on a low-chromium Torula yeast diet (< 100 
g/kg) mated with those on a normal diet, they were able to 
impregnate the females at a 100% conception rate only up to the age 
of 4 months.  After this age, the conception rate declined to 25%, 
25%, and 0%, at the age of 7, 8, and 9 months, respectively.  This 
decline was accompanied by a significant ( P < 0.01) decrease in 
the sperm count in the chromium-deficient males to approximately 
half of the count in supplemented controls at the age of 8 months 
(Anderson & Polansky, 1981). 

7.1.4.  Other effects of deficiency

    Male weanling rats, fed a 10% soya protein ration with a 
chromium content of less than 100 g/kg, developed a visible 
opacity of the cornea in one or both eyes. In several studies, the 
incidence of this effect ranged from 10 to 15% in deficient rats.  
No opacities developed in control animals receiving 2 mg 
chromium/kg diet (Roginski & Mertz, 1967). 

    Chromium deficiency has been shown to reduce the physical 
performance of rats under stress.  Ten male rats raised on a 
chromium-deficient diet (150 g/kg diet) swam for an average of 250 
min, until exhaustion, in contrast with 10 rats receiving a 
supplement of 10 mg chromium/kg diet, which were exhausted only 
after 320 min (Djahanschiri, 1976). 

7.1.5.  Mechanism of action of chromium as an essential nutrient

7.1.5.1.  Enzymes, nucleic acids, and thyroid

    Chromium is present in nucleic acids in very high 
concentrations, but the function of these is not clear at present 
(Mertz, 1969).  However, recent work suggests a biological function 
of chromium in nucleic acid metabolism (Okada et al., 1984).  
Ribonucleic acid synthesis in mouse liver was significantly 
increased by as little as 1 mol trivalent chromium, in the 
presence of DNA or chromatin (Okada et al., 1981).  These effects 
were also present when the DNA or chromatin were first complexed 
with chromium prior to incubation.  However, prior complexation of 
RNA polymerase with chromium depressed activity.  These effects 
were obtained  in vitro with a concentration (52 g/litre) that is 
similar to physiological levels.  Goncharov (1968) presented data 
suggesting that chromium is involved in the function of the thyroid 
gland.  These findings have been supported by Lifschitz et al. 
(1980). 

    An oligopeptide with a relative molecular mass of 1480, which 
was crystallized from liver tissue, had a specific affinity for 
chromium (Wu, 1981). 

7.1.5.2.  Interaction of chromium with insulin

    The interaction of chromium with insulin has been extensively 
studied and can therefore be presented in some detail, but this 
does not imply that this is the only, or the most important, 
function of chromium. 

    The effects of chromium  in vitro, and probably  in vivo, depend 
on the presence of endogenous or exogenous insulin, no effects 
having been demonstrated in  in vitro systems that did not either 
depend on, or contain, insulin. Chromium deficiency causes an 
impaired response to added insulin in rat epididymal fat tissue, 
and, when glucose uptake or glucose oxidation or utilization for 
lipid synthesis is measured, the dose-effect curve is flat.  
Addition of suitable chromium compounds significantly increases the 

slope of the curve (Fig. 3).  This demonstrates the true 
potentiation of the insulin action and indicates that chromium 
alone does not act as an insulin-like substance (Mertz et al., 
1961; Mertz & Roginski, 1971; Mertz, 1981).  Chromium was also 
shown to stimulate the transport of D-galactose into epididymal fat 
cells.  This suggests cell transport, the first step of sugar 
metabolism, as a major site of action for chromium (Mertz & 
Roginski, 1963).  Insulin-potentiating effects have also been 
observed on the swelling of liver mitochondria (Campbell & Mertz, 
1963) and on glucose utilization in isolated rat lens (Farkas & 
Roberson, 1965). 

Fig. 3

    Stimulation of the effects of insulin has been observed in a 
glucose-independent, but insulin-responsive, system.  Significantly 
more alpha-amino isobutyric acid (a non-metabolizable amino acid 
analogue) was incorporated into the heart and liver tissue of 
chromium-supplemented male rats than in the tissues of chromium-
deficient controls, in response to the  in vivo injection of the 
labelled analogue and insulin (Roginski & Mertz, 1969). 

    These observations suggest a peripheral action of chromium to 
facilitate the action of insulin; no evidence has been produced 
indicating that chromium plays any role in the production, storage, 
or release of insulin by the pancreas. Thus, the primary result of 
chromium deficiency is a diminution in the effectiveness of 
insulin.  The resulting metabolic impairment may be compensated for 
by increased insulin production in some cases, resulting in 
elevated concentrations of the hormone, but not enough data exist 
from experimental animal studies to assess the action of the 
element on insulin metabolism.  More information is available for 
human subjects and this is discussed in section 8.1.  The 
interaction between chromium, insulin, and receptor sites of liver 
mitochondrial membranes was studied using polarographic techniques.  
The results formed the basis for the hypothesis that chromium may 
facilitate bond formation between the intra-chain disulfide of 
insulin and sulfur-containing groups of the receptors, by 
participating in a ternary complex (Christian et al., 1963). 

    This hypothesis is consistent with results of studies on rats 
fed, either a low-chromium Torula yeast diet or a brewer's yeast 
diet known to be adequate in chromium.  While the insulin-binding 
capacity of hepatocytes was not significantly different, the 
insulin affinity of the cells was significantly greater ( P < 0.01) 
for the chromium-adequate rats than for the deficient Torula yeast 
rats (Steele et al., 1977b). 

7.1.6.  Chromium nutritional requirements of animals

    In the preceding sections, studies were evaluated in which the 
effects of chromium supplementation were determined in animals that 
were at least marginally chromium deficient.  In other studies, the 
effects of chromium were investigated in animal systems in which 
the existence of chromium deficiency was either not ascertained or 

not investigated.  Before these studies are described and 
interpreted for the determination of chromium nutritional 
requirements of animals, it is helpful to consider them against the 
background of Venchikov's (1974) model.  This model is generally 
applicable to trace element effects defining 3 zones of action, the 
zone of biological action, that of pharmacodynamic action, and that 
of toxicity (Fig. 4).  The biological zone, in response to 
supplements with low amounts of an element, represents the 
correction of a deficiency and the resulting level of biological 
activity is that of optimal function.  Increasing the amount of 
supplement further may lead to a certain depression, followed by a 
zone of new, increased activity, in which the element no longer 
acts as an essential nutrient, but as a drug.  Still greater 
supplements, beyond the homeostatic control capability of the 
organism produce toxic effects and death.  Because all the studies 
described subsequently involved amounts of chromium supplements 
that were higher than the levels normally needed to correct a 
deficiency, it is possible, according to Venchikov's definition, 
that the observed effects might be pharmacological. 

Fig. 4

    Tuman & Doisy (1977) studied the effects of yeast concentrates 
of high chromium (glucose tolerance factor) content and of 
synthetic chromium complexes with GTF activity (Tuman et al., 1978) 
in mice, raised on a presumably complete commercial stock diet.  
Six animals were used for each test, either genetically diabetic 
mice or their control litter mates of the C57Bl-KSI strain.  
Injections of either 5 mg of the GTF-containing yeast extracts or 
0.1 mg of the synthetic chromium complex, acutely reduced the 
elevated plasma-glucose levels in the diabetic and the non-fasting 
normal mice by 10 - 38% of the initial values ( P < 0.01) and the 
plasma-triglycerides by 26 - 56% ( P < 0.01), compared with control 
mice injected with saline.  Injection of insulin into diabetic mice 
produced only an 11 - 18% decrease in plasma-glucose levels, 
whereas injection of the GTF-containing extract together with 
insulin reduced plasma-glucose levels by 39 - 51% and plasma-
triglyceride levels by 76% (Table 11). 

    The results suggest either a much higher increase in the 
chromium requirement of the genetically diabetic mice or their 
inability to use chromium in the diet. 

Table 11.  Acute effects of GTF and exogenous insulin on non-
fasting plasma-glucose and plasma-triglyceride (TG) concentrations 
in 19-week-old genetically diabetic micea
------------------------------------------------------------------
Treatment  Plasma-      deltaGlucose   Plasma-         deltaTG
           glucoseb                    triglyceridesb
           (mg/litre)                  (mg/litre)
------------------------------------------------------------------
saline     11 120                     3960  160(5)c
           490(5)c

GTF        9320        -180 (16%)     2790  170(5)d  -117 (30%)
           280(5)d

insulin    9840        -128 (12%)     3020  400(5)   - 94 (24%)
           410(5)

insulin    7060        -406 (37%)     940  220(5)e   -302 (76%)
and GTF    840(5)e
------------------------------------------------------------------
a   Modified from: Tuman & Doisy (1977).
b   Glucose and triglyceride values represent mean  SEM for 6 mice in
    each treatment group. Dose of GTF was 5 mg (WL-10-AT) administered
    intraperitoneally, 12 h prior to collection of blood. Lente insulin
    (0.1 U per mouse) was administered subcutaneously, 12 h prior to
    collection of blood. Data were treated by analysis of variance to
    detect differences between the various treatment groups; independent
    orthogonal comparisons were performed in the following groups ( P value
    indicates level of significance for each comparison).
c   Saline versus all other treatments,  P < 0.005.
d   GTF versus insulin,  P < 0.05.
e   GTF and insulin alone versus combined GTF and insulin,  P < 0.005.
    Thus, GTF and insulin > GTF = insulin > saline.

    Steele & Rosebrough (1979) reported a significant stimulation 
of the growth rate of one-week-old turkey poults (both sexes) by 
supplementation of a practical ration with 20 mg chromium (as 
chloride)/kg.  The weight gains within the 2-week study were 235 g 
and 267 g for the 60 controls and 60 supplemented turkeys, 
respectively ( P < 0.001).  As the practical ration contained 
ground yellow corn and soybean meal, limestone, and dicalcium 
phosphate, chromium deficiency would appear unlikely.  The amount 
of the chromium supplement (20 mg/kg diet) is quite high, and 
further studies are needed to decide whether the observed effects 
were of a pharmaco-dynamic nature or truly nutritional, i.e., 
correcting a deficiency.  A similar interpretation should be 
applied to a report of improved egg quality in the laying hen 
(Jensen et al., 1978). 

    The quantitative aspects of the effects of chromium on animals 
can be summarized as follows: normal rats fed semi-purified, semi-
synthetic rations, with Torula yeast or individual proteins and 
sucrose or starch as the source of carbohydrates, develop mild 
signs of deficiency at a dietary level of 100 - 150 g chromium/kg.  
To prevent deficiency, most authors used very high supplements of 

several mg/kg diet and did not determine the biological 
availability of the chromium complexes used for the 
supplementation.  Diets containing raw ingredients and supplying 
chromium levels between 0.5 and 1 mg/kg do not induce signs of 
deficiency and probably meet the requirement of the rat.  A very 
tentative estimate of the dietary chromium need of the rat and 
probably the mouse would be approximately 0.5 mg/kg diet.  This 
estimate should be interpreted with caution, because of the lack of 
knowledge concerning the biological availability of chromium and of 
its interaction with dietary constituents. 

7.2.  Toxicity Studies

    The toxicology of chromium compounds has been reviewed by the 
US National Academy of Science (US NAS, 1974a), Langard & Norseth 
(1979), the International Agency for Research on Cancer (IARC, 
1980), Langard (1980a, 1982), and Burrows (1983). 

    In discussing toxicological problems, it is important to 
differentiate between the various oxidation states of chromium and 
its compounds.  Trivalent chromium, when administered to animals in 
food or water, does not appear to induce any harmful effects, even 
when given in large doses (US NAS, 1974a) (section 7.2.1).  Acute 
and chronic toxic effects of chromium are mainly caused by 
hexavalent compounds.  Since it has been shown that both industrial 
trivalent chromium compounds as well as reagent-grade trivalent 
chromium compounds can be contaminated by hexavalent chromium 
(Petrilli & DeFlora, 1978a; Levis & Majone, 1979), the evaluation 
of experimental studies becomes difficult, especially when the 
purity of the chemical compounds used is not known. 

    Discrimination between the biological effects, caused by 
hexavalent chromium and trivalent chromium is difficult, because, 
after penetration of membranes in tissues, hexavalent chromium is 
immediately reduced to trivalent chromium (Gray & Sterling, 1950; 
US NAS, 1974a), and it is not evident whether the observed 
phenomena are caused by this reduction or even by the trapping of 
trivalent chromium by ligands after uptake in the cells.  Another 
problem in evaluating the data is associated with the route of 
administration.  Hexavalent chromium, introduced by the oral route, 
is partly reduced to trivalent chromium by acidic gastric juice 
(Donaldson & Barreras, 1966; DeFlora & Boido, 1980); thus, the 
effects or lack of effects observed may be caused mainly by 
trivalent chromium and not by the hexavalent chromium, actually 
administered. 

7.2.1.  Effects on experimental animals

    Many local effects on human beings have been reported (section 
8.3), but only a few studies have verified these effects in 
experimental animals.  A comprehensive survey of hexavalent 
chromium-induced effects is given in Table 12 (US NAS, 1974a).  For 
most studies, details were not given of the length of exposure, 
number of treated animals and controls, etc.  Diagnoses were stated 
without presenting all the original data.  Thus, in this section, 

some papers will be discussed that refer to the most prominent 
local and systemic effects to support and clarify the effects shown 
in human beings. 

    It is evident that the toxicity of hexavalent chromium in 
animals varies with the route of entry into the body.  Low 
concentrations of hexavalent chromium may be tolerated, when 
administered in the feed or drinking-water, the extent of 
absorption being a factor of importance.  For example, rats 
tolerated hexavalent chromium in drinking-water at 25 mg/litre, for 
1 year, and dogs did not show any effects from chromium 
administered as potassium chromate at 0.45 - 11.2 mg/litre over a 
4-year period (US NAS, 1974a).  However, oral exposure of both male 
and female rabbits to sodium dichromate (0.1% solution, 0.2 - 5 
mg/kg body weight, for up to 545 days) resulted in significant 
morphological changes in the gonads, including atrophy of the 
epithelium and dystrophic alterations of the Sertoli and Leydig 
cells in the testes, and sclerotic and atrophic changes in ovaries 
(Kucher, 1966). 

    Larger doses of hexavalent chromium are highly toxic and may 
cause death, especially when injected iv, subcutaneously (sc), or 
intragastrically.  The LD50 of chromium compounds was determined 
for several experimental animal species.  The LD50 of potassium 
dichromate (hexavalent chromium), administered orally (stomach 
tube) to rats, was 177 mg/kg body weight in males and 149 mg/kg 
body weight in females (Hertel, 1982). When injected iv in mice 
(sex not given), the LD50 of chromium carbonyl was 30 mg/kg body 
weight (IARC, 1980). 

    Performing a life-time inhalation study on the rat, Glaser et 
al. (1984) found an LC50 for Na2Cr2O7 of 28.1 mg/m3 (range, 16.7 - 
47.3 mg/m3).  Assuming a deposition rate in the lung of 30% of the 
dose administered, the LC50 dose was 1 mg/kg body weight in male 
and 1.2 mg/kg in female rats. 

    A local corrosive action of hexavalent chromium on the skin, 
similar to that seen in man, was described by Samitz & Epstein 
(1962), who induced chrome ulcers in guinea-pigs at 4 trauma sites, 
with daily exposure to 0.34 MK2Cr2O7 solution for 3 days.  Mosinger 
& Fiorentini (1954) showed the same effects using potassium 
chromates. 


Table 12.  Effects of hexavalent chromium in animalsa
---------------------------------------------------------------------------------------------------------
Animal    Route       Compound(s)     Average dose      Duration       Effect            Reference
                                      or concentration
---------------------------------------------------------------------------------------------------------
Rabbit,   inhalation  chromates       1 - 50 mg/m3      14 h/day for   pathological      Lukanin (1930)
cat                                                     1 - 8 months   changes     
                                                                       in the lungs

Rabbit    inhalation  dichromates     11 - 23 mg/m3     2 - 3 h/day    none              Lehmann (1914)
                      as dichromate                     for 5 days

Cat       inhalation  dichromates     11 - 23 mg/m3     2 - 3 h/day    bronchitis,       Lehmann (1914)
                      as dichromate                     for 5 days     pneumonia           
                                                                       perforation of
                                                                       nasal septum  

Mouse     inhalation  mixed dust      1.5 mg/m3         4 h/day,       no tumours        Baetjer et al.
                      containing      as CrO3           5 days/week,                     (1959a);
                      chromates                         for 1 year                       Steffee &
                                                                                         Baetjer (1965)

Mouse     inhalation  mixed dust      16 - 27 mg/m3     1/2 h/day      tumours in        Baetjer et al.
                      containing      as CrO3           intermit-      some strains      (1959a);
                      chromates                         tently                           Steffee &
                                                                                         Baetjer (1965)

Mouse     inhalation  mixed dust      7 mg/m3           37 h over      increased         Baetjer et al.
                      containing      as CrO3           10 days        tumour rate       (1959a);
                      chromates                                                          Steffee &
                                                                                         Baetjer (1965)

Rat       inhalation  mixed dust      7 mg/m3           37 h over      barely            Baetjer et al.
                      containing      as CrO3           10 days        toleratedb        (1959a);
                      chromates                                                          Steffee &
                                                                                         Baetjer (1965)

Rabbit,   inhalation  mixed dust      5 mg/m3           4 h/day,       none marked       Baetjer et al.
guinea-               containing      as CrO3           5 days/week,                     (1959a);
pig                   chromates                         for 1 year                       Steffee &
                                                                                         Baetjer (1965)
---------------------------------------------------------------------------------------------------------

Table 12.  (contd.)
---------------------------------------------------------------------------------------------------------
Animal    Route       Compound(s)     Average dose      Duration       Effect            Reference
                                      or concentration
---------------------------------------------------------------------------------------------------------
Rat,      inhalation  hexacarbonyl    1.6 mg/m3         4 months,      anaemia; lipid    Roschina (1976)
rabbit                                                  4 h, 5 days    and/or protein      
                                                        a week         dystrophia  
                                                                       in liver          
                                                                       and kidneys       

Rat,      inhalation  hexacarbonyl    0.16 mg/m3        4 months,      anaemia; no       Roschina (1976)
rabbit                                                  4 h, 5 days    biochemical             
                                                        a week         or morphological
                                                                       effects         
                                                                                       
Rat       inhalation  hexacarbonyl    35 mg/m3          30 min         100% death        Roschina (1976)

Rat       inhalation  dichromates     0.006 - 0.2       28 days/       increase in       Glaser et al.
                                      mg/m3             90 days        lung-macrophages  (1985)
                                                        23 h/day                  
                                                        7 days/week    lymphocytes
                                                                       immunoglobulin,
                                                                       reduced Fe2O3
                                                                       lung clearance

Rat       intratra-   dichromates     5 per week        up to 30       toleratedc        Steinhoff
          cheal in-                   0.01 - 0.25       months                           et al. (1983)
          stillation                  mg/kg

Rat       intratra-   dichromates     1 per week        up to 30       tolerated;        Steinhoff
          cheal in-                   0.05 - 1.25       months         1.25 mg/kg        et al. (1983)
          stillation                  mg/kg                            harmful

Rat       oral        potassium       500 mg/litre      daily          maximal           Gross & Heller
                      chromate in                                      non-toxic         (1946)
                      drinking-water                                   concentration

Rat,      oral        zinc chromate   10 g/kg           daily          maximal           Gross & Heller
mouse                 in feed                                          non-toxic         (1946)
(mature)                                                               concentration
---------------------------------------------------------------------------------------------------------

Table 12.  (contd.)
---------------------------------------------------------------------------------------------------------
Animal    Route       Compound(s)     Average dose      Duration       Effect            Reference
                                      or concentration
---------------------------------------------------------------------------------------------------------

Rabbit    oral        sodium di-      0.2 - 5.0 mg/kg   545 days       morphological     Kucher (1966)
                      chromate                                         changes in               
                                                                       gonads (testes:          
                                                                       atrophy of               
                                                                       epithelium,              
                                                                       dystrophic               
                                                                       alterations of           
                                                                       Sertoli &                
                                                                       Leydiz alls.             
                                                                       Ovaries:                 
                                                                       sclerotic and            
                                                                       atrophic   
                                                                       changes)                 
                                                                       
Rat       oral        zinc chromate   1.2 g/kg          daily          maximal           Gross & Heller
(young)               in feed                                          non-toxic         (1946)
                                                                       concentration

Rat       oral        potassium       1.2 g/kg          daily          maximal           Gross & Heller
(young)               chromate                                         non-toxic         (1946)
                      in feed                                          concentration

Dog,      oral        monochromate    1.9 - 5.5 mg      29 - 685       none harmful      Lehmann (1914)
cat,                  or dichromates  chromium/kg       days
rabbit                                body weight per
                                      day 1 mg chrom-
                                      ium equivalent
                                      to 2.83 mg
                                      K2Cr2O7
                                      or 3.8 mg
                                      K2CrO4
---------------------------------------------------------------------------------------------------------

Table 12.  (contd.)
---------------------------------------------------------------------------------------------------------
Animal    Route       Compound(s)     Average dose      Duration       Effect            Reference
                                      or concentration
---------------------------------------------------------------------------------------------------------
Dog       oral        potassium       1 - 2 g as        daily          fatal in 3        Brard (1935)
                      dichromate      chromium                         months anaemia

Dog       stomach     potassium       1 - 10 g as       -              rapidly fatald    Brard (1935)
          tube        dichromate      chromium

Monkey    subcutan-   potassium       0.02 - 0.7 g in   -              fatald            Hunter & Roberts
          eous        dichromate      2% solution                                        (1933)

Dog       subcutan-   potassium       210 mg as         -              rapidly fatal     Brard (1935)
          eous        dichromate      chromium

Guinea-   subcutan-   potassium       10 mg             -              lethald           Ophls (1911a)
pig       eous        dichromate                                                         Ophls (1911b)

Rabbit    subcutan-   potassium       1.5 cc of 1%      -              80% fatald        Hasegawa (1938)
          eous        dichromate      solution/kg body
                                      weight

Rabbit    subcutan-   potassium       20 mg             -              lethald           Ohta (1940)
          eous        dichromate

Rabbit    subcutan-   potassium       0.5 - 1 cc of     -              nephritisd        Ohta (1940)
          eous        dichromate      0.5% solution/kg
                                      body weight

Rabbit,   subcutan-   sodium          0.1 - 0.3 g as    -              rapid deathd      Priestley
guinea-   eous or     chromate        CrO3                             fall in blood     (1877)
pig       intravenous                                                  pressure

Rabbit    intra-      potassium       0.7 cc of 2%      -              lethald           Mazgon (1932)
          venous                      solution/kg                      8-10 days after
                                      body weight                      injection

Dog       intra-      potassium       10 grains         -              instant death     Gmelin (1826)
          venous      chromate
---------------------------------------------------------------------------------------------------------

Table 12.  (contd.)
---------------------------------------------------------------------------------------------------------
Animal    Route       Compound(s)     Average dose      Duration       Effect            Reference
                                      or concentration
---------------------------------------------------------------------------------------------------------

Dog       intra-      potassium       1 grain           -              none marked       Gmelin (1826)
          venous      chromate

Dog       intra-      potassium       210 mg as         -              rapidly fatal     Brard (1935)
          venous      dichromate      chromium

Dog       intra-      potassium       3 mg/100 cc       2 doses        marked renal      Hepler & Simonds
          venous      dichromate      blood per dose                   damage            (1946); Simonds
                                                                                         & Hepler (1945)
---------------------------------------------------------------------------------------------------------
a  Modifed from: US NAS (1974a).
b  Pathological changes in experimental and control rats, 101 weeks after exposure.
c  The same weekly dose distributed over 5 days was clearly better tolerated than a single weekly 
   administration.
d  Renal damage.
    Following parenteral administration, the most common systemic 
effects of chromium were parenchymatous changes in the liver and 
kidney (Mosinger & Fiorentini, 1954).  Later studies showed 
selective damage in the renal proximal convoluted tubules, without 
evidence of glomerular damage, as demonstrated after one single sc 
injection of potassium dichromate of 10 mg/kg body weight (Schubert 
et al., 1970) or after one single intraperitoneal (ip) injection of 
sodium chromate of 10 or 20 mg/kg body weight (Evan & Dail, 1974). 
Effects have also been found in fish (Strik et al., 1975). After 32 
days of continuous exposure to 0.1, 1, or 10 mg hexavalent chromium 
(as potassium dichromate)/litre, the fish  Rutilus rutilus developed 
lysis of the intestinal epithelium with haemorrhages as well as 
hypertrophy and hyperplasia of the gill epithelium. 

    Franchini et al. (1978) found an increase in urinary protein, 
lysozyme, glucose, and beta-glucuronidase in rats after a single sc 
injection of potassium dichromate at 15 mg/kg body weight.  After 
sc injection (3 mg/kg body weight), every other day for 2 - 8 
weeks, the authors observed a correlation between the chromium 
contents of the renal cortex and chromium clearance. 

    Five-week-old male Wistar rats of the strain TNO-W-74 were 
continuously exposed in inhalation chambers to submicron aerosols 
of sodium dichromate at concentrations ranging from 25 (low level) 
to 200 g chromium/m3 (high level) (Glaser et al., 1985).  Exposure 
for 28 days to 25 or 50 g chromium/m3 resulted in "activated" 
alveolar macrophages with stimulated phagocytic activity, and 
significantly elevated antibody responses to injected sheep red 
blood cells.  After 90 days of low-level exposure, there was a more 
pronounced effect on the activation of the alveolar macrophages, 
with increased phagocytic activity. However, inhibited phagocytic 
function of the alveolar macrophages was seen at the high 
hexavalent chromium exposure level (200 g/m3).  In rats exposed to 
this chromium aerosol concentration for 42 days, the lung clearance 
of inert iron oxide was significantly reduced.  The humoral immune 
system was still stimulated at a low chromium aerosol concentration 
of 100 g/m3, but significantly depressed at 200 g chromium/m3. 

    Exposure of rats, through inhalation, to chromium carbide or 
chromium boride dust at very high levels (300 - 350 mg/m3 for each 
substance) for 3 months (2 h/day) resulted in effects on the 
vascular system of the lungs, e.g., endothelial hyperplasia.  
Bronchitis and a decrease in the blood-haemoglobin concentration 
were also observed (Roschina, 1964). The effects of chromium boride 
were more pronounced than those of chromium carbide. 

    Steinhoff et al. (1983) performed an intracheal injection study 
on rats (930 rats, 30 months, 0.05 - 1.25 mg Na2Cr2O7/kg body 
weight per week; 1.25 mg CaCrO4/kg body weight per week).  Half of 
the rats were intratracheally injected once a week and the other 
half received the same weekly dose distributed over 5 injections 
per week.  In rats receiving doses 5 times a week, there were some 
significant changes in levels of total plasma-protein and 
-cholesterol, in some haematological variables, in organ weights, 
and in survival times in females.  Only male rats receiving 1.25 mg 

sodium dichromate/kg body weight, once a week, showed a sharp 
reduction in body weight, female rats being less affected. Rats 
receiving calcium chromate in the same dose showed reduced body 
weight but to a lesser extent.  The weight of lung and trachea was 
increased by both substances in all doses. 

    Marked histopathological changes (congestion, fairly large 
areas of focal necrosis, bile duct proliferation) described after 
long-term exposure of rabbits to hexavalent chromium (ip injection 
of 2 mg chromium/kg body weight per day for 6 weeks) (Tandon et 
al., 1978), as well as the increase in hepatic metallothionein and 
decrease in cytochrome P-450 levels after ip injection of 400 mol 
chromium/kg per day (type of chromium compound not mentioned) 
(Eaton et al., 1980) need further confirmation.  The finding of an 
accumulation of hexavalent chromium in the reticuloendothelial 
system including bone marrow (Baetjer et al., 1959b; Langard, 1977) 
may be of importance for a disturbed blood picture. 

    Merkurieva et al. (1980a,b) studied the effects of potassium 
dichromate in the drinking-water on the activities of different 
enzymes in rats.  Exposure included daily doses of 0.0005, 0.005, 
0.05, or 0.5 mg/kg body weight for up to 6 months.  After 20 days 
of exposure at the highest dose level, enzyme activities increased 
by 15 - 28% in liver microsomes (inosine-5-diphosphatase), 
lysosomes (beta-D-galactosidase), and cytosol (lactate dehydrogenase 
(EC 1.1.1.27)).  For some of these enzymes, as well as for 
acetylesterase (EC 3.1.1.6), increases in activity of up to 54% 
were found in the gonads, kidneys, seminal fluid, and serum.  At a 
dose of 0.05 mg/kg, the only statistically significant finding was 
a 54% increase in the activity of acetylesterase in the gonads.  
After a 6-month exposure at this dose level, there was a 70% 
increase in lactate dehydrogenase activity in the seminal fluid as 
well as a 50% increase in free beta-galactosidase in the liver.  There 
were no changes in enzyme activities at the two lowest dose levels. 

    Painting of rat skin with an aqueous solution of potassium 
dichromate (0.5%), daily, for 20 days, resulted in a local 
inflammatory reaction, an increased level of hexose glyco-proteins 
in the skin and serum, and an elevated concentration of serotonin 
in the skin and liver (Merkurieva et al., 1982). Most of these 
effects were also seen earlier in the exposure period, though they 
were not as pronounced.  Ten days after the start of exposure, a 
nearly 3-fold increase in the serum-acetylcholine concentration 
occurred together with decreased acetylcholinesterase activity.  
Thus, the data of Merkurieva et al. show systemic effects following 
both oral and dermal exposure to hexavalent chromium. 

    Cats fed chromic phosphate or oxydicarbonate at 50 - 1000 mg/day 
for 80 days did not exhibit signs of illness or tissue damage.  
Similarly, toxic reactions were not observed in rats administered 
drinking-water containing 25 mg trivalent chromium/litre, for 1 
year, or 5 mg trivalent chromium/litre throughout their lifetime 
(US NAS, 1974a).  The toxicity of trivalent chromium is so low that 
even by parenteral administration, a chromic acetate level of 2.29 
g/kg body weight or a chromic chloride level of 0.8 g/kg body 

weight is required to kill mice.  Even very large doses given 
intragastrically were not fatal for dogs.  Brard (1935) reported 
that 10 or 15 g of chromium as chromic chloride proved fatal in one 
dog (US NAS, 1974a).  Some fatal doses of trivalent chromium 
compounds reported in the literature are listed in Table 13. 

    Rats exposed through inhalation to chromic oxide (trivalent 
chromium) at 42 mg/m3 or to chromic phosphate at 43 mg/m3 (5 h/day 
for 5 days/week) for 4 months developed chronic irritation of the 
bronchus and lung parenchyma, and dystrophic changes in the liver 
and kidney (Blokin & Trop, 1977). 

    Inhalation exposure of rats (number not given) to dusts 
containing 36 or 50% chromite for 4 months (2 h/day), at 
concentrations of 375 - 400 mg/m3, resulted in thickening of the 
walls of pulmonary vessels and bronchi (Roschina, 1959). The high 
exposure levels in these studies make it difficult to evaluate the 
effects. 

    Inhalation studies have also been performed with chromium 
carbonyl, where chromium is in the 0 oxidation state (Roschina, 
1976).  Twelve rabbits and 48 rats were exposed for 4 months (4 
h/day, 6 days/week) at a concentration of 1.6 or 0.16 mg/m3.  At 
both exposure levels, there was loss of body weight (25 and 12%, 
respectively) as well as anaemia and leukocytosis.  In the higher 
exposure group, the animals showed an elevated gamma-globulin level 
in serum and an increased transaminase activity.  The contents of 
cholesterol and SH-groups were reduced, and there was a decrease in 
cholinesterase (EC 3.1.1.7) activity.  Lipid and/or protein 
dystrophy were noted in several organs, e.g., in the liver and 
kidneys.  No such effects were detected in the animals in the low-
exposure group. 
Table 13.  Fatal doses of trivalent chromium in animalsa
---------------------------------------------------------------------------------------------
Animal  Number of  Routeb  Compound             Chromium       Effect  Reference
        animals            dose (g/kg)
---------------------------------------------------------------------------------------------
Dog     2          sc      chromic chloride     0.8            fatal   Brard (1935)
Rabbit  1          sc      chromic chloride     0.52           fatal   Brard (1935)
Rat     38         iv      chrome alum          0.01 - 0.018   LD50    Mertz et al.
                           chromium-hexaurea                           (1965a)
                           chloride
Mouse   -c         iv      chromic chloride     0.8            MLDd    Windholz et al. (1960)
Mouse   -c         iv      chromic acetate      2.29           MLD     Windholz et al. (1960)
Mouse   -c         iv      chromic chloride     0.4            MLD     Schroeder (1970)
Mouse   -c         iv      trivalent chromium ? 0.25 - 2.3     MLD     Windholz et al. (1960)
Mouse   -c         iv      chromic sulfate      0.247          MLD     Windholz et al. (1976)
Mouse   -c         iv      chromic sulfate      0.085          MLD     Schroeder (1970)
Mouse   -c         iv      chromium carbonyl    0.03           LD50    Schroeder (1970)
---------------------------------------------------------------------------------------------
a Modified from: US NAS (1974a).
b sc = subcutaneous; iv = intravenous.
c No figures given.
d Minimum lethal dose.
7.2.1.1.  Carcinogenicity

    Various types of chromium chemicals, methods of administration, 
and species of animals have been studied (IARC, 1980a). 

    Ideally, carcinogenicity should be tested with the methods 
recommended by IARC (1980b), but, in many of the early studies, 
this was not done.  Carcinomas of the lung have been reported in 
animals as a result of the administration of chromium chemicals.  
Hueper (1958) found 2 squamous cell carcinomas and one 
carcinosarcoma in 25 rats following intra-pleural injection of 
chromite ore roast.  After intrapleural implantation of strontium 
chromate lasting 27 months, Hueper (1961) found tumours (type 
unspecified) in 17/28 rats.  Laskin et al. (1970) and Levy & Venitt 
(1975) produced a number of bronchogenic carcinomas by implanting 
pellets of cholesterol mixed with various chromium compounds 
encased in a wire mesh cage in the bronchi of rats.  Calcium and 
zinc potassium chromate produced a number of bronchogenic 
carcinomas, but soluble chromates and trivalent chromium chemicals 
failed to produce cancer. 

    Using the same technique, Levy & Martin (1983) tested 21
different chromium-containing materials (pigments, intermediates, 
and residues from the bichromate-producing industry, relatively 
pure crystalline compounds) in 2250 random-bred rats and found that 
chromates, described as sparingly soluble, were carcinogenic in the 
rat lung.  These materials included strontium and calcium chromate 
and, to a far lesser extent, certain forms of zinc chromate.  
Barium and lead chromate evoked only a very weak carcinogenic 
response compared with strontium and calcium chromate.  In the 
study of Laskin et al. (1970), it was shown that chromium trioxide 
produced hepatocellular carcinomas in 2/100 rats (controls, 0/24). 

    After inhalation of 13 mg calcium chromate/m3 (5 h/day, 5
days/week, for lifetime), Nettesheim et al. (1971) found 14 lung 
adenomas in 136 treated mice and 5 in 136 untreated controls, but 
no carcinomas.  Steffee & Baetjer (1965), performing inhalation 
studies on rats, mice, guinea-pigs, and rabbits (inhalation of 
mixed chromate dust, corresponding to 3 - 4 mg CrO3/m3, 4 - 5 
h/day, 4 days/week, for lifetime, or 50 months, respectively) could 
only find 3 alveologenic adenomas in 50 treated guinea-pigs.  
Laskin (1972) and Laskin et al. (1970) found 1 squamous cell 
carcinoma of the lung, 1 of the larynx and 1 "peritruncal tumor" in 
rats (inhalation of calcium chromate, 2 mg/m3, 589 exposures of 5 h 
over 891 days) and 1 squamous cell carcinoma and 1 papilloma of the 
larynx in hamsters.  The number of treated animals was not 
specified in either paper.  Steinhoff et al. (1983) performed 
intratracheal instillations of chromates in rats for 30 months with 
one treatment/week and the same weekly dose distributed over 5 
treatments/week (Table 14).  In 880 exposed rats, 28 adenomas of 
alveolar-bronchiolar origin (benign) and 12 malignant tumours (3 
adenocarcinomas and 9 squamous cell carcinomas) were found.  All 
lung tumours developed very late and were only detected at the end 
of the lifetime study, often in lungs with callosities.  The 
tumours were tiny and none of them caused the animal to die.  

Sodium dichromate was not carcinogenic after exposure on 5 
days/week.  With calcium chromate, the carcinogenic effect was more 
pronounced after treatment once per week, than after treatment 5 
times per week. 

Table 14.  Incidence of benign and malignant lung tumours among 
880 rats intracheally injected with Na dichromate and Ca chromatea
----------------------------------------------------------------
                  Dose     Number of   Incidence of lung tumours
                  (mg/kg)  injections  benign   malignant
                           per week
----------------------------------------------------------------
Na2Cr2O7 x 2H20   0.25     5           none     none

Na2Cr2O7 x 2H20   1.25     1           12       8

CaCrO4            0.25     5           5        1

CaCrO4            1.25     1           11       3
----------------------------------------------------------------
a  From: Steinhoff et al. (1983).

    Hueper (1961) reported unspecified tumours at implantation 
sites in 12/34 rats, following intramuscular (im) implantation of 
sintered calcium chromate (25 mg). No tumours were observed in 32 
control animals. The same author found implantation-site tumours in 
15/33 animals treated with strontium chromate compared with no 
tumours in 32 control animals.  Single sc injections of 30 mg lead 
chromate (Maltoni 1974, 1976) resulted in injection-site sarcomas 
in 26/40 treated rats. After administration of the same amount of 
lead chromate oxide, injection-site sarcomas were found in 27/40 
rats; no sarcomas were found in 60 vehicle controls.  Following 9 
im injections of 8 mg lead chromate, Furst et al.  (1976) found 
injection-site sarcomas in 31/47 treated rats, and renal carcinomas 
in 3/24 treated rats; no sarcomas were found in 0/22 vehicle 
controls.  Heath et al. (1971) found injection-site sarcomas and 
other tumours in 7/74 treated rats after im injection of 28 mg 
cobalt-chromium alloy. 

    Administration of low levels of trivalent chromium acetate (5 
mg/litre in the drinking-water) to mice and rats for the lifetime 
did not result in increased tumour incidences compared with 
controls (Schroeder et al., 1964, 1965). 

    Trivalent chromium oxide incorporated in bread at 
concentrations of 10, 20, or 50 g/kg and fed to BD rats did not 
increase tumour incidence compared with controls (Ivankovic & 
Preussmann, 1975).  Hexavalent chromium compounds have not been 
tested by oral administration. 

    IARC (1980a) summarized the data of all available references 
and concluded as follows: "There is sufficient evidence for the 
carcinogenicity of calcium chromate and some relatively insoluble 
chromium (VI) compounds (sintered calcium chromate, lead chromate, 

strontium chromate, sintered chromium trioxide and zinc chromate) 
in rats. There is limited evidence for the carcinogenicity of lead 
chromate (VI) oxide and cobalt-chromium alloy in rats.  The data 
were inadequate for the evaluation of the carcinogenicity of other 
chromium  (VI) compounds and of chromium (III) compounds". 

    (a)   Interaction with other factors

    The possibility that chromium may act synergistically with 
other agents in the production of cancer has been tested in several 
studies.  Nettesheim et al. (1970) pretreated one group of mice 
with 100 R whole-body radiation and infected another group with PR8 
influenza virus.  These mice and control mice were exposed through 
inhalation to chromium oxide dust for 6 - 18 months.  No measurable 
effects of either of the pretreatments were found on the incidence 
of tumours.  In a similar study with inhalation of calcium chromate 
(CaCrO4, 5 h/day, 5 days per week for the lifetime), pre-exposure 
to X-rays did not affect the tumour rate, but PR8 influenza 
infection reduced tumour incidence (Nettesheim et al., 1971). 
Steffee & Baetjer (1965) also found that the infection of rats with 
PR8 influenza virus associated with intratracheal injection of 
chromates did not lead to the production of tumours.  Chromite ore 
injected iv did not affect the development of tumours induced by iv 
injection of 20-methyl-cholanthrene (Shimkin & Leiter, 1940).  
Thus, at present, there are not sufficient data to suggest that 
chromium acts synergistically with virus infections, ionizing 
radiation, or other chemical carcinogens to produce cancers. 

7.2.1.2.  Genotoxicity

    The mutagenicity of chromium compounds was reviewed by IARC 
(1980a), Petrilli & DeFlora (1980), Levis & Bianchi (1982), and 
Baker (1984).  Present knowledge, in the light of recent findings, 
is summarized in Table 15 (hexavalent chromium) and Table 16 
(trivalent chromium). 

    When evaluating the results of chromium mutagenicity tests, it 
is necessary to take into consideration several properties of the 
tested compound (oxidation state, solubility, ability to penetrate 
cell membranes, intracellular stability, and reactivity with 
cellular components).  Most of the  in vitro mutagenicity 
experiments have been performed with chromium chemicals, following 
the introduction of the reverse mutation test by Ames (1973).  
Bacterial strains of  Salmonella typhimurium (Petrilli & DeFlora, 
1977) containing mutants that require histidine for growth, and 
 Escherichia coli (Venitt & Levy, 1974) with mutants requiring 
tryptophan for growth have been used.  In each case, the bacterial 
cultures have been incubated with the test chromium compounds and 
the number of revertant colonies scored.  The chromium compounds 
studied included both hexavalent and trivalent compounds; a survey 
of the results is given in Table 17 (DeFlora, 1981).  Zhurkov 
(1981) performed an Ames test to study the mutagenic activity of 
potassium dichromate (K2Cr2O7) with  S. typhimurium TA 1535 and TA 
1538.  A medium degree of mutagenic activity without metabolic 
activation was shown by the strain TA 1535. 

    Only hexavalent chromium compounds have shown mutagenic 
effects.  Using the  Salmonella /mammalian microsome tests of Ames 
et al. (1973), DeFlora (1978) and Lfroth (1978) both showed a 
decrease in the mutagenicity of hexavalent chromium in the presence 
of an NADPH-generating system, suggesting reduction of mutagenic 
hexavalent chromium to trivalent chromium.  In this chromate 
metabolism, cytochrome P-450 functions as the reductase (Garcia & 
Wetterhahn Jennette, 1981).  In recent  in vitro studies, Wiegand et 
al. (1984b) showed that glutathione could reduce hexavalent 
chromium to trivalent chromium, without any further cofactors or 
metabolizing enzymes.  In rats, the most efficient tissue in 
decreasing hexavalent chromium mutagenicity was the liver, followed 
by the suprarenal glands, kidney, stomach, and lung (Petrilli & 
DeFlora, 1980).  These studies suggest a possible way of 
intracellular detoxification of hexavalent chromium in low doses. 

    Schoental (1975) suggested that hexavalent chromium caused the 
formation of epoxyaldehydes having mutagenic potential. Venitt & 
Levy (1974) assumed that chromates belong to the transition-
inducing class of mutagens.  They cause both frameshift and base-
pair substitutions (Petrilli & DeFlora, 1980).  The hypothesis of 
Kazantzis & Lilly (1979), that chromates cause guanine-cytosine to 
adenine-thymine transitions in the subsequent round of DNA-
replication, needs further confirmation. 
    
Table 15.  Genotoxic activity of chromium (VI) compoundsa
---------------------------------------------------------------------
Assay               Compounds       Activity  Reference
---------------------------------------------------------------------
DNA degradation     CaCrO4          -         Casto et al. (1976)
                    K2Cr2O7         -         Bianchi et al. (1983)
                    PbCrO4          -         Douglas et al. (1980)
                    K2CrO4          +         Whiting et al. (1979)

Decreased fidelity  PbCrO4,         + (1)     Levis & Majone (1981)
of DNA synthesis    K2Cr2O7
                    CrO3            +         Sirover & Loeb (1976)
                    K2Cr2O7         +         Bianchi et al. (1983)

Microbial DNA       K2CrO4,         +         Yagi & NishioKa (1977)
repair              K2Cr2O7
                    CrO3, K2CrO4,   +         Kanematsu et al. (1980)
                    K2Cr2O7
                    K2CrO4,         +         Nishioka (1975)
                    K2Cr2O7
                    K2CrO4,         +         Nakamuro et al. (1978)
                    K2Cr2O7
                    CrO3,           +         Gentile et al. (1981)
                    K2Cr2O7,
                    Na2Cr2O7,       +         Gentile et al. (1981)
                    (NH4)2Cr2O7
---------------------------------------------------------------------

Table 15.  (contd.)
---------------------------------------------------------------------
Assay               Compounds       Activity  Reference
---------------------------------------------------------------------
Microbial gene      K2Cr2O7         +  (2)    Bonatti et al. (1976)
mutation            CrO3            +  (2)    Fukunaga et al. (1982)
                    Na2Cr2O7,       +/-(3)    Petrilli & De Flora
                    CrO3,           +/-(3)    (1978a,b)
                    ZnCrO4xZn(OH)2  +/-(3)
                    K2Cr2O7         +         Zhurkov (1981)
                    Na2Cr2O7        +/-(3)    DeFlora (1978)
                    chromate (4)    +/-(3)    Lfroth (1978)
                    dichromate      +/-(3)
                    K2Cr2O7         -         Kanematsu et al. (1980)
                    K2CrO4,         +         Lfroth & Ames (1978)
                    K2Cr2O7         +
                    K2Cr2O7         +         Nishioka (1975)
                    K2CrO4, CaCrO4  +         DeFlora (1981)
                    (NH4)2CrO4,
                    CrO3,
                    Na2CrO4,        +         Venitt & Levy (1974)
                    K2CrO4
                    CaCrO4
                    K2Cr2O7         +         Bianchi et al. (1983)
                    Na2Cr2O7,
                    ZnCrO4
                    K2CrO4,         +         Nakamuro et al. (1978)
                    K2Cr2O7            
                    K2CrO4, CaCrO4  +         Petrilli & DeFlora
                    CrO3                      (1977)
                    Na2Cr2O7
                    K2CrO4          +         Green et al. (1976)
                    PbCrO4, CrO3    +         Nestmann et al. (1979)

Mammalian cell      K2Cr2O7         +         Bianchi et al. (1983)
gene mutation       K2Cr2O7,        +         Newbold et al. (1979)
                    ZnCrO4          +
                    PbCrO4          -
                    K2Cr2O7         + (5)     Bonatti et al. (1976)
                    K2Cr2O7         +         Pashin et al. (1982)
                    NaeCr2O         +         Pashin & Kozachenko
                    (NHy)2Cr2O7     +         (1981)

---------------------------------------------------------------------

Table 15.  (contd.)
---------------------------------------------------------------------
Assay               Compounds       Activity  Reference
---------------------------------------------------------------------
Mammalian cell      K2CrO4,         +         Umeda & Nishimura (1979)
chromosomal         K2Cr2O7         +
mutation            K2Cr2O7         +         Bigaliev et al. (1978)
                    K2CrO4,         +         Nakamuro et al. (1978)
                    K2Cr2O7         +
                    Na2CrO4,        +         Majone & Levis (1979)
                    K2CrO4          +
                    Na2Cr2O7,                 Levis & Majone (1979)
                    K2Cr2O7
                    CrO3, CaCrO4
                    PbCrO4          +         Douglas et al. (1980)
                    K2Cr2O7         +         Imreh & Radulescu (1982)
                    CrO3            +         Kaneko (1976)
                    Na2Cr2O7        +         Sarto et al. (1980)
                    K2Cr2O7         +
                    CrCl3           +
                    CrO3            +         Tsuda & Kato (1977)
                    K2Cr2O7         +         Raffetto (1977)
                    K2Cr2O7         +         Stella et al. (1982)
                    Na2Cr2O7,       +         Majone & Levis (1979)
                    K2Cr2O7         +
                    K2CrO4          +         Wild (1978)
                    Na2Cr2O7        + (7)     Krishnaja & Rige (1982)

Mammalian cell      CrO3, K2CrO4,   +         Ohno et al. (1982)
SCE                 K2Cr2O7         +
                    K2Cr2O7         +         Bianchi et al. (1983)
                    K2CrO4,
                    Na2CrO4         +         Levis & Majone (1979)
                    CrO3,           +
                    K2Cr2O7,        +         Majone & Levis (1979)
                    Na2Cr2O7        +
                    PbCrO4          +         Douglas et al. (1980)
                    K2Cr2O7         +         Imreh & Radulescu (1982)
                    CaCrO4, CrO3,   +         Gomez-Arroyo et al.
                    K2Cr2O7         +         (1981)
                    K2Cr2O7         +         Majone & Rensi (1979)
                    CrO3            + (6)     Stella et al. (1982)
                    K2Cr2O4,        +         Elias et al. (1983)
                    Na2CrO4,        +
                    Na2Cr2O7        +
                    K2Cr2O7,
                    K2CrO4          +         McRae et al. (1979)

---------------------------------------------------------------------

Table 15.  (contd.)
---------------------------------------------------------------------
Assay               Compounds       Activity  Reference
---------------------------------------------------------------------
Mammalian cell      CaCrO4, K2CrO4  + (8)     Casto et al. (1979)
transformation      ZnCrO4          + (9)
                    Na2CrO4,        
                    CaCrO4          +         Casto et al. (1976)
                                    +         Di Paolo & Casto (1979)
                    K2Cr2O7         +         Bianchi et al. (1983)
                    K2Cr2O7         +         Tsuda & Kato (1977)
                    CaCrO4          +         Fradkin et al. (1975)
                    K2Cr2O7         +         Raffetto (1977)
---------------------------------------------------------------------
a   Modified from: Baker (1984).

Note:

(1) As industrial pigments (Cr-yellow-orange; Zn-yellow; Mo-orange).
(2) Gene conversion.
(3) No mutagenicity in the presence of mammalian microsomal activation
    system (S-9 mix).
(4) No compounds given.
(5) Forward mutation was observed in 7/480 054 colonies (controls 0/84
    546).  A significant increase can be stated if comparison is made
    with the historical spontaneous mutation rate, i.e., no mutants in
    106 colonies.
(6) Occupatinal exposure.
(7) Induction of chromosomal aberrations in gill cells of the fish
     Boleophthalmus dussumieri (Goby).
(8) 2 times control levels.
(9) 4 times control levels.

    The results summarized in Table 17 show that the chromate ion 
(hexavalent chromium) induces different kinds of genetic damage, 
even at low doses, whereas the chromosome-damaging capacity of 
trivalent chromium was only observed when it was tested in very 
high doses. 

    In assays with whole-cell systems, trivalent chromium is 
inactive, unless there is a direct interaction with DNA, e.g., in 
studies in which purified DNA was exposed to trivalent chromium, 
where modifications of the physical and chemical properties, as 
well as decreased fidelity of DNA synthesis, were produced (Levis & 
Bianchi, 1982).  According to Warren et al. (1981), it appeared 
that trivalent chromium in a proper ligand environment could have 
considerable genetic toxicity. However, in recent studies, Bianchi 
et al. (1984) found that trivalent chromium (CrCl3, 10-3 to 10-5 M) 
was neither cytotoxic nor mutagenic in permeabilized hamster 
fibroblasts (BHK were incubated for 30 min in Ea or BSS made 
hypertonic with 4.2% NaCl). 


Table 16.  Genotoxic activity of chromium (III) compoundsa
---------------------------------------------------------------------------
Assay               Compounds            Activity  Reference
---------------------------------------------------------------------------
DNA degradation     CrCl3                +         Bianchi et al.
                                                   (1983)

Decreased fidelity  Cr2O3                +         Levis & Majone
of DNA synthesis                                   (1981)

Microbial DNA       cis-[Cr(bipy)2ox]    +         Warren et al. (1981)
repair              I x 4H2O

                    cis-[Cr(bipy)2Cl2]   +         Warren et al. (1981)
                    Cl x 2H2O

                    cis-[Cr(phen)2Cl2]   +         Warren et al. (1981)
                    Cl x 2,5H2O

                    [Cr(urea)6]          +         Warren et al. (1981)
                    Cl3 x 3H2O

                    [Cr(H2O)6]Cl3        -         Warren et al. (1981)

                    [Cr(en)3](SCN)3      +         Warren et al. (1981)

                    [Cr(en)3]Cl3 x 3H2O  +         Warren et al. (1981)

                    [Cr(pn)3]Cl3 x 3H2O  +         Warren et al. (1981)

                    trans-[Cr(en)2       +         Warren et al. (1981)
                    (SCN)2]SCN

                    CrCl3, Cr2O3,        -         Yagi & Nishioka
                    Cr(OH)3                        (1977)

                    K2Cr2(SO4)4          -         Yagi & Nishioka
                                                   (1977)
                    K2Cr2(SO4)4          -         Kanematsu et al.
                                                   (1980)

                    Cr2(SO4)3            -         Kanematsu et al.
                                                   (1980)
                    CrCl3                -         Nishioka (1975)

                    Cr(NO3)3,            +         De Flora (1981)
                    Cr(CH3COO)3

                    CrCl3                -         Nakamuro et al.
                                                   (1978)
                    CrCl3                +         Gentile et al.
                                                   (1981)
                    CrCl3, KCr(SO4)2,    -         Gentile et al.
                                                   (1981)
                    Cr2(SO4)3            -         Gentile et al.
                                                   (1981)
---------------------------------------------------------------------------

Table 16.  (contd.)
---------------------------------------------------------------------------
Assay               Compounds            Activity  Reference
---------------------------------------------------------------------------
Microbial gene      CrCl3, Cr(NO3)3      -         Lfroth & Ames
mutation                                           (1978)

                    Cr(CIO4)3            -         Lfroth & Ames
                                                   (1978)

                    CrCl3, Cr(NO3)3      -         Venitt & Levy (1974)

                    Cr2SO4,              -         Venitt & Levy (1974)
                    K2SO4 x 2H2O

                    Cr(CH3COO)3          +         Nakamuro et al.
                                                   (1978)

                    Cr(NO3)3             +         Nakamuro et al.
                                                   (1978)

                    CrCl3                -         Nakamuro et al.
                                                   (1978)

                    CrK(SO4)2 x 12H2O    -         Petrilli & De Flora
                                                   (1977)

                    CrCl3 x 6H2O         -         Petrilli & De Flora
                                                   (1978a)

                    Cr(NO3)3 x 9H2O      -         Petrilli & De Flora
                                                   (1978b)

Microbial gene      cis-[Cr(bipy)2ox]    +         Warren et al. (1981)
mutation            I x 4H2O

                    cis-[Cr(bipy)2Cl2]   +         Warren et al. (1981)
                    Cl x 2H2O

                    cis-[Cr(phen)2Cl2]   +         Warren et al. (1981)
                    Cl x 2,5H2O

                    [Cr(urea)6]          +         Warren et al. (1981)
                    Cl3 x 3H2O

                    [Cr(H2O)6]Cl3        -         Warren et al. (1981)

                    [Cr(en)3](SCN)3      -         Warren et al. (1981)

                    [Cr(en)3]Cl3 x 3H2O  -         Warren et al. (1981)

                    [Cr(pn)3]Cl3 x 3H2O  -         Warren et al. (1981)

                    trans-[Cr(en)2       -         Warren et al. (1981)
                    (SCN)2]SCN 
---------------------------------------------------------------------------

Table 16.  (contd.)
---------------------------------------------------------------------------
Assay               Compounds            Activity  Reference
---------------------------------------------------------------------------
Mammalian cell      CrCl3                -         Bianchi et al.
gene mutation                                      (1983)
  
                    Cr(CH3COO)3          -         Newbold et al.
                                                   (1979)

Mammalian cell      Cr2(SO4)3            -         Umeda & Nishimura
chromosomal                                        (1979)
mutation
                    Cr(CH3COO)3          +         Nakamuro et al.
                                                   (1978)

                    CrCl3, Cr(NO3)3      -         Nakamuro et al.
                                                   (1978)

                    Cr(NO3)3,            +         Levis & Majone
                                                   (1979)

                    KCr(SO4)2,           +         Levis & Majone
                                                   (1979)

                    Cr(CH3COO)3          +         Levis & Majone
                                                   (1979)

                    CrCl3                +         Kaneko (1976)

                    CrCl3                -         Sarto et al. (1980)

                    Cr2(SO4)3, CrCl3     -         Tsuda & Kato (1977)

                    CrCl3                +         Raffetto (1977)

                    CrCl3                -         Stella et al. (1982)

                    CrCl3                - (1)     Bianchi et al.
                                                   (1984)

Mammalian cell      CrCl3, Cr2O3         +         Elias et al. (1983)
SCE
                    Cr2O3                +         Levis & Majone
                                                   (1981)

                    Cr(NO3)3,            -         Levis & Majone
                    KCr(SO4)2                      (1979)

                    CrCl3, Cr(CH3COO)3   -         Levis & Majone
                                                   (1979)

                    CrCl3                + (2)     Ohno et al. (1982)

                    Cr2(SO4)3            -         Ohno et al. (1982)

---------------------------------------------------------------------------

Table 16.  (contd.)
---------------------------------------------------------------------------
Assay               Compounds            Activity  Reference
---------------------------------------------------------------------------

Mammalian cell      CrCl3                -         Bianchi et al.
SCE (contd).                                       (1983)

                    CrCl3                -         Majone & Rensi
                                                   (1979)

Mammalian cell      CrCl3                -         Bianchi et al.
transformation                                     (1983)
---------------------------------------------------------------------------
a   Modified from: Baker (1984).

Note:

(1)  Thymidine uptake, DNA replication, damage and repair and SCE were
     tested in permeabilized hamster fibroblasts.
(2)  Weakly positive.

    Levis & Buttignol (1977) and Levis et al. (1978) raised the 
question of whether trivalent chromium could be an active mutagenic 
agent within a cell.  Others, such as Bianchi et al. (1980), 
supported this theory, suggesting that trivalent chromium is bound 
to genetic material after reduction of the hexavalent form by an 
NADPH-dependent microsomal enzyme system (Norseth, 1978; Jennette, 
1979).  The studies of Sirover & Loeb (1976), showing a 30% error 
in DNA synthesis after application of 0.64 mM trivalent chromium 
compared with 16 mM of hexavalent chromium, support this theory. 

    Pashin et al. (1982) demonstrated the induction of dominant 
lethal mutations in mice.  They treated male mice with a single 
injection of potassium dichromate (0.5 - 20 mg/kg body weight, ip) 
or with daily injections (1 and 2 mg/kg, ip, for 21 days).  The 
single injections (0.5 - 2 mg/kg) did not induce any effects; 
repeated or higher dosages of potassium dichromate induced a 
statistically significant decrease in the survival of embryos from 
cells treated at the early spermatid and late spermatocyte stages. 

    Karyological alterations in mammalian cells were induced after 
exposure to concentrations of hexavalent chromium that were more 
than 100 times lower than the concentration of trivalent chromium 
causing the same changes (Majone & Rensi, 1979). 

    Analysing the effects of fume particles from stainless steel 
welding on sister chromatid exchanges and chromosome aberrations in 
cultured Chinese hamster cells, Koshi (1979) found an increase in 
cytogenic effects with increasing fume doses, due to the dissolved 
hexavalent chromium.  Hexavalent chromium and stainless steel 
welding fume particles containing chromium compounds produced 
positive results in the "mammalian spot test", a somatic tissue 
assay (Knudsen, 1980). 


Table 17.  Mutagenicity of chromium compoundsa
---------------------------------------------------------------------------------------------------------
Compound (source)               Reverted strains  Range of  Mutagenic  Effect of   Remarks
                                                  activity  potency    S9 mix
                                                  (nmoles/  (revs/     (rat
                                                  plate)    nmol)      liver
                                                                       Aroclor(R))
---------------------------------------------------------------------------------------------------------
L.  Hexavalent chromium compounds

1)  Sodium dichromate (Merck)   -  +w  +w  +w  +  50 - 250  4.4        decrease    toxic and mutagenic 
    Na2Cr2O7 x 2H2O                                                                Cr6+ was converted  
                                                                                   into inactive Cr3+  
2)  Potassium chromate (BDH)    -  +w  +w  +w  +  80 - 410  2.9        decrease    by reducing         
    K2CrO4                                                                         chemicals (ascorbic 
                                                                                   acid, sodium        
3)  Calcium chromate (BDH)      -  +w  +w  +w  +  60 - 290  3.2        decrease    sulfite) or         
    CaCrO4                                                                         metabolites (NADH, 
                                                                                   NADPH, GSH), by     
4)  Ammonium chromate           -  +w  +w  +w  +  50 - 320  3.7        decrease    human gastric juice 
    (Carlo Erba)                                                                   and erythrocyte     
    (NH4)2CrO4                                                                     lysates, by S9 mix  
                                                                                   containing human    
                                                                                   liver S9 fractions  
5)  Chromium trioxide or        -  +w  +w  +w  +  40 - 220  5.1        decrease    or rat tissue S9    
    chromic acid (Merck)                                                           fractions (in order 
    CrO3                                                                           of efficiency:      
                                                                                   liver>suprarenal   
                                                                                   glands>kidney>   
                                                                                   stomach>lung);     
                                                                                   pretreatment of    
                                                                                   rats (Aroclor(R)    
                                                                                   1254), ether,       
                                                                                   ethanol) influenced 
                                                                                   the efficiency of   
                                                                                   metabolic systems;  
                                                                                   conversely, Cr6+    
                                                                                   mutagenicity was not
                                                                                   affected by human   
                                                                                   serum or plasma nor
                                                                                   by S9 mix containing
                                                                                   other rat (spleen,  
                                                                                   colon, bladder, 
                                                                                   striated muscle) S9 
                                                                                   fractions
---------------------------------------------------------------------------------------------------------

Table 17.  (contd.)
---------------------------------------------------------------------------------------------------------
Compound (source)               Reverted strains  Range of  Mutagenic  Effect of   Remarks
                                                  activity  potency    S9 mix
                                                  (nmoles/  (revs/     (rat
                                                  plate)    nmol)      liver
                                                                       Aroclor(R))
---------------------------------------------------------------------------------------------------------
                                   
6)  Zinc yellow (Montedison)    -  +w  +w  +w  +  90 - 590  1.4        decrease    the mutagenic effects 
    ZnCrO4 x Zn(OH)2 +                                                             of Cr6+ compounds and
    10% CrO3                                                                       benzo( a)pyrene were
                                                                                   less than additive

7)  Chromyl chloride (BDH)      -  +w  +w  +w  +  100 - 430 1.8        decrease    liquid volatile 
    Cl2CrO2                                                                        compound; vapours
                                                                                   were also toxic and 
                                                                                   mutagenic

8)  Chromium orange or basic    -  -   -   -   +b 2 mg                             the three pigments 
    lead                                          (spot test)                      containing PbCrO4
    PbCrO4 x PbO                                                                   were scarcely  (L8), 
    chromate (Montedison)                                                          very scarcely  (L9), 
                                                                                   or totally  (L10) 
                                                                                   insoluble in water; 
                                                                                   they were assayed
                                                                                   by directly spotting 
                                                                                   these compounds at 
                                                                                   the centre of plates  
9)  Molybdenum orange or        -  -   -   -   +b 2 mg
    lead solfomolybdo-                            (spot test)
    chromat (Montedison)      
    PbCrO4      72-77%
    PbSO4       4-6%  
    Al2O3       2%    
    PbMoO4      12-14% 

---------------------------------------------------------------------------------------------------------

Table 17.  (contd.)
---------------------------------------------------------------------------------------------------------
Compound (source)               Reverted strains  Range of  Mutagenic  Effect of   Remarks
                                                  activity  potency    S9 mix
                                                  (nmoles/  (revs/     (rat
                                                  plate)    nmol)      liver
                                                                       Aroclor(R))
---------------------------------------------------------------------------------------------------------

10) Chromium yellow or          -  -   -   -   -b
    lead solfochromate        
    (Montedison)              
    PbCrO4      41-85%            
    PbSO4       4-45% 
    SiO2        0.1-3%
    Al2O3       2-6%  
                
11) Chromium                    -  -   -   -   -  -2.3x103  -          -           hexacoordinated 
    hexacarbonyl (BDH)                                                             compound; formally, 
    Cr(CO)6                                                                        its oxidation state 
                                                                                   is 0; insoluble in 
                                                                                   water, dissolved in 
                                                                                   ether

M.  Trivalent chromium compounds

1)  Chromic chloride            -  -   -   -   -  -3x104    -          -           inactive Cr3+ 
    (BDH) CrCl3 x 6H2O                                                             compounds could be 
                                                                                   converted into toxic 
                                                                                   and mutagenic Cr6+ 
                                                                                   only in the presence 
                                                                                   of oxidizing chemicals 
                                                                                   (potassium 
                                                                                   permanganate), while a 
                                                                                   variety of metabolic 
                                                                                   systems were 
                                                                                   ineffective 

2)  Chromic nitrate (Riedel-    -  -   -   -   -  -2x104    -          - 
    de Haen)
    Cr(NO3)3 x 9H2O

---------------------------------------------------------------------------------------------------------

Table 17.  (contd.)
---------------------------------------------------------------------------------------------------------
Compound (source)               Reverted strains  Range of  Mutagenic  Effect of   Remarks
                                                  activity  potency    S9 mix
                                                  (nmoles/  (revs/     (rat
                                                  plate)    nmol)      liver
                                                                       Aroclor(R))
---------------------------------------------------------------------------------------------------------

3)  Chromic potassium           -  -   -   -   -  -1.6x104  -
    sulfate (BDH)
    CrK(SO4)2 x 12H2O
                                                     
4)  Chromic acetate (BDH)       -  -   -   -   -  -7x104    -          -
    Cr(CH3COO)3
                                                                  
5)  Neochromium (Montedison)    -  -   -   -   -  -5x104    -          -
    Cr(OH)SO4   56-58%
    Na2SO4      23-24%
    H2O         18-21%

6)  Chromium alum (Montedison)  -  -   -   -   -  -4.3x104  -          -
    Cr2(SO4)3  37-39%
    K2SO4      16-18%
    H2O        43-37%

7)  Chromite (Montedison)       -  -   -   -   +  2 mg      -                      Contaminated with Cr6+ 
    Cr2O3      44-46%                             (spot test)                      traces ( sim-diphenyl-
    Fe2O3      29-30%                                                              carbazide reagent); 
    Al2O3      15-16%                                                              scarcely soluble in 
    SiO3       0.5-3%                                                              water; assayed by 
    CoO        0.5-2%                                                              directly spotting the 
                                                                                   powder at the centre 
                                                                                   of plates 
--------------------------------------------------------------------------------------------------------

Table 17 (contd.)

Note:

Sensitivity of  Salmonella strains:                   Range of activity:                       
                               
In the assays carried out in this study,             This column indicates the lower and      
the numbers of spontaneous revertants of             the upper limits (in nmol per plate)     
 Salmonella tester strains fell within the            of the mutagenic response, as in-    
following ranges:                                    ferred from dose-response curves           
TA 1535: 10-25, both with and without S9 mix;        with the most sensitive bacterial          
TA 1537: 3-18, both with and without S9 mix;         strain and under the most favourable       
TA 1538: 10-25 without S9 mix; 15-35 with S9 mix;    metabolic situation (i.e., with or         
TA 98: 20-35 without S9 mix; 25-40 with S9 mix;      without S9 mix) for each positive          
TA 100: 150-200 without S9 mix; 140-180 with S9 mix  compound; for negative compounds,          
                                                     the maximum dose tested is indicated       
The key for the interpretation of symbols in the                                                
column "Reverted strains" is the following:          Mutagenic potency:                         
+  clearly positive result indicated by a dose-                                                 
   related and reproducible increase of his+         the values presented have                  
   revertants over controls (at least a 3-fold       been calculated by dividing the number     
   increase);                                        of revertants in excess of controls        
+w weak positivity indicated by an increase of       by the corresponding amount of compounds   
   revertants 2 - 3 times in controls;               (in nmoles); the number of net revertants  
  reproducible but less than 2-fold increase        was determinated at the top level of the   
   of revertants;                                    linear part of dose-response curves, which 
No symbol: no conclusive experiment carried out      were drawn as indicated under the previous 
   with the corresponding strain.                    sub-heading.                               
                                                                                                
                                                     Effects of S9 mix                          
                                                                                                
                                                     The effect of S9 mix containing            
                                                     liver S9 fractions from        
                                                     Arochlor(R) pretreated rats on             
                                                     the mutagenicity of test                   
                                                     compounds is reported          
--------------------------------------------------------------------------------------------------------
a   From: DeFlora (1981).
b    L8, L9, and  L10, as well as PbCrO4, were positive in the plate test when 
    dissolved in 0.5 N NAOH.
    Embryonic fibroblast cell cultures showed significant 
chromosome aberrations, when potassium dichromate was added to the 
medium (Tsuda & Kato, 1976). When the potassium dichromate was 
reduced with sodium disulfite (Na2SO3), no significant aberrations 
occurred, even with 100 times the chromium concentrations. 

    At present, it is widely accepted that hexavalent chromium is 
genetically active, because of its ability to cross the membranes 
and enter the cells.  If reduction of hexavalent chromium takes 
place outside the cell (or even outside the cell nucleus, e.g., in 
mitochondria or microsomes) its genetic activity is suppressed; if 
the reduction takes place inside the nucleus (near, or at, the 
target DNA molecules) alterations in DNA can occur, depending on 
the oxidation power of hexavalent chromium or the formation of 
trivalent chromium complexes with nucleophilic sites of the DNA; 
thus, trivalent chromium could be the ultimate mutagenic form of 
chromium (Levis & Bianchi, 1982).  More recent investigations 
(Wiegand et al., 1984) have shown that hexavalent chromium may 
enter the body unreduced via the lung and be partly deposited in 
erythrocytes over a prolonged period of time.  From a DNA-repair 
test in bacteria, DeFlora et al. (1984) concluded that hexavalent 
chromium causes irritation in nucleotide pools and, due to its 
oxidizing power, induces single-strand breaks in DNA, while 
trivalent chromium induces DNA-protein and DNA-DNA cross-links and 
decreases the fidelity of DNA replication. 

7.2.1.3.  Developmental toxicity and other reproductive effects

    The teratogenicity of hexavalent chromium as chromium trioxide 
was tested in golden hamsters (Gale, 1974, 1978, 1982; Gale & 
Bunch, 1979) and that of trivalent chromium as chromic-chloride in 
ICR mice (Iijima et al., 1975; Matsumoto et al., 1976).  Injections 
of hexavalent chromium into the fertilized chick egg increased 
embryolethality and produced malformations in the survivors (Gilani 
& Marano, 1979). 

    The golden hamsters were treated with a single iv injection of 
chromium trioxide (5, 7.5, 10, or 15 mg/kg body weight) on the 8th 
day of gestation (Gale, 1978). 

    Dose-response relationships were demonstrated between the rate 
of absorption and the rate of malformations including delayed 
ossification of the skeletal system.  At 5 mg/kg body weight, 4% of 
the fetuses showed external abnormalities (oedema, exencephaly), 
and 34% showed cleft palate (controls: 2%), which increased to 85% 
with the higher doses of 7.5 or 10 mg/kg body weight.  Thirty-one 
percent of fetuses were retarded following treatment with 7.5 mg/kg 
body weight and 49% following 10 mg/kg body weight.  The dose of 15 
mg/kg body weight was lethal for 75% of the dams.  Gale & Bunch 
(1979) injected a single dose of 8 mg CrO3/kg body weight on day 7, 
8, 9, 10, or 11 of gestation in female golden hamsters (Table 18).  
The treated females were adversely affected (body weight loss, 
tubular necrosis of the kidneys).  In a later study, Gale (1982) 
injected 8 mg CrO3/kg iv in hamsters on day 8 of gestation.  An 
increased incidence of cleft palate was seen in strains LVG, LSH, 
and MHA, but no effects were reported in strains CB, LHC, and PD4. 

    ICR mice were injected sc with chromic chloride (Iijima et al., 
1975; Matsumoto et al., 1976).  In the first series (animals 
administered 9.8 or 19.5 mg/kg body weight, every other day, from 
the 0th to 16th day of gestation), according to the authors, a 
slight increase in the rate of malformations could not be excluded.  
In the second series, with ip injections of 9.8 - 24.4 mg/kg body 
weight, on the 8th day of gestation, the authors reported a dose-
dependent increase in the frequency of exencephaly, anencephaly, 
and the occurrence of rib fusion. 

    Danielsson et al. (1982) studied the rate of embryonic or fetal 
uptake of trivalent chromium and hexavalent chromium in early and 
late gestational mice (Table 19) and found placental passage of 
chromium.  Hexavalent chromium appeared in the fetus in high enough 
concentrations for a direct effect on embryonic structures to be 
likely, trivalent chromium may act on placental structures. 

    Gilani & Marano (1979) injected chromium trioxide into 840 
embryonating chicken eggs (air sack) at doses ranging from 0.002 to 
0.05 mg per egg, on days 0, 1, 2, 3, and 4 of incubation (0.1 ml 
physiol. saline injections per control egg).  All embryos were 
examined on day 8.  The following malformations were observed in 
the 720 eggs affected: short and twisted limbs, microphthalamia, 
exencephaly, short and twisted neck, everted viscera, oedema, and 
reduced body size. However, the incidence of abnormalities in the 
120 controls was reported to be "low". 

    Inhalation studies were conducted by Glaser et al. (1984) on 
Wistar rats (TNO-W-74 SPF) to study the effects of sodium 
dichromate on reproduction and teratogenicity in 3 generations.  
Whole-body exposures to sodium dichromate aerosols (0.2 mg 
chromium/m3) were performed with an exposure time of 130 days per 
generation.  No effects on reproduction were found.  All 
teratogenicity tests were negative, and there was no increase in 
fetal chromium content.  However, from generation to generation, 
there was an increase in immunosuppression and hyperplasia of 
organs (especially in the lungs) and changes in haematological 
variables. 


Table 18.  Embryotoxicity following maternal exposure to CrO3 on different days
of gestation in hamstersa
-------------------------------------------------------------------------------------
                                                          Findings in live fetuses
Day of     No. of   No. of        No. of   Frequency    External   Internal  Cleft
gestation  females  implantation  living   resorptions  defects    defects   palate
           treated  sites         fetuses  No.   %b     No.  %b    No.  %b   No.  %b
-------------------------------------------------------------------------------------
                                  Treated CrO3 8 mg/kg

7          6        64            10       54    84     1    10    1c   10   5    50
8          6        88            54       14    20     8d   15    4e   7    17   31
9          6        77            67       10    13     18f  27    0    0    25   37
10         6        77            77       0     0      0    0     0    0    0    0
11         6        68            67       1     1      0    0     0    0    0    0

                                  Controls H2O 5 ml/kg

7          3        35            33       2     6      0    0     0    0    0    0
8          3        44            41       3     7      0    0     0    0    0    0
9          3        37            36       1     3      0    0     0    0    0    0
10         2        20            19       1     5      0    0     0    0    0    0
11         3        34            33       1     3      0    0     0    0    0    0
-------------------------------------------------------------------------------------
a From: Gale & Bunch (1979).
b Underlined %, significantly different statistically from controls.
b Right hindlimb with two digits.
c Right kidney absent.
d Oedema (7), tail short (1).
e Small kidneys (3), right kidney absent (1).
f Oedema (17), omphalocele (1).

Table 19.  Comparison of concentrations of trivalent and hexavalent
chromium in fetuses, placentas, and maternal organsa,b
------------------------------------------------------------------
                 Day 13                       Day 16           
          Hexavalent   Trivalent       Hexavalent    Trivalent
          chromium     chromium        chromium      chromium
------------------------------------------------------------------
Fetus     0.3  0.01   0.03  0.002    0.5  0.04    0.1  0.01
Placenta  -            -               3.0  0.2     2.4  0.2
Liver     29.4  2.2   30.8  6.5      33.9  3.9    27.7  3.5
Kidney    38.1  1.9   5.3  0.7       36.0  4.3    8.7  2.3
Serum     2.6  0.2    9.3  0.9       2.8  0.4     11.0  1.6
------------------------------------------------------------------
a   From: Danielsson et al. (1982).
b   Trivalent chromium (51CrCl3) and hexavalent chromium 
    (Na251Cr2O7) were injected iv on day 13 and day 16 of gestation 
    at doses of 10 mg chromium/kg body weight. The pregnant animals 
    were autopsied after 1 h. Concentrations are expressed in 
    mg/litre or g  SEM (N = 4). 

7.2.1.4.  Cytotoxicity and micromolecular syntheses

    Wacker & Vallee (1959) reported that trivalent chromium was 
present in RNA from all sources examined; they hypothesized that 
chromium might contribute to the stabilization of the structure. 

    Administration of trivalent chromium to mice (ip injection of 
CrCl3 at 5 or 0.5 mg chromium/kg body weight;  P < 0.01) caused 
accumulation of chromium in the cell nucleus, which amounted to 
about 20% of the accumulated chromium content of the liver cell, 
and also enhanced RNA synthesis.  Hexavalent chromium inhibited RNA 
synthesis (K2CrO4 at 5 or 0.5 mg chromium/kg body weight; 
 P < 0.01) (Okada et al., 1983).  In further studies, Okada et al. 
(1984) pretreated rats with CrCl3 (ip injection of 5 mg chromium/kg 
body weight) and then partially hepatectomized the rats.  Chromium 
accumulated in the regenerating liver, and hepatic RNA synthesis 
was accelerated compared with that of partially hepatectomiced 
controls.  These findings suggest a direct participation of 
chromium in RNA synthesis. 

    Potassium dichromate enhanced the passive uptake of ribo-and 
desoxyribonucleosides (Levis et al., 1978; Bianchi et al., 1979), 
caused an inhibition of DNA replication to BHK fibroblasts, and 
reduced the colony-forming ability of BHK cells (doses: 10-4 - 20-7
mol).  Hexavalent chromium (potassium dichromate with a 
concentration of 5 x 10-7 mol/litre) reduced by half the 
proliferation of NHIK 3025 cells originating from a human cervix 
carcinoma (White et al., 1979). 

    The addition of calcium chromate to BHK21 cell cultures altered 
their growth characteristics.  Whereas these cells normally grow as 
elongated fibroblast cells in parallel orientation, the chromium-
exposed cells grew as shortened fibroblasts with enlarged nuclei 
and granular cytoplasm, randomly orientated.  When grown in 
carboxymethyl cellulose, the chromate-exposed cells underwent many 
divisions in contrast to the 1 or 2 divisions of normal cells.  
These alterations in growth properties persisted, even after 
transfer to a normal medium (Fradkin et al., 1975). 

    Cultures of HeLa and rat embryonic cells were incubated with 
various hexavalent and trivalent chromium compounds for 3 days and 
the 50% inhibitory dose (ID50) for cell growth was determined.  The 
ID50 for sodium and potassium chromate and dichromate and calcium 
chromate varied from 0.34 to 0.78 g/ml of the medium.  The ID50 
for the trivalent compounds varied over a wider range: chromic 
oxalate, 4; acetate, 52; nitrate, 720; chloride, 1030; and bromide, 
1500 mg/litre.  Similar results were found in rat embryonic cell 
cultures (Susa et al., 1977). 

7.2.1.5.  Fibrogenicity

    Because of the well-known fibrogenic effects of silica and 
asbestos minerals, studies were initiated to determine whether 
chromite and various other dusts exhibited similar properties. A 
single intratracheal injection in rats of 40 mg chromite particles 

(33% chromium, 0.7% SiO2, 99.9% of the particles being smaller than 
5 m) suspended in 1 ml Ringer's solution caused a moderate 
cellular reaction that reached a peak after 2 months and then 
decreased.  After 8 months (end of observation), the lung weight 
was within normal limits.  Only an increase in fibrils that was not 
significant was observed. The tissue reaction in regional lymph 
nodes was minimal (Swensson, 1977). 

    Chromite FeO(CrAl)2O3 (10 mg), ground to an average particle 
diameter of 1 m, was injected into the pleural cavities of 25 
mice.  The animals were killed at intervals ranging from 2 weeks to 
18 months after injection.  Chromite produced the least reaction of 
all the 15 dusts tested.  This material attracted very few cells 
and the eventual production of collagen was minimal (Davies, 1972). 

7.2.2.  Observations in farm animals

    Systemic poisoning of farm animals with chromates is rare and 
is mainly suspected to be a consequence of accidental industrial 
contamination of drinking-water.  The acute lethal dose for mature 
cattle is approximately 600 - 800 mg/kg body weight; chronic 
poisoning in young calves was produced by a daily dose of 30 - 40 
mg/kg body weight for one month (NZ Department of Agriculture, 
1954) with a clinical picture of profuse scouring, severe 
dehydration, low blood pressure, changes in the alimentary tract, 
including congestion and inflammation, and the rumen and abomasum 
showing ulceration near perforation. 

    High chromium levels were found in the blood and liver of 
calves that had died from poisoning.  The minimum tissue levels 
causing poisoning were 30 mg/kg in the liver and 4 mg/litre in 
whole blood (Harrison & Staples, 1955). According to Romoser et al. 
(1961), a level of 100 mg hexavalent chromium (as sodium 
chromate)/kg did not affect growing chicks. 

8.  EFFECTS ON MAN

8.1.  Nutritional Role of Chromium

    The physiological role of chromium and the need for small 
amounts of dietary chromium are indicated by: 

    (a) chromium-responsive cases of impaired glucose
        metabolism in malnourished children and middle-aged
        persons;

    (b) 2 cases of proved chromium deficiency in patients fed
        exclusively by parenteral alimentation; and

    (c) epidemiological studies suggesting a link between
        chromium deficiency and risk factors for cardiovascular 
        diseases.

8.1.1.  Biological measurements and their interpretation

    Biochemical methods for the diagnosis of the human nutritional 
chromium status are still at the developmental stage.  Blood- or 
urine-chromium concentrations are not indicative of chromium 
status.  Several studies suggest the validity of the "relative 
chromium response" in plasma or serum to the ingestion of 50 - 100 
g of glucose within 30 - 120 min; the response also appears in the 
urine.  Lack of this response suggests chromium deficiency, 
especially when combined with impaired glucose tolerance in the 
presence of normal or elevated plasma-insulin levels. 

8.1.2.  Chromium deficiency

8.1.2.1.  Adults

    Chromium deficiency is diagnosed mainly through therapeutic 
trials in which an impaired function is restored by supplementation 
of the diet with small amounts of chromium close to the estimated 
human requirement.  Glinsmann & Mertz (1966) studied 4 male 
diabetic patients for several months to 1 year, under the strictly 
controlled conditions of a metabolic ward.  The subjects, who were 
fed identical portions of a diet prepared before the start of the 
study, were allowed a measured amount of physical activity and were 
stabilized under these conditions before the beginning of the 
control periods. Three of the 4 patients responded to a chromium 
level of 180 - 1000 g/day as CrCl3 x 6H2O with a significant 
improvement in oral glucose tolerance; the fourth showed a very 
slight lowering of the glycaemic curve, which was not statistically 
significant.  A representative example is given in Table 20. 


Table 20.  Effect of chromium on mean glucose tolerancea,b
------------------------------------------------------------------------
Supplementation     Days       Number  Mean blood glucose concentration
                               of      ---------------------------------
                               tests   Fast-  Min after glucose load
                                       ing    30    60     90    120
------------------------------------------------------------------------
None                0 - 32     10      840    2170  2290   1950  1560
60 g, 3 x per day  33 - 74    12      850    2240  2380   2090  1620
60 g, 3 x per day  75 - 119   13      840    2100  2130   1860  1410
60 g, 3 x per day  120 - 140  5       840    2030  2010c  1750  1120c

None                180 - 194  1       960    2070  2900   2930  2370
60 g, 3 x per day  195 - 211  5       830    1960  1930c  1750  1180c

None                256 - 313  10      870    2200  2450   2240  1660
1 mg, 3 x per day   337 - 340  1       680    1480  1620   1510  960
------------------------------------------------------------------------
a   Modified from: Glinsmann & Mertz (1966).
b   A 46-year-old man with maturity-onset diabetes, controlled on diet;
    oral glucose tolerance test consisted of constant noon meal and 100 g
    glucose.
c   Mean values significantly different from control ( P < 0.025).

    The condition of one of 2 diabetic out-patients, observed over 
several months, was improved by chromium supplementation, the 
condition of the other was not.  Short-term treatment of 7 diabetic 
patients for 1 - 7 days with 1 mg chromium did not affect any 
variables of glucose metabolism, nor did chromium supplementation 
change the normal glucose tolerance tests of 10 healthy, young 
volunteers. 

    Glinsmann's positive results were not confirmed in a double-
blind crossover study on 4 normal volunteers and 10 diabetic 
persons, with a crossover after 16 weeks.  No effects of chromium 
were detected on glucose tolerance or on fasting or postprandial 
blood-glucose levels (Sherman et al., 1968). Schroeder et al. 
(1970), while reporting that 2 - 10 mg chromium/day "almost always" 
restored the impaired glucose tolerance in older, non-diabetic 
subjects to normal, found only erratic and mild improvement in 4 
out of 12 diabetic out-patients.  On the basis of these 
observations, Mertz (1969) concluded that chromium should not be 
considered a therapeutic agent for diabetic patients. 

    On the other hand, it was reported in a later study on chromium 
metabolism that chromium administration (500 g/day, for 2 weeks) 
produced a marked improvement in glucose utilization in both 
juvenile and maturity-onset diabetic patients.  Five of the 
patients were followed for more than 1 year after exposure and were 
found to maintain their improved glucose metabolism (Nath, 1976). 

    Of 10 non-diabetic elderly subjects with impaired glucose 
tolerance, 4 responded to 150 g chromium/day with complete 
normalization of oral glucose tolerance tests.  The remaining 6 

subjects were not affected by the supplements (Levine et al., 
1968).  Significant effects of a GTF-chromium-containing yeast 
preparation were reported by Doisy et al. (1976) in 6 out of 12 
elderly subjects with impaired glucose tolerance 
Table 21.  Effect of GTF supplementation on glucose tolerance tests in
elderly subjects with impaired tolerancea,b
-------------------------------------------------------------------------
              Mean plasma-glucose levels       Cholesterol  Triglyceride
                       (mg/litre)              (mg/litre)   (mg/litre)
             0 h         1 h        2 h
-------------------------------------------------------------------------
Before GTF   1060  40c  2010  70  1780  80  2450  90    1210  80
11 tests

After GTF    990  40    1620  110 1320  50  2050  100   1120  120
9 tests

Signifi-     NS          < 0.01     < 0.001     < 0.01      NS
canced
-------------------------------------------------------------------------
                 Mean serum-insulin levels
                      (microunits/ml)        
                0 h         1 h        2 h

Before GTF      24  6      78  17    118  17

after  GTF      26  12     70  8     83  8
-------------------------------------------------------------------------
a  From: Doisy et al. (1976).
b  Supplement: 4 g yeast per min/day (Yeastamin Powder 95, Staley Co.,
   Chicago, Illinois, USA). GTT: 100 g oral load.
c  Mean  SEM.
d  Using paired t test, difference is significant.

    In addition to the improvement in glucose tolerance in the 
presence of a reduced insulin response, plasma-cholesterol 
concentrations were significantly reduced.  Several other 
individual cases are reported in the publication of Doisy et al. 
(1976), all of whom showed a lower serum-insulin response to a 
glucose tolerance test during chromium supplementation. 

    Liu & Morris (1978) performed a similar study on the effects of 
a yeast-chromium supplementation in 27 women, 40 - 75 years old, of 
whom 15 had a normal and 12 an abnormal glucose tolerance test.  In 
11 of the normal subjects (73%), the integrated insulin response 
was significantly reduced from 436 to 335 U/ml ( P < 0.025) during 
supplementation, without a statistically significant change in 
glucose tolerance test. Significant reductions in the total glucose 
response (10 650 - 9820 mg/litre;  P < 0.001) and in the total 
insulin response to glucose were observed in the subjects with 
impaired glucose tolerance (1288 - 831 U/ml;  P < 0.001).  The 
glucose tolerance improved in 7 out of 12 women, but all 12 showed 
a reduction in plasma-insulin. 

    The effects of supplementation of the diet with 200 g 
chromium/day (as chloride) on the glucose tolerance of 76 normal 
adult volunteers was investigated in a double-blind cross over 
study, with each period lasting 3 months.  All 18 subjects entering 
the study with impaired glucose tolerance (serum-glucose equal to 
or greater than 1 g/litre, 90 min after a glucose load), showed 
significant improvement during chromium supplements, but not with a 
placebo, with an average decline in the 90-min serum-glucose levels 
of 180 mg/litre ( P < 0.01) (Anderson et al., 1983b). 

    In another placebo-controlled study, 24 elderly volunteers were 
given a daily supplement of either chromium-rich brewer's yeast or 
chromium-deficient Torula yeast (9 g/day, for 8 weeks).  The 
glucose tolerance of the subjects given brewer's yeast 
significantly improved with a concomitant decrease in plasma-
insulin levels, and a significant decline in plasma-cholesterol as 
well as total plasma-lipids.  No significant changes were observed 
in the control group given the chromium-poor Torula yeast 
(Offenbacher & Pi-Sunyer, 1980). 

    Additional, preliminary studies suggest a specific effect of 
brewer's yeast on individual lipoprotein cholesterol fractions.  
Twenty normal human subjects responded to daily supplementation 
with 18 g of brewer's yeast over a 8-week period with a significant 
reduction in low-density lipoprotein-cholesterol ( P < 0.01) and 
with a simultaneous increase of 14% in the high-density lipoprotein 
( P < 0.01) (Nash et al., 1979). 

    Similar results were observed in a 6-week supplementation trial 
involving 8 physician volunteers, each of whom received 7 g/day of 
brewer's yeast. Low-density lipoprotein-cholesterol declined by 
nearly 18% ( P < 0.01), whereas the high-density cholesterol 
fraction increased by 17.6%, resulting in a significant 
( P < 0.001) decrease in the LDL/HDL ratio of 28% (Riales, 1979). 

    These studies suggest that the primary effect of the 
supplementation must have been an increase in the effectiveness of 
the insulin, because glucose tolerance was maintained or improved 
in spite of lower insulin responses.  It is important to note that 
while the reduction in insulin levels occurred in all cases, an 
improvement in glucose tolerance occurred in only a fraction.  This 
suggests two possible interpretations of all the results discussed 
here, including those showing improvement in glucose tolerance in 
only some of the subjects or no improvement at all.  Lack of a 
response to chromium could suggest that the subjects were not 
chromium deficient and that their impaired glucose metabolism was 
the result of other causes.  Second, they may have responded with a 
reduction in circulating insulin levels, as did all the subjects 
with impaired glucose tolerance in whom the insulin response was 
measured.  Unfortunately, these measurements were not performed in 
the earlier studies. 

8.1.2.2.  Malnourished children

    Chromium deficiency has been implicated as a factor 
contributing to the impairment of glucose tolerance in children 

with protein calorie malnutrition in 3 countries, Jordan, Nigeria, 
and Turkey.  Hopkins et al. (1968) measured intravenous glucose 
tolerance in 10 malnourished infants from the mountainous area of 
Jordan and 9 equally malnourished infants from the valley area.  
They found a severely depressed glucose removal rate of 0.7%/min in 
the first group and a normal rate in the second, 3.8%/min (Table 
22).  The protein intake of both groups prior to hospitalization 
had been identical; it was supplied in the form of a milk powder 
with a chromium content of 18 g/litre, when reconstituted.  
However, analysis of 10 water samples revealed 3 times as much 
chromium in the samples from the valley as in those from the 
mountainous area (0.5 versus 1.6 g/litre).  This suggested the 
possibility of chromium being a major determinant in the glucose 
metabolism of these children, and the effects of supplementation 
were measured in 6 children from the hills, with a severely 
impaired tolerance test.  The morning after oral administration of 
250 g chromium, as CrCl3 x 6H2O, the glucose removal rate had 
markedly improved to 2.9%/min from a pretreatment level of 
0.6%/min.  Similar results were obtained in Nigeria (Table 22); 
these tests also included control children who did not receive 
chromium. 

    The immediate effects of chromium on these children were 
remarkable and different from the lag phase always present in the 
studies on adults.  Equally important, was the short duration of 
the effect of one dose demonstrated in a Jordanian child observed 
for a longer period of time. These observations suggest that a 
marked depletion in chromium stores must have existed in the 
children. 
Table 22.  Significance of the effect of chromium on the impaired glucose
tolerances of malnourished infantsa
---------------------------------------------------------------------------
Subjects                                 Number    Glucose   Significance
                                         of        removal   of
                                         infants   rate      difference
                                                   (%/min)
---------------------------------------------------------------------------
Jordanian infants from hill area with
0.5 g chromium/litre in drinking-water  10        0.7

Jordanian infants from valley with
1.6 g chromium/litre in drinking-water  9         3.8        P < 0.001

Jordanian infants;
initial glucose tolerance test           6         0.6        P < 0.001
after chromium treatment                 6         2.9

Nigerian infants;
initial glucose tolerance test           6         1.2
after chromium treatment                 6         2.9        P < 0.05

Non-treated infants:
Initial glucose tolerance test           5         1.9       not signi-
Repeated glucose tolerance test          5         2.1       ficant
---------------------------------------------------------------------------
a From: Hopkins et al. (1968).
    Similar results were reported from a study in the Istanbul area 
of Turkey (Grson & Saner, 1971).  Fourteen malnourished children 
with an impaired glucose removal rate of 1.71%/min were given 250 
g of chromium (CrCl3 x 6H2O), and a second test was performed 
after 15 h.  The removal rate increased to 3.91%/min ( P < 0.001).  
This average increase was due to a pronounced increase in 9 of the 
children; no change was observed in the remaining 5.  No 
improvement in glucose tolerance occurred in 5 control children 
receiving identical hospital treatment, except for the 
administration of the chromium.  The children receiving the 
chromium supplementation grew significantly more than the control 
children during the following 30 days, with the greatest growth 
rates found in the 9 children who had responded to administration 
of chromium with an improvement in glucose tolerance. 

    The fact that chromium deficiency interacts with protein-
calorie malnutrition only in certain geographical areas was 
confirmed by Carter et al. (1968), who gave chromium 
supplementation (250 g/day as CrCl3 x 6H2O) without effects on 
glucose tolerance in 9 Egyptian children tested. Plasma-chromium 
levels were in the normal range, and chromium levels in 
representative foods were high, ranging from 200 to 390 g/kg.  
These findings suggest that the chromium status of these subjects 
was normal, which would explain the lack of an effect. 

8.1.2.3.  Patients on total parenteral alimentation

    A female patient, maintained on total parenteral alimentation 
since the age of 35 years, developed an unexpected weight loss of 
15% after 5 years combined with peripheral neuropathy, impaired 
intravenous glucose tolerance, in spite of normal insulin response, 
and a decreased respiratory quotient of 0.66.  Insulin treatment 
(45 U/day) was ineffective.  A strongly negative chromium balance 
and low plasma- and hair-chromium levels suggested that the daily 
estimated chromium intake from the infusion fluids of 5.3 g had 
not met the patient's requirement and resulted in chromium 
deficiency. The insulin infusions were stopped and replaced by the 
daily infusion of 250 g chromium (as CrCl3 x 6H2O) for 2 weeks. 
The result was normalization of glucose tolerance and respiratory 
quotient, disappearance of signs and symptoms of neuropathy, return 
to the previous normal body weight, in spite of reduced caloric 
intake, disappearance of the requirement for exogenous insulin, and 
a positive chromium balance.  The nitrogen balance, which had been 
erratic and often negative, became consistently positive following 
chromium supplementation.  Reduction of the daily supplement to 20 
g chromium proved to be sufficient to maintain the patient in a 
state of well-being (Jeejeebhoy et al., 1977). 

    This case is the best demonstrated example of chromium 
deficiency in a human subject.  In addition to confirming the well-
known signs of chromium deficiency reported earlier, such as 
insulin resistance and its consequences, it was the first case to 
demonstrate the occurrence of peripheral neuropathy and disturbance 
of nitrogen balance as a result of deficiency. These disturbances 
require further study.  A second case of chromium deficiency as a 

consequence of long-term total parenteral alimentation was reported 
by Freund et al. (1979). Signs and symptoms were similar to those 
of the first case, except that central encephalopathy was present 
instead of peripheral neural disorder.  Supplementation with 150 g 
of chromium/day resulted in normalization of the deficiency signs.  
Chromium at that time was not routinely added to intravenous 
solutions, therefore it is possible that more cases of deficiency 
may exist in patients on long-term infusion treatment.  As an 
outcome of this study, an Expert Panel of the American Medical 
Association (AMA, 1979) suggested that the stable adult patient on 
total parenteral alimentation should receive 10 - 15 g chromium 
daily. 

8.1.2.4.  Epidemiological studies

    Two epidemiological studies suggest a link between chromium 
status and cardiovascular diseases (Schroeder et al., 1970; Punsar 
et al., 1975).  Lack of chromium is associated with impaired 
glucose tolerance, elevation of circulating cholesterol, and aortic 
plaques.  All of these variables are recognized risk factors for 
cardiovascular disease.  It has also been suggested that the 
elevated insulin levels, often present in chromium-deficient human 
subjects (Liu & Morris, 1978) represent a substantial risk for the 
development of cardiovascular disease (Strout, 1977). 

    Schroeder et al. (1970) have summarized their studies of 
chromium concentrations in normal and diseased tissues, 
particularly in aortas (Table 23).  The total body burden of 
chromium, excluding the lungs, was lower in the USA, where there is 
a higher incidence of cardiovascular disease, compared with other 
regions, 1.72 - 1.86 mg/kg ash weight in the USA compared with 7.7, 
9.6, and 2.7 mg in Africa, the Far East, and the Near East, 
respectively.  The only significant difference in tissue-chromium 
concentrations in deaths from heart disease compared with deaths 
from accidental causes was in the aorta (Table 23).  Concentrations 
in aortas from Africa, the Far and Near East were generally higher 
and did not show such a difference. 

Table 23.  Chromium in aortasa
----------------------------------------------------------
Location                   Chromium (mg/kg dry weight)    
                     Accident       P       Heart disease
----------------------------------------------------------
Africa               0.072 (5)b    NS      0.116 (2)

Far East             0.97  (8)     NS      0.246 (5)

Middle East          0.36  (8)     NS      0.216 (3)

USA (Nine cities)    0.26  (103)   0.005   0.052 (13)

USA (San Francisco)  0.228 (10)    0.005   0.048 (15)
----------------------------------------------------------
a   From: Schroeder et al. (1970).
b   The number in parenthesis denotes the number of cases 
    observed.

    The second epidemiological study was part of a cohort study 
conducted in Finland beginning in 1959 (Punsar et al., 1975). A 
total of 327 drinking-water samples were analysed for 22 
characteristics including pH, anions, bulk minerals, and several 
trace elements including chromium.  The study included 504 and 622 
men in the Western and Eastern areas of Finland, respectively, 
whose domicile had not changed since 1959. 

    The coronary heart disease mortality rate is much higher in the 
east of Finland than in the west.  As seen in Table 24, the 
chromium levels in drinking-water were much lower in the east than 
in the west, whereas the opposite was true for copper.  The metal 
concentrations in the drinking-water of those with heart disease 
and others only differed slightly (Table 24), but, according to the 
authors, the data suggest that low chromium levels may play a role 
in the high heart disease death rate of eastern Finland. 


Table 24.  Concentrations of copper and chromium in the 
drinking-water of men who died between 1969 and 1973, and 
of those who were alive in 1973a
-------------------------------------------------------------
                                           Alive
                    Deaths        (Clinical status in 1969)  
                 CHDb    Other    CHDb     Other    No
                                           heart    heart
                                           disease  disease
-------------------------------------------------------------
  West           N = 19  N = 23   N = 63   N = 31   N = 288

Copper       X   22.15c  20.17    20.05    20.94    20.15
(g/litre)   SD  3.92    4.69     4.69     5.12     4.74

Chromium     X   7.52    9.38     9.45     9.74     8.45
(g/litre)   SD  2.06    3.42     4.01     4.44     3.31


  East           N = 23  N = 26   N = 129  N = 44   N = 279

Copper       X   41.59   41.24    42.67    39.50    36.32
(g/litre)   SD  29.91   30.43    33.65    28.74    28.66

Chromium     X   2.20    2.09     2.04d    2.49     3.01
(g/litre)   SD  2.17    2.41     2.08     2.17     2.37
-------------------------------------------------------------
a From: Punsar et al. (1975).
b CHD = coronary heart disease.
c  P < 0.05.
d  P < 0.001.

 Note: Levels of significance refer to differences observed 
when the concentrations were compared with those in the 
"no heart disease" category. 

    Newman et al. (1978) measured serum-chromium concentrations in 
32 patients, 18 male and 14 female, aged 25 - 65 years, in whom 
coronary artery cine-arteriography was performed for medical 
reasons.  Serum-chromium was significantly lower in the 15 subjects 
with coronary artery disease than in the 17 subjects without 
involvement (2.51 versus 6.09 g/litre;  P < 0.01), whereas serum-
cholesterol, weight index, and systolic or diastolic blood pressure 
did not differ among the groups.  Serum triglycerides were higher 
in the group with coronary artery disease (1.84 versus 1.12 
g/litre;  P < 0.05). No subject with a serum-chromium  
concentration of more than 6 g/litre exhibited coronary artery 
involve- ment, and by regression analysis, serum-chromium was 
judged to explain 17% of the total variance of the disease. 

    These results were independently confirmed in a second study in 
which plasma chromium concentrations of 23 healthy persons were 
more than 8 times greater than those of 67 patients with coronary 
artery disease, as confirmed by cine-angiography (Simonoff et al., 
1984). 

8.1.3.  Mode of Action

    As in experimental animals, the best known action of chromium 
is the potentiation of insulin.  This is shown by the 
supplementation studies of Doisy et al. (1976) and Liu & Morris 
(1978) in which a reduction in insulin levels in response to 
glucose was observed, together with an improvement in glucose 
tolerance.  Direct proof, for example from  in vitro studies with 
human biopsy tissue, has not yet been obtained. Furthermore, it is 
not known whether the potentiation of insulin is responsible for 
all the effects observed during chromium supplementation, including 
the reduction of circulating cholesterol and the growth stimulation 
observed in malnourished children and during parenteral nutrition. 

    In the healthy, chromium-sufficient human subject, chromium 
levels in the bloodstream increases acutely following a glucose 
load or an injection of insulin.  Glinsmann et al. (1966) observed 
acute increases in 5 young, healthy volunteers during a glucose 
tolerance test, but not when the same subjects were given an 
equivalent volume of water.  Maturity-onset diabetic patients did 
not exhibit this chromium response initially, but did show a rise 
in plasma-chromium, after several weeks of chromium 
supplementation.  These observations were confirmed by Levine et 
al. (1968), Hambidge (1971), Behne & Diel (1972), and Liu & Morris 
(1978), who saw the acute chromium rise in some, but not all, 
subjects.  In the study of Liu & Morris (1978), which was the most 
detailed, the relative chromium response (CrR) was measured by 
neutron activation analysis in 15 women with normal glucose balance 
and in 12 with impaired tolerance. 

              (1-h serum-chromium)
       CrR = ------------------------  x 100
             (fasting serum-chromium)

Initially, the normal group had a mild positive response (CrR = 
107), compared with a negative response (CrR = 81) in the impaired 

subjects.  Following three months of supplementation with a 
chromium-rich yeast extract, the CrR of the normal subjects 
increased to 140, and that of the impaired group became positive 
with CrR = 149.  As discussed in section 8.1.2, these changes were 
accompanied by a significant decrease in the insulin response to 
glucose and an improvement in glucose tolerance.  The results of 
these studies are in apparent contrast with those of Davidson & 
Burt (1973), who found a significant decline in plasma-chromium 
levels following a glucose load in normal, non-pregnant women (mean 
age 26 years), but a mild to moderate increase in all but 1 of 10 
pregnant women (mean age 20 years).  As the time of the acute rise 
varied between women, statistical analysis at any one time did not 
produce any significant results.  Hambidge (1971) and Behne & Diel 
(1972) demonstrated an acute plasma-chromium response following 
injection of insulin; it can therefore be assumed that the effect 
of glucose on the chromium response is associated with 
hyperinsulinaemia.  The acute "relative chromium response" is 
believed to reflect the chromium status of human subjects.  It does 
not appear when stores from which the chromium increment must come 
are depleted.  Depleted stores can be replenished by 
supplementation, with a resulting reappearance of the response 
shown in the two previously discussed studies.  As it has been 
shown that chromium levels in urine increase following a glucose 
load (Wolf et al.  1974; Grson & Saner, 1978), it is likely that a 
fraction or all of the chromium increment is subsequently excreted. 

8.2.  Acute Toxic Effects

    In adults, the lethal oral dose of soluble chromates is 
considered to be between 50 mg/kg body weight (RTECS, 1978) and 70 
mg/kg body weight (Deichmann & Gerarde, 1969).  The clinical 
features of toxicity are vomiting, diarrhoea, haemorrhagic 
diathesis, and blood loss into the gastrointestinal tract causing 
cardiovascular shock.  If the patient survives about 8 days, the 
outstanding effects are liver necrosis (Brieger, 1920), tubular 
necrosis of kidneys, and poisoning of blood-forming organs 
(Langard, 1980).  A 14-year-old boy, who had ingested about 1.5 g 
of potassium dichromate, died 8 days later.  Kaufmann et al. (1970) 
also reported enlargement and oedema in the boy's brain. 

8.3.  Chronic Toxic Effects

    The chronic effects of trivalent and hexavalent chromium have 
been reviewed by Langard & Norseth (1979).  The most important 
features are changes in the skin and mucous membranes, and allergic 
dermal and broncho-pulmonary effects. Important systemic effects 
occur in the kidneys, liver, gastrointestinal tract, and 
circulatory system. 

    Mancuso (1951) studied several biological variables in persons 
occupationally exposed to chromate and related them to clinical 
signs and symptoms.  He found occasional leukocytosis or 
leukopenia, monocytosis, eosinophilia, reduced haemoglobin 
concentrations and prolonged bleeding times, but none of them were 
consistent enough to serve as reliable diagnostic tests. 

    Mild normochronic anaemia was reported by Myslyaeva (1965) in 
94 subjects exposed to chromium compounds with 68 of them showing 
signs of chronic toxicity.  Though the report of Baetjer et al. 
(1959b) was based only on 3 cases, it indicated that chromate 
attached preferentially to red blood cells. Koutras et al. (1964) 
reported the inhibition of the red blood cell enzyme gluthathione 
reductase by chromate concentrations of 5 - 25 mg/kg body weight.  
However, the lowest effective dose is far in excess of levels 
found, even in heavily exposed persons. Thus, all attempts made so 
far have failed to identify a specific sensitive biochemical test 
for the assessment of chronic chromium toxicity. 

    Long-term surveillance of pregnant women working at a plant 
producing dichromates and those living in its immediate vicinity 
(Shmitova, 1980) revealed increased chromium levels in the blood 
and urine, compared with those in the control group.  At 32 weeks 
of pregnancy, the blood concentrations of chromium were, 
respectively, 2.5 mg/litre in the women workers, 1.2 mg/litre in 
the women living near the plant, and 0.19 mg/litre in the controls; 
the levels in the urine were 1, 0.47, and 0.045 mg/litre, 
respectively.  Umbilical venous blood contained 1.8, 0.66, and 0.37 
mg chromium/litre, respectively.  The placental chromium contents 
in the surveyed women were 162, 179, and 40 g/kg, respectively, 
and the breast-milk levels were 119, 20, and 31 g/litre, which 
means that chromium is capable of transplacental entry into breast 
milk and into the fetal and infant organism.  Women working at the 
bichromate plant exhibited a high incidence of obstetric pathology 
and geotoses.  Chromium levels were estimated in fetal and 
placental tissues (abortive material) derived on the 12th week of 
pregnancy from women workers of the dichromate facility and those 
not exposed to chromium.  In the test group, chromium levels were 
1140 g/kg in the fetal tissues and 135 g/kg in the placental 
tissue, whereas, in the controls, they were 928 and 30 g/kg, 
respectively.  No teratogenic effects have been revealed (Shmitova, 
1980). 

8.3.1.  Effects on skin and mucous membranes

    Several different types of effects on skin and mucous membranes 
may result from exposure to chromium chemicals, and the main 
features are: 

    (a) primary irritation: ulcers (corrosive reactions),
        scarred and non-ulcerative contact dermatitis;

    (b) allergic contact dermatitis: eczematous and
        noneczematous.

    A general survey of the nature and cause of contact dermatitis 
is given by Fregert (1981). 

8.3.1.1.  Primary irritation of the skin and mucous membranes

    (a)   Skin

    Skin irritation, manifested by a sharp hyperaemia as well as by 
vesicular, papular, and rash pattern, may result from contact with 
chromates.  However, the major problems in the primary irritation 
dermatoses are ulcers, often called chrome holes or chrome sores.  
Ulceration is likely to occur among workers who have contact with 
high concentrations of chromic acid, sodium or potassium dichromate 
or chromate, or ammonium dichromate.  It does not result from 
contact with trivalent chromium compounds.  An ulcer may develop if 
the chromium compound, either a dust or a liquid, comes into 
contact with any break in the skin such as an abrasion, scratch, 
puncture, or a laceration.  Favoured sites for ulcer development 
are the nailroot areas, the creases over the knuckles, finger webs, 
the backs of the hands, and the forearms (Bloomfield & Blum, 1928). 

    Primary irritation by chromium can be attributed to hexavalent 
chromium, as the salts of trivalent chromium are not considered 
capable of producing such effects (Fregert, 1981).  However, 
prolonged exposure to trivalent chromium salts has been reported to 
cause skin lesions, less marked than those following exposure to 
hexavalent chromium salts (Domaseva, 1971).  Findings in 164 
patients with eczema showed that skin tests on people who had 
contact with trivalent chromium did not give positive results with 
dichromate (Valer & Racz, 1971). 

    Ordinarily, a chrome sore, if not deep, persists for about 3 
weeks after exposure is discontinued.  There is no evidence that 
the ulcers undergo malignant transformation. Furthermore, the 
presence of chromium ulcers did not influence the development of 
sensitization to chromates (Edmundson, 1951), evidenced by patch 
testing with a 0.5% solution of K2Cr2O7. 

    (b)   Nasal septal mucosa

    Perforation of the nasal septum was one of the main chronic 
effects in workers who had contact with chromates and chromic acid 
(Bloomfield & Blum, 1928; Langard & Norseth, 1979).  In a group of 
100 persons constantly in contact with chromium compounds, 44 had 
superficial ulceration of the anterior nasal septal mucosa.  
Twenty-one people had profound ulcers and 5 had perforations of 
various sizes in the cartilaginous part of the nasal septum.  
Perforation of the nasal septum and cicatricial alterations were 
observed in people with 3 or more years of service, whereas 
ulcerous lesions arose in 2 years of work with chromium compounds.  
An additional consequence of the effect on the nasal mucous 
membranes is a loss of the senses of smell and taste (Seeber et 
al., 1976).  In workers with profound ulcerous lesions of the nasal 
septal mucosa, strains of white staphylococcus with elevated 
resistance to chromium are sometimes isolated (Cherevaty et al., 
1965). 

    Pokrovskaya et al. (1976) studied 561 workers engaged in the 
open excavation of chromium ores (chromium content was 62% in the 
form of a complex compound of magnesium chromite and other chromium 
ores).  Almost half of the workers had worked there for more than 5 
years, and about 40% had been working there for 6 - 15 years.  
Changes in the nasal septal mucosa, typical of the effect of 
chromium compounds, were found in 8.2% of the workers.  The longer 
the service record, the greater the prevalence of these lesions.  
After 5, 11, and 15 years of work, the prevalence was 2.3%, 8.3%, 
and 11.2%, respectively. 

    The prevalence of nasal septum perforation in chromium plating 
workers was very high (24%) in the early 1950s in China (Yang, 
1956).  With the introduction of control measures, the prevalence 
dropped so that, in 1982, only 2 cases of nasal septum perforations 
were found among 393 chromium-exposed workers (Peng, 1982). 

    One hundred and four subjects (85 male, 19 female) exposed to 
chrome plating and 19 unexposed controls were studied by Lindberg & 
Hedenstierna (1983) with regard to changes in the nasal septum.  
Exposed subjects were employed at 13 different companies and 
included all who were working on the day of study at the particular 
company.  The median exposure time was 4.5 years (range, 0.1 - 36 
years).  Forty-three subjects were exposed almost exclusively to 
chromic acid and constituted both a "low exposure" group (8-h mean 
below 2 g/m3, N = 22) and a "high exposure" group (2 g/m3 or 
more, N = 21).  Their median exposure time was 2.5 years (range, 
0.2 - 23.6 years). The other 61 subjects were exposed to a mixture 
of chromic acid (0.2 - 1.7 g/m3) and other pollutants, such as 
nitric, hydrochloric, and boric acids, as well as caustic soda, 
nickel, and copper salts.  The last group was included to disclose 
any additive or synergistic effects of chromic acid and other 
pollutants and was studied with regard to lung function only.  The 
breakdown of subjects into various groups is shown in Table 25.  
Nasal septal ulceration and perforation were seen in 10 out of 14 
subjects exposed to peak levels of 20 - 46 g chromic acid/m3 or 
more; no one in the control group showed signs of atrophy, 
ulcerations, or perforations. 

8.3.1.2.  Allergic contact dermatoses

    Chromium is a very important skin sensitizer.  Sensitization 
is reported to require about 6 - 9 months, but can occur in less 
than 3 months (Piril & Kilpio, 1949).  Genetic factors appear to 
contribute to the appearance of chrome sensitivity within the 
Jewish population (Wahba & Cohen, 1979). 

    Apart from the primary irritation and ulceration effects, 
direct contact with small amounts of the chromates may cause 
allergic dermatosis (dermatitis and eczema).  As this allergic 
reaction is cell-mediated, i.e., antibody formation is intra-
cellular and not humoral, delayed allergic reactions are rarely 
observed. 

    Fregert et al. (1969) reported that the skin-patch test for 
chromium was positive in 8 - 15% of all patients suffering from 
eczema.  The dermatitis caused by chromium is described as a 
diffuse erythematous type with severe cases progressing to an 
exudative stage.  Persons sensitive to chromium react to patch and 
intracutaneous tests with nonirritant concentrations of potassium 
dichromate (K2Cr2O7).  Opinion is divided about the role of the 
oxidation state of chromium as a causal agent in allergic contact 
dermatoses (Morris, 1958; Fregert & Rorsman, 1964; Kogan, 1971).  
In a review, Polak et al. (1973) showed that hexavalent chromium, 
which penetrates the skin by a direct effect of a hapten, is 
reduced to the trivalent state, chiefly by sulfhydryl groups of 
aminoacids.  It then conjugates with proteins thus forming the full 
antigen that initiates sensitization. 

    Guinea-pigs sensitized with either trivalent chromium chloride 
or hexavalent potassium dichromate are capable of reacting  in vivo 
and  in vitro to challenges with both chromium salts.  This double 
reactivity is also found after repeated stimulation with only one 
of these chromium compounds.  Since it is not possible to select 
lymphocytes directed specifically against a chromium determinant of 
a particular valence, it is concluded that, by sensitization with 
chromium salts of different valences, a common determinant or 
closely related determinants are formed.  It is suggested that this 
determinant is formed by chromium in the trivalent form 
(Siegenthaler et al., 1983). 

    Two to three years after medical treatment, a follow-up study 
on 555 patients with contact dermatitis was completed by means of 
questionnaires (Fregert, 1975).  The eczema had healed in one-
quarter of the patients, one-half had periodic symptoms, and one-
quarter had permanent symptoms.  The prognosis for persons who 
changed their work or stopped working was the same as that for 
those who continued eczema-inducing work. 

    From 48 positively tested patients (0.5% potassium dichromate), 
38 persons, i.e., 79%, still had a positive patch test after 4 - 7 
years.  In 72% of the cases, a history of occupational exposure to 
chromates could be proved (Thormann et al., 1979). 

    A fairly rapid transformation of dermatitis into eczema is a 
characteristic feature of chromium-induced skin lesions. Kogan 
(1971) recognized the following important properties: (a) absence 
of adaptation, which makes it necessary to discontinue chromium 
handling until the slightest clinical manifestations have 
disappeared; (b) a persistent chronic development of an eczematous 
process; (c) a long-term latent period; and (d) absence of a direct 
correlation between the incidence of sensibilization in the exposed 
workers and the chromium concentration to which they have been 
exposed.


Table 25.  Series of exposed subjects and referencesa
--------------------------------------------------------------------------------------------------------
                                  Exposed subjects                            
                                                        Mixed exposure to
               Low exposure to    High exposure to        chromic acid
                chromic acid        chromic acid      (< 2 g/m3) and other
             (< 2 g Cr6+/m3)    (> 2 g Cr6+/m3)     acids and metallic salts   References
             -----------------   ------------------   -----------------------    -----------------
             Nb   Age (years)c   N    Age (years)     N     Age (years)          N    Age (years)
--------------------------------------------------------------------------------------------------
Men
Non-smokers  10   35.8  16.7    6    33.4  14.1     12    33.6  12.2          52   34.2  13.2
Smokers      6    30.8  9.7     16   30.2  11.8     36    42.8  13.1          67   30.5  8.9

Women
Non-smokers  3    30.7(17-46)    0                    9     48.3  13.0
Smokers      2    44.5(29-60)    1    51.2            4     31.0(19-43)
--------------------------------------------------------------------------------------------------
a  From: Lindberg & Hedenstierna (1983).
b  When N < 5, the range is given instead of SD.
c  X  SD.


    Patients suffering from chromium-induced allergic skin 
dermatoses had a tendency to develop cross-correlated hyper-
sensitivity to other metals, in particular, to cobalt and nickel 
(Rostenberg & Perkins, 1951; Geiser et al., 1960; Clark & Kunitsch, 
1972; Kogan et al., 1972). 

    Increased sensitivity to chromium is proved by skin reaction 
tests.  In a number of cases, additional immuno-haematological 
bioassays are made to confirm the specificity of these tests.  A 
method for studying the basophil (mast-cells) degranulation  in vivo, 
at the site of positive compress skin tests, was suggested by Kogan 
(1968).  The method was used as a basis for proving the specificity 
of cutaneous tests for chromium and other sensitising metals of the 
chromium group (cobalt and nickel) (Kogan, 1968; Kogan et al., 
1972). 

    Photosensitivity is sometimes observed in patients with chronic 
dermatitis.  Wahlberg & Wennerstein (1977) investigated patients 
allergic to chromium, with or without clinically observed light 
sensitivity, by a standardized photopatch test procedure.  A 
significantly more intense reaction was observed in 48% of the 
cases in the UV-irradiated sites (4/5 minimal erythema dose) 
compared with the non-irradiated control sites. 

    No cases of cancer of the skin have been reported to result 
from exposure to any form of chromium (Fregert, 1981). 

8.3.2.  Effects on the lung

    Airborne chromium trioxide is rapidly absorbed in the broncho-
pulmonary tract causing corrosive reactions (Borghetti et al., 
1977).  The absorption of chromium aerosols may depend on the 
physical and chemical properties of the particles (Taylor et al., 
1965), as well as on the  activity of alveolar macrophages, and the 
lymphatic drainage (Sanders et al.  1971). 

    Both Jindrichova (1978) and Keskinen et al. (1980) reported 
that welders using chromium-containing electrodes suffered from 
bronchitis.  Zober (1982) studied arc welders who had used filler 
metals containing chromium and nickel for some years.  Compared 
with controls, the welders reported more previous ailments of the 
respiratory system, mainly in the form of acute bronchitis.  In 
X-rays of welders, more roundish shadows were found, probably 
indicative of benign accumulations of ferrous dust.  The greater 
incidence of significant findings was clearly apparent in welders 
who smoked (probably a combined effect of tobacco smoke and welding 
fumes). Reggiani et al. (1973) studied 101 electroplaters by means 
of spirometric tests and found an obstructive disease pattern in 
13% of them.  After inhalation of acetylcholine, a bronchospastic 
reaction occurred in 23% of the workers.  In another spirometry 
study (Bovet et al., 1977) on 44 chromium electroplaters, an 
obstructive respiratory syndrome was found among the workers with a 
high urinary-chromium content.  The authors concluded that the 
influence of tobacco smoking on the spirometric tests was much less 
than the influence of chromium. 

    Studying lung function and generalized obstructive lung 
diseases in electrofurnace workers in a ferrochromium and 
ferrosilicon-producing plant, Langard (1980b) found a reduced 
forced vital capacity (FVC) and an increased prevalence of 
obstructive lung diseases.  Unable to document a connection between 
the presence of chromates and increased lung diseases, the author 
suggested that the effects were due to high levels of total dust, 
especially amorphous silica dust. 

    Lindberg & Hedenstierna (1983) studied lung function in more 
than 100 subjects exposed to chrome plating and in 119 car 
mechanics as controls (no car painters or welders).  In the exposed 
subjects, FVC and the forced expired volume in one second (FEV1) 
were both reduced by 0.2 litre, and the forced mid-expiratory flow 
was reduced by 0.4 litre/second.  The authors concluded that an 8-h 
mean exposure level of more than 2 g/m3 might cause a transient 
decrease in lung function. 

    Pneumoconiosis was diagnosed in Germany (Letterer et al., 1944) 
and again in chromite miners in South Africa (Sluis-Cremer & du 
Toit, 1968).  However, American medical officers could not confirm 
this feature when examining 897 workers in chromate-producing 
plants in the USA (US PHS, 1953).  It should be noted that chromium 
dusts had a poor fibrogenic potency in experimental animal studies 
(section 7.2.1.5). Davies (1974) X-rayed workers employed in the 
manufacture of ferro-chrome and found results similar to miliary 
lung tuberculosis.  The workers were in the immediate area of the 
furnace and were exposed to dust-particles, 90% of which were less 
than 2 m in diameter.  The dust deposited on girders consisted of 
95% SiO2 and 2.4% Cr2O3.  The author did not find any symptoms or 
signs of tuberculosis, but there was sufficient evidence to 
indicate an inhalation hazard in the ferro-chrome industry, thus 
underlining earlier observations of Princi et al. (1962). 

8.3.2.1.  Bronchial irritation and sensitization

    Chromium irritates mucous membranes, as has been seen with 
exposure to airborne chromium trioxide fume (Meyers, 1950) or mixed 
dust (Card, 1935; Broch, 1949; Williams, 1969).  The first symptom 
was an irritating cough, 4 - 8 h after exposure. Chromium causes 
sensitization that can result in asthmatic attacks.  These can last 
for 24 - 36 h, without treatment (Langard & Norseth, 1979).  An 
attack may recur on later exposure, even when this exposure is to a 
much lower concentration (US NAS, 1974a). 

    A double-blind experimental exposure study on an asthmatic 
patient, who had been exposed to chromium and nickel, showed that 
chromium was the main cause of the asthma (Novey et al., 1983).  
Keskinen et al. (1980) pretreated their patients, stainless steel 
welders, with both disodium cromoglycate and betamethasone and 
found an inhibition of this reaction. Placebo medication failed to 
produce this inhibition. 

8.3.3.  Effects on the kidney

    In the early part of this century, chromates and chromic acid 
were occasionally used as therapeutic chemicals for some skin 
lesions.  Fatal cases of acute nephritis occurred with albumin, 
hyaline, and granular casts and red cells appearing in the urine, 
accompanied by oliguria.  Autopsies revealed tubular necrosis, but 
not glomerular damage (Kaufman et al., 1970).  Acute toxic 
gastroenteritis developed, followed by arterial hypotonia, in 
suicide cases a few hours after swallowing 1.5 - 10 g potassium 
dichromate.  Within 2 - 4 days, all patients developed signs of 
acute renal insufficiency with oliguria, anuria, and hyperhydration 
and also evidence of acute toxic hepatitis (Luzhnikov et al., 
1976). Kidney damage has also occurred in industry, as a result of 
accidental exposure of the skin to large amounts of chromate, 
especially when associated with extensive skin damage (Luzhnikov et 
al., 1976). 

    The mortality from kidney diseases among workers in the 
chromium industry does not appear to have increased.  In one study, 
no deaths from nephritis and uraemia were found in 4 chromate-
producing plants; in only 1 plant was the mortality rate above that 
for the controls (Machle & Gregorius, 1948). Hayes et al. (1979) 
reported that 4 deaths from nephritis and nephrosis had occurred 
between 1945 and 1977 in workers in a chromate-producing plant, 
compared with 4.95 cases in the control population.  Satoh et al.  
(1981) found one case of nephritis and nephrosis in a group of 
chromate workers compared with an expected number of 2.18. 

    Some authors (Franchini et al., 1975; Borghetti et al., 1977; 
Gylseth et al., 1977; Tola et al., 1977) have concluded that 
urinary excretion and renal clearance of diffusible chromium can be 
used as biological indicators for evaluating the extent of exposure 
to airborne chromium and the body burden.  However, a dose-effect 
relationship could not be established between duration of exposure 
and either the level of chromium excretion (Tandon et al., 1977) or 
early nephrotoxic indicators (Mutti et al., 1979).  A dose-
response relationship for hexavalent chromium effects on the kidney 
was described by Mutti et al. (1979), measuring beta-glucuronidase, 
protein, and lysozyme in the urine.  Abnormal patterns were not 
observed in 39 stainless-steel welders during 4.5  3.2 years of 
exposure.  In another group of workers employed in welding armoured 
steel with special electrodes for 1  0.4 years, 22% showed an 
increase in beta-glucoronidase and 10% in protein in the urine.  In a 
study on 24 workers in the chromium-plating industry who were 
exposed for 8.9  7.3 years, the authors found increased urinary 
levels of beta-glucoronidase in 37% of the workers, an increase in 
protein in 17%, and an elevated level of lysozyme in 4%.  Urinary 
beta2-microglobulin was also studied by Lindberg & Vesterberg (1983b) 
in chromeplaters (24 males, mean age 36 years, working in 4 
different factories).  The exposure was measured using personal air 
samplers.  The 8-h mean value ranged between 2 and 20 g hexavalent 
chromium/m3 and averaged 6 g/m3.  Most of the workers showed 
symptoms of airway irritation, 2 of them had ulcerated nasal septum 
and another 2, complete perforation.  Significantly higher urine 

beta2-microglobulin levels (0.23 mg/litre; range, 0.04 - 1.24 mg/litre; 
SD, 0.27) were found in this group of workers in comparison with a 
reference group of workers of a comparable age (mean age, 38 years; 
mean urinary beta2-microglobulin level, 0.15 mg/litre; range, 0.06 - 
0.19 mg/litre; SD, 0.08).  A relationship was observed (Table 26) 
between the range of exposure and prevalence of urinary beta2-micro- 
globulin levels exceeding 0.3 mg/litre.  The 2 workers with 
perforated nasal septum were in the highest exposure group.  A 
difference in urinary beta2-microglobulin levels was not found between 
a group of workers employed several years earlier in an old 
chromeplating plant (mean, 0.25 mg/litre) and a group of workers of 
comparable age (mean, 0.29 mg/litre), but it should be noted that 
the mean age of both these groups exceeded 52 years. 

Table 26.  beta2-microglobulin U-beta2 levels in urine of workers
related to present exposure levelsa
-------------------------------------------------------------------------
Plant  Exposure  Number  Age     Persons with an "elevated"  U-beta2
No.    range     of      (mean)  (U-beta2 > 0.30 mg/litre)   range
       (g/m3)   workers         concentration               (mg/litre)
                                 No.    Ages
-------------------------------------------------------------------------
1      11 - 20   5       39      3      21, 37, 58           0.23 - 1.30
2 - 3  14 - 8    13      37      2      20, 21               0.04 - 0.44
4      2 - 3     6       6       -      -                    0.06 - 0.18
-------------------------------------------------------------------------
a From: Lindberg & Vesterberg (1983b).

8.3.4.  Effects on the liver

    Statistics on diseases of the liver are seldom published 
separately; they are usually included in the group of diseases of 
the digestive system.  The chromate industry was reported to have 
the same rate in this group of diseases as many other industries 
(US PHS, 1953).  The Federal Security Agency in the USA 
investigated 14 chromate workers reported to have "enlarged livers" 
but found that these cases were not related to the time spent in 
the industry.  Acute hepatitis with jaundice was described in one 
worker employed in a chromium-plating plant. 

    In an epidemiological study, Satoh et al. (1981) reported a low 
rate of cirrhosis of the liver in chromium workers and liver 
function test results that did not differ significantly from those 
of the controls. 

    However, following ingestion of high doses of potassium 
dichromate, liver necrosis (Brieger, 1920) and congested liver 
(Kaufman et al., 1970) with loss of its architecture have been 
described.  There are also case studies of liver function and 
histology in electroplaters (Pascale et al., 1952) and chromate 
chemical plant workers (Etmanova, 1965), but the results are 
difficult to interpret. 

8.3.5.  Effects on the gastrointestinal tract

    The following symptoms and signs were reported in workers 
engaged in the production of chromium salts (Sterekhova et al., 
1978): hyperchlorhydria, elevated pepsin and pepsinogen level, 
oedema, hyperaemia and erosion of the mucosa, polyposis, 
dyskinesia, and gastritis.  However, Satoh et al. (1981) reported 
that the incidence of peptic ulcer in chromate workers was below 
the expected rate, and another study showed that the mortality rate 
for diseases of the digestive system was lower in chromate workers 
than in the control population (Hayes et al., 1979). 

    The gastric juice has been shown to play a role in the 
detoxification of ingested hexavalent chromium by reducing it to 
trivalent chromium, which is poorly absorbed and eliminated with 
the faeces (Donaldson & Barreras, 1966; DeFlora & Boido, 1980). 

8.3.6.  Effects on the circulatory system

    A clinical study was performed by Kleiner et al. (1970) on 
myocardial function in more than 200 workers in the potassium 
chromate industry, suffering from pulmonary or gastrointestinal 
diseases, attributed by the authors to chromium poisoning.  A 
control group of 70 healthy individuals was included.  Pathological 
changes in the ECG and in other tests of heart function indicated 
disturbance of right heart function, which the authors considered 
secondary to the pulmonary pathology.  The full paper was not 
available and, consequently, the data could not be evaluated in 
detail.  It should be noted that no unexpected findings in 
cardiovascular mortality were cited in the epidemiological studies 
described in section 7.3.9. 

8.3.7.  Teratogenicity

    The only human data available concerning this topic were 
reported in an abstract (Morton & Elwood, 1974).  The authors did 
not find any correlation between frequency of malformations in the 
central nervous system and the chromium content in water samples 
collected in South Wales.  Furthermore, Suzuki et al. (1979) did 
not find any indication of accumulation of chromium in fetal 
tissues. 

8.3.8.  Mutagenicity and other short-term tests

    Few reports exist dealing with chromium-induced mutagenicity in 
human subjects, and only hexavalent chromium causes any effects. 

    Bigaliev et al. (1978) found a 3 - 8% increase in chromosomal 
aberrations of peripheral blood leukocytes in workers handling 
chromium-compounds, compared with 2% in unexposed controls. 

    When classified according to the Papanicolaou system, 
cytological samples of the sputum of 116 workers in the chromate-
production industry did not show any stages of tumour development 

(Maltoni, 1976).  However, intermediate stage lesions found in 30 
workers were described as atypical adenomatous proliferation, 
squamous-cell, and basal-cell dysplasia. 

    Studying cultured lymphocytes obtained from workers 
occupationally exposed to CrO3, Sarto et al. (1982) found an 
increased frequency of sister chromatid exchanges compared with 
controls, which was correlated with urinary-chromium levels and 
enhanced by smoking habits. 

8.3.9.  Carcinogenicity

8.3.9.1.  Lung cancer

    (a)   Epidemiological studies in chromate-producing plants

    The first recognition that cancer of the respiratory tract 
might be related to chromium exposures resulted from the reporting 
in 1932 of 2 cases of bronchogenic carcinoma that had occurred in 
an old German chromate chemical plant (Lehmann, 1932).  Gross & 
Klsch (1943) reported 10 deaths from lung cancer in small plants 
producing the chromates of lead and zinc.  By 1947, 52 such cases 
had been reported from this industry and 10 cases from a chrome 
pigment plant, also in the Federal Republic of Germany (Baetjer, 
1950a). 

    The first epidemiological study was reported in the USA in 
1948.  The mortality data were based on the records of the group 
life insurance policies of 6 chromate-producing plants in the USA 
compared with similar data from a non-chromium industry or from a 
life insurance company.  The study reported that 21.8% of all 
deaths between 1938 and 1947 in the chromate plants were due to 
cancer of the respiratory tract compared with 1.4% in the control 
group.  The crude death rate for cancer of the bronchi and lungs 
was 28 times that for the control groups (Machle & Gregorius, 
1948).  In one of these plants (Mancuso & Hueper, 1951), the cancer 
death rate was 15 times that of the general population in the 
county where the plant was located.  The US PHS (1953) also studied 
the respiratory cancer risk in these 6 plants and estimated a 
relative risk of 28.9 using the average cancer mortality rates for 
US males between 1940 and 1948 as a comparison. 

    In addition to these studies, where the cause of death was 
taken from insurance or death certificate records, a case-control 
study, using only cases diagnosed by autopsy or biopsy, was 
conducted by Baetjer (1950b).  Two hospitals near the largest 
chromate plant in the USA were asked to supply the histories of all 
cases diagnosed in 1924-46 as cancer of the lung bronchi, and to 
confirm histopathologically.  A group of non-cancer cases matched 
individually by age, sex, and date of admission was selected as 
controls.  Of the 290 confirmed cancer cases, 3.26% had been 
employed in the chromate plant, whereas none of the 900 control 
cases was found to have had chromate exposure.  The percentage of 
chromate workers in the lung cancer series was 28.6 times the 

percentage of chromate workers among the employed male population 
of the city.  The plant involved in this study was rebuilt in 1950, 
following the discovery of the cancer problems.  A new study of 
this plant was made by Hayes et al. (1979) to determine whether the 
risk of cancer had been eliminated.  The investigation covered 438 
deaths among 2101 males, who were initially employed between 1945 
and 1974 for more than 90 days, and who died between 1945 and 1977.  
The SMRa for malignant neoplasms of the trachea bronchi and lungs 
was 202.  Cancer deaths in the city in which the plant was located 
were used to calculate the expected number of cases.  No cases of 
respiratory cancer occurred in the plant between 1960 and 1977 
among workers employed only in the new plant.  Because of the long 
latent period, further follow-up is necessary. 

    Increased lung cancer rates among chromate workers in the USA 
have been confirmed by Taylor (1966), Enterline (1974), and Mancuso 
(1975), who also showed that the risks were especially high during 
the early years of the study of the cohorts, e.g., before 1950.  
Studies conducted in other countries have shown similar results.  
In a 1956 study on workers in chromium-producing plants in the 
United Kingdom, the rate of lung cancer mortality was 3.6 times the 
rate for England and Wales (Bidstrup & Case, 1956).  In a follow-up 
study on 2715 men who had worked at the 3 chromate-producing 
factories in the United Kingdom from 1948 to 1977, Alderson et al. 
(1981) found 116 deaths from lung cancer (expected, 48). Since 
modification of the one plant that is still in operation, the 
relative risk of lung cancer has decreased from over 3 to about 
1.8. 

    Two epidemiological studies have been conducted in the Japanese 
chromate industry.  In one plant, 5 lung cancer deaths occurred 
between 1960 and 1973 in 136 workers who had been exposed for more 
than 9 years; the SMR was 1510 (Watanabe & Fukuchi, 1975).  In 
another plant, the mortality rate for respiratory cancer was 
determined for 896 males who worked in the plant from 1918 to 1975 
and were followed to 1978; the SMR was 920 (expected deaths based 
on 1975 age-cause-specific mortality rates for Japanese males) 
(Satoh et al., 1981). 

    In the Federal Republic of Germany, a study was conducted in 2 
chromate-producing plants (Korallus et al., 1982). Comparing the 
SMR for lung cancer during the period 1948-79 for these 2 groups, a 
clearly decreasing tendency was observed.  In the first plant, for 
1948-52, the SMR was 512 and, for 1978-79, it was 98; for the other 
plant, the corresponding figures were 1905 and 150, respectively. 

    The newest data indicate a decreasing risk approaching the 
frequency in unexposed people (Korallus & Loenhoff, 1981). This is 
a result of occupational hygienic and technological measures, 
especially of a change in manufacture namely the "on line" 
--------------------------------------------------------------------
a   The SMR (standardized mortality ratio) is the ratio of
    observed to expected deaths times 100.

processing of the chrome ore, which has minimized the contents of 
the carcinogenic hexavalent chromium compounds within the process 
(Korallus et al., 1982). 

    Bittersohl (1972) described the results of a study on 30 000 
employees of a large chemical unit for the period 1921-70 in the 
German Democratic Republic.  In particular, 588 malignancies in men 
and 170 in women were evaluated for the period 1957-70.  In 1971, 
108 new malignancies in men and 29 in women came to light.  In a 
chromate factory, the rate of all cancers was far above average.  
The factory manufactured catalysts through the reaction of chromic 
acid and iron (III) oxide and nitric acid. The airborne 
concentrations of chromium were not reported in detail, but it was 
stated that short-term exposures above 400 g/m3 occurred.  The 
incidence of malignant neoplasms in employees in the chromate 
factory was 852 per 10 000 employees.  In "unexposed" personnel, 
the incidence of malignant neoplasms was 84 per 10 000 employees. 
Approximately 86% of all those with malignant neoplasms were 
smokers, and 78% of those without malignant neoplasms were also 
smokers, indicating that smoking is not likely to be a confounding 
factor. 

    In the USSR, a high incidence of cancer of the lungs was 
reported for men engaged in the production of chrome salts. The 
ratio of lung cancer in the plant to that in the control population 
was 6.4 for ages 50 - 59 (748 observed, 116 expected) and 15.7 for 
ages 60 - 69 (2657 observed, 170 expected) (Tyushnyakova et al., 
1974). 

    A survey was conducted in China in 1982 to investigate the 
problem of lung cancer among chromate-producing workers.  It 
covered 7 cities and included 2184 male and 798 female workers who 
had worked for at least one year in the industry.  The preliminary 
report revealed that 11 of the 101 deaths among male workers were 
due to lung cancer, but none of the 13 deaths among female workers 
was due to this cause.a

    (b)   Epidemiological studies - chrome pigment industry

    The first epidemiological study, conducted in 1973, covered 3 
small chrome pigment-manufacturing plants in the USA.  The 
percentage of lung cancer deaths was tentatively reported to be 
about 3 times that in unexposed workers (Equitable Environmental 
Health Inc., 1976). 

    Lung cancer mortality was studied among 1152 men working at 3 
chromate pigment factories in the United Kingom from the 1930s or 
1940s until 1981 (Davies, 1979, 1984).  Among workers at factory A, 
which produced both zinc and lead chromates, entrants to the 
factory between 1932-45 with high and medium exposures had excess 

---------------------------------------------------------------------------
a   Report of an Investigation Team for Cancer in Chromate
    Workers (1983).

risks of lung cancer (SMR = 223).  A similar excess was seen in 
1946-54 entrants, but the excess risk fell just short of 
statistical significance.  Highly significant excess risks of lung 
cancer were seen among 1947-64 entrants that had high or medium 
exposures at factory B, which also produced lead and zinc 
chromates.  Excesses were more severe in workers employed for more 
than 10 years.  In factory C, which produced only lead chromate, no 
excess of lung cancer was found.  However, the number of workers 
and the power of the study were small. 

    Twenty-four male workers, who had been employed in a small 
Norwegian company for more than 3 years between 1948 and 1972, were 
identified and followed up by Langard & Norseth (1975), because 
their principal exposure was to zinc chromate dust (measured 
routinely with readings occasionally up to 0.5 mg hexavalent 
chromium/m3).  By December 1980, 6 cases of lung cancer had been 
diagnosed, giving a relative risk of 44 compared with that of the 
general population in the country. The authors stated that 5 out of 
the 6 patients were smokers and only one had been exposed to 
chromates other than zinc chromates (Langard & Vigander, 1983). 

    Sheffet et al. (1982) undertook a detailed mortality study on 
workers employed in a pigment plant in Newark, where lead and zinc 
chromates were used.  Observed deaths from each cause among 1296 
white and 650 non-white males employed between 1940 and 1969, were 
compared with expected deaths, as computed from cause-, age-, and 
time-specific standard death rates for the USA.  A  statistically-
significant  relative risk  of  1.6  for lung cancer among white 
males, employed for 10 years or more, was found.  A relative risk 
of 1.9 was noted for individuals employed for at least 2 years, who 
were at least moderately exposed to chromates. 

    An epidemiological study covering several centres in Europe was 
conducted by Frentzel-Beyme (1983).  This study was designed to 
quantify the mortality from cancer and other diseases among workers 
in European factories producing chromate pigments (3 German, 2 
Dutch factories).  Observed deaths in factories were compared with 
expected deaths calculated on the basis of mortality figures for 
the region in which a given factory was located.  The overall 
mortality did not deviate from the expected rates.  Lung cancer 
rates were always in excess of expected numbers, but only in one 
cohort was the excess statistically significant.  The pattern of 
duration of exposure indicates that the lung-cancer risk was not 
clearly correlated with length of employment. 

    A slight excess of lung cancer risk in chrome pigment (zinc 
chromate) spray painters from 2 maintenance bases in the USA was 
reported by Dalager et al. (1980).  Among the 202 deaths 
identified, 21 were due to respiratory cancer (11.4 expected; 
comparison population: proportionate mortality, US males).  No 
statistically significant excess of lung cancer was found in a 
group of automobile painters in which 226 deaths, including 22 
cancer cases, were analysed using proportionate mortality for areas 
in which the plants were located as a comparison (Chiazze et al., 
1980). 

    (c)   Epidemiological studies - ferro-chrome industry

    Langard et al. (1980) reported that 7 cases of bronchogenic 
carcinoma occurred among 976 workers, who started work before 
January 1, 1960.  The expected number was 3.1 using national rates, 
1.8 using local rates, and < 1 when using an international 
reference rate for comparison.  The difference was not significant 
for the national and local rates, but was significant for the 
international rate. 

    A study in Sweden did not reveal any significant excess of 
respiratory cancer in ferro-chrome workers (Axelsson et al., 1980).  
The incidence of cancer among 1932 workers employed for at least 
one year between 1930 and 1975 was compared with the expected 
number based on the National Cancer Registry data for the county in 
which the plant was located.  Five cases of respiratory cancer were 
found against an expected 7.2 cases. 

    An excessive rate of lung cancer was reported for a ferro-
chrome plant in Russia (Pokrovskaya & Shabynina, 1973). The number 
of deaths from cancer between 1955 and 1969 was higher than that in 
the town in which the plant was located. The authors considered 
that both hexavalent and trivalent chromium exposures were 
responsible for the excess, since similar excessive rates were 
found in a nearby ore-crushing plant, where only trivalent chromium 
was present. The number of cases and the rates involved in these 
studies were not given. 

    Hexavalent chromium is produced in some types of welding. In 
section 7.2.1.2, it was mentioned that welding fume particles were 
positive in the mammalian spot test, indicating a mutagenic and 
possible carcinogenic potential. The incidence of lung cancer was 
determined by Sjgren (1980), in a cohort of 234 welders, who had 
welded stainless steel for more than 5 years between 1950 and 1965, 
and were followed to 1977.  Three welders died from lung cancer in 
comparison with an expected number of 0.68 in the general 
population ( P = 0.03). 

    Comparing lung cancer mortality in 2 parishes with ferro-alloy 
industries to mortality in other parishes of similar size without 
such industries from the same county, Axelson & Rylander (1980) 
were unable to detect an increased incidence of death due to lung 
cancer mortality.  The concentration of chromium in the ambient air 
of the most polluted areas ranged from 0.1 to 0.4 g/m3.  It should 
be noted that several possible confounding factors were not under 
control, e.g., migration, occupational exposure, and smoking 
habits. 

    (d)   Epidemiological studies - chromium-plating workers

    Epidemiological studies on workers in the chromium-plating and 
related industries were reviewed by Hayes (1982).  The relevant 
data from these studies are presented in Table 27. According to 
Hayes, the epidemiological evidence is not sufficient to determine 
the risk of cancer associated with industrial exposure to chromic 

acid and, if an excess risk exists, it is probably lower than that 
typically described for employment in the chromium-chemical 
producing industry. 

    In a more recent paper, Franchini et al. (1983) conducted a 
retrospective cohort study in 9 chromium-plating plants to examine 
the mortality of workers employed for at least one year during the 
period January 1951 to December 1981.  The study group totalled 178 
individuals; vital status ascertainment was 97% complete.  The 
total number of deaths was close to the expected figure (15 
observed, 15.2 expected), whereas death from lung cancer exceeded 
the expected number (3 observed, 0.7 expected;  P = 0.03).  The 
increased mortality from lung cancer among chromium-platers seemed 
to be related to exposure intensity. 

8.3.9.2.  Cancer in organs other than lungs

    A few cancers of the upper respiratory tract and oral region, 
but no excessive rates have been reported to occur in the chromate-
producing industry.  The cancers have involved the buccal cavity, 
pharynx, and oesophagus.  Cancers of the nasal septum have not been 
documented, with the exception of one case in Italy (Vigliani & 
Zurlo, 1955). 

    In a joint Danish-Finnish-Swedish case-reference investigation, 
initiated in 1977, the connection between nasal and sinonasal 
cancer and various occupational exposures was studied.  All new 
cases of nasal and sinonasal cancer were collected from the 
national cancer registers (Finland and Sweden) or from the hospitals 
(Denmark).  The results showed associations between nasal and 
sinonasal cancer and exposure to chromium, welding, flame-cutting, 
and soldering, hardwood or mixed wood dust, and softwood dust alone 
(13.4) (Hernberg et al., 1983). 

    In 5 plants in the USA, during the early years of extremely 
high exposures, the rate of cancer of the digestive tract varied 
from 0 to 3.04/1000 compared with a rate of 0.59/1000 for the 
controls (Machle & Gregorius, 1948).  The mortality rates from 
stomach cancer have been reported for chromate-producing plants in 
Japan (SMR = 90) (Satoh et al., 1981) the USA (SMR = 40) (Hayes et 
al., 1979).  No significant differences were reported between the 
incidence of stomach cancer in a Russian plant (Pokrovskaya & 
Shabynina, 1973) and the incidence in the surrounding area. 

    Studying cancer mortality in a pigment plant using lead and 
zinc chromates, Sheffet et al.  (1982) found an increased (but not 
statistically risk of stomach (SMR = 170) and pancreas (SMR = 200) 
cancer among the total cohort (1946 employees). 


Table 27.  Summary of epidemiological studies on respiratory cancer in 
workers employed in the chromium plating and related industriesa
------------------------------------------------------------------------------------------------
Study population            Follow-up                 Respiratory cancer  Comparison population
                                                      Number   Estimated
                                                        relative risk
------------------------------------------------------------------------------------------------
Chromium plating

1056 workers employed       Deaths in former and      24       1.8b       Unexposed workers in
> 3 months in 54 plants     current (followed 2                           plants and in 2 non-
in the United Kingdom       years) workers,                               plating industries
                            about 80% traced

About 5000 workers                                    49       1.4c       Mortality analysis,
employed since 1945 in                                                    method not specified
1 plating factory in
the United Kingdom

889 workers exposed > 6     Reports from management   0        < 1b        Tokyo mortality
months in Tokyo chromium    of plating firms and                          rates
plating plants, 1970-76     follow-up of retired
                            workers; 19 total deaths
                            reported

Related industries

1292 deaths among US        Union death benefit       62       1.1b       Proportionate
metal polishers and         claims                                        mortality, US males
platers, union members,
1951-69

238 deaths among employees  Pension, insurance and    39       2.1c       Proportionate
for 10 years in one US      benefit records                               mortality, US
plant for metal die
casting, finishing, and
electroplating, 1974-78.
------------------------------------------------------------------------------------------------
a   Adapted from: Hayes (1982).
b   Not statistically significant.
c    P  < 0.05, calculated using an assumption that the observed number is distributed as a 
    Poisson random variable.
8.3.9.3.  Relationship between cancer risk and type of chromium 
compound

    As the exposures are often poorly defined, it is sometimes not 
certain whether workers have been exposed to hexavalent chromium, 
trivalent chromium, or a combination of the two. Some authors have 
concluded that there is no increased risk of cancer mortality due 
to trivalent chromium compounds (Korallus et al., 1974 a,b,c; 
Axelsson et al., 1980; Langard et al., 1980; Norseth, 1980), 
whereas others do not exclude that trivalent chromium compounds 
have a carcinogenic capacity (Essing et al., 1971; Mancuso, 1975; 
Zober 1979). 

    Summing up the data from case reports as well as 
epidemiological studies in chromate-producing, chromate-pigment, 
chromium-plating, and ferrochromium industries, the IARC Working 
Group on the Evaluation of the Carcinogenic Risk of Chemicals to 
Humans (IARC, 1980) came to the conclusion that "there is 
sufficient evidence of respiratory carcinogenicity in men 
occupationally exposed during chromate production.  Data on lung 
cancer risk in other chromium-associated occupations and for cancer 
at other sites are insufficient.  The epidemiological data do not 
allow an evaluation of the relative contributions to carcinogenic 
risk of metallic chromium, trivalent chromium and hexavalent 
chromium or of soluble versus insoluble chromium compounds". 

9.  EVALUATION OF HEALTH RISKS FOR MAN

    Low levels of chromium are omnipresent in the environment. 
Under normal conditions, human exposure to chromium does not 
represent a toxicological risk, but it should be pointed out that 
too low an intake of chromium may lead to deficiency. Airborne 
concentrations of chromium, predominantly as trivalent chromium, 
are usually below 0.1 g/m3 and there are many places where the 
concentration is below the detection limit.  Concentrations in 
river water are typically in the range of 1 - 10 g/litre and do 
not constitute a health threat.  Drinking-water from municipal 
water supplies does not contribute more than a few micrograms of 
chromium to the daily human intake, but untreated water in certain 
areas may be contaminated by runoff or effluents from industrial 
sources and may contribute significant amounts of chromium.  The 
oceans contain less than 1 g/litre.  The daily human intake 
through food varies considerably between regions.  Typical values 
range from 50 to 200 g/day.  They do not represent a toxicity 
problem. 

    However, significant exposures exist in the occupational field.  
In the past, chromium-ore mining generated chromium-containing 
dusts, levels of which ranged up to 20 mg/m3 in different work-
places.  Other exposures ranged up to 150 mg/m3 and consisted of 
dust containing as much as 48% chromium (Cr2O3).  In production 
plants, hexavalent chromium can occur in the airborne state.  
However, implementation of protective measures at ferrochromium 
production sites reduced the airborne hexavalent chromium to levels 
of 30 - 60 g/m3. 

    The health effects of the two common oxidation states of 
chromium are so fundamentally different that they must be 
considered separately.  In the form of trivalent compounds, 
chromium is an essential nutrient and is relatively non-toxic for 
man and other mammalian species.  The hexavalent form is man-made 
by oxidation of naturally-occurring trivalent chromium minerals and 
is widely used.  Compounds of hexavalent chromium penetrate 
biological membranes easily and can thus interact with essential 
constituents of the cells, including genetic material which they 
can damage through oxidation and complexation with resulting 
trivalent species.  On the other hand, oxidation of trivalent 
chromium has not been demonstrated in the living organism, and for 
practical purposes, the reduction of hexavalent chromium to 
trivalent chromium in lungs and other animal tissues is 
irreversible. 

9.1.  Occupational Exposure

    A number of effects can result from occupational exposure to 
airborne chromium including irritative lesions of the skin and 
upper respiratory tract, allergic reactions, and cancers of the 
respiratory tract.  The data on other effects, e.g., in the 
gastrointestinal, cardiovascular, and urogenital systems are 
insufficient for evaluation. 

    Epidemiological studies have shown that workers engaged in the 
production of chromate salts and chromate pigments experience an 
increased risk of developing bronchial carcinoma.  No detailed data 
on dose-response relationships are available from epidemiological 
studies.  Although a suspicion of increased lung cancer risks in 
chromium plating workers has been raised, the available data are 
inconclusive as are data for other industrial processes where 
exposure to chromium occurs.  There is insufficient evidence on the 
role of chromium as a cause of cancer in any organ other than the 
lung.  Evidence from studies on laboratory animals shows that 
hexavalent chromium compounds, especially those of low solubility, 
can induce lung cancer. 

    In the lymphocytes of workers in chromium-plating factories, 
the frequency of sister chromatid exchanges was higher in exposed 
than in control groups. 

    Mutagenicity and related studies have convincingly shown that 
hexavalent chromium is genetically active.  Hexavalent chromium can 
cross cellular membranes and is then reduced to trivalent chromium, 
which can cause DNA cross-links and increase the infertility of DNA 
implication.  Trivalent chromium compounds have been shown to be 
genetically inactive in most test systems, except in systems where 
they can directly interact with DNA. 

9.1.1.  Effects other than cancer

9.1.1.1.  Respiratory tract

    It has been reported that the threshold for acute irritative 
effects in the upper respiratory tract is 25 g/m3 for the most 
sensitive individuals.  Long-term exposure to doses over 1 g 
chromic acid/m3 can cause nasal irritation, atrophy of the nasal 
mucosa, and ulceration of perforation of the nasal septum. 

    Bronchial asthma was previously attributed to exposure to 
chromium compounds, but scientific data are too scarce to draw 
conclusions. 

9.1.1.2.  Skin

    Skin rashes, ulcers, sores, and eczema have been reported among 
occupationally exposed workers.  Both trivalent and hexavalent 
chromium compounds can give rise to sensitization of skin, 
especially under certain environmental conditions, such as those 
encountered in the cement industry, where the high incidence of 
chromium-induced skin lesions can be attributed to the alkaline 
exposure conditions. 

    Eczematous dermatitis, which manifests first as a diffuse
erythematous type, progresses in severe cases to an exudative
stage and is associated in 8 - 15% of patients with sensitivity to 
chromium, as revealed by skin-patch tests.  Although opinion is 
divided on the oxidation state of chromium responsible for inducing 
sensitization, there is evidence of hexavalent chromium penetrating 

the skin as a hapten to be reduced to the trivalent state and 
conjugated with proteins and transformed into the full antigen 
that initiates the sensitization reaction, involving presumably 
only a cell-mediated immune response. It should be noted that 
patients suffering from chromium-induced skin allergy tend to 
become hypersensitive to cobalt and nickel.  Furthermore, 48% of 
cases of skin allergy induced by chromium, with or without 
clinically observed light sensitivity, showed a significantly more 
intense reaction by a standardized photopatch test procedure, when 
they were exposed to a 4/5 minimal erythema dose of irradiation. 

9.1.1.3.  Kidney

    After high-dose, short-term oral ingestion of chromium, acute 
nephritis and tubular necrosis were observed.  A few 
epidemiological studies on workers in chrome-plating industries 
include data on diseases of the kidney, most of them without giving 
exact exposure levels.  A recent study related increased urinary-beta2 
microglobulin levels to exposure ranges between 2 and 20 g/m3. 
The dose-response relationship observed in this study needs 
confirmation on a larger number of exposed workers. 

9.1.1.4  Other organs and systems

    There are no conclusive data to evaluate the effects of 
chromium compounds on the liver or gastrointestinal and circulatory 
systems. 

9.1.2.  Teratogenicity

    Both oxidation states, when injected at high levels 
parenterally into animals, are teratogenic, with the hexavalent 
form accumulating in the embryos to much higher concentrations than 
the trivalent.  The Task Group was not aware of any report 
indicating teratogenicity in human populations. 

9.2.  General Population

    Persons living in the vicinity of ferro-alloy plants, exposed 
to an ambient air concentration of up to 1 g/m3, did not show 
increased lung cancer mortality. 

    The results of many studies suggest that exposure to chromium 
through inhalation and skin contact can pose health problems for 
the general population.  Very little information is available on 
the health effects of chromium ingested through untreated drinking-
water, though, in a single study, a correlation was observed 
between frequency of malformation in the central nervous system and 
the chromium content of water samples (Morton & Elwood, 1974).  In 
order to assess the nature of the magnitude of these problems, 
there appears to be a need for more general population studies on 
the effects of inhaled, absorbed, or ingested chromium on 
respiratory, cardiovascular, and renal functions, and on the skin. 

    Studies on animals and man have established trivalent chromium 
as an essential micronutrient that interacts with insulin and 
enhances the physiological effects of the hormone. Supplementation 
trials in a number of countries including Finland, Jordan, Nigeria, 
Sweden, Turkey, and the USA have shown that segments of the 
population could improve their glucose metabolism and, in some 
instances, fat metabolism, by ingesting trivalent chromium 
compounds.  These observations suggest that some populations are at 
risk of chromium deficiency.  Children suffering from protein-
energy malnutrition may be at special risk. 

    As chromium concentrations in the body fluids of unexposed 
persons are generally less than 1 g/litre, analysis for chromium 
requires the strictest quality control, including measures to 
exclude sample contamination.  Even with adequate analytical 
methods, it is not possible, as yet, to diagnose chromium 
deficiency in individuals by chemical or biochemical methods alone.  
Therefore, a quantitative assessment of the prevalence of chromium 
deficiency in human populations is not yet possible. 

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    See Also:
       Toxicological Abbreviations
       Chromium (ICSC)
       Chromium (IARC Summary & Evaluation, Volume 49, 1990)