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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 134







    CADMIUM







    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

    First draft prepared by Dr. L. Friberg and Dr C.G. Elinder
    (Karolinska Institute, Sweden) and Dr. T. Kjellstr÷m
    (University of Auckland, New Zealand)

    World Health Organization
    Geneva, 1992


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    WHO Library Cataloguing in Publication Data

    Cadmium.

        (Environmental health criteria ; 134)

        1.Cadmium - adverse effects  2.Cadmium-toxicity 
        3.Environmental exposure  4.Environmental pollutants
        I.Series

        ISBN 92 4 157134 9        (NLM Classification: QV 290)
        ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR CADMIUM

    1.   SUMMARY AND CONCLUSIONS

         1.1   Identity, physical and chemical properties,
               and analytical methods
         1.2   Sources of human and environmental exposure
         1.3   Environmental levels and human exposure
         1.4   Kinetics and metabolism in laboratory animals
               and humans
         1.5   Effects on laboratory mammals
         1.6   Effects on humans
         1.7   Evaluation of human health risks
               1.7.1   Conclusions
                       1.7.1.1   General population
                       1.7.1.2   Occupationally exposed population

    2.   IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
         METHODS

         2.1   Physical and chemical properties
         2.2   Analytical methods
               2.2.1   Collection and preparation of samples
               2.2.2   Separation and concentration
               2.2.3   Methods for quantitative determination
                       2.2.3.1   Atomic absorption spectrometry
                       2.2.3.2   Electrochemical methods
                       2.2.3.3   Activation analysis
                       2.2.3.4    In vivo methods
         2.3   Quality control and quality assurance
               2.3.1   Principles and need for quality control
               2.3.2   Comparison of methods and laboratories
               2.3.3   Quality assurance
         2.4   Conclusions

    3.   SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1   Natural occurrence and cycling
         3.2   Production
         3.3   Uses
         3.4   Sources of environmental exposure
               3.4.1   Sources of atmospheric cadmium
               3.4.2   Sources of aquatic cadmium
               3.4.3   Sources of terrestrial cadmium
         3.5   Conclusions

    4.   ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1   Atmospheric deposition
         4.2   Transport from water to soil
         4.3   Uptake from soil by plants
         4.4   Transfer to aquatic and terrestrial organisms
         4.5   Conclusions

    5.   ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1   Inhalation route of exposure
               5.1.1   Ambient air
               5.1.2   Air in the working environment
               5.1.3   The smoking of tobacco
         5.2   Ingestion routes of exposure
               5.2.1   Levels in drinking-water
               5.2.2   Levels in food
               5.2.3   Other sources of exposure
               5.2.4   Daily intake of cadmium from food
         5.3   Total intake and uptake of cadmium from all
               environmental pathways
               5.3.1   General population, uncontaminated areas
               5.3.2   General population, contaminated areas
               5.3.3   Occupational exposure to cadmium
         5.4   Conclusions

    6.   KINETICS AND METABOLISM IN LABORATORY MAMMALS AND HUMANS

         6.1   Uptake
               6.1.1   Absorption by inhalation
               6.1.2   Absorption via the intestinal tract
               6.1.3   Absorption via skin
               6.1.4   Transplacental transfer
         6.2   Transport
         6.3   Distribution
               6.3.1   In animals
                       6.3.1.1   Single exposure
                       6.3.1.2   Repeated exposure
               6.3.2   In humans
         6.4   Body burden and kidney burden in humans
         6.5   Elimination and excretion
               6.5.1   Urinary excretion
                       6.5.1.1   In animals
                       6.5.1.2   In humans
               6.5.2   Gastrointestinal and other routes of
                       excretion
         6.6   Biological half-time and metabolic models
               6.6.1   In animals
               6.6.2   In humans

         6.7   Biological indices of cadmium exposure, body
               burden, and concentrations in kidneys
               6.7.1   Urine
               6.7.2   Blood
               6.7.3   Faeces
               6.7.4   Hair
         6.8   Metallothionein
               6.8.1   Nature and production
               6.8.2   The role of metallothionein in transport,
                       metabolism, and toxicity of cadmium
         6.9   Conclusions

    7.   EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         7.1   Single exposure
               7.1.1   Lethal dose and lethal effects
               7.1.2   Pathological changes affecting specific
                       systems in the body
                       7.1.2.1   Acute effects on testes and ovaries
                       7.1.2.2   Acute effects on other organs
         7.2   Repeated and/or long-term exposure
               7.2.1   Effects on the kidneys
                       7.2.1.1   Oral route
                       7.2.1.2   Respiratory route
                       7.2.1.3   Injection route
                       7.2.1.4   Pathogenesis of cadmium
                                 nephrotoxicity
                       7.2.1.5   General features of renal effects;
                                 dose-effect and dose-response
                                 relationships
               7.2.2   Effects on the liver
               7.2.3   Effects on the respiratory system
               7.2.4   Effects on bones and calcium metabolism
               7.2.5   Effects on haematopoiesis
               7.2.6   Effects on blood pressure and the cardio-
                       vascular system
               7.2.7   Effects on reproductive organs
               7.2.8   Other effects
         7.3   Fetal toxicity and teratogenicity
         7.4   Mutagenicity
         7.5   Carcinogenicity
         7.6   Host and dietary factors; interactions with other
               trace elements
         7.7   Conclusions

    8.   EFFECTS ON HUMANS

         8.1   Acute effects
               8.1.1   Inhalation
               8.1.2   Ingestion

         8.2   Chronic effects
               8.2.1   Renal effects and low molecular weight
                       proteinuria
                       8.2.1.1   In industry
                       8.2.1.2   In the general environment
                       8.2.1.3   Methods for detection of tubular
                                 proteinuria
                       8.2.1.4   Significance of cadmium-induced
                                 proteinuria
                       8.2.1.5   Glomerular effects
                       8.2.1.6   Relationship between renal cadmium
                                 levels and the occurrence of effects
                       8.2.1.7   Reversibility of renal effects
               8.2.2   Disorders of calcium metabolism and bone
                       effects
                       8.2.2.1   In industry
                       8.2.2.2   In the general environment
                       8.2.2.3   Mechanism of cadmium-induced bone
                                 effects
               8.2.3   Respiratory system effects
                       8.2.3.1   Upper respiratory system
                       8.2.3.2   Lower respiratory system
               8.2.4   Hypertension and cardiovascular disease
               8.2.5   Cancer
                       8.2.5.1   In industry
                       8.2.5.2   In the general environment
               8.2.6   Mutagenic effects in human cells
               8.2.7   Transplacental transport and fetal effects
               8.2.8   Other effects
         8.3   Clinical and epidemiological studies with data
               on both exposure and effects
               8.3.1   Studies on respiratory disorders
               8.3.2   Studies on renal disorders in industry
               8.3.3   Studies on renal disorders in the general
                       environment
                       8.3.3.1   Health surveys in Japan
                       8.3.3.2   Toyama prefecture (Fuchu area)
                       8.3.3.3   Hyogo prefecture (Ikuno area)
                       8.3.3.4   Ishikawa prefecture (Kakehashi area)
                       8.3.3.5   Akita prefecture (Kosaka area)
                       8.3.3.6   Nagasaki prefecture (Tsushima area)
                       8.3.3.7   Other Japanese areas
                       8.3.3.8   Belgium
                       8.3.3.9   Shipham area in the United Kingdom
                       8.3.3.10  USSR
         8.4   Conclusions

    9.   EVALUATION OF HUMAN HEALTH RISKS

         9.1   Exposure assessment
               9.1.1   General population exposure
               9.1.2   Occupational exposure
               9.1.3   Amounts absorbed from air, food, and water
         9.2   Dose-effect relationships
               9.2.1.  Renal effects
               9.2.2   Bone effects
               9.2.3   Pulmonary effects
               9.2.4   Cardiovascular effects
               9.2.5   Cancer
               9.2.6   Critical organ and critical effect
         9.3   Critical concentration in the kidneys
               9.3.1   In animals
               9.3.2   In humans
         9.4   Dose-response relationships for renal effects
               9.4.1   Evaluation based on data on industrial
                       workers
               9.4.2   Evaluation based on data on the general
                       population
               9.4.3   Evaluation based on a metabolic model and
                       critical concentrations

    10.  CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH

         10.1  Conclusions
               10.1.1  General population
               10.1.2  Occupationally exposed population
         10.2  Recommendations for protection of human health

    11.  FURTHER RESEARCH

    12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    RESUME ET CONCLUSIONS

    RESUMEN Y CONCLUSIONES

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR CADMIUM

     Members

    Professor K.A. Bustueva, Communal Hygiene, Central Institute
         for Advanced Medical Training, Moscow, USSR

    Dr S.V. Chandra, Industrial Toxicology Research Centre, Mahatma
       Gandhi Marg, Lucknow, India

    Dr M.G. Cherian, Department of Pathology, University of Western
       Ontario, London, Ontario, Canada  (Joint Rapporteur)

    Dr B.A. Fowler, School of Medicine, University of Maryland,
       Baltimore, Maryland, USA  (Joint Rapporteur)

    Dr R.A. Goyer, Department of Pathology, University of Western
       Ontario, London, Ontario, Canada  (Chairman)

    Professor G. Kazantzis, London School of Hygiene and Tropical
       Medicine, University of London, London, United Kingdom

    Professor G. Nordberg, Department of Environmental
       Medicine, University of Umea, Umea, Sweden

    Dr J. Parizek, Czechoslovak Academy of Sciences, Institute of
       Physiology, Videnska, Prague, Czechoslovakia

    Dr I. Shigematsu, Radiation Effects Research Foundation, Hijiyama
       Park, Minami-Ku, Hiroshima, Japan  (Vice-Chairman)

    Dr M.J. Thun, Division of Epidemiology and Statistics, American
       Cancer Society, Atlanta, Georgia, USA

     Observers

    Professor K. Nogawa, Department of Hygiene, Chiba University
       School of Medicine, Chiba, Japan

    Dr K. Nomiyama, Department of Environmental Health, Jichi Medical
       School, Minamikawachi-Machi Kawachi-Gun, Tochigi-Ken, Japan

     Secretariat

    Dr G.C. Becking, International Programme on Chemical Safety,
       Interregional Research Unit, World Health Organization,
       Research Triangle Park, North Carolina, USA  (Secretary)

    Dr L. Friberg, Karolinska Institute, Department of Environmental
       Hygiene, Stockholm, Sweden

    Dr C.G. Elinder, Section for Renal Medicine, Department of
       Internal Medicine, Karolinska Hospital, Stockholm, Sweden

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

         Every effort has been made to present information in the
    criteria monographs as accurately as possible without unduly
    delaying their publication. In the interest of all users of the
    environmental health criteria monographs, 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.

                            *     *     *

         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. 7988400 or
    7985850).

    ENVIRONMENTAL HEALTH CRITERIA FOR CADMIUM

         A WHO Task Group on Environmental Health Criteria for Cadmium
    met in Geneva from 27 November to 1 December 1989. Dr M. Mercier,
    Manager, IPCS, opened the meeting on behalf of the heads of the
    three IPCS cooperating organizations (UNEP/ILO/WHO). The Task Group
    reviewed and revised the draft criteria document and made an
    evaluation of the risks to human health from exposure to cadmium.

         The first draft of this monograph, which was reviewed by a
    Working Group in January 1984, was prepared by Dr L. Friberg and
    Dr C.G. Elinder (Karolinska Institute, Stockholm, Sweden), and Dr T.
    Kjellström (University of Auckland, New Zealand)1. Based on the
    discussions of the Working Group, recent scientific data, and
    comments from the IPCS Contact Points, a Task Group draft was
    prepared by Dr R. Goyer (University of Western Ontario, Canada).

         The Secretariat wishes to acknowledge the contributions made by
    Professor K. Tsuchiya (Keio University, Tokyo, Japan), Dr M.
    Piscator (Karolinska Institute), Dr G.F. Nordberg (University of
    Umea, Sweden), and Professor R. Lauwerys (University of Louvain,
    Brussels, Belgium) for their preparation and review of earlier draft
    document on cadmium, which assisted greatly in the preparation of
    this monograph.

         Dr G.C. Becking (Interregional Research Unit) and Dr P.G.
    Jenkins (IPCS Central Unit) were responsible for the overall
    scientific content and technical editing, respectively, of this
    monograph. The efforts of all who helped in the preparation and
    finalization of the document are gratefully acknowledged.

                 

    1 Present affiliation: Division of Environmental Health, World
      Health Organization

    ABBREVIATIONS


    AAS       atomic absorption spectrometry

    CC        critical concentration

    CI        confidence interval

    EEC       European Economic Community

    ETA       electrothermal atomization

    GESAMP    Group of Experts on the Scientific Aspects of Marine
              Pollution

    GFR       glomerular filtration rate

    GOT       glutamic-oxaloacetic transaminase

    GPT       glutamic-pyruvic transaminase

    ICD       International Classification of Diseases

    IDMS      isotope dilution mass spectrometry

    IU        international units

    LDH       lactate dehydrogenase

    LMW       low molecular weight

    MMAD      mass median aerodynamic diameter

    PCV       packed-cell volume

    PMR       proportional mortality rate

    PMSG      pregnant mare serum gonadotrophin

    RBP       retinal binding protein

    RIA       radio-immuno assay

    SMR       standard mortality ratio

    TRP       tubular reabsorption of phosphate

    XRF       X-ray-generated atomic fluorescence

    PREFACE

         The definitions of terms used in this monograph were derived
    from the meeting of the Scientific Committee on the Toxicology of
    Metals, Permanent Commission and International Association on
    Occupational Health, in Tokyo in 1974 (Task Group on Metal Toxicity,
    1976). The term "critical concentration" in an organ was defined as
    "the concentration of a metal in an organ at the time any of its
    cells reaches a concentration at which adverse functional changes,
    reversible or irreversible, occur in the cell". These first adverse
    changes would be the "critical effect". The critical concentration
    is thus established on an individual level and varies between
    individuals. The term "critical organ" was defined as "that
    particular organ which first attains the critical concentration of a
    metal under specified circumstances of exposure and for a given
    population".

         The dose-response relationship expressing the occurrence rate
    (response) of the particular effect as a function of metal
    concentration in the critical organ, displays the frequency
    distribution of individual critical concentrations. In risk
    estimations it is thus essential to define the variability of the
    critical concentration among a population or specific group of
    people.

         The term that was chosen to predict the variability of the
    critical concentration of cadmium occurring in a particular group of
    people is the predicted prevalence of the critical concentration.
    For example, the critical concentration 5 (CC5) would be the
    concentration at which 5% of the population had reached their
    individual critical concentrations, and the CC50 would be the
    critical concentration occurring in 50% of a defined group of
    people. The term "critical concentration" is synonymous with the
    term "population critical concentration" used in the WHO publication
    on Evaluation of Certain Food Additives and Contaminants (1989).

         The critical concentrations and the dose-response relationships
    are very much dependent on the definition of critical effect. The
    early effects of cadmium on the kidney can be measured as an
    increased urinary excretion of low molecular weight (LMW) proteins.
    An operational definition is needed to create a cut-off point above
    which the proteinuria indicates an "adverse functional change".
    Different studies of cadmium effects have used different operational
    definitions, which has made it difficult to merge the data into a
    dose-response relationship. Examples of these problems are given in
    section 8.3.2. The relationship between dose and different types of
    effect or different severities of the same effect is called the
    dose-effect relationship.

         In animal studies, the individual critical concentrations have
    not been calculated. Both dose and effect data are based on groups
    of animals, and these groups are usually rather small (section 7).
    Few animal studies attempt to quantitatively measure the
    dose-response relationships within the group (section 7.2.1.4). The
    reports of effects occurring at a certain concentration of cadmium
    in the kidney cortex may therefore best be interpreted as the
    concentration at which 50% or more of the animals suffered the
    effect. A 5-10% response will occur at lower cadmium concentrations.

         The effects of cadmium on the environment are discussed in
    Environmental Health Criteria 135: Cadmium - Environmental Aspects
    (WHO, in press).

    1.  SUMMARY AND CONCLUSIONS

    1.1  Identity, physical and chemical properties, and analytical
         methods

         Several methods are available for the determination of cadmium
    in biological materials. Atomic absorption spectrometry is the most
    widely used, but careful treatment of samples and correction for
    interference is needed for the analysis of samples with low cadmium
    concentrations. It is strongly recommended that analysis be
    accompanied by a quality assurance programme. At present, it is
    possible under ideal circumstances to determine concentrations of
    about 0.1 µg/litre in urine and blood and 1-10 µg/kg in food and
    tissue samples.

    1.2  Sources of human and environmental exposure

         Cadmium is a relatively rare element and current analytical
    procedures indicate much lower concentrations of the metal in
    environmental media than did previous measurements. At present, it
    is not possible to determine whether human activities have caused a
    historic increase in cadmium levels in the polar ice caps.

         Commercial cadmium production started at the beginning of this
    century. The pattern of cadmium consumption has changed in recent
    years with significant decreases in electroplating and increases in
    batteries and specialized electronic uses. Most of the major uses of
    cadmium employ cadmium in the form of com- pounds that are present
    at low concentration; these features constrain the recycling of
    cadmium. Restrictions on certain uses of cadmium imposed by a few
    countries may have widespread impact on these applications.

         Cadmium is released to the air, land, and water by human
    activities. In general, the two major sources of contamination are
    the production and consumption of cadmium and other non-ferrous
    metals and the disposal of wastes containing cadmium. Areas in the
    vicinity of non-ferrous mines and smelters often show pronounced
    cadmium contamination.

         Increases in soil cadmium content result in an increase in the
    uptake of cadmium by plants; the pathway of human exposure from
    agricultural crops is thus susceptible to increases in soil cadmium.
    The uptake by plants from soil is greater at low soil pH. Processes
    that acidify soil (e.g., acid rain) may therefore increase the
    average cadmium concentrations in foodstuffs. The application of
    phosphate fertilizers and atmospheric deposition are significant
    sources of cadmium input to arable soils in some parts of the world;
    sewage sludge can also be an important source at the local level.

    These sources may, in the future, cause enhanced soil and hence crop
    cadmium levels, which in turn may lead to increases in dietary
    cadmium exposure. In certain areas, there is evidence of increasing
    cadmium content in food.

         Edible free-living food organisms such as shellfish,
    crustaceans, and fungi are natural accumulators of cadmium. As in
    the case of humans, there are increased levels of cadmium in the
    liver and kidney of horses and some feral terrestrial animals.
    Regular consumption of these items can result in increased exposure.
    Certain marine vertebrates contain markedly elevated renal cadmium
    concentrations, which, although considered to be of natural origin,
    have been linked to signs of kidney damage in the organisms
    concerned.

    1.3  Environmental levels and human exposure

         The major route of exposure to cadmium for the non-smoking
    general population is via food; the contribution from other pathways
    to total uptake is small. Tobacco is an important source of cadmium
    uptake in smokers. In contaminated areas, cadmium exposure via food
    may be up to several hundred µg/day. In exposed workers, lung
    absorption of cadmium following inhalation of workplace air is the
    major route of exposure. Increased uptake can also occur as a
    consequence of contamination of food and tobacco.

    1.4  Kinetics and metabolism in laboratory animals and humans

         Data from experimental animals and humans have shown that
    pulmonary absorption is higher than gastrointestinal absorption.
    Depending on chemical speciation, particle size, and solubility in
    biological fluids, up to 50% of the inhaled cadmium compound may be
    absorbed. The gastrointestinal absorption of cadmium is influenced
    by the type of diet and nutritional status. The nutritional iron
    status appears to be of particular importance. On average, 5% of the
    total oral intake of cadmium is absorbed, but individual values
    range from less than 1% to more than 20%. There is a maternal-fetal
    gradient of cadmium. Although cadmium accumulates in the placenta,
    transfer to the fetus is low. Cadmium absorbed from the lungs or the
    gastrointestinal tract is mainly stored in the liver and kidneys,
    where more than half of the body burden will be deposited. With
    increasing exposure intensity, an increasing proportion of the
    absorbed cadmium is stored in the liver. Excretion is normally slow,
    and the biological half-time is very long (decades) in the muscles,
    kidneys, liver, and whole body of humans. The cadmium concentrations
    in most tissues increase with age. Highest concentrations are
    generally found in the renal cortex, but excessive exposures may
    lead to higher concentrations in the liver. In exposed people with

    renal damage, urinary excretion of cadmium increases and so the
    whole body half-time is shortened. The renal damage leads to losses
    of cadmium from the kidney, and the renal concentrations of cadmium
    will eventually be lower than in people with similar exposure but
    without renal damage.

          Metallothionein is an important transport and storage protein
    for cadmium and other metals. Cadmium can induce metallothionein
    synthesis in many organs including the liver and kidney. The binding
    of intracellular cadmium to metallothionein in tissues protects
    against the toxicity of cadmium. Cadmium not bound to
    metallothionein may therefore play a role in the pathogenesis of
    cadmium-related tissue injury. The speciation of other cadmium
    complexes in tissues or biological fluids is unknown.

         Urinary excretion of cadmium is related to body burden, recent
    exposure, and renal damage. In people with low exposure, the urine
    cadmium level is mainly related to the body burden. When
    cadmium-induced renal damage has occurred, or even without renal
    damage if exposure is excessive, urinary excretion increases.
    Cadmium-exposed people with proteinuria generally have higher
    cadmium excretion than such people without proteinuria. After high
    exposure ceases, the urine cadmium level will decrease even though
    renal damage persists. The interpretation of urinary cadmium is thus
    dependent on a number of factors. Gastrointestinal excretion is
    approximately equal to urinary excretion but cannot be easily
    measured. Other excretory routes such as lactation, sweating or
    placental transfer are insignificant.

         The level of cadmium in faeces is a good indicator of recent
    daily intake from food in the absence of inhalation exposure.
    Cadmium in blood occurs mainly in the red blood cells, and the
    plasma concentrations are very low. There are at least two
    compartments in blood, one related to recent exposure with a
    half-time of about 2-3 months, and one which is probably related to
    body burden with a half-time of several years.

    1.5  Effects on laboratory mammals

         High inhalation exposures cause lethal pulmonary oedema. Single
    high-dose injection gives rise to testicular and non-ovulating
    ovarian necrosis, liver damage, and small vessel injury. Large oral
    doses damage the gastric and intestinal mucosa.

         Long-term inhalation exposure and intratracheal administration
    give rise to chronic inflammatory changes in the lungs, fibrosis,
    and appearances suggestive of emphysema. Long-term parenteral or

    oral administration produces effects primarily on the kidneys, but
    also on the liver and the haematopoietic, immune, skeletal, and
    cardiovascular systems. Skeletal effects and hypertension have been
    induced in certain species under defined conditions. The occurrence
    of teratogenic effects and placental damage depends on the stage of
    gestation at which exposure occurs, and may involve interactive
    effects with zinc.

         Of greatest relevance to human exposure are the acute
    inhalation effects on the lung and the chronic effects on the
    kidney. Following long-term exposure, the kidney is the critical
    organ. The effects on the kidney are characterized by tubular
    dysfunction and tubular cell damage, although glomerular dysfunction
    may also occur. A consequence of renal tubular dysfunction is a
    disturbance of calcium and vitamin D metabolism. According to some
    studies, this has led to osteomalacia and/or osteoporosis, but these
    effects have not been confirmed by other studies. A direct effect of
    cadmium on bone mineralization cannot be excluded. The toxic effects
    of cadmium in experimental animals are influenced by genetic and
    nutritional factors, interactions with other metals, particularly
    zinc, and pretreatment with cadmium, which may be related to the
    induction of metallothionein.

         In 1976 and 1987, the International Agency for Research on
    Cancer accepted as sufficient the evidence that cadmium chloride,
    sulfate, sulfide, and oxide can give rise to injection site sarcomas
    in the rat and, for the first two compounds, induce interstitial
    cell tumours of the testis in rats and mice, but found oral studies
    inadequate for evaluation. Long-term inhalation studies in rats
    exposed to aerosols of cadmium sulfate, cadmium oxide fumes and
    cadmium sulfate dust demonstrated a high incidence of primary lung
    cancer with evidence of a dose-response relationship. However, this
    has not so far been demonstrated in other species. Studies on the
    genotoxic effects of cadmium have given discordant results.

    1.6  Effects on humans

         High inhalation exposure to cadmium oxide fume results in acute
    pneumonitis with pulmonary oedema, which may be lethal. High
    ingestion exposure of soluble cadmium salts causes acute
    gastroenteritis.

         Long-term occupational exposure to cadmium has caused severe
    chronic effects, predominantly in the lungs and kidneys. Chronic
    renal effects have also been seen among the general population.

         Following high occupational exposure, lung changes are
    primarily characterized by chronic obstructive airway disease. Early
    minor changes in ventilatory function tests may progress, with
    continued cadmium exposure, to respiratory insufficiency. An
    increased mortality rate from obstructive lung disease has been seen
    in workers with high exposure, as has occurred in the past.

         The accumulation of cadmium in the renal cortex leads to renal
    tubular dysfunction with impaired reabsorption of, for instance,
    proteins, glucose, and amino acids. A characteristic sign of tubular
    dysfunction is an increased excretion of low molecular weight
    proteins in urine. In some cases, the glomerular filtration rate
    decreases. Increase in urine cadmium correlates with low molecular
    weight proteinuria and in the absence of acute exposure to cadmium
    may serve as an indicator of renal effect. In more severe cases
    there is a combination of tubular and glomerular effects, with an
    increase in blood creatinine in some cases. For most workers and
    people in the general environment, cadmium-induced proteinuria is
    irreversible.

         Among other effects are disturbances in calcium metabolism,
    hypercalciuria, and formation of renal stones. High exposure to
    cadmium, most probably in combination with other factors such as
    nutritional deficiencies, may lead to the development of
    osteoporosis and/or osteomalacia.

         There is evidence that long-term occupational exposure to
    cadmium may contribute to the development of cancer of the lung but
    observations from exposed workers have been difficult to interpret
    because of confounding factors. For prostatic cancer, evidence to
    date is inconclusive but does not support the suggestion from
    earlier studies of a causal relationship.

         At present, there is no convincing evidence for cadmium being
    an etiological agent of essential hypertension. Most data speak
    against a blood pressure increase due to cadmium and there is no
    evidence of an increased mortality due to cardiovascular or
    cerebrovascular disease.

         Data from studies on groups of occupationally exposed workers
    and on groups exposed in the general environment show that there is
    a relationship between exposure levels, exposure durations, and the
    prevalence of renal effects.

         An increased prevalence of low molecular weight proteinuria in
    cadmium workers after 10-20 years of exposure to cadmium levels of
    about 20-50 µg/m3 has been reported.

         In polluted areas of the general environment, where the
    estimated cadmium intake has been 140-260 µg/day, effects in the
    form of increased low molecular weight proteinuria have been seen in
    some individuals following long-term exposure. More precise
    dose-response estimates are given in section 8.

    1.7  Evaluation of human health risks

    1.7.1  Conclusions

         The kidney is considered the critical target organ for the
    general population as well as for occupationally exposed
    populations. Chronic obstructive airway disease is associated with
    long-term high-level occupational exposure by inhalation. There is
    some evidence that such exposure to cadmium may contribute to the
    development of cancer of the lung but observations from exposed
    workers have been difficult to interpret because of confounding
    factors.

    1.7.1.1  General population

         Food-borne cadmium is the major source of exposure for most
    people. Average daily intakes from food in most areas not polluted
    with cadmium are between 10-40 µg. In polluted areas it has been
    found to be several hundred µg per day. In non-polluted areas,
    uptake from heavy smoking may equal cadmium intake from food.

         Based on a biological model, an association between cadmium
    exposure and increased urinary excretion of low molecular weight
    proteins has been estimated to occur in humans with a life-long
    daily intake of about 140-260 µg cadmium, or a cumulative intake of
    about 2000 mg or more.

    1.7.1.2  Occupationally exposed population

         Occupational exposure to cadmium is mainly by inhalation but
    includes additional intakes through food and tobacco. The total
    cadmium level in air varies according to industrial hygiene
    practices and type of workplace. There is an exposure-response
    relationship between airborne cadmium levels and proteinuria. An
    increase in the prevalence of low molecular weight proteinuria may
    occur in workers after 10-20 years of exposure to cadmium levels of
    about 20-50 µg/m3.  In vivo measurement of cadmium in the liver
    and kidneys of people with different levels of cadmium exposure have
    shown that about 10% of workers with a kidney cortex level of
    200 mg/kg and about 50% of people with a kidney cortex level of
    300 mg/kg would have renal tubular proteinuria.

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND
       ANALYTICAL METHODS

         This monograph covers cadmium and its inorganic compounds
    alone, since there is no evidence that organocadmium compounds
    (where the metal is bound covalently to carbon) occur in nature.
    Although cadmium may bind to proteins and other organic molecules
    and form salts with organic acids (e.g., cadmium stearate), in these
    forms it is regarded as inorganic.

         The mobility of cadmium in the environment and the effects on
    the ecosystem depend to a large extent on the nature of its
    compounds.

         Since this monograph evaluates only the health hazards for
    humans (and not those for the environment), only chemical data on
    cadmium compounds relevant for such an evaluation are included. Data
    on cadmium compounds occurring in or toxic to lower animals and
    plants are reviewed in Environmental Health Criteria 135:
    Cadmium - Environmental Aspects (WHO, in press).

    2.1  Physical and chemical properties

         Cadmium (atomic number 48; relative atomic mass 112.40) is a
    metal that belongs, together with zinc and mercury, to group IIb in
    the Periodic Table. Naturally-occurring isotopes are 106 (1.22%),
    108 (0.88%), 110 (12.39%), 111 (12.75%), 112 (24.07%), 113 (12.26%),
    114 (28.86%), and 116 (7.50%) (Weast, 1974).

         Cadmium has a relatively high vapour pressure. Its vapour is
    oxidized rapidly in air to produce cadmium oxide. When reactive
    gases or vapour, such as carbon dioxide, water vapour, sulfur
    dioxide, sulfur trioxide or hydrogen chloride are present, cadmium
    vapour reacts to produce cadmium carbonate, hydroxide, sulfite,
    sulfate or chloride, respectively. These compounds may be formed in
    stacks and emitted to the environment. An example of these reactions
    during cadmium emissions from coal-fired power plants is described
    by Kirsch et al. (1982).

         Some cadmium compounds, such as cadmium sulfide, carbonate, and
    oxide, are practically insoluble in water. There is, however, a lack
    of data on the solubility of these compounds in biological fluids,
    e.g., in the gastrointestinal tract and lung. These water-insoluble
    compounds can be changed to water-soluble salts in nature under the
    influence of oxygen and acids; cadmium sulfate, nitrate, and halides
    are water-soluble. Most of the cadmium found in mammals, birds, and
    fish is probably bound to protein molecules.

         The speciation of cadmium in soil, plants, animal tissues, and
    foodstuffs may be of importance for the evaluation of the health
    hazards associated with areas of cadmium contamination or high
    cadmium intake. For example, although soil cadmium levels in
    Shipham, United Kingdom, were found to be very much higher than in
    Toyama, Japan, cadmium uptake by edible plants in Shipham was only a
    small fraction of that in Toyama (Tsuchiya, 1978; Sherlock et al.,
    1983). Very few data on the occurrence and speciation of cadmium
    compounds in nature are available.

    2.2  Analytical methods

         Only a few nanograms (or even less) of cadmium may be present
    in collected samples of air and water, whereas hundreds of
    micrograms may be present in small samples of kidney, sewage sludge,
    and plastics. Different techniques are therefore required for the
    collection, preparation, and analysis of the samples.

         In general, the technique available for measuring cadmium in
    the environment and in biological materials cannot differentiate
    between the different compounds. With special separation techniques,
    cadmium-containing proteins can be isolated and identified. In most
    studies to date, the concentration or amount of cadmium in water,
    air, soil, plants, and other environmental or biological materials
    has been determined as the element.

    2.2.1  Collection and preparation of samples

         The degree of uncertainty in any health risk assessment of
    cadmium based on the analysis of environmental or biological samples
    depends on how representative the samples are. Each type of material
    has specific problems in this respect, and each study should include
    an evaluation of the sampling procedures utilized. For example, the
    measurement of cadmium in workplace air can be made with "static"
    samples or "personal" samples. The latter supposedly gives a better
    estimate of true exposure levels. When both are measured, personal
    samples usually give higher results, indicating that static samples
    may underestimate the exposure.

         For the collection of samples, standard trace element methods
    can generally be used (LaFleur, 1976; Behne, 1980). The amount of
    material needed for analysis varies according to the sensitivity of
    the analytical methods and the cadmium concentration in the
    material. During recent years, methods have improved and usually
    smaller amounts (ml or g) of biological materials are now needed
    than those required previously.

         In the handling and storage of samples, particularly liquid
    samples, special care must be taken to avoid contamination. Coloured
    materials in containers, especially plastics and rubber, should be
    avoided. Contamination of blood samples has been reported when blood
    was collected in certain types of evacuated blood collection tubes
    (Nackowski et al., 1977; Nise & Vesterberg, 1978). Disposable
    coloured micropipette tips have been found to contaminate acid
    solutions with cadmium (Salmela & Vuori, 1979).

         Glass and transparent cadmium-free polyethylene, polypropylene
    or teflon containers are usually considered as suitable for storing
    samples. All containers and glassware should be pre-cleaned in
    dilute nitric acid and deionized water. Water samples or standards
    with low cadmium concentrations should be stored for only a short
    period of time in order to avoid possible adsorption of cadmium on
    the container wall. However, experiments carried out within the
    UNEP/WHO programme (Vahter, 1982; Friberg & Vahter, 1983) using
    haemolysed blood samples spiked with 109Cd showed that, if
    properly handled, blood can be stored at room temperature for
    several months without any change in the cadmium concentration. Some
    solutions, such as urine, should be acidified to prevent
    precipitation of salts, thus ensuring that the cadmium remains in
    solution.

         To prepare samples for analysis, inorganic solid samples (such
    as soil or dust samples) are usually dissolved in nitric acid or
    other acids. Organic samples need to be subjected to wet ashing
    (digestion) or dry ashing. Wet ashing, i.e. heating under reflux
    with nitric acid followed by the addition of sulfuric or perchloric
    acid, is an adequate method for the digestion of most organic and
    biological samples. Heating with perchloric acid is usually avoided
    in modern methods because of the explosive nature of the fumes.
    Biological samples may also be dissolved using tetramethylammonium
    hydroxide (Kaplan et al., 1973).

         Dry ashing can also be used without significant losses of
    cadmium, provided that the temperature is kept at or below 450 °C
    (Kjellström et al., 1974; Koirtyohann & Hopkins, 1976).
    Low-temperature (about 100 °C) dry ashing at a high oxygen
    concentration has also been used successfully (Gleit, 1965).

    2.2.2  Separation and concentration

         Some biological samples such as kidneys contain relatively high
    concentrations of cadmium; this makes it possible to analyse without
    significant interference from other compounds. Dry ashing, followed

    by dissolving the ash in acid, is sometimes sufficient for analysis
    by atomic absorption spectrometry and other modern methods. When the
    cadmium concentration is low, special treatment is sometimes needed.
    The procedures for separating cadmium from interfering compounds and
    concentrating the samples are very important steps in obtaining
    adequate results.

         One technique for the solvent extraction of cadmium, which has
    been widely used, is based on the APDC/MIBK system, where ammonium
    pyrrolidine dithiocarbamate chelate (APDC) is extracted into methyl
    isobutyl ketone (MIBK) (Mulford, 1966; Lehnert et al., 1968). Other
    chelating agents that can be used to extract cadmium into an organic
    solvent are dithiozone (Saltzman, 1953) and sodium diethyl
    dithiocarbamate (Berman, 1967).

         Ion exchange resins have also been applied for separating and
    concentrating cadmium from digested food samples (Baetz & Kenner,
    1974) and from urine and blood samples acidified with hydrochloric
    acid (Lauwerys et al., 1974c; Vens & Lauwerys, 1982).

    2.2.3  Methods for quantitative determination

         A number of methods have been developed for cadmium analysis,
    but none of them are known to produce absolutely "true"
    concentrations of cadmium in any material. The accuracy of a method
    also depends on how high the concentration is.

         The nearest approximation to the "true" value when analysing
    complex organic materials with low cadmium concentration is probably
    attained with the isotope dilution mass spectrometry (IDMS) method
    carried out in "ultraclean" facilities. However, IDMS is extremely
    expensive compared with other methods, and has been used mainly for
    quality control of other methods and for certified reference
    materials.

         The most commonly used methods, at present, are atomic
    absorption spectrometry, electrochemical methods, and neutron
    activation analysis. These three methods will be discussed in detail
    below. Other methods are colorimetry with dithiozone, atomic
    emission spectrometry, atomic fluorescence spectrometry, and
    proton-induced X-ray emissions (PIXE) analysis. Analytical methods
    for cadmium have been reviewed by Friberg et al. (1986).

         In addition,  in vivo analysis of cadmium in kidney and liver
    has been carried out by certain investigators (Ellis et al. 1981a;
    Roels et al. 1981b; Roels et al. 1983a, 1983b). The method uses the
    principles of neutron activation and is discussed in section 8.2.1.6
    of this monograph.

         The validity and accuracy of any method should ideally be
    ascertained by adequate quality assurance data (section 2.3). In the
    absence of such data, the results should at least be accompanied by
    intra-laboratory quality control data, results of analysis of
    certified standard materials, or inter-laboratory comparison data
    (section 2.3). Older basic chemical analysis methods may be as
    accurate as newer more complex and expensive methods, at least in
    the higher concentration range, and no analytical results should be
    dismissed or accepted until the method used has been carefully
    evaluated.

    2.2.3.1  Atomic absorption spectrometry

         The basic principle is to pass the sample into a
    high-temperature flame (burner) or furnace and measure the
    absorption from the atoms in the ground state. A lamp with a cathode
    made up from the pure metal or an alloy of the desired element,
    emitting the narrow line spectrum of this element, is used as an
    external light source. Atomic absorption spectrometry (AAS) is the
    method most commonly used at present for cadmium determination,
    because the procedure is relatively simple and fast, and its
    detection limit is sufficient for most environmental and biological
    materials. The absorption is measured at the cadmium line
    (228.8 nm).

         There are two main methods for atomization of a sample, the
    flame method and electrothermal atomization (ETA). The latter is
    also called the heated graphite atomization, graphite furnace or
    flameless method. Flame methods are generally used for liquid
    samples that can be aspirated into a flame, usually an air-acetylene
    flame. The detection limit for cadmium in pure water is of the order
    of 1-5 mg/litre and, in biological materials, it is about 0.1 mg/kg.
    At lower levels, it is usually necessary to increase the sensitivity
    by some accessory or by preconcentration during sample treatment.
    One important modification of the flame technique is the use of a
    micro-crucible or cup made of nickel (Delves, 1970; Fernandez &
    Kahn, 1971; Ediger & Coleman, 1973). The atoms are held much longer
    in the light beam that passes through the tube, and this increases
    the sensitivity considerably.

         ETA methods have undergone rapid development in recent years.
    The sample, usually in solution (1-100 ml), is first inserted into a
    graphite furnace, which is surrounded by a constant flow of inert
    gas, such as argon or nitrogen. The temperature is then increased in
    order to dry, ash, and atomize the sample. During atomizing, the
    specific absorption from cadmium is deduced from the light beams
    passing through or just above the furnace. The detection limit is
    extremely low (of the order of a few pg). There have been several

    detailed reports describing the analysis, using ETA, of cadmium in
    biological samples such as blood and urine (Lundgren, 1976; Castilho
    & Herber, 1977; Stoeppler & Brandt, 1978, 1980; Vesterberg &
    Wrangskogh, 1978; Gardiner et al., 1979; Delves & Woodward, 1981;
    Subramanian & Meranger, 1981; Jawaid et al., 1983). The lowest
    detectable concentration of cadmium in blood and urine using ETA is
    of the order of 0.1-0.3 mg/litre (Delves, 1982).

         Although the atomic absorption spectrometry for cadmium is
    specific, the method is not free from problems when applied to
    measurements in biological samples. Several important sources of
    interference exist, especially light scattering from particles and
    nonspecific absorption from the broad molecular absorption band
    formed by, for instance, sodium chloride and phosphate ions.
    Piscator (1971) showed that sodium chloride, at a concentration of
    0.5 mol/litre, gave a signal corresponding to a concentration of
    0.1 mg cadmium/litre when using ordinary air-acetylene flame atomic
    absorption equipment without background correction. The actual
    concentration was less than 0.4 mg cadmium/litre. Many problems
    related to interfering salts may be compensated by the use of a
    background correction system. A deuterium or hydrogen lamp is
    usually used. The nonspecific absorption can thus be measured and
    the signal, measured as the difference between the specific and
    nonspecific absorption, is proportional to the actual cadmium
    concentration (Kahn & Manning, 1972). Background correction for fine
    structure nonspecific absorption can also be made by utilizing the
    Zeeman effect on incoming light when it is modulated by strong
    magnetic fields (Koizumi et al., 1977; Alt, 1981; Pleban et al.,
    1981). Some kind of background correction is necessary when the
    microcrucible or electrothermal atomization techniques are used for
    cadmium analysis, since the nonspecific absorption increases as the
    atoms are kept in the light for a relatively long period of time.

    2.2.3.2  Electrochemical methods

         Cadmium can be determined by different types of
    electro-chemical methods such as classic polarographic methods or
    the more recently developed anodic stripping voltammetry and
    cadmium-selective electrodes. The basic principle behind the
    electrochemical methods is the change in the electrochemical
    potentials formed when electrons are transferred from one metal to
    another. A dropping mercury electrode is placed in a solution where
    the metal concentration is to be determined. By changing the charge
    of the electrode, different metals will be reduced and form an
    amalgam (a solid solution of metal atoms and mercury) with the
    mercury electrode. Polarographic waves can thus be recorded.
    Different metals can be determined simultaneously in a liquid
    sample, since they form amalgams at different charges.

         Anodic stripping voltammetry is based on the reverse process,
    i.e. the release of metals that have already been reduced and are
    bound to the mercury electrode. During oxidation and release from
    the amalgam, a peak current can be recorded at a potential that is
    characteristic for the particular metal. Anodic stripping
    voltammetry is one of the most sensitive methods for cadmium
    determination available. The most crucial aspects are complete
    destruction of all organic materials and the transfer of cadmium
    ions from the sample into a non-contaminated electrolyte. The method
    is especially suitable for water analysis, where no sample treatment
    is necessary (Piscator & Vouk, 1979), but has also been used for the
    measurement of cadmium in various biological materials such as urine
    (Jagner et al., 1981), foodstuffs, and tissues (Danielsson et al.,
    1981). In urine, a detection limit of about 0.1 mg/litre was
    obtained when using a computerized potentiometric stripping analysis
    (Jagner et al., 1981).

         Specific cadmium-selective electrodes are commercially
    available, but their sensitivity is insufficient for cadmium
    measurement in most biological materials. Furthermore, the
    electrodes are not ion specific, and problems can easily arise from
    various contaminants in the solution used (Hislop, 1980).

    2.2.3.3  Activation analysis

         Cadmium has a number of stable isotopes. Irradiation with
    neutrons yields new radioactive cadmium isotopes, which can be
    quantitatively measured on the basis of their specific energy and
    half-life. A procedure for determining cadmium in human liver
    samples by neutron activation analysis has been reported by
    Halvorsen & Steinnes (1975). The irradiated sample is usually
    digested before the radioactivity is measured. Sometimes, it may be
    necessary to concentrate cadmium by chemical methods and to separate
    the cadmium ions from other isotopes that have an energy spectrum
    overlapping the one for cadmium before measurement can be carried
    out. Non-radioactive cadmium can also be added after irradiation to
    enable measurement of the recovery after digestion and various
    concentration steps. The detection limit for neutron activation
    analysis is low, of the order of 0.1-1 mg cadmium/kg or
    0.1-1 mg/litre, in most biological materials. However, the method is
    expensive since the samples have to be irradiated in a reactor, and
    so it is not normally used for screening programmes. Neutron
    activation analysis has been used as a reference method for accuracy
    tests of other methods (Kjellström et al., 1975b; Kjellström, 1979;
    Jawaid et al., 1983).

         Neutron activation analysis is not ideal for liquid samples
    such as blood and urine, where the detection limit of the method is
    very close to the normal values. Furthermore, ampoules filled with
    liquid samples sometimes explode as gases are formed when the sample
    is irradiated in the reactor.

         Irradiation with protons, proton-induced X-ray emission (PIXE),
    can also be used for activation analysis of cadmium. Several
    elements are measured at the same time. The main advantage of the
    method is its ability to detect and quantify cadmium in very small
    samples such as thin slices of tissues weighing less than 1 mg
    (Hasselmann et al., 1977; Mangelson et al., 1979).

    2.2.3.4   In vivo methods

         A non-invasive technique for  in vivo determination of liver
    and kidney cadmium has been developed (Biggin et al., 1974; Harvey
    et al., 1975; McLellan et al., 1975) using the principle of neutron
    activation analysis and taking advantage of the very large capture
    cross-section area for thermal neutrons of one of the
    naturally-occurring stable isotopes of cadmium (113Cd; natural
    abundance, 12.26%). A portable system using a 238Pu-Be source of
    neutrons (instead of the original, which was cyclotron dependent)
    has made this technique more easily available (Thomas et al., 1976).

         The lowest detection limit for "field-work" techniques
    currently in use for this method is about 1.5 mg/kg in liver and
    15 mg/kg in whole kidney (Ellis et al., 1981a). These limits are too
    high to measure accurately tissue levels in people with "normal"
    environmental exposure (section 6.4). In people with occupational
    exposure, cadmium levels of up to 100 mg/kg in liver and 400 mg/kg
    in whole kidney have been reported (Ellis et al., 1981a; Roels et
    al., 1981b). The method is still not developed to its full capacity,
    and the results are greatly affected by, for instance, the
    variability in the location of the kidney (Al-Haddad et al., 1981).

         An alternative method for  in vivo determination of cadmium
    concentration in kidney cortex using X-ray-generated atomic
    fluorescence (XRF method) has been reported (Ahlgren & Mattson,
    1981; Christofferson & Mattson, 1983). Skerfving et al. (1987) found
    the limit of detection to be 17 µg/g kidney cortex (three standard
    deviations above the background). The precision is 23%.

         The validity and accuracy of these  in vivo neutron activation
    and XRF methods have not been studied sufficiently. A comparison of
    the results obtained by  in situ determination of liver and kidney
    cadmium in deceased people with those found by chemical analysis of
    the same tissues is needed.

    2.3  Quality control and quality assurance

    2.3.1  Principles and need for quality control

         There is a great need for strict quality control procedures in
    the monitoring of trace elements in biological materials. The
    purpose of these is to ensure that published data are as accurate as
    possible. Quality control involves intra-laboratory or
    inter-laboratory procedures that check whether the method gives
    acceptable results on samples with known concentrations. Quality
    assurance is usually given a broader meaning to cover the whole
    system of activities that are carried out to increase the quality of
    the operation. Thus, quality assurance includes not only the
    chemical analysis, but also the whole pre-analytical chain, data,
    handling, reporting, etc.

         A review of published data (Vahter, 1982) showed that mean
    blood cadmium concentrations in the general population as high as
    20-50 mg/litre have been reported. Such values are definitely
    unrealistic (section 6.2). Furthermore, most published reports lack
    quality control or quality assurance data. Valid comparisons of
    cadmium exposure based on blood cadmium levels can, therefore,
    seldom be made. Results from interlaboratory comparisons amplify the
    need for quality control (section 2.3.3).


    2.3.2  Comparison of methods and laboratories

         As indicated above, AAS (direct or combined with a separation
    procedure by organic solvent extraction or ion exchange) is the
    common method and can be applied to ordinary environmental or
    biological samples. Each of the other methods has its particular
    characteristics and can be used effectively according to the need
    for sensitivity and to the type of sample. Of special concern are
    methods used for the determination of cadmium in, for instance,
    food, blood, and urine, where cadmium concentrations are generally
    low and the matrices are complicated. Attempts to evaluate the
    accuracy by comparing the proposed method with another method have
    seldom been made. When testing a new method for the determination of
    cadmium or a new application of a method to a different type of
    sample, it is advisable to compare it with another method based on
    quite different principles.

         Since the principle of neutron activation analysis is quite
    different from that of other methods, it is a good method for
    comparison. Thus, Linnman et al. (1973) and Kjellström et al. (1974,
    1975b) found good agreement between a flameless atomic absorption
    method and destructive neutron activation analysis (the sample is

    irradiated and then treated chemically so the original material is
    "destroyed") for cadmium in wheat at concentrations down to around
    20 mg/kg wheat. In the latter study (Kjellström et al., 1975b), good
    agreement was also found between cadmium concentrations in urine
    (above 5 µg/litre), determined by AAS after extraction into organic
    solvent, and cadmium concentrations determined by neutron
    activation. Because of technical problems of neutron activation
    analysis of liquid samples, Kjellström et al. (1975b) could not
    evaluate the accuracy at urine concentrations of around 1 µg/litre.
    However, Jawaid et al. (1983) have used neutron activation to
    confirm the accuracy of atomic absorption analyses of urine in the
    range of 0.2-4 µg/litre.

         Further comparisons of destructive neutron activation analysis
    and different AAS methods conducted in different laboratories have
    been carried out for faeces, rice, wheat, liver, and muscle
    (Kjellström, 1979). The best agreement was found for liver, in which
    the cadmium concentrations were the highest, but, there was also
    reasonable agreement between most of the methods in the case of
    other materials.

         Another possibility for testing a method is to add radioactive
    cadmium to the samples (Kjellström et al., 1974) or to inject
    radioactive cadmium into animals and then compare results of
    radioactive measurements with those obtained by chemical analysis.

         Since there has been a need for comparing cadmium levels in
    different areas of the world, studies among laboratories in
    different countries have been undertaken to ensure that the
    analytical methods give comparable results.

         An intercomparison programme involving several European
    laboratories, which used flame atomic absorption, flameless atomic
    absorption, colorimetry, polarography, and anodic stripping
    voltammetry, indicated great variability in results (Lauwerys et
    al., 1975). Thus, reported concentrations in the same sample of
    blood were from 1 to 92 µg/litre in one case, from 0 to 73 µg/litre
    in another, and from 0 to 110 mg/litre in a third. A wide range of
    values was also reported in the case of aqueous solutions. Only 29%
    of participating laboratories measured cadmium in blood with
    sufficient precision. The conclusion from this study was that
    several participating laboratories had not yet adequately developed
    the technique required for precisely measuring cadmium in blood,
    urine, and water.

    2.3.3  Quality assurance

         An extensive quality assurance programme of cadmium analysis
    involving laboratories in nine different countries has been carried
    out (Vahter, 1982). This was a part of the UNEP/WHO Global

    Environmental Monitoring Programme and involved the analysis of
    cadmium in blood and kidney tissue as well as of lead in blood. A
    series of quality control samples (spiked specimens), the
    concentrations being known or unknown to the participating
    laboratories, was used to check the accuracy of the methods before
    the population samples were analysed. This procedure was repeated up
    to 12 times, development work on the methods being carried out in
    between, in order to improve the accuracy of the methods. After
    improvement of the techniques and practice, the agreement became
    excellent. An overview of various aspects of quality assurance has
    been presented by Friberg (1988).

    2.4  Conclusions

         There are several methods available for the determination of
    cadmium in biological materials. Atomic absorption spectrometry
    (AAS) is the most widely used, but careful treatment of samples and
    correction for interference is needed for the analysis of samples
    with low cadmium concentrations. It is strongly recommended to
    accompany analysis with a quality assurance programme. At present,
    it is possible under ideal circumstances to determine concentrations
    of about 0.1 µg/litre in urine and blood and 1-10 µg/kg in food and
    tissue samples.

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         The metal cadmium belongs, together with copper and zinc, to
    group IIb of the Periodic Table. It is a relatively rare element and
    is not found in the pure state in nature. Cadmium is mainly
    associated with the sulfide ores of zinc, lead, and copper, although
    purification first took place in 1817 from zinc carbonate.
    Commercial production only became significant at the beginning of
    this century. Cadmium is often considered as a metal of the 20th
    century; indeed, over 65% of the cumulative world production has
    taken place in the last two decades (Wilson, 1988).

         Cadmium is commonly regarded as a pollutant of worldwide
    concern. The metal has been reviewed by the International Register
    of Potentially Toxic Chemicals of the United Nations Environment
    Programme. As a result, it has been included on the list of chemical
    substances and processes considered to be potentially dangerous at
    the global level (IRPTC, 1987).

    3.1  Natural occurrence and cycling

         Cadmium is widely distributed in the earth's crust at an
    average concentration of about 0.1 mg/kg. However, higher levels may
    accumulate in sedimentary rocks, and marine phosphates often contain
    about 15 mg cadmium/kg (GESAMP, 1984). Weathering also results in
    the riverine transport of large quantities of cadmium to the world's
    oceans and this represents a major flux of the global cadmium cycle;
    an annual gross input of 15 000 tonnes has recently been estimated
    (GESAMP, 1987).

         Some black shale deposits in parts of the United Kingdom and
    USA contain elevated cadmium levels, thus leading to high soil
    concentrations in these areas (Lund et al., 1981). High soil
    concentrations are more commonly found in areas containing deposits
    of zinc, lead, and copper ores. Indeed, such areas are often
    characterized by both soil and aquatic contamination at the local
    level. The mining of these ore bodies has further increased the
    extent of such contamination. In background areas away from such
    deposits, surface soil concentrations of cadmium typically range
    between 0.1 and 0.4 mg/kg (Page et al., 1981) while fresh water
    contains < 0.01-0.06 ng/litre (Shiller & Boyle, 1987).

         Volcanic activity is a major natural source of cadmium release
    to the atmosphere. Emissions of cadmium take place both during
    episodic eruptions and continuous low-level activity. Difficulties
    exist in quantifying the global flux from this source but an
    estimate of 100-500 tonnes (Nriagu, 1979) has been made. Deep sea
    volcanism is also a source of environmental cadmium release, but the
    role of this process in the global cadmium cycle remains to be
    quantified.

         Older measurements of cadmium in the atmosphere and marine
    waters from background areas generally yielded much higher values
    than those obtained by more recent studies. Improved sampling and
    analytical techniques are considered to be responsible for these
    changes. Recent measurements of atmospheric concentrations in remote
    areas are typically in the range of 0.01-0.04 ng/m3 (GESAMP,
    1985). Airborne cadmium concentrations around volcanoes can be
    markedly elevated; for example, the plume of Mount Etna, Sicily,
    contains about 90 ng/m3 (Buatmenard & Arnold, 1978).

         Current measurements of dissolved cadmium in surface waters of
    the open oceans give values of < 5 ng/litre. The vertical
    distribution of dissolved cadmium in ocean waters is characterized
    by a surface depletion and deep water enrichment, which corresponds
    to the pattern of nutrient concentrations in these areas (Boyle et
    al., 1976). This distribution is considered to result from the
    absorption of cadmium by phytoplankton in surface waters, its
    transport to the depths incorporated in biological debris, and its
    subsequent release. In contrast, cadmium is enriched in the surface
    waters of areas of upwelling, and this leads to elevated levels in
    plankton unconnected with human activity (Martin & Broenkow, 1975;
    Boyle et al., 1976). Oceanic sediments under-lying these areas of
    high productivity can contain markedly elevated cadmium levels as a
    result of inputs associated with biological debris (Simpson, 1981).

         Ice and snow deposits from the polar regions represent a unique
    historical record of pollutants in atmospheric precipitation.
    However, the problems of contamination are great and no reliable
    data are at present available from historic samples; this prevents
    an insight into temporal changes in the cycling of cadmium.
    Nevertheless, current ice samples have been analysed; those from the
    Arctic contain on average 5 pg/g, while corresponding values from
    the Antarctic (0.3 pg/g) are much lower (Wolff & Peel, 1985).

    3.2  Production

         Cadmium is a by-product of zinc production. As a result, the
    level of cadmium output has closely followed the pattern of zinc
    production, little being produced prior to the early 1920s. The
    subsequent rapid increase corresponded to the commercial development
    of cadmium electroplating. Worldwide production reached a plateau in
    the 1970s but in the 1980s output appeared to be increasing again
    (Wilson, 1988b). The worldwide production of cadmium in 1987 was
    18 566 metric tonnes (Wilson, 1988b).

    3.3  Uses

         Cadmium has a limited number of applications but within this
    range the metal is used in a large variety of consumer and
    industrial materials. The principal applications of cadmium fall
    into five categories: protective plating on steel; stabilizers for

    poly-vinyl chloride (PVC); pigments in plastics and glasses;
    electrode material in nickel-cadmium batteries; and as a component
    of various alloys. Detailed consumption statistics are only
    available for a limited number of countries but from these it is
    apparent that the pattern of use can vary considerably from country
    to country (Wilson, 1988b).

         Examination of the reported trends in cadmium consumption over
    the last 25 years reveals considerable changes in the relative
    importance of the major applications. The use of cadmium for
    electroplating represents the most striking decrease; in 1960 this
    sector accounted for over half the cadmium consumed worldwide, but
    in 1985 its share was less than 25% (Wilson, 1988b). This decline is
    usually linked to the widespread introduction of progressively
    stringent effluent limits from plating works and, more recently, to
    the introduction of general restrictions on cadmium consumption in
    certain countries. In contrast, the use of cadmium in batteries has
    shown considerable growth in recent years from only 8% of the total
    market in 1970 to 37% by 1985. The use of cadmium in batteries is
    particularly important in Japan and represented over 75% of the
    total consumption in l985 (Wilson, 1988b).

         Of the remaining applications of cadmium, pigments and
    stabilizers are the most important, accounting for 22% and 12%,
    respectively, of the world total in 1985. The share of the market by
    cadmium pigments remained relatively stable between 1970 and l985
    but the use of the metal in stabilizers during this period showed a
    considerable decline, largely as a result of economic factors. The
    use of cadmium as a constituent of alloys is relatively small and
    has also declined in importance in recent years, accounting for
    about 4% of total cadmium use in l985 (Wilson, 1988b).

    3.4  Sources of environmental exposure

         Numerous human activities result in the release of significant
    quantities of cadmium to the environment. The relative importance of
    individual sources varies considerably from country to country. The
    major sources of anthropogenic cadmium release can be divided into
    three categories. The first is made up of those activities involved
    in the mining, production, and consumption of cadmium and other
    non-ferrous metals. The second category consists of inadvertent
    sources where the metal is a natural constituent of the material
    being processed or consumed. Sources associated with the disposal of
    materials that had earlier received cadmium discharges or discarded
    cadmium products make up the third category.


        Table 1.  Estimates of atmospheric cadmium emissions (tonnes/year) from human
              activities on a national, regional and worldwide basis
                                                                                  

              Source                     United       EECb     Worldwidec
                                         Kingdoma
                                                                                  

    Natural sources                        ND          20         800d

    Non-ferrous metal
    production

              mining                       ND          ND         0.6-3
              zinc and cadmium                         20       920-4600
              copper                       3.7          6       1700-3400
              lead                                      7        39-195

    Secondary production                               ND        2.3-3.6

    Production of cadmium-containing
     substances                            ND           3          ND

    Iron and steel production              2.3         34        28-284

    Fossil fuel combustion

              coal                         1.9          6        176-882
              oil                                      0.5       41-246

    Refuse incineration                     5          31        56-1400

    Sewage sludge incineration             0.2          2         3-36

    Phosphate fertilizer manufacture       ND          ND        68-274

    Cement manufacture                      1          ND        8.9-534

    Wood combustion                        ND          ND        60-180

              TOTAL EMISSIONS              14          130       3900-12800
                                                                                  

    a    From: Hutton & Symon (1986); data apply to 1982-1983
    b    From: Hutton (1983); data apply to 1979-1980 (the EEC consisted, at
         that time, of Belgium, Denmark, Federal Republic of Germany, Italy,
         Luxembourg, The Netherlands, Republic of Ireland, and
         the United Kingdom)
    c    From: Nriagu & Pacyna (1988); data apply to 1983
    d    From: Nriagu (1979)
    ND Not determined
        3.4.1  Sources of atmospheric cadmium

         Estimates of cadmium emissions to the atmosphere from human and
    natural sources have been carried out at the world-wide, regional,
    and national levels; examples of such inventories are shown in
    Table 1.

         The median global total emission of the metal from human
    sources in 1983 was 7570 tonnes (Nriagu & Pacyna, 1988) and
    represented about half the total quantity of cadmium produced in
    that year. In comparison, the worldwide emission of lead from human
    activities was about 10% of the total lead produced in 1983 (Nriagu
    & Pacyna 1988). In both the European Economic Community (EEC) and on
    a worldwide scale (Nriagu, 1979), about 10-15% of total airborne
    cadmium emissions arise from natural processes, the major source
    being volcanic action.

         Considerable differences exist in the relative importance of
    different sources of atmospheric cadmium between the worldwide
    situation and that in the United Kingdom and the EEC as a whole.
    This is particularly marked for non-ferrous metal production, which
    accounts for about 75% of the total anthropogenic emissions
    worldwide but only 25% in the EEC. This partly reflects the
    extensive emission controls operated by these industries in Europe
    compared with many parts of the world. In addition, of the two basic
    methods of zinc production, thermal smelting and electrolyte
    refining, only the former releases significant atmospheric cadmium
    emissions. In recent years, electrolytic refining has assumed the
    major share of the world's production of zinc and cadmium and has
    largely replaced thermal processes in Europe. The once important
    vertical and horizontal retort smelters, which emit large quantities
    of atmospheric cadmium, have been phased out in most developed
    countries, but are still in operation in several developing
    countries (ILZSG, 1988).

         Other industries that employ thermal processes, e.g., iron
    production, fossil fuel combustion, and cement manufacture, all
    release airborne cadmium, the metal being a natural constituent of
    the raw materials. The cadmium content of these materials is
    generally relatively low but this is offset by the vast quantities
    consumed. Furthermore, in common with other thermal processes, the
    elevated temperatures employed result in the volatilization of
    cadmium. It subsequently condenses in a preferential manner on the
    smallest particles in the stack gases, the size range least
    efficiently retained by conventional particulate control measures
    (Smith, 1982). Despite mechanisms that enhance the release of
    cadmium, the quantities emitted from the three processes are now
    considered to be smaller than they were in the past, particularly in
    the case of fossil fuel combustion (Rauhut, 1980). Municipal refuse
    is a waste-related source, the cadmium being derived from discarded

    nickel-cadmium batteries and plastics that contain cadmium pigments
    and stabilizers. The incineration of refuse, a practice generally
    restricted to developed countries, is a major source of atmospheric
    cadmium release at the national, regional, and worldwide levels
    (Table 1). Indeed, this activity accounts for about one third of the
    total cadmium emissions in the United Kingdom and the EEC as a
    whole. Cadmium release from this sector originates from a large
    number of plants, while the emissions from the non-ferrous metal
    industry are derived from relatively few facilities.

         Sewage sludge receives cadmium from industrial sources,
    particularly from the discharges of plating operations and pigment
    works. One disposal option, the incineration of sewage sludge, is a
    relatively minor source of airborne cadmium, reflecting the small
    quantities of sludge disposed of in this manner (Table 1).

         Steel production can also be considered as a waste-related
    source, as large quantities of cadmium-plated steel scrap are
    recycled by this industry, at least in developed countries. As a
    result, steel production is responsible for considerable emissions
    of atmospheric cadmium.

    3.4.2  Sources of aquatic cadmium

         Non-ferrous metal mines represent a major source of cadmium
    release to the aquatic environment. Contamination can arise from
    mine drainage water, waste water from the processing of ores,
    overflow from the tailings pond, and rainwater run-off from the
    general mine area. The release of these effluents to local
    water-courses can lead to extensive contamination downstream of the
    mining operation. The cadmium content of the ore body and mine
    management policies, as well as climatic and geographical
    conditions, all influence the quantities of cadmium released from
    individual sites. Flood and storm conditions, for example, will
    enhance the mobilization of cadmium contained in particulate
    material. Aquatic inputs of cadmium are not restricted to active
    mine sites, and mines disused for many years can still be
    responsible for the continuing contamination of adjacent
    watercourses (Johnson & Eaton, 1980).

         At the global level, the smelting of non-ferrous metal ores has
    been estimated to be the largest human source of cadmium release to
    the aquatic environment (Nriagu & Pacyna, 1988). Discharges to fresh
    and coastal waters arise from liquid effluents produced by gas
    scrubbing together with the site drainage waters.

         Concerning the locations where environmental health effects of
    cadmium have been reported, the water and air contamination from
    non-ferrous metal mining and production are the predominant sources
    of cadmium. All the major areas of Japan with elevated cadmium
    levels have been affected by these sources (Tsuchiya, 1978),
    although contamination through the natural mobilization of cadmium
    from ore bodies may also have been involved.

         Cadmium is a natural constituent of rock phosphates and
    deposits from some regions of the world contain markedly elevated
    levels of the metal. The manufacture of phosphate fertilizer results
    in a redistribution of the cadmium in the rock phosphate between the
    phosphoric acid product and the gypsum waste. In many cases, the
    gypsum is disposed of by dumping in coastal waters, which leads to
    considerable cadmium inputs. Some countries, however, recover the
    gypsum for use as a construction material and thus have negligible
    cadmium discharges (Hutton, 1982).

         The atmospheric fall-out of cadmium to fresh and marine waters
    represents a major input of cadmium at the global level (Nriagu &
    Pacyna, 1988). Indeed, a GESAMP study of the Mediterranean Sea
    indicated that this source is comparable in magnitude to the total
    river inputs of cadmium to the region (GESAMP, 1985). Similarly,
    large cadmium inputs to the North Sea (110-430 tonnes/year) have
    been estimated, based on the extrapolation from measurements of
    cadmium deposition along the coast (van Aalst et al., 1983a,b).
    However, another approach based on model simulation yielded a modest
    annual input of 14 tonnes (Krell & Roeckner, 1988).

         Acidification of soils and lakes may result in enhanced
    mobilization of cadmium from soils and sediments and lead to
    increased levels in surface and ground waters (WHO, 1986). The
    corrosion of soldered joints or zinc galvanized plumbing by acidic
    waters can dissolve cadmium and produce increased levels of the
    metal in drinking-water. In one study from Sweden, cadmium levels in
    tap water from areas susceptible to acidic deposition were double
    those from a control area (Svensson et al., 1987).

    3.4.3   Sources of terrestrial cadmium

         Solid wastes from a variety of human activities are disposed of
    in landfill sites, resulting in large cadmium inputs at the national
    and regional levels when expressed as a total tonnage (Hutton, 1982;
    Hutton & Symon, 1986). However, this simple approach exaggerates the
    significance of landfilled cadmium in certain high volume wastes
    with relatively low concentrations of cadmium. Examples include the
    ashes from fossil fuel combustion, waste from cement manufacture,
    and the disposal of municipal refuse and sewage sludge. Of greater

    potential environmental significance are the solid wastes from both
    non-ferrous metal production and from the manufacture of
    cadmium-containing articles, as well as the ash residues from refuse
    incineration. All three waste materials are characterized by
    elevated cadmium levels and as such require disposal to controlled
    sites to prevent the mobilization of the cadmium in ground water.

         Soil cadmium contamination is a characteristic feature around
    non-ferrous metal mines and smelters, particularly in the case of
    those handling zinc ores. Contamination from mining is generally
    local but may be widespread in areas of high mineral content
    (Tsuchiya, 1978). Soil contamination from smelters is generally
    greatest next to the source and decreases exponentially with
    distance, although cadmium concentrations can still be above the
    background level 20 km from the source (Buchauer, 1972). Shipham,
    United Kingdom, is a site of extreme soil cadmium contamination.
    Between 1650 and 1850 the village of Shipham was the site of a major
    zinc mine. Once the mining stopped the area was flattened and
    developed for agriculture and housing. Cadmium levels in
    agricultural and garden soils are some of the highest ever reported
    worldwide (Thornton, 1988).

         The agricultural application of phosphate fertilizers
    represents a direct input of cadmium to arable soils. The cadmium
    content of phosphate fertilizers varies widely and depends on the
    origin of the rock phosphate. It has been estimated that fertilizers
    of West African origin contain 160-255 g cadmium/tonne of phosphorus
    pentoxide, while those derived from the southeastern USA contain
    only 35 g/tonne (Hutton, 1982).

         The annual rate of cadmium input to arable land from phosphate
    fertilizers had been estimated for the countries of the EEC, taking
    into account differences in application rates and the cadmium
    contents of the fertilizers used (Hutton, 1982). The average cadmium
    input (5 g/ha) only represents about 1% of the surface soil cadmium
    burden. Despite the relatively small size of this input, long-term
    continuous application of phosphate fertilizers has been shown to
    cause increased soil cadmium concentrations (Williams & David, 1973,
    1976; Andersson & Hahlin, 1981).

         The application of municipal sewage sludge to agricultural soil
    as a fertilizer can also be a significant source of cadmium. In many
    industrialized countries, control measures have reduced the cadmium
    content of sewage sludge and at the same time national and regional
    regulations have limited the input of cadmium from agricultural
    sludge applications (Davis, 1984). Nevertheless, large increases in
    soil cadmium concentration have resulted in the past from the
    application of contaminated sludge in both North America and Europe

    (Davis, 1984). Even today, the high application rates used for
    sewage sludge result in relatively large cadmium inputs, a value of
    80 g/ha having been estimated for the United Kingdom (Hutton &
    Symon, l986). On a national or regional basis, however, these inputs
    are much smaller than those from either phosphate fertilizers or
    atmospheric deposition (see section 4.2).

    3.5   Conclusions

         Cadmium is a relatively rare element and current analytical
    procedures indicate much lower concentrations of the metal in
    environmental media than do older measurements. At present, it is
    not possible to determine whether human activities have caused a
    historic increase in cadmium levels in the polar ice caps.

         Commercial cadmium production started at the beginning of this
    century. The pattern of cadmium consumption has changed in recent
    years with significant decreases in electroplating and increases in
    batteries and specialized electronic uses. Most of the major uses of
    cadmium employ it in the form of compounds that are present at low
    concentration. This makes it difficult to recycle cadmium in order
    to decrease the potential for environmental contamination.
    Restrictions on certain uses of cadmium imposed by a few countries
    may have widespread impact on the applications of cadmium.

         Cadmium is released to the air, land, and water by human
    activities. In general, the two major sources of contamination are
    the production and consumption of cadmium and other non-ferrous
    metals and the disposal of wastes containing cadmium. Areas in the
    vicinity of non-ferrous mines and smelters often show pronounced
    cadmium contamination.

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND
        TRANSFORMATION

    4.1   Atmospheric deposition

         Cadmium is removed from the atmosphere by dry deposition and by
    precipitation. Total deposition rates have been measured at numerous
    localities worldwide and values have generally been found to
    increase in the order: background < rural < urban < industrial.
    In rural areas of Scandinavia, annual deposition rates ranged from
    0.4 to 0.9 g/ha (Laamanen, 1972; Andersson, 1977). Similarly, in a
    rural region of Tennessee, USA, a deposition rate of 0.9 g/ha was
    observed (Lindberg et al., 1982). Hutton (1982) concluded that
    3 g/ha per year is a representative value for the atmospheric
    deposition of cadmium to agricultural soils in rural areas of the
    EEC. This may be compared with a corresponding input of 5 g/ha per
    year for these areas from the application of phosphate fertilizers
    (see 3.4).

         Many industrial sources of cadmium possess tall stacks, which
    bring about the wide dispersion and dilution of particulate
    emissions. Indeed, it is often assumed that < 10% of such emissions
    are deposited locally, the remainder being available for long-range
    transport (Krell & Roeckner, 1988). Nevertheless, cadmium deposition
    rates around smelter facilities are often markedly elevated nearest
    the source and generally decrease rapidly with distance (Hirata,
    1981). This pattern of contamination can be reflected in surface
    soils and vegetation, and in the former case, contamination will
    reflect the long-term history of metal inputs from the atmosphere.
    As a result, soil cadmium concentrations in excess of 100 mg/kg are
    commonly encountered close to long-established smelters (Buchauer,
    1972). In some urban areas, the high density of non-ferrous metal
    works results in a city-wide elevation of cadmium deposition (Roels
    et al., 1981a).

         The possibility that cadmium deposition is enhanced around
    atmospheric sources of cadmium other than smelters has been
    investigated on a number of occasions. One assessment of studies
    conducted around coal-fired power stations concluded that this
    source was unlikely to cause any marked local accumulation of
    cadmium (Chadwick & Lindman, 1982). In contrast, significant cadmium
    contamination was found in surface soil downwind of a phosphate
    fertilizer processing plant in the USA, the levels being up to
    40 mg/kg (Hutchison et al., 1979). Little attention has been paid to
    the pattern of cadmium deposition around refuse incinerators; one
    study of a large facility in the United Kingdom observed moderately
    elevated deposition rates downwind of the plant (Hutton et al.,
    1988).

         Crop plants growing near to atmospheric sources of cadmium may
    contain elevated cadmium levels (Carvalho et al., 1986). However, it
    is not always possible to distinguish whether the cadmium is derived
    directly from surface deposition or originates from root uptake,
    since soil levels in such areas are generally higher than normal.
    One study in Denmark has suggested that atmospheric deposition can
    also be an important direct source of cadmium in crop plants even in
    background areas (Hovmand et al., 1983).

    4.2  Transport from water to soil

         Rivers contaminated with cadmium can contaminate surrounding
    land, either through irrigation for agricultural purposes, by the
    dumping of dredged sediments, or through flooding (Forstner, 1980;
    Sangster et al., 1984). For example, agricultural land adjacent to
    the Neckar River, Germany, received dredged sediments to improve the
    soil, a practice that produced soil cadmium concentrations in excess
    of 70 mg/kg (Forstner, 1980).

         Much of the cadmium entering fresh waters from industrial
    sources is rapidly absorbed by particulate matter, where it may
    settle out or remain suspended, depending on local conditions. This
    can result in low concentrations of dissolved cadmium even in rivers
    that receive and transport large quantities of the metal (Yamagata &
    Shigematsu, 1970). Rivers can transport cadmium considerable
    distances from the source of the input. In Japan, there are several
    areas where soils have been contaminated with irrigation water up to
    50 km from the source (Tsuchiya, 1978).

    4.3  Uptake from soil by plants

         It has been shown repeatedly that an increase in soil cadmium
    content results in an increased plant uptake of the metal. This has
    been demonstrated for soils with naturally elevated cadmium levels
    (Lund et al., 1981), those contaminated by non-ferrous metal mining
    (Alloway et al., 1988), and those that have received cadmium via
    sewage sludge applications (Davis & Coker, 1980). It is this basic
    relationship that makes the soil-crop pathway of human exposure
    susceptible to increased levels of soil cadmium. Indeed, since the
    major sources of cadmium exposure for the general population are
    food and tobacco (see section 5), it is important to assess those
    soil and plant factors that influence cadmium uptake by crop plants.

         The most important soil factors influencing plant cadmium
    accumulation are soil pH and cadmium concentration (Davis & Coker,
    1980; Page et al., 1981). Soil cadmium is distributed between a
    number of pools or fractions, of which only the cadmium in soil
    solution is thought to be directly available for uptake by plants.

    Soil pH is the principal factor governing the concentration of
    cadmium in the soil solution. Cadmium absorption to soil particles
    is greater in neutral or alkaline soils than in acidic ones and this
    leads to increased cadmium levels in the soil solution. As a
    consequence, plant uptake of cadmium decreases as soil pH increases.

         Other soil factors that influence the distribution of cadmium
    between the soil and soil solution include cation exchange capacity
    and the contents of the hydrous oxides of manganese and iron,
    organic matter, and calcium carbonate. Increases in these parameters
    result in decreased availability of cadmium to plants owing to a
    reduction of the level of cadmium in the soil solution.

         A comparative study of cadmium-contaminated soils from
    different sources illustrates the importance of the above soil
    factors (Alloway et al., 1988). Soils from Shipham, United Kingdom,
    contained the highest total cadmium levels but the soil solution
    concentrations were lower than in other soils. The small proportion
    of soluble cadmium in Shipham soils (0.04%) was related to the high
    pH (7.7) and high calcium carbonate and hydrous oxide content of
    these soils. In contrast, a paddy soil from the Junzu Valley, Japan,
    contained 4% soluble cadmium and possessed a low pH (5), low calcium
    carbonate content, and very low hydrous oxide concentration (Alloway
    et al., 1988).

         Much attention has been paid to the plant availability of
    cadmium in agricultural soils to which sewage sludge has been
    applied. It has been observed that the repeated application of
    sludge to soils can alter the availability of cadmium, and although
    soil cadmium levels may increase, crop levels do not always reflect
    this increase (Page et al., l981). The long-term availability of
    cadmium to plants is uncertain, availability having been reported to
    remain constant, decrease, or even increase with time (Tjell et al.,
    l983). In another study there were no clear changes in the plant
    availability of cadmium over a period of five years after sewage
    sludge was applied to the soil (Carlton-Smith, l987).

         Concern over the long-term implications of present-day cadmium
    inputs to European arable soils has led to modelling studies of the
    future cadmium exposure for the general population (Tjell et al.,
    1981; Hutton, 1982). It was estimated by Tjell et al. (1981) that
    cadmium inputs from phosphate fertilizers and atmospheric deposition
    will cause an annual increase of 0.6% in Danish soil cadmium levels.
    The corresponding increases in crop cadmium concentrations would
    lead to a predicted 70% increase in dietary cadmium intake 100 years
    hence. Similar soil and dietary cadmium increases have been
    predicted for the EEC as a whole, although the precise values varied
    according to the soil properties and crop consumption patterns
    employed (Hutton, 1982).

         Indirect support for these forecasts was provided by an
    investigation of the time trends in soil and crop cadmium levels
    using archived samples. Jones et al. (1987) found that the cadmium
    content of agricultural soils from a site in the United Kingdom had
    increased by 27-55% since the 1850s. Trends in the cadmium
    concentrations of wheat grain were less clear, possibly due to
    confounding factors such as changes in varieties grown and altered
    soil properties.

    4.4  Transfer to aquatic and terrestrial organisms

         In general, cadmium concentrations in terrestrial and aquatic
    biota from uncontaminated localities are low, corresponding to the
    geochemical abundance of this metal. However, in certain situations,
    cadmium displays a propensity for marked bioaccumulation, a feature
    that has implications for human dietary exposure and may be of
    toxicological significance for the organisms concerned.

         It appears that cadmium shows greatest mobility in certain
    marine ecosystems. Phytoplankton in areas of oceanic upwelling
    contain raised cadmium levels (Martin & Broenkow, 1975), and
    filter-feeding molluscs can accumulate significant concentrations of
    cadmium even in coastal localities that are only moderately
    contaminated (Bryan et al., 1980). Oysters, in particular, are
    well-known cadmium accumulators, levels of up to 8 mg/kg wet weight
    having been recorded in New Zealand (Nielsen, 1975). Certain edible
    crustaceans such as crab and lobster also contain relatively high
    cadmium concentrations, the metal being localized in the
    hepatopancreas or "brown meat" (Buchet et al., l983).

         Some marine birds and mammals contain remarkably elevated
    cadmium burdens in the kidney and liver (Martin et al., 1976;
    Stoneburner, 1978; Nicholson & Osborn, 1983). In the case of oceanic
    species, this accumulation is probably a natural process associated
    with the feeding habits and longevity of the organism in question.
    Even so, the high cadmium levels in pelagic sea-birds have been
    linked in one study to morphological signs of kidney damage
    (Nicholson & Osborn, 1983).

         Terrestrial mosses and lichens display a high capacity for
    retention of metals deposited from the atmosphere and these plants
    have been used to map both local contamination from point sources
    and regional patterns of cadmium deposition (MARC, 1986). The
    fruiting bodies of some macrofungi contain remarkably high cadmium
    concentrations even in areas uncontaminated with cadmium (MARC,
    1986). This phenomenon has implications for human dietary exposure
    as some accumulator species are edible.

         In addition to humans, certain long-lived terrestrial mammals
    such as the horse and moose may possess considerable cadmium burdens
    in the kidney and liver (Elinder & Piscator, 1978; Frank et al.,
    1981; Jeffery et al., 1989). It has been shown that cadmium
    accumulates with age in horse kidney.

    4.5  Conclusions

         Increases in soil cadmium content result in an increase in the
    uptake of cadmium by plants; the pathway of human exposure from
    agricultural crops is thus susceptible to increases in soil cadmium.
    The uptake by plants from soil is greater at low soil pH. Processes
    that acidify soil (e.g., acid rain) may therefore increase the
    average cadmium concentrations in foodstuffs. The application of
    phosphate fertilizers and atmospheric deposition are significant
    sources of cadmium input to arable soils in some parts of the world;
    sewage sludge can also be an important source at the local level.
    These sources may, in the future, cause enhanced soil and hence crop
    cadmium levels, which in turn may lead to increases in dietary
    cadmium exposure. In certain areas, there is evidence of increasing
    cadmium content in food.

         Edible free-living food organisms such as shellfish,
    crustaceans, and fungi are natural accumulators of cadmium. Regular
    consumption of these items can result in elevated human exposure.
    Certain marine vertebrates contain markedly elevated renal cadmium
    concentrations, which, although considered to be of natural origin,
    have been linked to signs of kidney damage in the organisms
    concerned.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         Human uptake of cadmium occurs via the inhalation of air and
    the ingestion of food and drinking-water. Accidental ingestion of
    cadmium through the contamination of foods in contact with
    cadmium-containing materials has occurred in the past. Accidental
    high-level inhalation exposure during welding operations and cadmium
    smelting is still a considerable hazard.

         Chronic exposure to cadmium via food or workplace air is the
    main concern in assessing the health risks of cadmium.

    5.1  Inhalation route of exposure

    5.1.1  Ambient air

         Many countries carry out regular monitoring programmes for
    cadmium in the air. An assessment of the available data from various
    European countries showed that average values range from 1 to
    5 ng/m3 in rural areas, 5 to 15 ng/m3 in urban areas, and 15 to
    50 ng/m3 in industrialized areas (WHO, 1987). Examination of some
    individual national data (Table 2) suggests that urban values are
    likely to occupy the lower end of the range indicated above
    (McInnes, 1979; RIVM, 1988).

         Much higher air cadmium concentrations are found in areas close
    to major atmospheric sources of the metal. However, these values can
    fluctuate widely as a result of changing emission characteristics
    and weather conditions (Muskett et al., 1979).

         Studies of the particle size distributions of cadmium in urban
    aerosols generally show that the metal is associated with
    particulate matter in the respirable range (Greenberg et al., 1978).
    The enrichment of cadmium on these smaller particles can be linked
    to the behaviour of the metal in thermal facilities that are sources
    of airborne cadmium (see section 3.4.1).

         An air quality study revealed no differences between indoor and
    outdoor air cadmium levels when the dwellings of non-smokers were
    examined (Moschandreas, 1981). However, significantly higher indoor
    air cadmium levels were observed in those houses where smoking took
    place.


    Table 2.  Typical levels of cadmium in ambient air
                                                                                  

    Type of area          Cadmium concentration  Sampling  Reference
                          range (ng/m3)          periodb
                                                                                  

    Remote rural

       Pacific atoll         0.0025-0.0046       NR        Duce et al. (1983)
       Europe                   0.1-0.3          NR        Heindryckx et al. (1974)
       Atlantic           3 x 10-6-6.2 x 10-4    NR        Duce et al. (1975)

    Rural

       Belgium                    1a             24 h      Janssens & Dams (1974)
       Federal Republic
       of Germany                0.1-1           < 24 h    Neeb & Wahdat (1974)
       Japan                      1-4            24 h      Japanese Environment
                                                           Agency (1974)

    Urban

       Belgium                    50a            24 h      Janssens & Dams (1974)
       Federal Republic
       of Germany               10-150           < 24 h    Neeb & Wahdat (1974)
       Japan                     3-6.3           1 year    Japanese Environment
                                                           Agency (1974)

       Poland                    2-51            1 year    Just & Kelus (1971)
       USA (New York)            3-23            1 year    Kneip et al. (1970)
                                                                                  

    a  Mean value                  b  NR = not reported

    5.1.2   Air in the working environment

         Elevated air cadmium levels arise in the smelting of
    non-ferrous metals and in the production and processing of
    cadmium-containing articles. The thermal operations associated with
    these processes are mainly responsible for producing cadmium dusts
    and, if temperatures are sufficiently high, cadmium fume.

         Airborne cadmium concentrations found in the occupational
    setting vary considerably according to the type of industry and the
    specific working conditions in each plant. Markedly elevated values,
    in the mg/m3 range, were prevalent in the 1940s to 1960s (Friberg,
    1950; Adams et al., 1969; Tarasenko & Vorobjeva, 1973). Considerable

    improvements in occupational hygiene have taken place in developed
    countries since then and these have led to progressive reductions in
    ambient levels in the workplace. Table 3 illustrates the temporal
    decline in air cadmium levels in a Swedish battery factory
    (Adamsson, 1979). The lowest values shown in Table 3 may not be
    typical for all occupational facilities; levels of 1-5 mg/m3 were
    reported for one pigment plant in the mid 1970s (De Silva & Donnan,
    1981).

    Table 3.  Average air cadmium concentrations in a Swedish cadmium
              battery planta

                                                            

    Time period     Number of       Cadmium concentration
                    observations         (µg/m3)
                                                            

       1946             10                   5000
    1947-1949           16                    750
    1950-1960           94                    650
    1965-1973          393                     70
    1973-1975          373                     40
    1975-1976          573                     15
                                                            

    a  From: Adamsson (1979)

         In general, only total air cadmium concentrations are monitored
    in the working environment; factors influencing respiratory
    absorption, such as the speciation of cadmium and the size
    distribution of the collected particles, are not taken into account.
    In one study of workplaces with high total airborne cadmium levels,
    Lauwerys et al. (1974b) found, in general, that less than 25% of the
    total cadmium in air was in the respirable range and that this
    percentage decreased as the total value increased.
    Cadmium-containing dust particles that are too large to be delivered
    to the pulmonary region of the lung can enter the gastrointestinal
    tract by mucociliary transfer.

    5.1.3   The smoking of tobacco

         The tobacco plant naturally accumulates relatively high cadmium
    concentrations in its leaves. As a result, this material represents
    an important source of exposure for smokers. It has been reported
    that one cigarette contains about 1-2 µg cadmium (Friberg et al.,
    1974) and that about 10% of the cadmium content is inhaled when the
    cigarette is smoked (Elinder et al., 1983). One study has suggested
    that modifications in cigarette construction and the increasing

    popularity of filter cigarettes have reduced cadmium exposure from
    this source in recent years (Scherer & Barkemeyer, 1983). Regional
    differences exist in the cadmium concentration of cigarettes, and
    lower values (0.1-0.5 µg) have been found in samples from Argentina,
    India, and Zambia (Nwankwo et al., 1977; Elinder et al., 1983).

         Biological monitoring surveys of the general population have
    shown that cigarette smoking can cause significant increases in the
    concentration of cadmium in the kidney (Lewis et al., 1972; Vahter,
    1982).

         Occupationally exposed workers who smoke tobacco may be subject
    to higher exposure levels than their non-smoking colleagues. This
    may be because the original content of tobacco can be considerably
    increased when handled during work (Piscator et al., 1976). In
    addition, the hand-to-mouth route of exposure may be more important
    in workers who are tobacco smokers (Adamsson, 1979).

    5.2  Ingestion routes of exposure

    5.2.1  Levels in drinking-water

         Drinking-water generally contains low cadmium levels and a
    value of 1 µg/litre or less is often assumed to be a representative
    value in most situations (Meranger et al., 1981). Thus, cadmium
    exposure from drinking-water and water-based beverages is relatively
    unimportant compared with the dietary contribution.

         In a study of drinking-water in Seattle, USA, Sharrett et al.
    (1982) reported a median cadmium level of 0.01 µg/litre in tap water
    delivered by copper pipes; the corresponding value from homes with
    galvanized piping was 0.25 µg/litre. Water samples left to stand in
    both types of piping showed increases in cadmium levels with median
    values of 0.06 and 0.63 µg/litre in copper and galvanized supplies,
    respectively. In a survey from the Netherlands, about 99% of
    drinking-water samples in 1982 contained less than 0.1 µg/litre
    (RIVM, 1988).

    5.2.2  Levels in food

         The cadmium content of agricultural crops varies according to
    species, variety cultivated and season (Davis & Coker, 1980). The
    results of an extensive nationwide survey of cadmium in different
    classes of raw agricultural crops from uncontaminated localities
    illustrate the range of values encountered within and between crop
    classes (Wolnik et al., 1983, 1985). It is evident that cadmium is a
    normal constituent of most foodstuffs (Tables 4 and 5).

    Table 4.  Cadmium concentrations in the major types of crop from
              various regions of the USAa

                                                                      

                             Cadmium concentration (mg/kg wet weight)
    Crop         Sample size     Median      Minimum        Maximum
                                                                   

    Rice            166          0.0045      < 0.001        0.23

    Peanuts         320          0.060         0.010        0.59

    Soybeans        322          0.041         0.002        1.11

    Wheat           288          0.030       < 0.0017       0.207

    Potatoes        297          0.028         0.002        0.18

    Carrots         207          0.017         0.002        0.13

    Onions          230          0.009         0.001        0.054

    Lettuce         150          0.017         0.001        0.160

    Spinach         104          0.061         0.012        0.20

    Tomatoes        231          0.014         0.002        0.048
                                                                      

    a  From: Wolnik et al. (1983, 1985).


         Meat, fish, and fruit generally contain similar cadmium levels
    and values of 5-10 µg/kg fresh weight are representative for these
    food classes. Most plant-based foodstuffs contain higher cadmium
    concentrations and a value of 25 µg/kg fresh weight is considered
    representative for the staple items, cereals and root vegetables.
    Offal from adult animals and certain shellfish contain even higher
    concentrations (see section 4.4); values in excess of 50-100 µg/kg
    fresh weight are considered normal. Food preparation can result in
    cadmium losses from plant-based items. The milling of wheat grain
    results in a reduction of about 50% in the cadmium content of the
    white flour produced (Linnman et al., 1973). The washing, peeling,
    and cooking of vegetables can also lead to reductions in the
    concentrations of cadmium but, in general, these are relatively
    small.

         The use of glazed ceramic containers to store foodstuffs can
    lead to significant cadmium contamination, particularly in the case
    of foods that are acidic liquids (Beckman et al., 1979).


        Table 5.  Cadmium concentrations in different food items from various European
              countries (values in µg/kg fresh weight)
                                                                                   

    Food Group            United     Finlandb   Swedenc   Denmarkd       The
                          Kingdoma                                   Netherlandse    
                                                                                   

    Bread and cereals     20-30       20-40     31-32       30          25-35
    Meat                 < 20-30      < 5-5      2-3       6-30         10-40
    Offal

         pork kidney       450         180       190       1000
         pork liver        130         70        50         100

    Fish                  < 15       < 5-20     1-20        14           15

    Eggs                  < 30          4         1        < 10           2

    Oils and dairy
     products            < 20-30      3-20      1-23       < 30         10-30

    Sugars and preserves  < 10        < 10        3         30            5

    Fresh fruit           < 10         < 2       1-2        11            5

    Vegetables

         cabbage          < 10          5         4         10
         cauliflower      < 20         10        10
         spinach           120         150       43
         broccoli          10          10
         legumes         < 10-30     < 2-30      1-4        15
         lettuce          < 60         50        29         43
         potatoes         < 30         30        16         30           30
         carrots          < 50         30        41
                                                                                   

    a    From: Bucke et al. (1983)
    b    From: Koivistoinen (1980)
    c    From: Jorhem et al. (1984)
    d    From: Andersen (1979)
    e    From: RIVM (1988)
             Crops grown in cadmium-contaminated localities have been shown
    to contain elevated levels of the metal compared with normal values.
    The extent of enrichment depends on several factors (see section
    4.3). The cadmium concentrations in selected vegetable crops grown
    at three contaminated sites in the United Kingdom are shown in Table
    6. Highest levels were generally found at Shipham, where soil
    cadmium concentrations are markedly elevated, and the greatest
    increase was noted in leafy vegetables. Potato, a staple food item,
    showed similar values at the three locations and these were about
    five times greater than background.

         Large scale surveys of cadmium in rice have been carried out in
    areas of Japan where environmental contamination was suspected
    (Japanese Environment Agency, 1972, 1982). The results of the
    earlier survey revealed that large numbers of rice samples contained
    elevated cadmium levels; the corresponding data from the later study
    indicated that decreases had occurred over the intervening ten
    years. More detailed investigations at specific localities have also
    been carried out in Japan, often as part of studies on health
    effects of the general population (Table 7).

    5.2.3  Other sources of exposure

         Young children may ingest household dust or garden soil. This
    habit may be a source of cadmium exposure, as has been identified
    for lead (Duggan et al., 1985). The representative daily intake of
    dust via the hands in young children is considered to be 100 mg
    (Lepow et al., 1974). In an extensive survey of metals in household
    dusts in the United Kingdom, an average cadmium level of 6.9 mg/kg
    was obtained from over 4500 samples (Culbard et al., 1988). These
    data suggest that the hand-to-mouth route is a minor source of
    cadmium intake (about 0.7 µg daily).

         The hand-to-mouth exposure pathway may be a significant source
    of cadmium in areas around point sources of the metal. In the
    vicinity of a small lead refinery in the United Kingdom, cadmium
    levels in household dust were reported to be 193 mg/kg (Muskett et
    al., 1979). The daily ingestion of 100 mg of this dust would result
    in the intake of about 20 ßg cadmium. Buchet et al. (1983) observed
    a correlation between cadmium intake from dust and the levels of
    blood and urinary cadmium in children from areas of Belgium
    subjected to air contamination. Despite markedly elevated soil
    cadmium levels in the gardens of Shipham, United Kingdom, Thornton
    (1988) found that household dust concentrations were only four times
    greater (at an average of 27 mg/kg) than background.


        Table 6.  Mean cadmium concentrations (µg/kg fresh weight) in selected vegetable crops grown at three contaminated sites
              in the United Kingdom
                                                                                                                              
    Location      Source of cadmium      Cabbage    Leafy      Potato    Carrot     Reference
                  contamination                     salad
                                                                                                                              
    
    Shipham       zinc mine              250a       680        130       340        Sherlock et al. (1983)

    Walsall       atmospheric inputs     73         190        103       120        Tennant (1984)
                  from a copper
                  refinery

    Heathrow      sewage sludge          24         180        150       150        Chumbley & Unwin (1982)
                  applications
                                                                                                                              

    a   Median value
    

    5.2.4  Daily intake of cadmium from food

         Three approaches are used for estimating the daily intake of
    cadmium in food. The first is the total-diet collection method in
    which the foods are prepared for consumption and are analysed either
    individually or combined in one or more food group composites in
    proportions based on available food consumption data. The total
    cadmium intake is calculated as the product of the concentration and
    the estimated amount of food eaten. In the second approach, a market
    basket study, representative samples of individual foodstuffs are
    collected from retail outlets and analysed. The cadmium
    concentrations are then multiplied by the average amount of intake
    of each foodstuff to give the cadmium intakes for each food item.
    The sum gives the total dietary intake. The third way of estimating
    cadmium intake is the collection of a duplicate sample of the meals
    consumed. The combined food sample is homogenized and the cadmium
    analysed. Table 8 presents some published estimates of dietary
    cadmium intakes from different countries based on these three
    methods.

         Another method for estimating the daily intake of cadmium is to
    determine the daily faecal output, because only about 5% of ingested
    cadmium is absorbed on average (section 6.1.2). In Table 9 the
    available data on faecal cadmium are summarized. There is general
    agreement with the data presented in Table 8, but in the USA the
    estimated dietary exposure based on faecal analysis is considerably
    lower than direct estimates of dietary intake.

         Tables 8 and 9 show that daily intakes of cadmium in Europe,
    New Zealand, and the USA are usually about 10-25 ßg. These are
    average values, and large individual variations do occur due to
    variability in dietary habits and age-dependent changes in energy
    intake. The highest daily intake of cadmium is likely to occur among
    teenagers, since they have the highest caloric intake (Kjellström et
    al., 1978). Individuals from the general population who are extreme
    consumers of certain food items with elevated cadmium levels may
    have exposure levels above the average. It has been estimated that
    10% of the population consume twice the average quantity of a
    particular food class and 2.5% consume three times the average
    (Sherlock & Walters, 1983). Estimates of the daily cadmium intake in
    areas of Japan considered normal are consistently higher than in
    other parts of the world and generally range from 30 to 50 µg. In
    areas of elevated exposure, average daily intakes range from 150 to
    250 µg (Tables 8 and 9).


        Table 7.  Environmental cadmium levels in Japan: a summary of the surveys of cadmium levels in rice and
              health status of local populations
                                                                                                                                          
    Area                Cadmium          Daily       Source of cadmium          Number     Health       References
    (prefecture)        concentration    cadmium     contamination                 of      effects
                        in rice          intake                                 peoplea    reportedb
                        (mg/kg fresh     (µg/day)c
                        weight)
                                                                                                                                          

    Fuchu, Toyama         0.6-2.0          600       zinc, lead, and cadmium     7650      yes          Ishizaki et al. (1969); 
                                                     mine and refinery                                  Kato & Abe (1978)

    Ikuno, Hyogo          0.2-1.0                    silver, copper, and zinc   13 000     yes          Hyogo Prefectural Gov't (1972);
                                                     mine                                               Tsuchiya & Nakamura (1978)

    Tsushima,             0.5-0.8        213-255     lead and zinc mines         2400      yes          Shigematsu et al. (1975);
    Nagasaki                                                                                            Takabatake (1978b)

    Kakehashi,            0.2-0.8          160       copper mines                2800      yes          Ishizaki (1972); Kawano & Kato
    Ishikawa                                                                                            (1978)

    Kosaka, Akita         0.2-0.6          185       silver and copper mines      800      yes          Kojima et al. (1975); Shigematsu &
                                                                                                        Kawaguchi (1978)

    Yoshino, Yamagata       0.6                      gold, silver, copper, and   8000      NS           Uruno et al. (1975); Shigematsu &
                                                     zinc mines                                         Kawaguchi (1978)

    Annaka and            0.4-0.5          281       zinc refinery               4400      NS           Shigematsu et al. (1975);
    Takasaki, Gunma                                                                                     Fukushima (1978)

    Uguisuzawa, Miyagi    0.6-0.7          180       lead and zinc mines          800      NS           Shigematsu et al. (1975);
                                                                                                        Takabatake (1978a,b)

    Watarase, Gunma         0.3                      copper mine                 4700      NS           Fukushima et al. (1975);
                                                                                                        Fukushima (1978)
                                                                                                                                          

    Table 7 (contd).
                                                                                                                                          

    Area                Cadmium          Daily       Source of cadmium          Number     Health       References
    (prefecture)        concentration    cadmium     contamination                 of      effects
                        in rice          intake                                 peoplea    reportedb
                        (mg/kg fresh     (µg/day)c
                        weight)
                                                                                                                                          

    Shimoda, Shizuoka     0.4-1.1                    gold and copper mine        1100      NS           Tsuchiya (1978)

    Bandai, Fukushima     0.2-0.4                    zinc refinery               1800      NS           Shigematsu & Kawaguchi (1978)

    Kurobe, Toyama          0.6                      copper refinery             8000      NS           Tsuchiya (1978)

    Kiyokawa, Oita        0.2-0.5          391       tin, copper, lead, zinc,     700      NS           Takabatake (1978a);
                                                     and arsenic mine                                   Shigematsu et al. (1975)

    Ohmuta, Fukuoka         0.7                      zinc refinery               2540      NS           Yamamoto (1972); Tsuchiya (1978)
                                                                                                                                          

    a    Indicates the approximate number of people living in exposed area. The figure usually includes only people over 30 years
         old considered to consume rice with more than 0.4 mg cadmium/kg.
    b    NS denotes health examinations were made, but effects were not significantly different from those in control areas.
    c    From: Tsuchiya (1978)


    

         Of particular interest is the village of Shipham, United
    Kingdom, where markedly elevated soil cadmium levels are present.
    Cadmium levels in locally grown vegetables have also been found to
    be elevated and ranged from 5 to 20 times above normal values (Table
    6). Three dietary and crop sampling surveys were performed to
    estimate heavy metal intake from both fresh and cooked food
    (Sherlock et al., 1983). A duplicate portion study and two market
    basket studies were performed to coincide with periods of
    significant consumption of home-grown vegetables. The total cadmium
    dietary intake estimated from the market basket studies averaged
    36 µg per day, of which 14 µg per day was contributed by locally
    grown fruit and vegetables. The duplicate portion study gave an
    average total cadmium intake of 29 µg per day, of which 17 µg per
    day was attributed to locally grown fruit and vegetables. Four
    individuals from the study population showed cadmium intakes greater
    than 400 µg/week. Both methods indicated that cadmium intakes in
    Shipham were higher than the United Kingdom average. However,
    exposures were not as high as would have been expected, considering
    the extent of cadmium contamination of the local vegetables,
    suggesting that most inhabitants did not rely heavily on local
    crops.

    5.3  Total intake and uptake of cadmium from all environmental
         pathways

    5.3.1  General population, uncontaminated areas

         Assuming an air cadmium concentration of 10 ng/m3 for both
    indoor and outdoor air and a daily inhalation rate of 15 m3 for an
    adult, the average intake of cadmium from the atmosphere would be
    0.15 µg, of which about 25% (Friberg et al., 1974) or 0.04 µg will
    be absorbed. Smoking a pack of 20 cigarettes daily can result in the
    inhalation of 2-4 µg cadmium, the amount varying considerably
    according to the country or origin of the tobacco. Of this amount,
    25-50% may be absorbed via the lungs, resulting in an uptake of
    1-2 µg, a much larger amount than from air alone. Those individuals
    who smoke two or more packs of cigarettes daily will absorb
    correspondingly greater quantities of cadmium.

         Cadmium intake from drinking-water based on a daily consumption
    of 2 litres is usually less than 1 µg. Average daily intake from
    food in most countries is probably at the lower end of the range of
    10-25 µg. At an absorption rate of 5%, daily uptake from water and
    food would be 0.6-1.3 µg cadmium. Thus, heavy smokers from the
    general population in uncontaminated areas may absorb more cadmium
    from the inhalation pathway than from dietary sources.


        Table 8.  Estimates of average daily dietary intake of cadmium based on food
              analysis in various countries
                                                                                   

         Country         Method of   Estimates (µg       Reference
                         samplinga   cadmium per day)
                                                                                   

    Areas of normal exposure

         Belgium            D              15            Buchet et al. (1983)
         Finland            M              13            Koivistoinen (1980)
         Japan              D              31            Yamagata & Iwashima (1975)
         Japan              D              48            Suzuki & Lu (1976)
         Japan              D              49            Ushio & Doguchi (1977)
         Japan              D              35            Iwao (1977)
         Japan              M              49            Ohmomo & Sumiya (1981)
         Japan
    (mean of 3 areas)       D              59            Iwao et al. (1981a)
         Japan              D         43.9 (males)       Watanabe et al. (1985)
                                     37.0 (females)

         New Zealand        D              21            Guthrie & Robinson (1977)

         Sweden             D              10            Wester (1974)
         Sweden             M              17            Kjellström (1977)

         United Kingdom   M, D            10-20          Walters & Sherlock (1981)

         USA                M              41            Mahaffey et al. (1975)

    Areas of elevated exposure

         Japan              M            211-245         Japan Public Health
         Japan              D            180-391         Association (1970)
         Japan
    (mean of 3 areas)       D              136           Iwao et al. (1981a)

         United Kingdom     M              36            Sherlock et al. (1983)
         United Kingdom     D              29            Sherlock et al. (1983)

         USA                D              33            Spencer et al. (1979)
                                                                                   

    a  M - Sample of foodstuffs individually analysed; market basket method
       D - Duplicate portion study
     

        Table 9.  Estimates of average daily faecal cadmium elimination in various countries

                                                                                              

    Country                Subjects investigated        Estimates (µg      Reference
                                                        cadmium/day)
                                                                                              

    Areas of normal exposure

    Federal Republic
     of Germany            23, sex and age of subjects  31             Essing et al. (1969)
                           not given

    Japan                  12 men, 50-59 years          81             Haga & Yamawaki (1974)
    Japan                  13 women, 50-59 years        56             Haga & Yamawaki (1974)
    Japan                  2 men, 35 and 37 years       36             Suzuki & Lu (1976)
                             (60 specimens)
    Japan                  7 men, 21-22 years           41-79          Tati et al. (1976)
                             (35 specimens)
    Japan                  64 men and women,            41             Kojima et al. (1975)
                            50-69 years
    Japan                                               24-36          Iwao (1977)
    Japan (rural area)     30 men, 50 years and over    49             Tsuchiya & Iwao (1978)
    Sweden                 4 adults (2 men, 23 years;   6-13           Wester (1974)
                           2 women, 28 and 31 years)
    Sweden                 70 men and 10 women          18             Kjellström et al. (1978)
                             (3-day collect)

    USA                    216 (men and women)          10-15          Kowal et al. (1979)

    Areas of elevated exposure

    Japan, Kosaka          40 men, 50-69 years          149            Haga & Yamawaki (1974)
    Japan, Kosaka          47 women, 50-69 years        177            Haga & Yamawaki (1974)
    Japan, Kosaka          118 men and women            146            Kojima et al. (1977)
                                                                                              

    Table 9. cont'd.
                                                                                              

    Country                Subjects investigated        Estimates (µg      Reference
                                                        cadmium/day)
                                                                                              

    Japan, Kakehashi,      30 men, 50 years and over    149            Iwao et al. (1981b)
     Kosaka, Tsushima
     (rural areas)

    New Zealand,           45 men and women,            50-500         McKenzie et al. (1982)
     Bluff                 20-70 years
                                                                                              

    

    5.3.2  General population, contaminated areas

         Airborne cadmium in contaminated areas may reach levels of
    0.5 µg/m3, which would lead to a daily inhalation of 7.5 µg and an
    absorption of about 2 µg. For smokers, the contribution from tobacco
    at 1-2 µg for every pack will not be changed, leading to a total
    uptake of 3-4 µg from inhalation in such individuals.

         The intake of cadmium from food and water varies considerably
    and is related to both the extent of contamination and the reliance
    on locally grown food items or local water supplies. Daily intakes
    of 150-200 µg have been reported in contaminated areas where the
    majority of the staple food items were of local origin. At an
    absorption rate of 5%, the daily uptake from diet would be 8-10 µg.
    The total daily cadmium uptake will depend on the nature of cadmium
    contamination, i.e. whether food, water, and air levels are
    elevated, but is unlikely to exceed 20 µg.

         Cadmium intake in children via the ingestion of household dusts
    is unlikely to be important except in the most contaminated
    localities.

    5.3.3  Occupational exposure to cadmium

         Inhalation of workplace air is the dominant exposure pathway.
    With air concentrations of 10-50 µg/m3 and the inhalation of
    10 m3 air during a work-shift, the daily cadmium intake would be
    100-500 µg. An absorption rate of 25% would thus lead to daily
    uptakes of 25-125 µg. Dust particles cleared from the lungs may be
    swallowed and dust-contaminated food items can also make a
    significant contribution to the ingestion pathway. At an absorption
    rate of 5% this could lead to an additional uptake 10-15 µg cadmium
    to the total uptake.

         Tobacco carried by workers can become contaminated and may
    contribute up to 10 times more cadmium to the daily uptake than
    under normal conditions (Piscator et al., 1976).

    5.4  Conclusions

         The major route of exposure to cadmium for the non-smoking
    general population is via food; the contribution from other pathways
    to total uptake is small. Tobacco is an important source of cadmium
    uptake in smokers. In contaminated areas, cadmium exposure via food
    may be up to several hundred µg/day. In exposed workers, lung
    absorption of cadmium following inhalation of workplace air is the
    major route of exposure. Increased uptake in workers can also occur
    as a consequence of contamination of food and tobacco.

    6.  KINETICS AND METABOLISM IN LABORATORY MAMMALS
        AND HUMANS

    6.1  Uptake

    6.1.1  Absorption by inhalation

         Three processes in the lungs, i.e. deposition, mucociliary
    clearance, and alveolar clearance, determine the absorption of
    inhaled particles (Task Group on Lung Dynamics, 1966). Uptake into
    epithelial cells, interstitium or the systemic circulation depends
    on physical and biochemical processes in the respiratory tract after
    deposition (e.g., mechanical clearance, solubilization, and
    transport). The retained or accumulated dose at the local or
    systemic target site resulting from the deposited dose may
    eventually lead to biological effects. Length of exposure is of
    major importance for chronic effects, particularly lung cancer.
    Therefore, chronic effects might be expected to correlate with
    retained or accumulated dose rather than deposited dose.

         Extrapolation models of inhaled cadmium dosage from animal
    models to humans and from high exposures (experimental) to low
    (environmental) must incorporate the above variables. When
    extrapolating from one species to another, specific pulmonary
    retention must be taken into account. In both acute and chronic
    inhalation exposures, a dose-response relationship is best described
    with accumulated rather than deposited dose (Oberdorster, 1988).

         The absorption of cadmium compounds may vary greatly. As
    discussed in section 5.1.2, the proportion of particles in
    industrial air that are respirable, i.e. up to 5 µm MMAD, may vary
    widely (Materne et al., 1975). These particles will be deposited in
    the alveoli (Task Group on Lung Dynamics, 1966).

         There are some empirical data on the overall absorption of
    cadmium. In various acute and chronic animals experiments, 5 to 20%
    of inhaled cadmium has been found to be deposited in the lungs
    (Friberg et al., 1986). Actual absorption may vary between 50 and
    100% of the amount deposited and may continue for weeks after the
    deposition of a single dose. The absorption of an aerosol of cadmium
    chloride is higher than that of cadmium oxide, and alveolar
    absorption is higher after intratracheal instillation than after
    inhalation of an aerosol (Friberg et al., 1985).

         If the particles are deposited in the alveoli, then the
    majority will sooner or later be absorbed, regardless of solubility.
    Cadmium chloride passes the alveolar-blood barrier with ease,
    although inhaled cadmium sulfide has a greater tendency to be

    retained in the lungs, indicating slower absorption. Three weeks
    after exposure of Syrian hamsters to cadmium chloride aerosol, about
    25-35% of the initial lung burden was present in the liver, kidneys,
    and skull. The lungs still contained 50% of the initial lung burden
    at this time (Henderson et al., 1979).

         Data on the respiratory absorption of cadmium in humans comes
    largely from comparisons of smokers and non-smokers. On the basis of
    data on organ burdens of cadmium and smoking history, Elinder et al.
    (1976) calculated that about 50% of the cadmium inhaled via
    cigarette smoke could be absorbed.

    6.1.2  Absorption via the intestinal tract

         Factors affecting the absorption of ingested cadmium include
    animal species, type of compound, dose, frequency of administration,
    age of experimental animals, pregnancy and lactation, presence or
    absence of drugs, and interactions of cadmium with various nutrients
    (Nomiyama, 1978). A study in which cadmium chloride was given in
    drinking-water to rats over a period of 12 months showed retention
    in the kidney and liver of less than 1% of the total amount ingested
    (Decker et al., 1958). There have been many reports of single
    exposure studies. These may be summarized as follows: the individual
    absorption of cadmium nitrate or chloride after single exposure
    ranges from 0.5 to 8% (Friberg et al., 1974). Limited observations
    in humans given radioactive cadmium indicate that the average
    absorption is about 5% (Kitamura, 1972; Rahola et al., 1972;
    Yamagata et al., 1974; Flanagan et al., 1978).

         Metallothionein-bound cadmium in food does not appear to be
    absorbed and/or distributed in the same way as inorganic cadmium
    compounds. Mice exposed to cadmium-thionein (Cherian et al., 1978)
    had lower blood and liver cadmium levels but a higher kidney level
    than mice exposed to the same amount of cadmium as the chloride.
    Similar results were reported by Sullivan et al. (1984) in mice fed
    inorganic or oyster-incorporated radiolabelled cadmium. Cadmium in
    New Zealand Bluff oysters is to a great extent bound to a
    metallothionein-like protein (Nordberg et al., 1986). However, in
    other species of oysters, most of the cadmium is bound to proteins
    with relative molecular masses above 50 000 and lesser amounts to
    small proteins (< 3000) (Casterline & Yip, 1975; Kodama et al.,
    1978). Bluff oyster fishermen with an extremely high cadmium intake
    (up to 500 µg per day) from oyster consumption were found to have
    increased blood and urine cadmium levels (Sharma et al., 1983), but
    the increase was not as great as expected from the total cadmium
    ingested. This indicates that in humans, as in other animal species,
    metallothionein-bound cadmium in food may be dealt with in a
    different way from other cadmium compounds.

         There are no data from humans studies showing a relationship
    between gastrointestinal absorption of cadmium and age. Studies on
    mice reported by Matsusaka et al. (1972), however, show
    approximately 10% whole body retention 2 weeks after ingestion for
    young mice, while the corresponding figure for adult mice was 1%.
    Kello & Kostial (1977) and Engstrom & Nordberg (1979b) also
    demonstrated that neonatal mice absorbed cadmium to a much greater
    extent than adult mice.

         Diets with low levels of calcium and protein promote increased
    absorption of cadmium through the intestinal tract, up to 3 times
    the absorption having been noted in several studies in experimental
    animals (Friberg et al., 1974, 1975). It has also been shown that
    iron-deficient animals may have a higher absorption of cadmium
    (Hamilton & Valberg, 1974), and these findings have been confirmed
    in humans (Flanagan et al., 1978). Women with low body iron stores,
    as reflected by low serum ferritin levels, had on average, a
    gastrointestinal absorption rate twice as high (about 10%) as a
    control group of women. The highest individual absorption rate was
    about 20%. Interrelationships between cadmium exposure and the
    absorption of copper, zinc, and calcium will be discussed in section
    7.5.

    6.1.3  Absorption via skin

         Limited skin penetration (1.8% per 5 h) of soluble cadmium
    compounds can take place when they are applied as a solution to the
    skin (Skog & Wahlberg, 1964). The dermal absorption rate was
    estimated by Kimura & Otaki (1972) in shaved rabbits and nude mice
    painted with an aqueous solution of cadmium chloride. Rabbits
    painted 5 times in 3 weeks showed a combined cadmium accumulation of
    0.4-0.6% of the amount applied, and mice painted 1-4 times in one
    week showed an accumulation of 0.2-0.8% of the applied dose.

    6.1.4  Transplacental transfer

         The movement of cadmium through the placenta is limited. It has
    been shown that cadmium given to pregnant mice and hamsters during
    early pregnancy reaches the yolk sac and the primitive gut of the
    embryo, which are connected by the vitelline duct (Dencker et al.,
    1983). However, after closure of the vitelline duct during the later
    stages of pregnancy, very little cadmium reaches the fetus (Ahokas &
    Dilts, 1979). Sonawane et al. (1975) found that less than 0.02% of
    the total dose of cadmium injected intravenously into rat dams
    reached the fetus.

         The cadmium concentration of the human placenta is usually
    about 5-20 µg/kg wet weight (Thieme et al., 1977; Copius-Peereboom
    et al., 1979). The placentas of women who smoke during pregnancy
    have higher levels than those of non-smokers (Copius-Peereboom et
    al., 1979).

         Fetal (umbilical cord) blood cadmium levels are about 40-50%
    less than those of maternal blood. However, levels of the
    metabolically related essential metals zinc and copper in fetal
    blood are similar to or higher than those in maternal blood, this
    resulting in a fetal-maternal gradient (Lauwerys et al., 1978; Roels
    et al., 1978; Kuhnert et al., 1982; Korpela et al., 1986). The
    effectiveness of the gradient or its mechanism, as well as the
    potential toxicity of cadmium to the fetus, is not really known.
    Transplacental transport of cadmium is minimized in the normal
    healthy placenta presumably by the binding of cadmium to
    metallothionein. Metallo-thionein also serves as a site for
    intracellular zinc and copper sequestration. These observations
    suggest that there is a selective barrier to transplacental
    transport of cadmium. This is not the case with lead or mercury
    where fetal blood levels are similar to maternal levels (Lauwerys et
    al., 1978; Korpela et al., 1986).

    6.2  Transport

         Human data on the transport of cadmium from the site of
    absorption to the various organs are not available. This section is,
    therefore, based on animal studies, although there are some
    indications that similar mechanisms operate in humans. For instance,
    metallothionein has been isolated from human tissues (section 6.8)
    and has been measured in human plasma (Nordberg et al., 1982), where
    it binds cadmium being transported between tissues.

         A study on dogs showed that, immediately after parenteral
    administration, most of the cadmium was present in the plasma (Walsh
    & Burch, 1959). This has been verified in a large number of animal
    studies (Friberg et al., 1974). Plasma concentrations decrease
    rapidly during the first hours after injection, reaching a level
    that is less than 1% of the initial value at 24 h, and this level
    then decreases much more slowly. During the early, fast-elimination
    phase, cadmium in mouse plasma is mainly bound to plasma proteins
    with a molecular weight of 40 000 to 60 000 (probably albumin),
    whereas in the slower phase (more than 24 h after injection), it is
    partly bound to a low molecular weight (LMW) protein of the same
    size as metallothionein (Nordberg, 1978). After rats were repeatedly
    exposed by subcutaneous injection (up to 14 weeks), the cadmium in
    plasma was partly bound to proteins with a molecular weight of
    40 000 to 60 000 and partly to a LMW protein with a molecular weight
    similar to that of metallothionein (Cherian & Shaikh, 1975; Shaikh &
    Hirayama, 1979). The proportion of plasma cadmium bound to
    metallothionein and larger proteins, respectively, is considered to
    vary with the length and type of exposure. It is likely that the LMW
    cadmium-binding protein is in fact metallothionein, since it was
    shown by Vander Mallie & Garvey (1979) by a radioimmunological
    technique that the metallothionein concentration increased in the
    plasma of rats given 40 intraperitoneal injections of cadmium
    chloride in saline (0.12 mg/day, five days/week).

         The concentration of cadmium in blood cells increases rapidly
    after a single intravenous injection (1 mg/kg body weight) and,
    within a few hours, reaches a first peak concentration exceeding
    that of the plasma. Although the levels of cadmium per cell may be
    10 times higher in leucocytes than in red cells, the total cadmium
    in the leucocyte portion of the blood is negligible compared to that
    in the red cells (Garty et al., 1981).

         Cadmium in erythrocytes may partly be bound to haemoglobin
    (Carlson & Friberg, 1957; Nomiyama et al., 1978a). However, during
    the first hour after a single subcutaneous injection, a large
    proportion of the cadmium in erythrocytes is bound to proteins with
    a molecular weight larger than haemoglobin (Nordberg, 1972). Between
    96 and 196 h after a single injection (1 mg/kg body weight), it has
    been shown in mice (Nordberg, 1972), as well as in rats (Garty et
    al., 1981), that cadmium is also bound to a LMW protein. Whether
    this protein is identical with metallothionein is uncertain
    (Nordberg, 1984). A part of the erythrocyte cadmium in rats was also
    found in erythrocyte ghosts (membranes) (Garty et al., 1981). When
    mice were exposed by subcutaneous injection to cadmium chloride
    (0.25 mg/kg body weight) for periods of between 6 days and 5 months
    (Nordberg et al., 1971), most of the erythrocyte cadmium was bound
    to a LMW protein similar to metallothionein.

         Since metallothionein-bound cadmium is quickly cleared from the
    plasma by the kidneys (Nordberg & Nordberg, 1975; Vostal, 1976),
    this LMW fraction may be of great importance for the transport of
    cadmium from liver to kidney during long-term exposure. Hepatic
    metallothionein may be released into the blood in the same manner as
    hepatic enzymes and transported to the kidney and urine in some
    types of hepatic disorders (Tanaka, 1982).

    6.3  Distribution

    6.3.1  In animals

         The highest cadmium levels in exposed animals are generally
    found in the liver and renal cortex. However, the distribution in
    the body varies according to the route of administration.

    6.3.1.1  Single exposure

         Studies on various species have shown that, after a single
    administration of cadmium by the oral or parenteral routes, the
    highest organ burden of cadmium is initially found in the liver.
    However, kidney levels of cadmium increase for up to 8 months after
    exposure and may then exceed the liver levels (Gunn & Gould, 1957).
    The pancreas and spleen also show relatively high concentrations
    (Nordberg & Nishiyama, 1972). This topic has been reviewed by
    Friberg et al. (1974) and Nomiyama (1978).

    6.3.1.2  Repeated exposure

         The literature on the fate of cadmium in animals after repeated
    exposure via various routes has been reviewed by Friberg et al.
    (1985) and, with emphasis on Japanese studies, by Nomiyama (1978).
    Liver cadmium levels increase rapidly, and a re-distribution of
    cadmium to the kidney occurs over a period of time. The higher the
    intensity of exposure, the higher the initial liver-to-kidney
    concentration ratio. The route of administration has been shown to
    be an important variable affecting the distribution of cadmium. When
    cadmium was administered subcutaneously, 11 times more was deposited
    in the liver than in the kidneys, whereas orally administered
    cadmium was distributed almost equally between these two organs
    (Nomiyama et al., 1976).

         When rabbits were injected subcutaneously with 0.5 mg cadmium
    chloride daily, concentrations of cadmium in the liver and renal
    cortex reach a peak after about 10 and 15 weeks exposure,
    respectively. In cases of renal damage, urinary excretion increases
    (section 6.5.1.1) and the renal and liver concentrations decrease
    (Bonnell et al., 1960; Nomiyama et al., 1982b).

    6.3.2  In humans

         Cadmium is stored to the greatest extent in the liver and
    kidneys, the renal cortex showing the highest concentration in
    people who have not been exposed to excess cadmium (Friberg et al.,
    1974). The lowest concentrations (wet weight) are found in the
    brain, bone, and fat (Sumino et al., 1975; Cherry, 1981). Cadmium
    levels in the organs of second and third trimester fetuses (Chaube
    et al., 1973) and in newborn babies and young children (Henke et
    al., 1970) are lower by three orders of magnitude than in adult
    females. The placenta contains somewhat higher concentrations than
    maternal blood, brain or fat (section 6.1.4).

         It has been calculated that about a third of the body burden in
    a non-smoking male from the USA is in the kidney and about a quarter
    in the liver and muscles. These are the tissues with the longest
    biological half-time of cadmium (section 6.6.2). In spite of the low
    cadmium concentration in the muscles, the contribution to the total
    body burden is great due to the large weight of the muscles. Other
    tissues that contribute significantly to body burden are bone, skin,
    and fat (Kjellström (1979).

         In cadmium workers and people in the general environment
    exposed to high levels of cadmium, the liver or kidneys show the
    highest concentration, depending on exposure time, exposure levels,
    and the level of renal function (Friberg et al., 1974, 1985).

    6.4  Body burden and kidney burden in humans

         The newborn baby is practically free of cadmium (section
    6.1.4), and the concentrations of cadmium in the organs increase
    with age (Schroeder & Balassa, 1961; Anke & Schneider, 1974; Elinder
    et al., 1976; Tsuchiya et al., 1976; Kowal et al., 1979; Chung et
    al., 1986). The accumulation in human liver and muscles is shown in
    Figs. 1 and 2, respectively. These data and those of Vahter (1982)
    (Fig. 3) reveal important differences between people from different
    countries. Great individual variation also exists, even among people
    from the same area (Tsuchiya et al., 1976). For example, the
    geometric mean concentration of cadmium in the renal cortex of 117
    adults aged between 30 and 59 in Stockholm was 19 mg/kg (Elinder et
    al., 1976). The individual concentrations followed a log-normal
    distribution with a geometric standard deviation of 2.0. This means
    that about 15% of the population would have values higher than
    38 mg/kg, and 2.5% values higher than 76 mg/kg. Similarly shaped
    distributions were found for the kidneys, liver, pancreas, and
    muscle (Tsuchiya & Iwao, 1978; Kowal et al., 1979; Vuori et al.,
    1979).

         The critical organ in long-term exposure to low concentrations
    of cadmium is the kidney (section 6.7). Initial cadmium-induced
    effects occur mainly in the proximal tubules, situated in the cortex
    of the kidney. Therefore, cadmium concentrations in the renal cortex
    and the distribution of cadmium within the kidney are of key
    importance. The weight of the renal cortex is about 2-3 times
    greater than the weight of the renal medulla, and early estimates of
    renal cortex cadmium concentrations (Friberg et al., 1974) were 1.5
    times higher than the whole kidney concentrations. A recent study
    specifically aimed at measuring this concentration ratio
    (Svartengren et al., 1986) yielded an average value of 1.25 for
    people aged 30-50. This figure will be used in this document when it
    is necessary to recalculate whole kidney concentrations from renal
    cortex concentrations for that age group. This is the best estimate
    available at present, although the ratio may vary depending upon the
    age groups and racial types studied.

         Table 10 shows the average cadmium concentrations in renal
    cortex and liver for the 20-59-year age group, and includes the
    major studies that have reported age-specific data. Unfortunately,
    no information on smoking habits was given in most studies. It has
    been shown that smoking cigarettes may significantly increase the
    body burden of cadmium (Lewis et al., 1972). Elinder et al. (1976)
    showed that Swedish smokers have, on average, about twice the tissue
    cadmium concentration of non-smokers. Except for the data from India
    (Fig. 3), there appears to be a constant difference (10 mg/kg)
    between smokers and non-smokers in the cadmium concentrations of the
    renal cortex. Fig. 3 also shows that the 90th percentile is usually
    about twice the geometric mean value. In most countries referred to
    in Table 10, the average cortex cadmium concentration was in the

    FIGURE 1

    FIGURE 2


    FIGURE 3


    range 10-40 mg/kg, while in Japan values of between 50 and 100 mg/kg
    were reported. In workers highly exposed to cadmium, but without
    functional impairment of the kidney, concentrations in the renal
    cortex may range from 180 to 450 mg/kg wet weight. In cases where
    there is severe renal dysfunction, the cadmium concentrations are
    generally lower and range between 20 and 120 mg/kg wet weight, i.e.
    they are of the same magnitude as those of the general population
    (Friberg et al., 1974). This seemingly paradoxical relationship is
    discussed in more detail in section 6.

         If exposure to cadmium throughout life remains constant and low
    in amount, the concentrations in the kidneys become higher (by about
    10-20 times) than those in the liver. Average liver cadmium
    concentrations are about 1-2 mg/kg wet weight at age 50 in some
    European countries and the USA, but in Japan average concentrations
    are between 5 and 10 mg/kg (Table 10). Although renal concentrations
    generally decrease after age 60 (Fig. 4), liver concentrations reach
    a plateau but do not show a clear decrease in aged populations
    (Fig. 1). In exposed workers, liver concentrations from 20 to about
    300 mg/kg have been recorded and in Itai-itai patients they are
    between 63 and 132 mg/kg (Friberg et al., 1974). In people with
    severe cadmium-induced renal dysfunction, kidney cadmium levels are
    low, but the liver levels may be very high (Ishizaki, 1972).


        Table 10.  Cadmium concentrations in the renal cortex and liver of people from various geographical areasa
                                                                                                                                          

    Country                 Number   Sex     Age group    Smoking     Renal cortex       Liver cadmium        Reference
                                                          category    cadmium level      level (mg/kg
                                                                      (mg/kg wet         wet weight)
                                                                      weight)
                                                                                                                                          

    Belgium (Liege)            51    M, F      40-59       mixed           46b                -               Vahter (1982)

    German Democratic          20      M       40-59       mixed           22c                -               Anke & Schneider (1974)
     Republic
                               20      F       40-59       mixed           11c                -               Anke & Schneider (1974)

    India                      26    M, F      40-59       mixed           24b                -               Vahter (1982)

    Israel (Jerusalem)         11    M, F      40-59       mixed           28b                -               Vahter (1982)

    Japan (Kobe)                6    M, F      50-59       mixed           54                 5.0             Kitamura et al. (1970)
    Japan (Kanazawa)            9    M, F      40-59       mixed           95                10               Ishizaki (1972)
    Japan (Tokyo)              17    M, F      40-59       mixed           99                 5.7             Tsuchiya et al. (1976)
    Japan (Tokyo)              23    M, F      40-59       mixed           76b                -               Vahter (1982)

    Sweden (Stockholm)         83    M, F      40-59       mixed           20                 0.76            Elinder et al. (1976)
                               45      M       40-59       mixed           18                 0.69            Elinder et al. (1976)
                               38      F       40-59       mixed           23                 0.88            Elinder et al. (1976)
                                7    M, F      40-59    non-smoker         11                 0.51            Elinder et al. (1976)
                               28    M, F      40-59      smoker           23                 0.97            Elinder et al. (1976)

    USA (North Carolina)       19      M       40-59       mixed           27d                2.2             Hammer et al. (1973)
                               10      F       40-59       mixed           23d                2.2             Hammer et al. (1973)
                               10      M       40-79    non-smoker         14d                1.6             Hammer et al. (1973)
                               18      M       40-79      smoker           28d                3.2             Hammer et al. (1973)
                                                                                                                                          

    Table 10 (contd).
                                                                                                                                          

    Country                 Number   Sex     Age group    Smoking     Renal cortex       Liver cadmium        Reference
                                                          category    cadmium level      level (mg/kg
                                                                      (mg/kg wet         wet weight)
                                                                      weight)
                                                                                                                                          

    USA (Dallas)               58      M       40-59       mixed           29                 1.4             Kowal et al. (1979)
                               47      M       20-59    non-smoker         13                 1.02            Kowal et al. (1979)
                              115      M       20-59      smoker           24                 1.31            Kowal et al. (1979)
    USA (Baltimore)            10    M, F      40-59       mixed           30b                -               Vahter (1982)

    Yugoslavia (Zagreb)        28    M, F      40-59       mixed           38b                -               Vahter (1982)
                                                                                                                                          


    a  The cadmium concentrations are arithmetic mean values and have been rounded off.
    b  Original data were geometric means. Adjusted according to the findings of Elinder et al. (1976) (x 1.18).
    c  Original data were for whole kidney (dry weight). Data adjusted for whole kidney (x 1.25) and dry weight (x 0.21).
    d  Original data were based on ash weight. Data adjusted for ash weight (x 0.011).
    

          In vivo neutron activation analysis (see section 2.2.3.3) has
    recently been used to measure kidney and liver cadmium
    concentrations in exposed workers. In one study, the detection
    limits were about 15 mg/kg for kidney and 1.5 mg/kg for liver (Ellis
    et al., 1981a), while in another study detection limits were higher
    by a factor of 2 for kidney and 5 for liver (Roels et al., 1981b).
    Thus, this method is still not sufficiently sensitive to measure
     in vivo tissue levels in a "normal" population. Liver levels of up
    to 120 mg/kg and kidney cortex levels of up to 600 mg/kg have been
    found among cadmium workers (Ellis et al., 1981a). A decreasing
    trend of the kidney levels after a maximum at about 300 mg/kg in
    kidney cortex was evident. At this point, the liver level was about
    30 mg/kg (Fig. 5). A very similar situation was found in another
    factory (Roels et al., 1981b); most workers with high liver cadmium
    levels had low kidney levels, and then also showed elevated urinary
    excretion of ß2-microglobulin. In exposed workers, the average
    ratio of the cadmium concentration in the renal cortex to that in
    the liver has been reported to be about 8 (Ellis et al., 1981a) or 7
    (Roels et al., 1981b), values that are lower than for the general
    population (Table 9). This corresponds to animal data (section
    6.3.1.2) showing a greater proportion of accumulated cadmium in the
    liver when the exposure level increases.

         The total body burden of cadmium in a middle-aged person within
    the general population is about twice the amount in kidneys and
    liver together (Table 10), i.e. 5-7 mg in a non-smoker in Europe or
    the USA and 8-13 mg in a smoker (Kjellström, 1979). In Japan, higher
    body burdens have been reported (Tipton et al., 1960; Ishizaki et
    al., 1971; Sumino et al., 1975; Tsuchiya et al., 1976). An extensive
    review of data from several countries (Cherry, 1981) found total
    body burdens to lie within the range 5-20 mg.

         In conclusion, the average total body burden of a person of 50
    years of age, living in an area not subject to pollution, varies
    within the range 5-20 mg in different regions of the world, and the
    average cadmium concentration in the renal cortex varies within the
    range 11-100 mg/kg wet weight. There is a great individual
    variation, and the 90th percentile in those groups studied is about
    twice the median value.

         Smoking increases the body burden. After long-term low-level
    exposure, about half the body burden of cadmium is localized in the
    kidneys and liver, a third of the total being in the kidneys. At
    higher levels of exposure, a greater proportion of the body burden
    is found in the liver. After the development of severe
    cadmium-induced renal dysfunction, cadmium is lost from the renal
    tissue.

   FIGURE 4


    FIGURE 5

    6.5  Elimination and excretion

    6.5.1  Urinary excretion

    6.5.1.1  In animals

         Nordberg (1972) demonstrated that after subcutaneous injection
    for up to 24-25 weeks, the average daily urinary cadmium excretion
    (on a group basis) in mice, prior to the onset of tubular
    proteinuria, represented about 0.01-0.02% of the body burden
    (section 6.7.1). Elinder & Pannone (1979) showed that one month
    after repeated subcutaneous exposure ceased, the excretion was only
    0.001% of the body burden.

         Similar low excretion rates have been found in rabbits given
    subcutaneous injections (Nomiyama, 1973a; Nomiyama & Nomiyama,
    1976a), and in rabbits (Nomiyama & Nomiyama, 1976a,b) and monkeys
    (Nomiyama et al., 1979, 1982a) given cadmium orally. In addition, it
    has been reported that, over a range of doses, an increase in
    urinary excretion of cadmium is associated with an increase of
    cadmium in the renal cortex (Nomiyama & Nomiyama, 1976a; Suzuki,
    1980; Bernard et al., 1981).

         Studies on several mammalian species, mainly involving repeated
    subcutaneous injection of cadmium salts, have shown that urinary
    excretion of cadmium increases slowly for a considerable time but,
    as kidney dysfunction develops, a sharp increase in excretion occurs
    in rabbits (Friberg, 1952; Axelsson & Piscator, 1966a; Nomiyama &
    Nomiyama, 1976a), mice (Nordberg & Piscator, 1972), and rats
    (Suzuki, 1980). This leads to a decrease in renal and liver cadmium
    concentrations (Axelsson & Piscator, 1966a; Suzuki, 1980; Nomiyama &
    Nomiyama, 1976a).

         When renal tubular lesions were induced by uranyl acetate
    injections in animals previously exposed to cadmium, there was no
    increase in urinary cadmium excretion (Nomiyama & Nomiyama, 1976a)
    or decrease in the level of cadmium in the renal cortex. This
    contrasts with the increase in cadmium excretion brought about by
    cadmium-induced tubular lesions.

    6.5.1.2  In humans

         Several studies have shown that in the general population
    urinary cadmium excretion increases with age (Katagiri et al., 1971;
    Tsuchiya et al., 1976; Elinder et al., 1978; Kowal et al., 1979)
    (Fig. 6), this increase coinciding with the increased body burden.
    Smokers have higher urinary excretion than non-smokers (Elinder et
    al., 1978; Kowal et al., 1979). The mean concentration of urinary
    cadmium in such groups of people not exposed to high cadmium levels
    is < 0.5-2.0 µg/litre or approximately 0.01% of the total body
    burden.

         Increased urinary cadmium excretion occurs when tubular
    proteinuria develops (Lauwerys et al., 1974a; Kojima et al., 1977).
    In cadmium exposed workers, high urinary cadmium concentrations in
    the absence of proteinuria can be found after only short exposures
    (Lauwerys et al., 1976, 1979a,b) (section 6.7.1).

         Most of the cadmium in urine is probably transported bound to
    metallothionein. The urinary metallothionein concentration can now
    be measured quantitatively with a sensitive radioimmunoassay (Vander
    Mallie & Garvey, 1979). Using this technique, Tohyama et al. (1981b)
    found good correlation between urinary metallothionein and cadmium
    in 67 people exposed in the general environment, and Roels et al.
    (1983b) confirmed this correlation in 94 cadmium workers.

    6.5.2  Gastrointestinal and other routes of excretion

         It is extremely difficult to study gastrointestinal excretion
    after oral exposure, since it is not possible to distinguish net
    gastroin-testinal excretion from unabsorbed cadmium in faeces.

         Animal studies of gastrointestinal excretion following
    injections of cadmium (summarized by Friberg et al., 1974) generally
    show that a few percent of the dose is excreted in the faeces within
    the first few days after injection. The faecal excretion is
    initially higher than the urinary excretion after either single or
    repeated exposure (Nomiyama, 1978). The mechanism for such excretion
    probably involves a transfer of cadmium via the intestinal mucosa,
    but biliary excretion may also be involved. The biliary excretion in
    the first 24 h after intravenous injection of cadmium is dependent
    on the dose (Cirkt & Tichy, 1974; Nomiyama, 1974; Klaassen &
    Kotsonis, 1977). In rats given 67, 90 or 120 ßg cadmium (Cikrt &
    Tichy, 1974), the cumulative 24 h excretion reached 0.83% at the
    lowest dose and 5.68% at the highest dose. The highest excretion
    rate was detected between 15 and 30 min after dosing. It has been
    reported that after the initially rapid excretion the biliary
    excretion is 0.015-0.04% of the body burden per hour over three
    consecutive days (Nordberg et al., 1977; Elinder & Pannone, 1979).
    Biliary cadmium has been partially characterized as a glutathione
    complex (Cherian & Vostal 1977).

         Both during and after parenteral exposure to cadmium, the total
    gastrointestinal cadmium excretion is considerably higher than the
    urinary excretion (Nordberg, 1972; Elinder & Pannone, 1979). A large
    proportion of the gastrointestinal excretion is directly related to
    the daily dose. After chronic exposure of rats, faecal excretion
    amounted to about 0.03% of the body burden, which was considerably
    more than the urinary excretion (Elinder & Pannone, 1979).

    FIGURE 6

         There are no available quantitative human data to indicate the
    net gastrointestinal excretion.

         Cadmium is also eliminated through hair (Anke et al., 1976) and
    breast milk (Schroeder & Balassa, 1961), but these routes are of
    limited importance for total excretion and do not significantly
    alter the biological half-time.

    6.6  Biological half-time and metabolic models

    6.6.1  In animals

         Several studies have been carried out in order to assess the
    biological half-times of cadmium in experimental animals. Various
    animals species, including mice, rats, rabbits, dogs, and monkeys,
    have been studied, and single exposures have normally been used. The
    reported half-times have varied from weeks to two years (or as long
    as half the life-span of the animal). The development of metabolic
    models has shown that the body contains several compartments for
    cadmium accumulation, each with a different half-time. Thus, in
    whole body half-time measurements, one may find several different
    half-times. In order to observe the slowest half-time components, it
    is necessary to study the animals for many months.

         The biological half-time of cadmium in the kidney and whole
    body decreases when renal tubular dysfunction occurs because of
    increased urinary excretion (section 6.5.1). However, some studies
    have indicated that the biological half-time may change with dose
    and body burden of cadmium even before renal damage occurs. For
    instance, Engstrom & Nordberg (1979a) reported that in mice
    half-time increased with increasing single or repeated oral dose. In
    these studies, body burden and renal burden were considerably lower
    than the maximum that can be reached in long-term exposure. Nomiyama
    (1978) reported that half-time decreased with increasing dose when
    animals with the shortened half-time had reached the maximum renal
    burden. Even shorter half-times were reported when renal tubular
    dysfunction occurred after exposure to high doses (Nomiyama, 1978).

         A number of studies on biological half-time and metabolic
    models for animals have been reviewed by Friberg et al. (1974) and
    Nomiyama (1978).

         The wide difference in the results obtained by investigators
    may be explained by variations in exposure level and type, the
    different animal species used, and interactions between cadmium and
    other exposure factors. Reported half-times range from several weeks
    in mice to 22 years in monkeys (Friberg et al., 1974; Nomiyama et
    al., 1979; Nomiyama et al., 1984). The variations in half-times in
    specific tissues between different species or individuals may be due
    to variations in the production of metallothionein, which binds
    tissue cadmium and contributes to its retention.

    6.6.2  In humans

         Experimental and epidemiological evidence indicates strongly
    that the biological half-time in the whole body is extremely long
    (many years). Experimental evidence from one study (Shaikh & Smith,
    1980), in which one subject was given radioactive cadmium and

    examined periodically for the next 2 years, showed a biological
    half-time of 26 years. In three similar studies, in which a small
    number of subjects were followed up for a limited period (about 100
    days), half-times of 93-202 days were reported (Rahola et al., 1972;
    Flanagan et al., 1978; McLellan et al., 1978). Only one of these
    studies (Rahola et al., 1972) gave confidence limits for the
    estimated biological half-time (130 days to infinity).

         Another approach to estimate the half-time used involves
    comparing total daily excretion with total body burden, applying a
    one-compartment model to the body as a whole (Friberg et al., 1974;
    Task Group on Metal Toxicity, 1976). A further approach analyses the
    accumulation in the kidney using a one-compartment model taking into
    consideration age-related variations in daily cadmium exposure and
    kidney weight (Tsuchiya & Sugita, 1971; Kjellström, 1971). More
    recently, an elaborate model has been developed that includes
    separate compartments for, for instance, kidney, liver, and blood,
    and incorporates age-related variations in daily intake, tissue
    weights, and renal function (Kjellström & Nordberg, 1978).

         These models rely on many assumptions concerning the cadmium
    concentration in food, calorific intake, absorption rates, and other
    factors. Inevitably, the data produced by these models are only
    tentative, but they are important for future research. Using data
    from Japan on the accumulation of cadmium with age, Tsuchiya et al.
    (1976) used a series of one-compartment mathematical models
    developed by Tsuchiya & Sugita (1971) to estimate biological
    half-times of cadmium in various organs. These authors estimated the
    biological half-time in the kidneys to be about 17 years and that in
    the liver 7 years.

         Elinder et al. (1976) used autopsy data from non-smokers in
    Sweden and a one-compartment model (Kjellström, 1971) to estimate
    the biological half-time in the renal cortex. They assumed that the
    daily intake of cadmium had doubled in 50 years (Kjellström et al.,
    1975a) and estimated the half-time to be 20-50 years (30 years being
    the best estimate).

         Using an 8-compartment model (Kjellström & Nordberg, 1978), the
    biological half-times of cadmium in the liver and kidney were
    estimated to be 7.5 and 12 years, respectively (Kjellström &
    Nordberg, 1978). The longest half-time was calculated for the "other
    tissues" compartment. This included muscle tissue, which was found
    to have the longest half-time in an autopsy study (Kjellström,
    1977). However, it should be pointed out that when using this type
    of model to simulate the chemobio-kinetics of cadmium, the
    individual half-times of different tissues are less important than
    the dynamics of the model as a whole.

         After high cadmium exposure, as occurs among certain industrial
    workers, the biological half-time may not be the same as that during
    normal exposure in the general environment. Current models, however,
    do not consider this factor. If the exposure level is very high, the
    ratio of rapid components to slow components may be altered. An
    example of this is the very high urinary excretion found after only
    a short exposure to high air cadmium levels (Lauwerys et al., 1976,
    1979b). The biological half-time is also shorter if there is renal
    tubular dysfunction. Fletcher et al. (1982) carried out
     in vivo neutron activation analysis of the liver of 13 cadmium
    workers twice within a period of 3 to 4 years (the occupational
    cadmium exposure of these workers had ceased before the first
    analysis). Three workers showed proteinuria and an average cadmium
    half-time in the liver of 2 years. The other 10 workers had an
    average half-time of 6.4 years, nine of whom had an average
    half-time of 13.5 years and no proteinuria.

         Jarup et al. (1983) studied the half-time of cadmium in blood
    of five smelter workers who had previously experienced high cadmium
    exposure. Repeated blood analysis carried out over a 10-to 13-year
    period revealed short-term (75-128 days) and a long-term (7.4-16
    years) half-time components. The long-term component in two workers
    with proteinuria was shorter than in the other workers.

    6.7  Biological indices of cadmium exposure, body burden, and
         concentrations in kidneys

         There is no easy way to measure directly the whole body burden
    or concentrations of cadmium in different tissues of a living
    person.  In vivo neutron activation methods have been used in
    special circumstances (Ellis et al., 1981a; Roels et al., 1981b;
    Tohyama et al., 1981a).

         At present, it is necessary to study concentrations in easily
    available indicator media in order to evaluate exposure and
    accumulation of cadmium. The suitability of certain indicator media
    for such purposes is supported by studies on both animals and
    humans; urine, blood, faeces, and hair have all been used as
    indicator media. Methods for the biological monitoring of cadmium
    levels in blood and urine have been reviewed by Nordberg & Nordberg
    (1988) and WHO (1980).

    6.7.1  Urine

         The human and animal studies summarized in section 6.5.1 allow
    the following interpretation of the significance of cadmium in urine
    (Lauwerys et al., 1980b). In the absence of episodes of high-level
    exposure to cadmium and provided that cadmium-binding sites in the
    organism are not saturated and cadmium-induced nephropathy has not

    yet occurred, the urine cadmium level increases in proportion to the
    amount of cadmium stored in the body. In such situations, which
    prevail mainly in the general population and in workers moderately
    exposed to cadmium, there is significant correlation between urinary
    cadmium and cadmium in kidney. Episodes of high exposure to cadmium,
    however, may lead to a transient increased urinary excretion.

         If exposure to cadmium has been excessive, the cadmium-binding
    sites in the organism become progressively saturated and, despite
    continuous exposure, the cadmium concentration in the renal cortex
    tends to plateau. Once this point is reached, the cadmium that is
    still absorbed cannot be further retained in the kidney and is
    rapidly excreted in the urine. Under these conditions, urinary
    cadmium is also influenced by the recent intake. The relative
    influence of the body burden and the recent exposure on urinary
    cadmium depends on the exposure intensity. If exposure continues, a
    certain percentage of individuals may develop renal damage. This is
    associated with a progressive loss of cadmium accumulated in the
    kidney, which gives rise to a further increase in urinary cadmium.
    Eventually, the amount of cadmium that can be released from the
    kidney decreases progressively and the urinary cadmium concentration
    follows the same trend. The changes in the urinary metallothionein
    level parallel those of cadmium (section 6.8.2).

         In summary, several factors (duration and intensity of exposure
    to cadmium, the presence of renal dysfunction and its duration) must
    be taken into consideration when interpreting urinary cadmium (and
    metallothionein) levels.

    6.7.2  Blood

         Plasma cadmium levels are considered to be related to recent
    exposure but are often so low that they cannot be measured routinely
    (section 6.2). Most of the cadmium in the blood is in the
    erythrocytes.

         Cadmium levels in whole blood mainly reflect the exposure
    during recent weeks or months. In cadmium workers, the level
    increases markedly within the first few months after occupational
    exposure starts (Kjellström & Nordberg, 1978; Lauwerys et al.,
    1979b). It is probable that a portion of the blood cadmium level
    reflects body burden rather than present exposure in view of the
    known transport of cadmium via blood from the liver to the kidneys
    and other tissues (section 6.2) and the long-term half-time
    component demonstrated by Jarup et al. (1983). Workers with
    relatively long exposure durations but whose cadmium exposure has
    ceased have elevated blood cadmium levels for several years (Friberg
    et al., 1974; Jarup et al., 1983).

         Reports of blood cadmium levels in the general population have,
    in the past, often been unreliable, owing largely to the
    difficulties encountered in the analysis of blood cadmium (Lauwerys
    et al., 1975). However, improvements in analytical techniques have
    since been achieved through biological standards for blood and
    systematic quality assurance programmes (Stoeppler et al., 1979;
    Vahter, 1982). Average blood cadmium values up to 10 µg/litre or
    more have been reported in the past, but the analytical procedures
    used mean that the accuracy of these data is in doubt (Vahter, 1982;
    Friberg & Vahter, 1983).

         Various aspects of blood cadmium analysis have been discussed
    in a UNEP/WHO study, which also included a quality assurance
    programme and data from 10 countries (Vahter, 1982; Friberg &
    Vahter, 1983). It was found that even in the countries with the
    highest blood cadmium levels, the average was less than 4 µg/litre.
    Furthermore, smokers were found to have higher values than
    non-smokers, and non-smokers, in most countries, had mean levels
    below 1 µg/litre. Although only slightly above 1 µg/litre, the
    levels for non-smokers in Japan were about twice as high as the
    levels in the USA, which probably reflects the difference in average
    daily cadmium intake via food (section 5.2.2).

         Reported cadmium concentrations in the blood of exposed workers
    are generally between 5 and 50 µg/litre, but levels of between 100
    and 300 µg/litre have resulted from extreme exposures (Roels et al.,
    1982; Hassler et al., 1983).

    6.7.3  Faeces

         Gastrointestinal absorption amounts to only a few percent of
    the cadmium ingested daily (section 6.1.2), and the quality of
    cadmium excreted gastrointestinally is small compared to the
    unabsorbed portion of ingested cadmium. Thus, daily faecal cadmium
    can serve as a good indicator of the daily amount of cadmium
    ingested via food and water or cleared from the lungs after
    occupational exposure to large dust particles. Faecal cadmium
    correlates very closely with daily energy intake (section 5.2.4),
    and average cadmium intake estimates for different countries agree
    well with reported average faecal cadmium amounts.

         A portion of the cadmium in human faeces is related to the body
    burden (section 6.5.2). In workers with high body burdens but low
    daily cadmium intakes via food, this portion might be greater than
    the unabsorbed part of ingested cadmium, because the faecal
    excretion is similar to the urinary excretion.

    6.7.4  Hair

         Cadmium in hair is not a reliable indicator of either recent
    exposure or body burden. The main problem is external contamination
    of the hair, which cannot be distinguished from the endogenous
    cadmium (Nishiyama & Nordberg, 1972). However, a correlation was
    found between air cadmium levels of cities in the USA and cadmium
    levels in the hair of 10-year-old children living in these cities
    (Hammer et al., 1971). In a study of cadmium workers (Ellis et al.,
    1981b), a higher average hair cadmium level was found among exposed
    workers than among controls, but there was a poor relationship
    between hair cadmium and cadmium in the blood, urine, liver or
    kidney. Cadmium concentrations in the hair of people without
    excessive exposure are usually between 0.5 and 2 mg/kg.

    6.8  Metallothionein

    6.8.1  Nature and production

         Metallothionein is a metal-binding protein of low molecular
    weight, which has a key role in the metabolism of cadmium. It is
    rich in cysteine but contains no aromatic amino acids or histidine
    (Kagi & Vallee, 1960, 1961).

         This protein was identified for the first time by Margoshes &
    Vallee (1957) in horse kidney cortex. Its molecular weight is about
    6600 (6000 for the apoprotein moiety, thionein), and it has a
    non-globular shape. On gel filtration, however, it moves like a
    spherical protein with a molecular weight of about 10 000 (Kagi &
    Nordberg, 1979). There have been several reports dealing with the
    function and biochemistry of metallothionein (Kagi & Nordberg, 1979;
    Brady, 1982; Foulkes, 1982; Webb & Cain, 1982; Kagi & Kojima, 1987).

         Piscator (1964) suggested that metallothionein played a role in
    cadmium transport and detoxication, and it has subsequently been
    identified in human kidney and liver (Pulido et al., 1966; Chung et
    al., 1986) as well as in those of various experimental animals (Kagi
    & Nordberg, 1979).

         The structure and genetic expression of mouse and human
    metallothionein have now been identified. Two major forms of
    metallothionein are present in most mammalian tissues, particularly
    liver and kidney, i.e. metallothionein I (Mt-I) and metallothionein
    II (Mt-II). Induction of synthesis is under the control of a large
    group of genes and is stimulated by glucocorticoids and the

    essential metals zinc and copper, as well as by the toxic metals
    cadmium and mercury (Karin et al., 1981; Karin & Richards, 1982).
     In vitro binding affinities have been demonstrated for a number of
    other toxic metals, including bismuth, cobalt, silver, and gold
    (Cherian & Nordberg, 1983). Metallothionein binds seven metal ions
    per molecule between two separate metal-cysteine clusters, and a
    single molecule may contain more than one metal, e.g., cadmium and
    zinc, mercury and copper.

    6.8.2  The role of metallothionein in transport, metabolism, and
           toxicity of cadmium

         Piscator (1964) suggested that some of the cadmium-binding
    metallothionein in the liver may migrate into the blood stream. As
    discussed in section 6.2, part of the plasma cadmium in animals
    exposed for a long time to cadmium is bound to a protein with the
    same molecular weight as metallothionein. When metallothionein-bound
    cadmium is present in the plasma, it is quickly cleared by
    glomerular filtration and reabsorbed in the renal tubules or
    excreted in the urine (Cherian & Shaikh, 1975; Nordberg et al.,
    1975; Webb & Etienne, 1977; Fowler & Nordberg, 1978).

         At low levels of cadmium-metallothionein in the plasma, tubular
    reabsorption is almost complete, whereas the uptake in the tubular
    cells from the tubular fluid is saturated in the presence of high
    concentrations (Nomiyama & Foulkes, 1977; Foulkes, 1982). Thus, high
    urinary excretion of cadmium-metallothionein occurs shortly after
    the administration of larger doses, i.e. doses exceeding about
    0.1 mg cadmium/kg body weight (Cherian & Shaikh, 1975; Nordberg &
    Nordberg, 1975).

         It has been demonstrated in animal and  in vitro tissue
    studies that metallothionein provides a protective role for cadmium
    toxicity (Cherian & Nordberg, 1983). Mice pretreated with cadmium
    have increased tolerance to subsequent cadmium exposure (Nordberg et
    al., 1971), and exposure to cadmium may protect from subsequent
    mercury toxicity (Piotrowski et al., 1974). In addition, the
    inhibition of certain mixed-function oxidases by cadmium is reduced
    by prior induction of metallothionein by cadmium in immature mice
    (Asokan et al., 1984). Pre-exposure of cultured kidney cells to
    cadmium protects from subsequent exposure (Cherian, 1980; Jin et
    al., 1986).

         Nordberg et al. (1975) showed that metallothionein isolated
    from rabbit and mouse liver produced acute renal tubular cell
    toxicity when injected subcutaneously into mice. Further study
    (Cherian et al., 1976; Fowler & Nordberg, 1978; Squibb et al., 1982,
    1984) suggested that parenterally administered
    cadmium-metallothionein enters proximal renal tubular lining cells

    in pinocytotic vesicles that fuse with lysosomes. The
    metallothionein is degraded, releasing cadmium into the cytosol and
    producing cellular degeneration and necrosis within 8-24 h. The
    renal tubular cell toxicity produced by metallothionein with
    different ratios of cadmium and zinc is proportional to the cadmium
    content of the metallothionein (Suzuki, 1982). Zinc-thionein does
    not have a similar effect.

         The pathogenesis of renal tubular cell toxicity is thought to
    be related to non-metallothionein-bound cadmium, which becomes
    rapidly bound to existing metallothionein sites or induces the
    synthesis of new metallothionein (section 7.2.1.4).

         The prevalence of nephrotoxicity rather than hepatotoxicity in
    chronic cadmium exposure may be due to several factors. Firstly, the
    release of hepatic cadmium-metallothionein or its presence in the
    blood can result in preferential accumulation of cadmium in the
    kidneys. Secondly, it has been shown in experimental animals that
    the kidney can accumulate metallothionein mRNA in response to
    cadmium exposure to only about half the level of the liver
    (Koropatnick & Cherian, 1988). Thus, the kidney may not be able to
    synthesize metallothionein as efficiently as the liver in response
    to cadmium exposure, resulting in an accumulation of
    non-metallothionein cadmium in the kidney but not in the liver.

         Nomiyama et al. (1982a) studied the concentrations of total
    cadmium, metallothionein-cadmium, and non-metallothionein-cadmium in
    the renal cortex of monkeys fed diets containing 30 mg cadmium/kg
    food for 12 months. They found that the concentration of
    non-metallothionein-cadmium increased with dose of cadmium to about
    35 mg/kg tissue and total cadmium to about 200 mg/kg tissue when the
    total dose of cadmium was 0.4 g. Similar measurements were made in
    rabbits given cadmium chloride (0.5 mg cadmium/kg body weight)
    subcutaneously every day for 21 weeks. There were parallel increases
    of total cadmium and non-metallothionein-bound cadmium during the
    initial 4 weeks of dosing; these remained unchanged until the 14th
    week when striking renal dysfunction appeared. At that time, total
    cadmium and non-metallothionein-bound cadmium levels fell despite
    the continued administration of cadmium (Nomiyama & Nomiyama, 1982).
    Increased knowledge of the intracellular binding or speciation of
    non-metallothionein-bound cadmium should improve our understanding
    of the relative roles of metallothionein-bound and
    non-metallothionein-bound cadmium.

         When Cherian et al. (1978) exposed mice by injection and
    feeding to both cadmium chloride and cadmium-metallothionein, both
    compounds were absorbed and distributed in the body. However, in the
    short term, cadmium-metallothionein was selectively accumulated in
    the kidney and cadmium chloride in the liver.

         Most cadmium in human urine is bound to metallothionein
    (Tohyama et al., 1981b), and good correlation has been found between
    the urinary cadmium and metallothionein concentrations both in
    elderly women exposed in the general environment (Tohyama et al.,
    1981b) and in male cadmium workers (Nordberg et al., 1982; Roels et
    al., 1983b). Measurement of urinary metallothionein thus provides a
    good indication of the urinary cadmium level and offers the
    advantage over cadmium analysis of avoiding the possibility of
    external contamination. Women were found to have much higher urinary
    metallothionein concentrations than men, even at similar cadmium
    levels.

    6.9  Conclusions

         Data from experimental animals and humans have shown that
    pulmonary cadmium absorption is greater than gastrointestinal
    absorption. Depending on chemical speciation, particle size, and
    solubility in biological fluids, up to 50% of the inhaled cadmium
    compound may be absorbed. The gastrointestinal absorption of cadmium
    is influenced by the type of diet and nutritional status, iron
    status appearing to be particularly important. On average, 5% of the
    total oral intake of cadmium is absorbed, but individual values
    range from less than 1% to more than 20%. Cadmium may also be
    transported to the fetus. However, although cadmium accumulates in
    the placenta, little is transferred to the fetus.

         Cadmium absorbed from the lungs or the gastrointestinal tract
    is stored principally in the liver and kidneys where more than half
    of the body burden is deposited. Highest cadmium concentrations are
    generally found in the renal cortex, but as exposure levels
    increase, a greater proportion of the absorbed cadmium is stored in
    the liver. The cadmium excretion rate is normally low, and the
    biological half-time is very long (decades) in the kidneys, muscles,
    liver, and total body of humans. The cadmium concentrations in most
    tissues increase with age. In exposed people with renal damage,
    urinary excretion of cadmium increases and, thus, the whole body
    half-time is shortened. The renal damage leads to losses of cadmium
    from the kidney, and the renal concentrations are eventually lower
    than in people with similar exposure but without renal damage.

         Metallothionein is an important transport and storage protein
    for cadmium and other metals. Cadmium can induce metallothionein
    synthesis in many organs including the liver and kidney. The binding
    of intracellular cadmium to metallothionein in tissues protects
    against cadmium toxicity. Non-metallothionein-bound cadmium may,
    therefore, have a role in the pathogenesis of cadmium-related tissue
    injury. The speciation of other cadmium complexes in tissues or
    biological fluids is unknown.

         Urinary excretion of cadmium is related to body burden, recent
    exposure, and renal damage. In people with low exposures, cadmium in
    urine is mainly related to body burden. Cadmium-exposed people with
    proteinuria generally exhibit greater cadmium excretion than such
    people without proteinuria. After high exposure ceases, urinary
    cadmium decreases even though renal damage persists. The
    interpretation of urinary cadmium is thus dependent on a number of
    factors. The magnitude of gastrointestinal excretion is similar to
    that of urinary excretion, but it cannot be easily measured. Other
    excretory routes such as lactation, sweating or placental transfer
    are insignificant.

         Cadmium in faeces is a good indicator of recent daily intake
    from food in the absence of inhalation exposure. Cadmium in blood
    occurs mainly in the blood cells, and the plasma concentrations are
    very low. There are at least two blood compartments, one being
    related to recent exposure with a half-time of about 2-3 months, and
    the other probably related to body burden with a half-time of
    several years.

    7.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

    7.1  Single exposure

    7.1.1  Lethal dose and lethal effects

         LD50 inhalation values are in the range of 500 to
    15 000 mg/m3.min for different species (Barrett et al., 1947;
    Harrison et al., 1947; Hadley et al., 1979). The cause of death is
    pulmonary oedema.

         The LD50 after the injection of soluble cadmium compounds is
    in the range of 2.5-25 mg/kg body weight (Friberg, 1950; Eybl &
    Sykora, 1966; Commission of the European Communities, 1978). Shortly
    after large doses are injected, severe endothelial damage is seen in
    the small vessels of the peripheral nervous system (Gabbiani, 1966)
    and in the testis (Parizek, 1957). If the animal survives for some
    hours, the most pronounced changes are found in the liver (Dudley et
    al., 1982), and liver damage is probably the lethal effect of a
    single high parenteral exposure.

         For most cadmium compounds, the LD50 after oral
    administration is about 10-20 times higher than after parenteral
    administration, and the readily soluble compounds have a lower
    LD50 values than the insoluble ones (Table 11).

         Nomiyama et al. (1978b) showed that the LD50 in mice was
    lower at cold temperatures (+8 °C) than at higher temperatures
    (+22 or +37 °C), both after oral and peritoneal exposure.

    7.1.2  Pathological changes affecting specific systems in the body

         The chronic effects of long-term exposure to low doses of
    cadmium constitute the main problem for non-occupationally exposed
    humans. Therefore, the effects of single exposure in animals will be
    dealt with only briefly, and the main emphasis will be on chronic
    effects.

         Specific effects from a single high dose of cadmium have been
    described by several investigators and have been reviewed by Friberg
    et al. (1974, 1986), Commission of the European Communities (1978),
    and Kawai (1978). One of the most pronounced effects seen was in the
    gonads (testis and ovary).


        Table 11.  LD50 values for cadmium compounds given to mice and rats by intragastric administration
                                                                                                                                          

    Species   Compound                  Molecular formula  Relative molecular   LD50 with confidence   LD50 for cadmium
                                                           massa                limits (mg/kg)b        ion alone (mg/kg)
                                                                                                                                          

    Mouse     cadmium (element)               Cd                 109               890 (636-1246)             890
              cadmium oxide                   CdO               128.4                72 (41-113)               63
              cadmium sulfate                CdSO4              208.5              88 (69.8-100.2)             47
              cadmium chloride               CdCl2              183.3             93.7 (75.5-111.9)            57
              cadmium nitrate              Cd(NO3)2             236.4             100 (78.7-121.8)             48
              cadmium iodide                 CdI2               366.2               166 (139-193)              51
              cadmium caprylate          Cd(C7H15COO)2          394.8               300 (196-459)              85
              cadmium carbonate              CdCO3               169                310 (215-404)             202
              cadmium stearate          Cd(C17H35COO)2          679.4               590 (556-624)              98
              cadmium sulfide                 CdS               144.5             1166 (1135-1197)            907
              cadmium sulfoselenide        CdSe.CdS             335.8             2425 (2393-2457)           1623
              barium-cadmium stearate  BaCd(C17H35COO)4        1383.7             3171 (2763-3579)            258

    Rat       cadmium caprylate          Cd(C7H15COO)2          394.8              950 (613-1472)             270
              cadmium stearate          Cd(C17H35COO)2          679.4              1225 (875-1574)            203
              barium-cadmium stearate  BaCd(C17H35COO)4        1383.7             1980 (1736-2224)            161
                                                                                                                                          

    a   From: Weast (1974)
    b   From: Tarasenko et al. (1974), Vorobjeva & Sabalina (1975), and Vorobjeva & Bubnova (1981)

    

    7.1.2.1  Acute effects on testes and ovaries

         Testicular necrosis occurs in experimental animals given single
    injections of salts corresponding to 2-4 mg cadmium/kg body weight
    (Parizek & Zahor, 1956; Parizek, 1957). At a later stage, Leydig
    cells regenerate (Parizek, 1957, 1960; Allanson & Deanesly, 1962).
    Gabbiani et al. (1974) detected dilation of interendothelial clefts
    in the small blood vessels of the testis as early as 15 min after an
    intravenous injection of cadmium salts. Effects on the testis have
    been extensively reviewed by Gunn & Gould (1970).

         The marked effects on the testis after cadmium injection are
    probably the result of endothelial damage. In the small vessels this
    damage gives rise to increased capillary permeability. This leads to
    vascular escape of fluids and blood plasma substances into the
    interstitium, which results in oedema, decreased capillary blood
    flow, ischaemia, and testicular cell necrosis (Aoki & Hoffer, 1978;
    Francavilla et al., 1981).

         A single injection of cadmium salts at a dose that induces
    testicular haemorrhagic necrosis has been shown to induce
    haemorrhages and necroses in the ovaries of prepubertal rats (Kar et
    al., 1959), and in the ovaries of adult rats in persistent oestrus
    (Parizek et al., 1968a). The effect of cadmium on the testis was not
    dependent on the presence of the hypophysis (Parizek, 1960). Ovarian
    effects can be prevented by the administration of PMSG hormones
    (Parizek et al., 1968a). Numerous studies on the effects of cadmium
    on the testes and other reproductive organs were reviewed by Barlow
    & Sullivan (1982).

    7.1.2.2  Acute effects on other organs

         A single inhalation exposure to cadmium at concentrations of
    5-20 mg/m3 for 50-120 min gives rise to pulmonary oedema in rats
    and rabbits (Hayes et al., 1976; Bouley et al., 1977; Bus et al.,
    1978; Dervan & Hayes, 1979; Boisset & Boudene, 1981; Fukuhara et
    al., 1981). The morphological changes seen in the lung have been
    described in detail by Strauss et al. (1976).

         After the parenteral administration of cadmium at dose levels
    similar to the LD50, pronounced effects were seen in the small
    blood vessels of, for instance, the nervous system (Gabbiani et al.,
    1974). Hoffman et al. (1975) noted profound morphological effects in
    the liver of rats given 6 mg cadmium/kg body weight, and Dudley et
    al. (1982), examining liver effects from a single injection of
    cadmium (3.9 mg/kg body weight), concluded that liver was the major
    target organ in rats for acute cadmium toxicity. Changes in blood
    pressure shortly after the acute administration of cadmium have also
    been recorded (Dalhamn & Friberg, 1954; Perry et al., 1970).

         Oral administration of cadmium compounds induces epithelial
    desquamation and necrosis of the gastric and intestinal mucosa,
    together with dystrophic changes of the liver, heart, and kidneys
    (Tarasenko et al., 1974; Vorobjeva & Sabalina, 1975).

    7.2  Repeated and/or long-term exposure

    7.2.1  Effects on the kidneys

         Since the kidney is the critical organ in humans exposed for
    long periods to relatively small amounts of cadmium (section 8.2.1),
    results from relevant animal studies will be dealt with in some
    detail. Even though it is difficult to extrapolate quantitative
    information from the findings in animals, experiments have provided
    valuable information concerning mechanisms of cadmium-induced
    nephropathy and the significance of various biological indicators of
    exposure and effect, and have supported the findings in humans. For
    example, Friberg (1950) verified in animal experiments that exposure
    to cadmium caused a type of proteinuria similar to the one he had
    found in exposed workers.

         Animal studies that have given data on renal effects as well as
    the corresponding renal cadmium concentrations are summarized in
    Table 12. An evaluation of organ dose-effect and dose-response
    relationships is included in section 7.2.1.4.

    7.2.1.1  Oral route

         Renal lesions were first reported by Prodan (1932) and Wilson
    et al. (1941) after cats and rats were given large oral doses of
    cadmium for several months. Prodan (1932) reported varying degrees
    of desquamation in proximal tubular epithelium (and no changes in
    the glomeruli) after feeding cats 100 mg cadmium per day for one
    month. Wilson et al. (1941) reported slight tubular changes in rats
    after they were exposed for 3 months to a diet containing 62 mg
    cadmium/kg.

         Studies utilizing high exposures have also been performed by
    Stowe et al. (1972). Ten rabbits received cadmium in drinking-water
    (160 mg/litre) for 6 months. Kidney function was not investigated,
    but histopathological examination revealed pronounced morphological
    changes in the proximal tubules. The mean renal concentration of
    cadmium was 170 mg/kg wet weight, which would correspond to about
    210 mg/kg wet weight in the renal cortex (section 6.4). Still higher
    doses (300 mg/kg diet) were given to rabbits for 54 weeks by
    Nomiyama et al. (1975), who observed aminoaciduria and enzymuria
    after 16 weeks. At this stage, the cadmium concentration in the
    renal cortex was 200 mg/kg wet weight. Proteinuria and glycosuria
    appeared at a later stage, 37 and 42 weeks, respectively, after
    exposure had started. The cadmium concentration in the renal cortex
    was 300 mg/kg wet weight after 40 weeks.


        Table 12.  Summary of animal studies with data on both renal cadmium levels and effects
                                                                                                                                               

    Species   Route of          Exposure      Duration    Average cadmium      Renal changes                   Reference
              administration    level         (months)    level in kidney
                                                          cortex (mg/kg
                                                          wet weight)
                                                                                                                                               

    Mouse      subcutaneous     0.25 mg/kg        6          110-170a        no effects                      Nordberg & Piscator (1972)
                                body weight

    Mouse      subcutaneous     0.5 mg/kg         6            170a          tubular protein patterns        Nordberg & Piscator (1972)
                                body weight                                  in urine

    Rat      intraperitoneal    0.75 mg/kg        3            200a          no effects                      Bonnell et al. (1960)
                                body weight

    Rat      intraperitoneal    0.75 mg/kg        4            300a          histological changes in         Bonnell et al. (1960)
                                body weight                                  60% of animals

    Rat       subcutaneous      0.65 mg/kg        3             200          histological changes            Goyer et al. (1984)
                                body weight

    Rat           water         10 mg/litre      8.5            11a          no histological changes         Kawai et al. (1976)

    Rat           water         50 mg/litre      8.5            35a          slight histological changes     Kawai et al. (1976)

    Rat           water         100 mg/litre     8.5            90a          histological changes            Kawai et al. (1976)

    Rat           water         200 mg/litre     8.5           145a          histological changes            Kawai et al. (1976)

    Rat           water         200 mg/litre     11             200          total proteinuria and low       Bernard et al. (1981)
                                                                             molecular weight proteinuria

    Rat           water         50 mg/litre       3            100a          decreased insulin and PAH       Kawamura et al.(1978)
                                                                             clearance; histological
                                                                             changes
                                                                                                                                               

    Table 12 (contd).
                                                                                                                                               

    Species   Route of          Exposure      Duration    Average cadmium      Renal changes                   Reference
              administration    level         (months)    level in kidney
                                                          cortex (mg/kg
                                                          wet weight)
                                                                                                                                               
    Rat           water         50 mg/litre      2.5            235          slight histological changes     Axelsson & Piscator (1966a);
                                                                             in proximal tubules             Axelsson et al. (1968)

    Rabbit    subcutaneous      0.25 mg/kg       2.5            235          slight histological changes     Axelsson & Piscator (1966a);
                                body weight                                  in proximal tubules             Axelsson et al. (1968)

    Rabbit    subcutaneous      0.25 mg/kg        4             460          more severe histological        Axelsson & Piscator (1966a);
                                body weight                                  changes; reduction of alkaline  Axelsson et al. (1968)
                                                                             phosphatase activity in renal
                                                                             cortex; total proteinuria

    Rabbit    subcutaneous      0.5 mg/kg        2.5            300          total proteinuria               Nomiyama et al. (1982b)
                                body weight

    Rabbit    subcutaneous      0.5 mg/kg        0.7            200          proteinuria, glucosuria, and    Nomiyama & Nomiyama
                                body weight                                  aminoaciduria; decrease in      (1982)
                                                                             CIN and TmPAH

    Rabbit    subcutaneous      0.5 mg/kg         1             120          ß2-microglobulin                Nomiyama et al. (1982b)
                                body weight

    Rabbit    subcutaneous      1.5 mg/kg         1           50-200         decreased tubular               Nomiyama (1973a);
                                body weight                                  readsorption                    Nomiyamaet al. (1978a)

    Rabbit    subcutaneous      0.5 mg/kg         2            160a          slight histological changes     Kawai et al. (1976)
                                body weight

    Rabbit        water         160 mg/litre      6            170a          extensive fibrosis; pronounced  Stowe et al. (1972)
                                                                             changes
                                                                                                                                               

    Table 12 (contd).
                                                                                                                                               

    Species   Route of          Exposure      Duration    Average cadmium      Renal changes                   Reference
              administration    level         (months)    level in kidney
                                                          cortex (mg/kg
                                                          wet weight)
                                                                                                                                               
    Rabbit        water         50 mg/litre      10             58           slight tubular atrophy          Kawai et al. (1976)

    Rabbit        water         200 mg/litre     10             200          severe interstitial and         Kawai et al. (1976)
                                                                             tubular fibrosis

    Rabbit        diet          300 mg/kg         4             200          aminoaciduria, enzymuria        Nomiyama et al. (1975)

    Rabbit        diet          300 mg/kg        10             300          proteinuria, glucosuria         Nomiyama et al. (1975)

    Pig           diet          50-350 mg/kg    < 12a                        equimolar increase in zinc      Cousins et al. (1973)
                                                                             in kidney

    Pig           diet          50-350 mg/kg     78a                         decrease in renal leucine       Cousins et al. (1973)
                                                                             aminopeptidase

    Horse         diet          no cadmium    lifelong          75           renal tubular interstitial      Elinder et al. (1981a,b)
                                added        (up to 240)                     changes and fibrosis in
                                                                             25% of animals

    Bird      subcutaneous      0.16 mg/kg       1.5            20b          histological changes            Nicholson & Osborn (1983)
                                body weight
                                                                                                                                          

    a    These values are whole kidney concentrations; about 0.8 times kidney cortex values, on average.
    b    Denotes concentrations (wet weight) calculated as 0.2 times dry weight concentrations.

    

         Morphological changes of the renal tubules were reported by
    Kawai et al. (1976) in rats given 50 mg cadmium/litre drinking-water
    for 8.5 months. The average renal cadmium concentration was about
    38 mg/kg wet weight which corresponds to about 50 mg/kg in the renal
    cortex.

         Histological lesions in the proximal renal tubules were also
    found in rats exposed to 200 mg cadmium/litre for 2 months (Itokawa
    et al., 1978). Histochemical examination of the kidney showed that
    the proximal tubular epithelium had particularly high cadmium
    concentrations. The average renal concentrations were 48 mg/kg and
    80 mg/kg, respectively, in rats with sufficient and deficient
    calcium intakes. These levels would correspond to about 60 and
    100 mg cadmium/kg in the renal cortex (section 6.4). Inulin
    clearance was reduced to about a third of the control values in the
    cadmium-exposed groups, indicating considerable functional damage to
    the glomeruli. The only reported change in renal tubular function
    was that the fractional excretion of calcium was increased about 50%
    in the cadmium-exposed groups.

         In a study of 50 rats exposed to 200 mg cadmium/litre in
    drinking-water for up to 11 months (Bernard et al., 1981), there was
    an increased prevalence of total proteinuria in the 8th month, when
    the average cadmium concentration in the renal cortex was about
    200 mg/kg.

         Kajikawa et al. (1981) also reported morphological changes in
    the kidneys of rats given drinking-water containing 200 mg cadmium
    chloride/litre for 91 weeks. Histologically, they found degenerative
    changes in the proximal convoluted tubules and, using electron
    microscopy, proliferation of smooth endoplasmic reticulum,
    vacuolization, and coagulative necrosis of the tubular cells. No
    significant changes were observed in the glomeruli or interstitial
    tissue.

         When Cousins et al. (1973) gave large amounts of cadmium
    chloride to pigs (50, 150, 450, and 1350 mg/kg diet), there was a
    decrease in the activity of leucine aminopeptidase in the kidney
    cortex at a renal cadmium concentration of 78 mg/kg wet weight,
    corresponding to a renal cortex concentration of about 100 mg/kg wet
    weight (section 6.4).

         An extensive data base on the renal effects of cadmium in
    monkeys has been developed in Japan. Several of these studies are
    summarized in Table 13.

         Study I (Nomiyama et al., 1979) was carried out using ten male
    rhesus monkeys (three years of age). The monkeys were given 100 g of
    solid feed containing 0, 3, 30, or 300 mg cadmium/kg daily for 37
    weeks, followed by 130 g of feed for 18 weeks. Even the solid feed
    given to the control group contained cadmium at a concentration of
    0.13 mg/kg.

         In study II, Nomiyama et al. (1987) used 36 male rhesus monkeys
    (three years of age) and gave them 100 g of solid feed containing 0,
    3, 10, 30, or 100 mg cadmium/kg daily for 52 weeks. During the
    following 52 weeks 150 g was given, and then for the remaining 358
    weeks 200 g was given. The solid feed given to the control group
    contained cadmium at 0.27 mg/kg and zinc at 30 mg/kg.

         Study III (Nomura et al., 1988) was performed with 40 female
    rhesus monkeys given 150 g of solid feed for nine years (Table 14).

         In study IV, Nomiyama & Nomiyama (1988) used nine male
    crab-eating monkeys. Two of the animals were used as controls, and
    three were given a diet containing cadmium concentrations of 3 mg/kg
    (190 µg/day) as cadmium chloride (the pelleted food also contained
    (30 mg zinc/kg)). The remaining four were fed 80 µg cadmium/day in
    the form of contaminated rice.

         In studies I and II, monkeys that had been given feed
    containing cadmium at 300 mg/kg and 100 mg/kg showed indi-cations of
    renal dysfunction, such as proteinuria, glucosuria, and
    aminoaciduria, after 15-16 and 48-91 weeks, respectively. The
    appearance of increased ß2-microglobulin was delayed until the
    30th and 138th weeks, respectively. However, no definite disturbance
    of proximal renal tubular function, such as reduced tubular
    reabsorption of phosphorus, hypophosphataemia or acidosis, was noted
    during the one-year follow-up. The dose-effect relationship for
    renal dysfunction was similar to those which have been observed in
    rabbits and rats, and thus the hypothesis that the susceptibility of
    monkeys to cadmium may be exceptionally low was not corroborated.

         In study II, the group of monkeys given feed containing
    30 mg/kg developed urine findings (e.g., proteinuria, glucosuria,
    aminoaciduria) indicative of renal dysfunction in the sixth year.
    Postmortem examination revealed degeneration of the proximal renal
    tubules, but there was no reduction in tubular reabsorption of
    phosphorus. When the administration of cadmium was discontinued in
    the fifth year, no abnormality of renal function developed during
    the follow-up period of four years.


        Table 13.  Renal effects of cadmium in monkeysa
                                                                                                                                          

    Study  Duration   Sex     No. of   Exposure level      Average cadmium   Renal effects (timing,         Other effects (timing,
           (weeks)            monkeys  (mg/kg diet)        level in renal    in weeks, of effects)          in weeks, of effects)
                                                           cortex (mg/kg)
                                                                                                                                          

    I      55         male       2            0                 163
                                 2            3                 202          no biological effects          no biological effects
                                 3           30                 596          no biological effects          no biological effects
                                 3           300               380b          renal dysfunction (15-16)      hepatic dysfunction (12-54)
                                                               757b          ß2-microglobulinuria (30)      slight anaemia (20)

    II     462        male       6            0                 328
                                 8            3                 700          no biological effects          no biological effects
                                 8           10                1070          no biological effects          erythrocytopenia (360)
                                 8           30                1170b         renal dysfunction (300-306)    erythrocytopenia (240)
                                                                             ß2-microglobulinuria (311)
                                 6           100               635b          renal dysfunction (48-91)      erythrocytopenia (120)
                                                                             ß2-microglobulinuria (138)     depressed age-related increase
                                                                             in blood pressure (80)

    III    See Table 14.

    IV     308        male       2            0                 18
                                 3            3                 570          no biological effects          no biological effects
                                 4    contaminated rice         230          no biological effects          no biological effects
                                        (1.33 mg/kg)
                                                                                                                                          

    a    From: Nomiyama et al. (1979), Nomiyama et al. (1987), Nomura et al. (1988), Nomiyama & Nomiyama (1988)
    b    The numbers with asterisks are the critical concentrations of cadmium in the renal cortex.

    Table 14.  Bone and renal effects of cadmium in female monkeysa
                                                                                                                                               

    Group   No. of   Exposure  Low protein,       Low vitamin D   Average renal     Renal effects            Bone effectsd
            monkeys  level     calcium and        dietc           cortex cadmium
                     (mg/kg)   phosphorus dietb                   level (mg/kg)
                                                                                                                                               

    1         5        0            -                  -               58           no biological effects    no biological effects

    2         4        0            +                  -                            no biological effects    slightly disturbed calcification
                                                                                                             (after 154 weeks)

    3         4        0            -                  +                            no biological effects    low plasma vitamin D3

    4         4        0            +                  +                            no biological effects    osteomalacic change (after 77
                                                                                                             weeks) reversible by vitamin D3

    5         5        30e          -                  -              1511          no biological effects    no biological effects

    6         4        30e          +                  -                            ß2-microglobulinuriaf    disturbed calcification (after
                                                                                    (2000 to 12 000 µg/day,  154 weeks)
                                                                                    67%)

    7         4        30e          -                  +                            no biological effects    low plasma vitamin D3

    8         10       30e          +                  +                            ß2-microglobulinuriag    osteomalacic change (after 77
                                                                                    (up to 2000 µg/day)      weeks) reversible by vitamin D3
                                                                                                                                               

    a    From: Nomura et al. (1988); duration of experiment was 463 weeks (9 years)
    b    14% protein instead of 20%; 0.3% calcium instead of 0.9%; 0.3% phosphorus instead of 0.9%
    c    No vitamin D3 was added (240 IU was added to the normal diet)
    d    In Group 5 to 8, as depressed age-related increase in blood pressure was seen after 103 weeks of treatment.
    e    3 mg/kg for the first 52 weeks
    f    Non-progressive lesion, reversibility uncertain; renal effect noted after 193 weeks
    g    Reversible by normal diet and vitamin D3 treatment; renal effect noted after 154 weeks
    

         The monkeys in study III (Table 14) given the low nutrition
    feed plus 30 mg cadmium/kg developed renal function abnormalities
    after the fourth year. In addition to reduced phenolsulfonphthalein
    (PSP) clearance and a variable increase in urinary
    ß2-microglobulin concentration, many of the monkeys showed mild
    degenerative changes of the proximal tubular epithelia, but there
    was no decrease in the tubular reabsorption of phosphorus. However,
    elevated urinary ß2-microglobulin did not progress further with
    continued administration of cadmium. Mild degenerative changes of
    the proximal tubular epithelia were also noted in the groups of
    monkeys that had been given a normal diet, low vitamin D diet or low
    nutrition plus low vitamin D diet, each supplemented with 30 mg
    cadmium/kg. However, the elevated urinary ß2-microglobulin level
    soon returned to normal in those animals fed a normal diet,
    regardless of continued cadmium administration. This may indicate
    that the elevated urine ß2-microglobulin in this group was not
    caused solely by cadmium exposure.

         In study II, some of the monkeys given feed containing 3 mg/kg
    or 10 mg/kg of cadmium showed cadmium concentrations in the renal
    cortex as high as 760 mg/kg and 1070 mg/kg, respectively. However,
    no effect upon renal function was observed during the nine-year
    period, nor was there any increase in urinary ß2-microglobulin
    concentration.

         The above data suggest that mild renal dysfunction
    (proteinuria, glucosuria, and aminoaciduria, but no decrease in the
    tubular reabsorption of phosphorus) was produced in monkeys exposed
    to high concentrations of cadmium (30 mg/kg diet or more). It seems,
    however, that no effects on renal function occur with low-level
    exposure (10 mg/kg or less). The development of renal dysfunction is
    assumed to depend upon the amount of cadmium absorbed per day rather
    than the total amount absorbed in the body.

         In study IV, the urinary cadmium level occasionally exceeded
    10 µg/litre, but no clinical chemistry changes were reported.
    Cadmium concentrations in the renal cortex increased proportionally
    to the dose level and duration of exposure, reaching an average of
    450 mg/kg in the group given cadmium chloride and 290 mg/kg in the
    group fed contaminated rice. This suggests that the chemical form of
    cadmium does not affect the severity of health effects.

    7.2.1.2  Respiratory route

         Princi & Geever (1950) could find no evidence of renal
    morphological changes in the kidney of dogs after prolonged
    inhalation exposure (up to one year) to cadmium oxide or cadmium
    sulfide dust (average concentration of 4 mg/m3). Routine analysis
    was performed, but neither the methods used nor the results obtained

    were described. Friberg (1950) exposed rabbits for about 8 months
    (3 h per day, about 20 days per month) to cadmium oxide dust with an
    average concentration of about 8 mg/m3 . After 4 months of
    exposure, moderate proteinuria was detected by the trichloroacetic
    acid test. Histological examination of the kidneys after 8 months
    revealed interstitial infiltration of leucocytes in the majority of
    the exposed rabbits; this was not found in the control group.

    7.2.1.3  Injection route

         Friberg (1950) detected proteinuria in rabbits given
    subcutaneous injections of cadmium sulfate (0.65 mg cadmium/kg body
    weight) 6 days per week. Electrophoretic analysis of urine proteins
    revealed that the proteinuria differed from that caused by
    injections of uranium salts. More recently, many studies utilizing
    parenteral administration (with doses generally in the range of
    0.25-1.5 mg/kg body weight), different routes of exposure
    (subcutaneous and intraperitoneal), and a duration of 1-12 months
    have been performed in mice, rats, and rabbits (Table 12). These
    experiments have confirmed the nephrotoxic effects of cadmium.

         When rabbits were exposed for 16 weeks by subcutaneous
    injection of either 0.25 mg or 0.5 mg cadmium/kg body weight 3 times
    a week, there was a significant increase in urinary
    ß2-microglobulin excretion indicative of renal tubular dysfunction
    in the high-dose group after 7 weeks. There was only a slight
    increase in the serum ß2-microglobulin/creatinine ratio. Urinary
    ß2-microglobulin levels were not related to serum
    ß2-microglobulin levels (Piscator et al., 1981).

         Rats dosed intraperitoneally, five days/week with 0.6 mg
    cadmium/kg body weight, showed no abnormal effects after 5 or 6
    weeks when renal cadmium levels reached about 100 mg/kg. However, in
    renal tubular lining cells an increase in lysosomes, microbodies,
    and smooth endoplasmic reticulum was noted. After 8 weeks renal
    cadmium levels had reached about 200 mg/kg of tissue and tissue
    necrosis was observed. The early changes (with a renal cadmium
    concentration of up to 100 mg/kg) were considered to be adaptive and
    possibly reversible, whereas morphological changes after 8 weeks
    with a renal concentration of 200 mg/kg were considered to be
    irreversible (Goyer et al., 1984).

         Nomiyama et al. (1982a) found that non-metallothionein-bound
    cadmium increased up to about 35 mg/kg tissue in parallel with total
    cadmium. At that stage, the total cadmium concentration in the renal
    cortex was in the range 200-800 mg/kg, the total dose of cadmium
    having been approximately 1 g.

    7.2.1.4  Pathogenesis of cadmium nephrotoxicity

         Various hypotheses have been proposed to explain the
    pathogenesis of cadmium nephrotoxicity, particularly the role of the
    metal-binding protein metallothionein (see section 6.8). This
    protein is inducible by a number of essential metals (Cherian &
    Goyer, 1978) and may have as its primary function the intracellular
    storage of zinc and copper (Panemangalore et al., 1983; Templeton et
    al., 1985). It is also induced following exposure to cadmium. It is
    now thought that metallothionein protects against cadmium toxicity
    and that intracellular cadmium bound to metallothionein is nontoxic
    (Nordberg, 1971; Goyer et al., 1989). There is considerable support
    for this hypothesis. Pre-treatment of experimental animals with
    small doses of cadmium prevents the acute toxic effects of a large
    dose of cadmium (Nordberg et al., 1975). Parenteral administration
    of cadmium-metallothionein causes acute tubular toxic effects in the
    kidney (Nordberg, 1971; Nordberg et al., 1975; Cherian & Nordberg,
    1983). By treatment of animals with repeated doses of cadmium,
    metallothionein synthesis in the renal cortex can be induced. This
    prevents against subsequent renal toxicity by parenteral
    cadmium-metallothionein at dose levels that normally give rise to
    renal damage (Jin et al., 1987a). Rat renal cortical cells isolated
    from animals pretreated with cadmium were resistant to normally
    toxic concentrations of cadmium  in vitro (Jin et al., 1987b).
    Similar protective effects were observed in kidney cells pretreated
    with cadmium  in vitro (Jin et al., 1987b). Human cells in tissue
    culture, where metallothionein has been induced by pre-treatment
    with cadmium, become resistant to previously lethal exposure to
    cadmium (Glennas & Rugstad, 1984).

         With this evidence for the protective role of intracellular
    metallothionein, several theories have been proposed to explain the
    nephrotoxicity of cadmium. One hypothesis attributes the
    nephro-toxicity to that fraction of intracellular cadmium not bound
    to metallothionein (Nordberg et al., 1975; Nomiyama & Nomiyama,
    1982; Squibb et al., 1984). Another hypothesis is that
    extra-cellular cadmium bound to metallothionein is toxic (Cherian et
    al., 1976). Cadmium-metallothionein derived from cadmium-induced
    synthesis in reticulocytes (Tanaka et al., 1985) or released from
    liver cells is filtered by the renal glomeruli and reabsorbed by the
    proximal tubular lining cells where it is catabolized, releasing
    cadmium ions that cause renal damage (Dudley et al., 1985). This
    hypothesis is supported by the fact that parenterally administered
    cadmium-metallothionein is very toxic to renal tubular cells and
    that the plasma metallothionein level increases with cadmium
    exposure (Goyer et al., 1984; Shaikh & Hirayama, 1979).

         Still another hypothesis is that intracellular cadmium
    interacts with cell membranes resulting in lipid peroxidation
    (Stacey et al., 1980) and that cadmium may displace essential metals
    from metallothionein (Petering et al., 1984), thereby depriving
    important metalloenzymes of essential metal cofactors.

         These hypotheses are not mutually exclusive and the relative
    significance of each of these mechanisms may differ under particular
    circumstances of exposure.

         Goering et al. (1985) reported the development of calcuria in
    rats injected with cadmium-metallothionein, using the model
    described by Squibb et al. (1984). Jin et al. (1987a) confirmed
    their observations, which suggest that this biological effect may be
    an early event in the development of renal tubular damage. Data from
    the above studies further validate the use of the
    cadmium-metallothionein injection model for studying the mechanisms
    of cadmium-induced tubular injury, since calcuria is also observed
    in people with chronic elevated cadmium exposure.

    7.2.1.5  General features of renal effects; dose-effect and
             dose-response relationships

         The available data show that long-term exposure to cadmium
    leads to renal tubular lesions with proteinuria, glucosuria, and
    aminoaciduria, and to histopathological changes (Table 12).

         It has been reported that cadmium-induced proteinuria differs
    from glomerular proteinuria (Friberg, 1950) and involves low
    molecular weight proteins in particular (Axelsson & Piscator, 1966a;
    Nomiyama et al., 1982b). Thus, this type of proteinuria resembles
    the "tubular proteinuria" seen in humans. Microscopic examination
    reveals typical tubular nephropathy, i.e. atrophy and degeneration
    of tubular cells, especially proximal tubular cells, and
    interstitial fibrosis (Bonnell et al., 1960; Axelsson et al., 1968;
    Kawai et al., 1976).

         Electron microscopic changes are characterized by interstitial
    fibrosis and thickening of the basement membrane of the proximal
    tubular cells (Kawai et al., 1976). The smooth endoplasmic reticulum
    is dilated or undergoes proliferation, and there is apical cyst
    formation (Stowe et al., 1972). An increase in the number of
    lysosomes and swelling of the mitochondria have also been observed.
    In addition to tubular findings, there have been reports of
    pathological changes in 30% of the mesangium cells of the glomeruli
    of dogs (Murase et al., 1974) and increased thickness of the
    glomerular basement membrane in rats (Scott et al., 1977).

         Investigations into renal function have also revealed
    substantial changes, mainly in tubular function, e.g., reabsorption
    of glucose (Axelsson & Piscator, 1966a), whereas the changes in
    glomerular filtration are relatively small (Axelsson & Piscator,
    1966a). Effects have generally been seen at average renal cortex
    concentrations of 200-300 mg/kg wet weight, but some studies have
    reported effects at considerably lower concentrations.
    Histopathological changes in rats, rabbits, horses, and birds have
    been reported at renal cortex concentrations below 100 mg/kg (Table
    12). However, in chronically exposed monkeys, signs of renal tubular
    changes were reported at around 400-1200 mg cadmium/kg (Table 13).

         After renal cortex concentrations of cadmium have reached a
    level of 200-300 mg/kg wet weight, they level off or decrease. No
    further increase is seen even with continued exposure (Axelsson &
    Piscator, 1966a; Nomiyama & Nomiyama, 1976a; Bernard et al., 1981).
    It has also been shown (Friberg, 1952; Axelsson & Piscator, 1966a;
    Nordberg & Piscator, 1972; Nomiyama & Nomiyama, 1976a) that urinary
    excretion of cadmium is low during the initial exposure period but a
    marked increase in the excretion of cadmium occurs subsequently,
    which coincides with an increase in protein excretion (Friberg,
    1952; Axelsson & Piscator, 1966a; Nordberg & Piscator, 1972)
    (section 6).

         Animal studies have shown that, as the cadmium concentration in
    the renal cortex increases, the first effects to appear are the
    histopathological changes in the renal tubular cells. The low
    molecular weight proteinuria and aminoaciduria develop at somewhat
    higher cadmium concentrations in the renal cortex and, at even
    higher concentrations, glucosuria, total proteinuria, and other
    indications of damaged renal function develop. The diagnosis of
    these effects depends greatly on the sensitivity of the method for
    analysing the effect. For instance, a method for analysing low
    molecular weight proteinuria that can accurately measure levels
    considered normal (0.1 mg/litre or less) will be able to diagnose
    proteinuria at an earlier stage than a method with a detection limit
    of 7 mg/litre.

         Most of the studies referred to in Table 12 included no data on
    the prevalence of renal effects in the animals. The results were
    given in a qualitative way, stating the average cadmium level in the
    renal cortex at which effects were seen.

         Some dose-response data are available from animal studies.
    Bernard et al. (1981) produced proteinuria in rats exposed to
    cadmium in drinking-water (200 mg/litre) for up to 11 months. After
    8-9 months, a significant increase in group-average proteinuria was
    seen, coinciding with a 25% prevalence of increased individual
    proteinuria. The renal cortex cadmium concentration at that time was

    about 200 mg cadmium/kg (Bernard et al., 1981). Elinder et al.
    (1981a) studied horses exposed to cadmium present in their normal
    food. Histopathological changes in the renal cortex were classified
    and coded in a blind manner, and the prevalence of different degrees
    of change was calculated for subgroups of horses with different
    renal cortex cadmium concentrations. The "background" prevalence was
    25-30% and there was an increased prevalence (up to 60-75%) with
    increased average renal cadmium level. At a renal cortex cadmium
    concentration of about 75 mg/kg, there was a significant increase in
    the prevalence of histopathological changes.

    7.2.2  Effects on the liver

         Friberg (1950) demonstrated fibrotic changes in the liver of
    rabbits exposed to repeated subcutaneous injections of cadmium.
    Periportal and interlobular collagen deposition was found in the
    liver of rabbits given 160 mg cadmium/litre in drinking-water for 6
    months (Stowe et al., 1972). Liver function tests, however, remained
    within normal limits. The cadmium concentration in the liver was
    188 mg/kg wet weight. Tarasenko et al. (1974) demonstrated by
    histological techniques that dystrophic changes occur in the liver
    of rats after repeated intragastric administration of cadmium
    caprylate in a total dose corresponding to 47 mg cadmium/kg body
    weight per day. These authors also noted an increased level of
    lactic acid in the blood serum of the animals. Larionova et al.
    (1974) detected decreased activity of alanine transaminase in liver
    tissue and depletion of glycogen in rats given barium cadmium
    laurate by gavage for 8-10 days at a dosage of 169 mg/kg body weight
    per day (as the laurate). After intraperitoneal injection of cadmium
    (up to 1.25 mg/kg body weight for periods of up to 6 weeks),
    decreased glycogen content and increased daily activity of
    gluconeogenic enzymes in rat liver were reported by Merali et al.
    (1974) and Chapatwala et al. (1982).

         In long-term studies, rabbits given 300 mg cadmium/kg diet for
    54 weeks (Kawai et al. 1976) showed some amyloid deposition in the
    liver. Studies on rats after exposure for 335 days to 1 mg
    cadmium/litre in drinking-water (Sporn et al., 1970) revealed
    changes in liver enzyme activities. Rhesus monkeys exposed to 300 mg
    cadmium/kg in the diet for 12 weeks (Nomiyama et al., 1979)
    developed increased levels of plasma enzymes (GOT, GPT, and LDH).

    7.2.3  Effects on the respiratory system

         Interstitial pneumonitis and emphysema were found in rabbits
    exposed to cadmium iron oxide dust (approximately 8 mg/m3) for 4-8
    months (Friberg, 1950) and in rats observed for 4-7 months after a
    single intratracheal administration of cadmium iron oxide dust

    (3.5 mg/kg body weight) (Vorobjeva, 1957). However, only very slight
    pulmonary effects were detected in rabbits and rats exposed to
    nickel-graphite dust at dose levels several times higher than the
    concentrations of cadmium iron oxide dust.

         Yoshikawa et al. (1975) exposed rats to cadmium oxide fumes
    (0.1 or 1.0 mg cadmium/m3) for up to 3 months. There were 10 rats
    in each group, and three of the rats in the high exposure group died
    after about 7 weeks. Lung fibrosis and the first stage of emphysema
    were observed at the end of the experiment in the high-dose group.
    Free macrophage cells in the alveoli were more numerous in both
    groups, and there was an increased surface tension of the
    surfactants.

         Snider et al. (1973) observed signs of emphysema in rats 10
    days after 5-15 daily 1-h periods of exposure to cadmium chloride
    aerosol (10 mg/m3). Also, long-term exposure to comparatively low
    air concentrations of cadmium oxide (24-50 µg cadmium/m3) gave
    rise to pathological changes in the lungs similar to emphysema as
    well as to cell proliferation in the bronchi (Prigge, 1978). A
    long-term study (14 months), in which mice and golden hamsters were
    exposed to different concentrations of cadmium chloride (30 and
    90 µg/m3), cadmium sulfate (30 and 90 µg/m3), cadmium sulfide
    aerosols (90-100 µg/m3), cadmium oxide fume (10-90 µg/m3), and
    dust (10-270 µg/m3), revealed a significantly increased incidence
    of alveolar hyperplasia and interstitial fibrosis in most of the
    exposed groups (Heinrich et al., 1989).

         Single intratracheal administration of several cadmium
    compounds (e.g., oxide, sulfide, carbonate, sulfoselenide,
    caprylate, stearate, cadmium-barium laurate, and cadmium-barium
    stearate) in doses from 0.5 mg (as the oxide) to 15 mg (as the
    sulfide) caused the development, over 6 months, of chronic
    inflammatory changes, emphysema, and atelectasis leading to
    fibrosis. Exposure to cadmium oxide and caprylate gave rise to the
    development of nodules of hyaline connective tissue; these resembled
    silicotic nodules (Vorobjeva & Sabalina, 1975).

    7.2.4  Effects on bones and calcium metabolism

         Male rats fed a normal diet and exposed to cadmium sulfate by
    inhalation (3 and 0.3 mg/m3, 4 h daily for 4 months) showed
    decreased serum and urinary calcium concentrations compare to
    controls. Female rats similarly exposed to cadmium sulfate
    (2.8 mg/m3, 3 h/week) during pregnancy showed radiological
    evidence of osteoporosis in addition to hypocalcaemia (Tarasenko et
    al., 1975).

         In a study by Kogan et al. (1972), cadmium chloride and cadmium
    sulfate were administered subcutaneously to rats at a daily dose of
    1 mg/kg body weight for up to 12 months. At 12 months, X-ray
    analysis of the bones indicated osteoporosis and osteosclerosis.
    Subsequent histopathology showed an increase in osteoclasts and a
    bone structure described by the authors to be indicative of
    osteomalacia.

         Oral administration of cadmium chloride in drinking-water to
    male rats (1 or 4 µg/kg body weight daily for six months) resulted
    in changes in calcium metabolism and bone structure characteristic
    of osteomalacia, which were not observed in the control group. No
    effects were noted in a group of animals given a daily dose of
    0.01 µg/kg body weight (Likutova & Belova, 1987).

         Rats given 50 mg cadmium/litre in drinking-water for about 9
    months showed reduced calcium and phosphorus absorption from the
    intestine (Sugawara & Sugawara, 1974). In addition, some of the
    animals showed histological changes in the duodenal mucosa, a
    finding also reported in Japanese quail (Richardson & Fox, 1974).

         Several mineral balance studies have been made on animals fed
    cadmium. Simultaneous administration of cadmium with a low-protein,
    low-calcium diet led to a decrease in the calcium and zinc content
    of bone (Itokawa et al., 1973). Furthermore, Kobayashi (1974)
    reported that cadmium feeding led to a negative calcium balance in
    rats.

         The decreased calcium absorption and negative calcium balance
    in cadmium-exposed rats could result from the inhibitory effects of
    cadmium on the activation of vitamin D in renal cortical cells
    (Feldman & Cousins, 1973). The renal conversion of
    25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol has been
    found to be inhibited by high dietary cadmium exposure in rats fed a
    normal calcium diet, but this effect was not seen on a low-calcium
    diet (Lorentzon & Larsson, 1977). The metabolically active form of
    vitamin D (1,25-dihydroxycholecalciferol) is necessary for the
    normal absorption of calcium from the intestine. Ando et al. (1981)
    found that the stimulation of calcium absorption by 1-alpha-hydroxy
    vitamin D3 was inhibited in rats exposed to cadmium by gastric
    intubation. Furthermore, the concentration of calcium-binding
    protein in intestinal mucosa may be decreased by cadmium exposure
    (Fullmer et al., 1980).

         Administration of drinking-water containing 10 mg cadmium per
    litre to rats fed a normal diet over a 9-month period gave rise to
    decalcification and cortical atrophy in the skeleton (Kawai et al.,
    1976). Other workers have also reported effects in the bones of rats
    following several months exposure to cadmium in drinking-water

    (Itokawa et al., 1974; Kawamura et al., 1978) and in the diet
    (Takashima et al., 1980; Nogawa et al., 1981a), and following
    subcutaneous injection (Nogawa et al., 1981a). In these studies, the
    bones were reported to show more or less severe osteoporosis and
    osteomalacia. On the other hand, Kajikawa et al. (1981) did not find
    either osteoporosis or osteomalacia after rats were exposed for 2
    years to cadmium in drinking-water (200 mg/litre).

         Anderson & Danylchuk (1979) found that exposure of Beagle dogs
    for six months to cadmium (25 mg/litre in drinking-water) reduced
    bone turnover rate, a metabolic abnormality consistent with calcium
    deficiency or osteomalacia. Kawashima et al. (1988) found that
    feeding a cadmium-contaminated rice diet or a diet containing 3 mg
    cadmium chloride/kg for six years to crab-eating monkeys did not
    produce any change in vitamin D metabolism, and there was no
    evidence of renal dysfunction. In another series of experiments
    rhesus monkeys were fed diets containing 3, 10, 30 or 100 mg
    cadmium/kg for 9 years. Serum vitamin D metabolites and renal
    production of vitamin D remained unchanged, but in animals fed 30 or
    100 mg cadmium/kg of diet there was slight but not statistically
    significant depression of renal 25-hydroxy vitamin D1-hydroxylase
    activity. No skeletal abnormalities were found in any of these
    animals.

         Bhattacharyya et al. (1988) studied the effects of 0, 0.25, 5
    or 50 mg cadmium/kg diets on female mice bred for six consecutive
    42-day cycles of pregnancy and lactation and on non-pregnant
    controls. The multiparous mice exposed to 50 mg/kg experienced
    significant decreases in body weight (3-11%) and femur calcium
    content (15-27%), and the femur calcium to dry weight ratios
    decreased by 5-7%. These results were thought by the authors to
    provide evidence that the combination of cadmium exposure and
    multiparity has a synergic effect on bone metabolism.

         In the Japanese monkey study III (section 7.2.1 and Table 14),
    osteomalacic changes were found in the low-nutrition plus
    low-vitamin-D diet group (group 4) after 77 weeks. These effects
    were not further exacerbated by feeding cadmium (group 8). These
    changes were found to be reversed by the administration of vitamin
    D. Renal effects were found in group 8 after 154 weeks. Therefore,
    the osteomalacia found in group 8 was diagnosed as not being renal
    osteomalacia.

         Most of the findings discussed above indicate a direct effect
    of cadmium on bone mineralization, possibly related to calcium
    deficiency, and an indirect effect on calcium absorption via vitamin
    D hydroxylation, perhaps leading to osteomalacia. The direct effects
    develop after long-term cadmium exposure, whereas the indirect
    effect on vitamin D metabolism occurs only when renal damage is seen
    in the animals. Osteomalacia only occurred in monkeys fed a diet low
    in protein, phosphorus, calcium, and vitamin D. Cadmium
    administration did not increase these effects.

    7.2.5  Effects on haematopoiesis

         Anaemia is a common finding in animals after both dietary
    (Wilson et al., 1941) and parenteral (Friberg, 1950) exposure to
    cadmium. After dietary exposure, decreased haemoglobin concentration
    (Decker et al., 1958) and decreased haematocrit (PCV) (Prigge et
    al., 1977) are among the early signs of cadmium toxicity.

         Fox & Fry (1970) and Fox et al. (1971) reported that the
    cadmium-induced anaemia could be prevented by simultaneous feeding
    with iron or ascorbic acid. Decreased gastrointestinal absorption of
    iron due to cadmium may be one mechanism for this anaemia.

         After parenteral exposure, iron administration has a beneficial
    effect on the anaemia (Friberg, 1955). Berlin & Friberg (1960)
    showed that cadmium injections caused erythrocyte destruction, but
    there was no indication of an interference with haemoglobin
    production. Haemolytic anaemia in rabbits was also reported by
    Axelsson & Piscator (1966b).

    7.2.6  Effects on blood pressure and the cardiovascular system

         Chronic oral administration of cadmium compounds to rats (Perry
    & Erlanger, 1974) induced statistically significant elevation of
    blood pressure. However, the systolic pressure changes were much
    smaller than those previously reported by Schroeder & Vinton (1962)
    and by Schroeder (1964). Furthermore, a different effect was
    obtained with lower, as compared with higher, doses of cadmium. Rats
    given 1, 2.5, or 5 mg cadmium/litre in drinking-water for one year
    had significantly higher blood pressure values than controls. Six
    months after the beginning of exposure, a statistically significant
    increase in blood pressure was also observed in rats given 10 or
    25 mg/litre, but the increase was not statistically significant
    after one year of exposure. In rats receiving 50 mg/litre, a
    statistically significant increase in systolic blood pressure was
    observed after 12 months of exposure. As discussed in section 8.2.4,
    these results may be of basic importance in evaluating data on the
    possible effects of cadmium on the human cardiovascular system.

         Several mechanisms have been postulated (Perry & Erlanger,
    1974) to explain the effects of chronic cadmium exposure on the
    cardiovascular system. Oral adminstration of cadmium doses that
    induce hypertension (and also parenteral administration of cadmium)
    was shown to increase circulatory renin activity (Perry & Erlanger,
    1973). Injection of cadmium into the renal artery of dogs increased
    sodium reabsorption by the exposed kidney (Vander, 1962), and
    repeated intramuscular (Perry et al., 1971) or chronic oral
    administration of cadmium (Lener & Musil, 1971) was reported to
    increase sodium retention in the body. By morpho-metric methods,
    Fowler et al. (1975) demonstrated effects on the renal blood vessels
    of rats exposed to various concentrations of cadmium (up to
    200 mg/litre in drinking-water) for several weeks. Significantly
    smaller arteriolar diameters were found in the exposed animals than
    in the controls.

         Perry et al. (1977) studied the influence of exposure duration
    (from 3 to 24 months) and cadmium dose levels in water (from 0.1 to
    10 mg/litre) on the blood pressure of Long-Evans rats. A small
    increase in blood pressure occurred even at the lowest exposure
    level after 3 months exposure. The greatest increase in blood
    pressure (3.2 kPa; 24 mmHg) occurred after 24 months exposure to
    1 mg/litre, when the average renal cortex cadmium level was 12 mg/kg
    wet weight. At higher dose levels, the blood pressure increase was
    less and, at the highest dosage (10 mg/litre for 24 months), the
    blood pressure did in fact decrease.

         Perry et al. (1976) found hypertensive effects in
    Sprague-Dawley as well as Long-Evans rats. Petering et al. (1979)
    reported that male rats were more susceptible to these effects than
    female rats after exposure via drinking-water, but Ohanian & Iwai
    (1980) found the opposite for rats exposed parenterally. In several
    studies (e.g., Kotsonis & Klaassen, 1977; Whanger, 1979; Fingerle et
    al., 1982), there was no increase in blood pressure after various
    cadmium doses were given via drinking-water. The type of diet
    appears to be crucial for the development of hypertension (Whanger,
    1979); it can usually only be produced in rats fed a rye-based diet
    (Perry & Erlanger, 1982). Nishiyama et al. (1986) postulated that
    cadmium exposure increases sodium and water retention, which are
    important factors controlling the development of hypertension.

         A detailed review of factors influencing the effects of cadmium
    on the cardiovascular system was reported by the Task Group on Metal
    Toxicity (1976), with particular reference to those factors that
    might modify the dose-effect and dose-response relationships.

         Rats exposed to cadmium (5 mg/litre) in drinking-water (Kopp et
    al., 1980a,b, 1983) developed electrocardiographic and biochemical
    changes in the myocardium, and impairment of the functional status
    of the myocardium. These effects could be related to (i) decreased
    high-energy phosphate storage in the myocardium, (ii) reduced
    myocardial contractility, or (iii) diminished excitability of the
    cardiac conduction system. Jamall & Sprowls (1987) found that rats
    fed a diet supplemented with copper (50 mg/kg), selenium
    (0.5 mg/kg), and cadmium (50 mg/kg) had marked reductions in heart
    cytosolic glutathione peroxidase, superoxide desmutase, and
    catalase. They suggested that heart mitochondria are the site of the
    cadmium-induced biochemical lesion in the myocardium.

         Reviews of all aspects of the cardiovascular effects of cadmium
    on experimental animals have been reported by Perry & Kopp (1983)
    and Jamall & Smith (1986).

    7.2.7  Effects on reproductive organs

         Cadmium-induced testicular necrosis (section 7.1.2.1) generally
    results in permanent infertility (Barlow & Sullivan, 1982). Ramaya &
    Pomerantzeva (1977) found markedly reduced testis weights 1, 3, and
    6 months after mice were administered 4 mg cadmium/kg. The animals
    were sterile and microscopic examination revealed morphological
    changes in the testis. Krasovskii et al. (1976) noticed decreased
    spermatozoa motility and spermatogenesis index in rats continuously
    exposed via food to 0.5-5.0 mg cadmium/kg body weight. In male mice
    exposed repeatedly by daily subcutaneous injection of cadmium
    chloride (0.5 mg/kg per day) for 6 months (Nordberg, 1975), there
    was a decrease in normal testosterone-dependent proteinuria.
    Morphological examination of the seminal vesicles revealed a smaller
    weight and size as well as histological indications of lower
    secretory activity, this being consistent with decreased
    testosterone activity in these animals.

    7.2.8  Other effects

         Effects on the immune system have been reported after both
    chronic and acute cadmium exposure. A decrease in the number of
    antibody-forming cells in the spleen as well as a decrease in
    antibody production was seen in mice after long-term exposure to
    cadmium in drinking-water (Koller et al., 1975). An inhibition of
    the cell-mediated immune response occurred in mice after repeated
    intraperitoneal injections (Bozelka & Burkholder, 1982). However, no
    data are available linking these effects to increased susceptibility
    to infection or other secondary dysfunctions.

         Gestational exposure to cadmium (4.2 and 8.4 µg/ml in
    drinking-water) results in decreased birth weight, retarded growth,
    delayed development of the sensory motor coordination reflexes, and
    increased motor activity. Cadmium exposure during critical periods
    of development might result in developmental and behavioural
    deficits with long-term implications for adult behaviour (Mohd et
    al., 1986).

    7.3   Fetal toxicity and teratogenicity

         In several species of laboratory rodents, large doses of
    cadmium salts induce severe placental damage and fetal deaths when
    given at a late stage of pregnancy, and teratogenic effects, such as
    exencephaly, hydrocephaly, cleft lips and palate, microphthalmia,
    micrognathia, clubfoot, and dysplastic tail, when given at early
    stages of gestation.

         A single subcutaneous injection of cadmium chloride, acetate,
    or lactate (4.5 mg cadmium/kg body weight) given to Wistar rats from
    the 17th to the 21st day of pregnancy (Parizek, 1964) led to the
    rapid development of severe placental damage in all rats and to
    fetal death. Placental damage was not dependent on the presence of
    fetuses, but it was not possible to decide whether fetal lethality
    resulted from the placental lesion or from a direct effect of
    cadmium on the fetuses (Parizek, 1964). Similar effects were
    observed at a dose level of 3.3 mg cadmium/kg body weight (Parizek
    et al., 1968b). Placental damage and fetal deaths were also observed
    after cadmium administration to pregnant Swiss albino mice
    (Chiquoine, 1965).

         Teratogenic effects can be observed when doses close to the
    LD50 (Table 11) for cadmium salts are administered to pregnant
    females at critical stages of embryogenesis. These effects were
    demonstrated with intravenous injections of cadmium sulfate in
    hamsters (Ferm & Carpenter, 1968; Mulvihill et al., 1970; Ferm,
    1972) and with intraperitoneal (Barr, 1973), subcutaneous (Chernoff,
    1973), or dietary (Scharpf et al., 1972) administration of cadmium
    chloride in rats. Teratogenic effects induced by cadmium salts have
    also been demonstrated in mice (Ishizu et al., 1973).

         The character of the changes induced is dependent on the
    species and on the stage of embryogenesis. As little as 123 µg/litre
    in mouse embryo cultures produced exencephaly apparently by
    re-opening the closed neural tube (Schmid et al., 1985). Either
    facial defects or limb abnormalities were induced by cadmium when
    administered to pregnant hamsters on day 8 or 9 of gestation (Ferm,
    1971). Both jaw defects and cleft palate were observed in the
    offspring of rats given daily subcutaneous cadmium chloride

    injections (8 mg/kg body weight) on days 13-16 or 14-17 of
    pregnancy, but cleft palate was not observed when this dosage was
    given on days 15-18 or 16-19 of pregnancy (Chernoff, 1973).
    Anophthalmia or microphthalmia and dysplastic ears were induced by
    approximately 2 mg of cadmium as the chloride given
    intra-peritoneally to pregnant rats on the 9th but not on the 11th
    day of pregnancy (Barr, 1973). Other effects observed in these
    studies included decreased lung weight in the offspring of rats
    subjected to cadmium during pregnancy (Chernoff, 1973) and
    deficiencies in bone formation and delays in bone ossification
    (Mulvihill et al., 1970; Scharpf et al., 1972).

         The dose-dependent fetal mortality and teratogenicity response
    was established in studies with subcutaneous administration of
    cadmium chloride to rats (Chernoff, 1973) and mice (Ishizu et al.,
    1973). The no-observed-effect level with respect to malformations
    was found in the latter study to be 0.33 mg/kg body weight.

         All the teratogenic effects mentioned above were induced by
    parenteral administration of very high doses of cadmium salts.
    However, in a rat study by Scharpf et al. (1972), very high peroral
    doses (20, 40, 60, or 80 mg/kg body weight given by gavage daily
    from days 6 to 19 of pregnancy) of cadmium chloride were used with
    the simultaneous administration of sodium chloride, and internal
    teratological examinations were performed. Heart and kidney
    abnormalities were the major internal defects, but their incidence
    was not directly related to the dose of cadmium chloride
    administered. At the lowest dose level, heart abnormalities were
    detected in 19.7% of the 127 fetuses (abnormalities in the control
    group were seen in 6.6% of 107 fetuses) and teratoma of the kidney
    was observed in 15.7% of these fetuses.

         Cvetkova (1970) exposed pregnant female rats via the
    respiratory route to cadmium sulfate (2.8 mg/m3, 4 h daily) and,
    on the 22nd day, killed half of them to examine the embryos. The
    number of embryos in exposed rats was the same as in a control
    group, but the mean weight was lower in the exposed group. In the
    exposed rats, where pregnancies were allowed to proceed to full
    term, the average weight of the offspring was lower than in the
    controls both at birth and after 8 months. The rats born to the
    exposed group also had increased mortality during the first 10 days
    after birth.

         When mice were exposed for several generations to cadmium in
    drinking-water (10 mg/litre), fetal mortality, runting, and
    malformations were observed (Schroeder & Mitchener, 1971). The
    external malformations, consisting of sharp angulation of the distal
    third of the tail, were observed in 16.1% of 255 offspring (F1 and
    F2A generation), and 87 deaths before weaning (30.5%) were
    recorded.

         Ferm & Carpenter (1968) showed that zinc injected
    simultaneously with cadmium could protect against the teratogenic
    effects of cadmium, and a similar protective action was found for
    selenium (Holmberg & Ferm, 1969). Maternal zinc deficiency can
    produce congenital malformations (Hurley et al., 1971). This was
    confirmed by Parzyck et al. (1978), who also found that
    intraperitoneal injection of 1.5 mg cadmium/kg body weight to
    pregnant rats increased the prevalence of malformations. The
    increase was greater at this cadmium dose than the increase due to
    zinc deficiency. Combined zinc deficiency and cadmium exposure
    caused a very high incidence of fetal deaths.

         Further experimental data on rats provided by Samarawickrama &
    Webb (1979) indicate that maternal cadmium exposure gives rise to a
    fetal zinc deficiency and that this is one cause of the teratogenic
    effects observed. Intravenous cadmium injections to pregnant rats at
    doses ranging from 0.25 to 1.25 mg/kg body weight on day 12 of
    gestation produced a dose-related decrease in fetal uptake of a dose
    of 65 mg zinc given 4 h later. Maternal cadmium exposure (1.25 mg/kg
    body weight) was shown to result in decreased activity of a fetal
    zinc-dependent enzyme thymidine kinase, which is responsible for the
    incorporation of thymidine in DNA. Additional evidence that
    cadmium-induced fetotoxicity is related to a cadmium-induced fetal
    zinc deficiency was reported by Daston (1982), who found that
    co-administration of zinc (12 mg/kg body weight) almost totally
    eliminated severe fetal lung lesions when pregnant rats were given
    cadmium (8 mg/kg body weight) on gestation days 12-15.

    7.4  Mutagenicity

         Studies on Drosophila (Ramel & Friberg, 1971; Vorobjeva &
    Sabalina, 1975) failed to show any chromosomal abnormalities after
    exposure to various cadmium compounds. Some  in vitro studies of
    cultured human lymphocytes and fibroblasts were also negative (Paton
    & Allison, 1972; Deknudt & Deminatti, 1978; Kogan et al., 1978).
    Shiraishi et al. (1972) reported a marked increase in the frequency
    of chromatid breaks, translocations, and dicentric chromosomes in
    leucocytes, from one person, cultured in a medium containing 62 mg
    cadmium/litre (as the sulfate) for 4-8 h.

         Andersen et al. (1983) found that the average chromosome length
    in human lymphocytes was initially reduced when they were cultured
    in a medium containing cadmium chloride (1.1 mg cadmium/litre), but
    subsequently returned to normal. This effect was probably related to
    the synthesis of metallothionein and complexing with cadmium.
    Watanabe et al. (1979) observed aneuploidy in rat oocytes with
    cadmium accumulation in the ovary after exposure to cadmium chloride
     in vivo.

         Rohr & Bauchinger (1976) found a reduced mitotic index in
    hamster fibroblasts cultured in 100 µg cadmium/litre (as the
    sulfate) and chromosome damage at concentrations above 500 µg
    cadmium/litre. Deaven & Campbell (1980) showed that the effects on
    cultured hamster cells depended on the type of medium used.

         There appears to be an acute effect of cadmium following the
    injection of 0.6-2.8 mg cadmium/kg body weight (Felten, 1979). After
    6 h, there was an increased frequency of chromatid breaks in bone
    marrow cells and chromosome gaps and breaks in spermatocytes, which
    could be associated with the acute effects on haematopoiesis
    (section 7.2.5) and on the testis (section 7.1.2.1).

         A summary and graphical presentation of the available evidence
    on genetic and related effects of cadmium in various  in vivo and
     in vitro test systems has been presented by IARC (1987a). Although
    prokaryote test systems reveal no effects, variable results have
    been observed in lower eukaryotes, mammalian cells in vitro, and
    mammals  in vivo.

    7.5  Carcinogenicity

         Intramuscular or subcutaneous administration of metallic
    cadmium or cadmium compounds can induce sarcomata at the site of
    injection. This local effect of cadmium was demonstrated with
    intramuscular administration of metallic cadmium (cadmium powder in
    fowl serum) to hooded rats (Heath et al., 1962), subcutaneous
    administration to Chester Beatty rats of cadmium as the sulfide and
    oxide (Kazantzis, 1963; Kazantzis & Hanbury, 1966) or sulfate
    (Haddow et al., 1964), intramuscular injection of cadmium chloride
    to Wistar rats (Gunn et al., 1967), and subcutaneous injection to
    Sprague-Dawley rats (Nazari et al., 1967). Transplantability of
    tumours induced in these studies (Heath & Webb, 1967) and metastases
    into regional lymph nodes and into lungs (Kazantzis & Hanbury, 1966)
    were reported. Intratesticular injection of cadmium chloride to
    White Leghorn cockerels was reported to induce teratoma at the site
    of injection (Guthrie, 1964).

         After Hoffman et al. (1985) injected 1.9 mg cadmium chloride
    (1.2 mg/kg body weight) directly into the ventral prostatic lobe of
    100 12-month-old male rats, simple hyperplasia was found in 38 of
    the rats, atypical hyperplasia in 29, atypical hyperplasia with
    severe dysplasia in 11, and invasive prostatic cancer in 5 animals.
    Hoffman et al. (1988) reported changes in the ultrastructure of
    prostate epithelial cells in rats injected into the ventral prostate
    with 2.2 or 3.3 mg cadmium/kg body weight. In animals given oral
    treatment via the drinking-water (29.9 or 115 mg cadmium/kg body
    weight), there were changes ranging in severity up to dysplasia but
    no evidence of carcinoma.

         A single parenteral administration of cadmium salts can induce
    necrosis of the testis (see section 7.1.2.1). After one year, the
    remnants of the necrotic testis were shown to contain masses of
    cells showing the typical structure of Leydig cells (Parizek, 1960).
    This regeneration of testicular Leydig cells damaged by cadmium can
    result in Leydig cell neoplasia (Gunn et al., 1963, 1965; Lucis et
    al., 1972). The ultrastructural features of cadmium-induced Leydig
    cell tumours correspond in most respects with the fine structural
    features of normal Leydig cells (Reddy et al., 1973).

         Other injection studies and peroral studies did not demonstrate
    increased malignancy (Schroeder et al., 1964, 1965; Loser, 1980),
    but the doses were low compared to those necessary to induce renal
    damage. In one peroral study (Kanisawa & Schroeder, 1969), rats were
    exposed to 5 mg cadmium/litre in drinking-water for up to 2 years.
    There were 7 malignant tumours among 47 cadmium-exposed male rats
    and 2 tumours among 34 male control rats. This indicates a doubling
    of the tumour rate, but because of the low statistical power of the
    study, the increase was not statistically significant and the
    authors concluded that ingestion of these cadmium doses was not
    carcinogenic.

         Some studies have been specially designed to investigate the
    possible role of cadmium in cancer of the prostate. The prostate
    gland, like the testis, is of particular interest with respect to
    cadmium toxicity because these organs contain greater concentrations
    of zinc than any other tissues and it has been suggested that
    cadmium may affect prostate growth by competition with zinc (Gunn et
    al., 1961). Levy et al. (1973) gave three groups of rats weekly
    subcutaneous injections of cadmium sulfate at concentrations of
    0.022, 0.044 or 0.087 mg cadmium per rat (average weight 220 g at
    the start and 410 g at the end of the 2-year exposure). Weekly
    injections of water were given to the 75 control rats. The liver
    cadmium level was 80 mg/kg in the highest-dose group, but no
    malignant changes were found in the prostate. No difference was seen
    between exposed and control rats with respect to malignant changes
    in other organs.

         Levy & Clack (1975) and Levy et al. (1975) conducted 2-year
    studies in rats and mice designed to detect carcinogenic effects in
    the prostate. The animals in both experiments were given weekly
    administrations of cadmium sulfate by stomach tube. The rats were
    given from 0.08 to 0.35 mg/kg body weight and the mice 0.44 to
    1.75 mg/kg. Extremely low levels of cadmium were found in the kidney
    after 2 years (5 mg/kg wet weight in rats), but no macroscopic or
    microscopic changes were seen in any tissue at these low doses.

         In a long-term study on Fisher rats, Sanders & Mahaffey (1984)
    administered cadmium oxide (25 µg) in single or repeated doses by
    intratracheal instillations. There was no evidence for pulmonary or
    prostate carcinogenicity, but increases in mammary tumours and in
    tumours at multiple sites in male rats were reported.

         It has been reported that inhalation of a cadmium aerosol
    causes lung cancer in Wistar rats (Takenaka et al., 1983). Three
    groups of 40 rats were continuously exposed to cadmium chloride
    aerosols for 18 months, the air cadmium concentrations being 12.5,
    25, and 50 µg/m3. A control group of 41 rats was also studied. The
    study was terminated after 31 months, and no lung cancers were seen
    in the control group. However, in the exposed groups, the incidence
    was 15%, 53% and 71%, respectively, at increasing exposure levels.
    Even at these relatively low exposure levels, there was a clear
    dose-response relationship. Histologically the experimentally
    induced tumours were adenocarcinomas, epidermoid carcinomas,
    mucoepidermoid carcinomas, and combined epidermoid and
    adenocarcinomas.

         In a subsequent study, rats were exposed to inhalable aerosols
    of cadmium sulfate and cadmium oxide and fume and dust at > 30 µg
    cadmium/m3 and to cadmium sulfide at > 90 µg cadmium per m3 for
    periods of up to 18 months. Bronchoalveolar benign and malignant
    adenomas, squamous cell carcinomas, and combined forms developed at
    high primary tumour rates with all four forms of cadmium tested even
    after discontinuous exposure for 40 h/week for 6 months. No primary
    tumour was found with cadmium oxide fume at a concentration of 10 µg
    cadmium/m3 or cadmium oxide dust (at 30 µg cadmium/m3) when
    combined with a zinc oxide aerosol (Oldiges et al., 1989).

         In a further study, male and female Syrian golden hamsters and
    female NMRT mice were exposed to cadmium chloride, sulfate, oxide,
    and sulfide at concentrations of between 10 and 270 µg cadmium/m3.
    The exposure was continuous (19 h/day, 5 days/week) for 50 to 70
    weeks and was followed by a 50-week observation period. No increase
    in the lung tumour rate was observed in either the mice or hamsters
    (Heinrich et al., 1989), but in both species exposure to cadmium
    caused multifocal bronchoalveolar hyperplasia, the extent of which
    varied with the compound used, its concentration, and the length of
    exposure. The most severe changes were found after cadmium oxide
    inhalation (Aufderheide et al., 1990).

         A synergistic effect has been shown in rat renal tumours
    induced by dimethylnitrosamine when followed by cadmium chloride
    given by intramuscular injection. In this study, cadmium appeared to
    enhance the initiation of dimethylnitrosamine-induced cancer (Wade,
    1987). 

    7.6  Host and dietary factors; interactions with other trace
         elements

         The toxic effects of cadmium in experimental animals have been
    shown to be dependent on genetic factors, stage of ontogenic
    development, functional state of the organism, and simultaneous or
    previous exposure to certain environmental influences, including
    exposure to certain nutrients.

         Resistance to cadmium-induced testicular necrosis is determined
    by a single autosomal recessive gene (cdm) in inbred mice (Taylor et
    al., 1973). The teratogenic effects of cadmium are dependent on the
    stage of embryogenesis (section 6.3). The stage of postnatal
    development of certain organs may be of importance for the toxic
    effects of cadmium, as has been shown for the testis (Parizek, 1957,
    1960), ovaries (Kar et al., 1959), and central nervous system
    (Gabbiani et al., 1967).

         Pretreatment with small, non-toxic doses of cadmium salts has
    been shown to induce resistance to testicular or lethal effects
    (Terhaar et al., 1965; Ito & Sawauchi, 1966). The probable mechanism
    is induction of metallothionein synthesis by the pretreatment. This
    enables the subsequent dose of cadmium to be bound rapidly to
    metallothionein, which renders it less acutely toxic (Nordberg,
    1971). Similarly, the protective effect of zinc against cadmium
    toxicity could also be, at least in part, dependent on the induction
    of an increased synthesis of metallothionein-like proteins (Webb,
    1972; Davies et al., 1973).

         Selenium compounds are known to be highly effective in
    preventing the reproductive toxic effects of cadmium (Kar et al.,
    1960; Mason & Young, 1967; Parizek et al., 1968a,b), lethality to
    rats (Parizek et al., 1968b) and mice (Gunn et al., 1968), and
    teratogenicity (Holmberg & Ferm, 1969). Fetal lethality (Parizek et
    al., 1968b) and teratogenic effects (Holmberg & Ferm, 1969) can be
    prevented when selenium compounds are given at the same time as
    cadmium.

         Simultaneous administration of mercuric and cadmium compounds
    has been shown to have an additive effect (Gale, 1973). Oral
    administration of nitrilotriacetate with large oral doses of cadmium
    chloride provided protection against the lethality of cadmium and
    had no potentiating effect on the teratogenicity and fetal
    accumulation of cadmium (Scharpf et al., 1972). This was confirmed
    by Engström (1979), who also showed that simultaneous oral exposure
    to cadmium and sodium tripolyphosphate decreased the mortality
    expected at the cadmium level used. However, when nitrilotriacetate

    or sodium tripolyphosphate was given subcutaneously with cadmium,
    the mortality rates were increased (Engström & Nordberg, 1978;
    Andersen et al., 1982). The chelation of cadmium in the
    gastrointestinal tract decreased the uptake of cadmium, whereas
    parenteral exposure to cadmium and chelating agents caused a higher
    renal cadmium concentration than cadmium alone.

         The interaction of cadmium with certain trace elements can
    produce symptoms characteristic of trace element deficiencies. As a
    result, chronic cadmium toxicity in certain animal species closely
    resembles zinc and/or copper deficiency and can be prevented by
    administering higher doses of the salts of these trace elements
    (Petering et al., 1971, 1979; Mills & Delgarno, 1972). Cadmium-
    calcium interactions are discussed in section 7.2.4.


         An increased toxicity of cadmium was reported in animals on
    low-protein diets (Fitzhugh & Meiller, 1941), this being due partly
    to rapid intestinal absorption of cadmium (Suzuki et al., 1969).
    Lack of dietary calcium seems to play a role similar to lack of
    dietary protein in increasing the toxicity of cadmium (Suzuki et
    al., 1969). Supplements of dietary ascorbic acid almost completely
    prevented cadmium-induced anaemia and improved the growth rate (Fox
    & Fry, 1970).

         Ambient temperature (Nomiyama et al., 1978b) and the energy or
    protein level in the diet have been reported to influence the LD50
    of cadmium in mice.

         Various aspects of the interactions between cadmium and other
    trace elements were discussed in greater detail by the Task Group on
    Metal Interactions (1978).

    7.7  Conclusions

         Inhalation exposure at high levels causes lethal pulmonary
    oedema. Single high-dose injection gives rise to testicular and
    non-ovulating ovarian necrosis, liver damage, and small vessel
    injury. Large oral doses damage the gastric and intestinal mucosa.

         Long-term inhalation exposure and intratracheal administration
    give rise to chronic inflammatory changes in the lungs, fibrosis,
    and appearances suggestive of emphysema. Long-term parenteral or
    oral administration produces effects primarily on the kidneys, but
    also on the liver and the haematopoietic, immune, skeletal, and
    cardiovascular systems. Skeletal effects and hypertension have been
    induced in certain species under defined conditions. Teratogenic
    effects and placental damage occur, depending on the relation
    between the exposure and the stage of gestation, and may involve
    interactive effects with zinc.

         Of greatest relevance to human exposure are the acute
    inhalation effects on the lung and the chronic effects on the
    kidney. Following long-term exposure, the kidney is regarded as the
    critical organ. The effects on the kidney are characterized by
    tubular dysfunction and cell damage, although glomerular dysfunction
    may also occur. A consequence of renal tubular dysfunction is a
    disturbance of calcium and vitamin D metabolism. According to some
    studies, this has led to osteomalacia and/or osteoporosis, but these
    effects have not been confirmed by other studies. A direct effect of
    cadmium on bone mineralization cannot be excluded. The toxic effects
    of cadmium in experimental animals are influenced by genetic and
    nutritional factors, interactions with other metals, in particular
    zinc, and pretreatment with cadmium, which may be related to the
    induction of metallothionein.

         IARC (1976, 1987b) accepted as sufficient the evidence that
    cadmium chloride, sulfate, sulfide, and oxide can give rise to
    injection-site sarcomata in the rat and that the chloride and
    sulfate can induce interstitial cell tumours in the testis of rats
    and mice, but found oral studies inadequate for evaluation. One
    recent life-time study (18 months), in which rats were subjected to
    continuous inhalation of a cadmium chloride aerosol at low
    concentration, showed a high incidence of primary lung cancer with
    evidence of a dose-response relationship. Studies on the genotoxic
    effects of cadmium have given discordant results, most of the
    positive results indicating chromosomal effects after short-term
    high-level exposure.

    8.  EFFECTS ON HUMANS

         Most of the available epidemiological studies or group
    observations, as well as the clinical studies, have been performed
    either on occupationally exposed workers or on Japanese populations
    in cadmium-polluted areas. A great deal of epidemiological data has
    resulted from studies in polluted areas of Japan (Cooperative
    Research Committee on Itai-itai Disease, 1967; Shigematsu et al.,
    1978; Japan Cadmium Research Committee, 1989) and, more recently,
    from smaller studies in other countries (Drasch et al., 1985;
    Philipp, 1985; Hahn et al., 1987; Roels et al., 1989; Thun et al.,
    1989; Likutova, 1989). Comprehensive summaries of these studies have
    also been published (Tsuchiya, 1978; Friberg et al., 1986; Nomiyama,
    1986).

         Many of these studies have focused on the detection of early
    signs of kidney dysfunction. Others have investigated clinical signs
    of disease such as renal stones and pulmonary impairment. Until the
    middle of the 1970s, particular attention was given in Japan to the
    detection of and screening for bone disease (e.g., Itai-itai
    disease). More recently the role of cadmium in human carcinogenesis
    and mortality has also been studied.

         Exposure to cadmium produces a wide variety of effects
    involving many organs and systems. From the point of view of
    preventive medicine, the detection of early effects on the kidneys
    is of particular importance in order to prevent more serious renal
    effects and those on the lungs or bones. Recent studies indicating
    that chronic exposure to cadmium may give rise to cancer will be
    reviewed in some detail.

    8.1   Acute Effects

    8.1.1  Inhalation

         Acute cadmium poisoning and, in some cases, death have been
    reported among workers shortly after exposure to fumes when cadmium
    metal or cadmium-containing materials have been heated to high
    temperatures (Beton et al., 1966; Blejer, 1966; Dunphy, 1967). The
    principal symptom in acute cases, both fatal and non-fatal, is
    respiratory distress due to chemical pneumonitis and oedema
    (MacFarland, 1979; Lucas et al., 1980). At an early stage, the
    symptoms may be confused with those of "metal fume fever".

         In working environments where cases of acute poisoning
    occurred, cadmium concentrations were usually very high. For
    instance, in one case the fatal air concentration of cadmium oxide
    fume from a furnace was approximately 50 mg/m3 for a period of

    about 1 h (a dose of 2900 mg/m3.min) (Barrett & Card, 1947). In
    another case, the lethal dose was 2600 mg/m3.min (Beton et al.,
    1966), i.e. a 5-h exposure to 8.6 mg/m3. Friberg et al. (1974)
    estimated that an 8-h exposure to 5 mg cadmium/m3 may well be
    lethal.

    8.1.2  Ingestion

         During the period 1940-50, cases of acute food poisoning
    occurred mainly due to the substitution of cadmium for scarce
    chromium in the plating of many cooking utensils and containers.
    Food contamination arose when acid foods and drinks were prepared
    and stored in contact with cadmium-plated surfaces. Rapid onset with
    severe nausea, vomiting, and abdominal pain were characteristic
    symptoms (US Public Health Service, 1942; Cole & Baer, l944; Lufkin
    & Hodges, 1944). Effects also occurred following the consumption of
    drinks with a cadmium concentration of approximately 16 mg/litre
    from an automatic vending machine in which drinking-water was cooled
    in a tank constructed with cadmium-containing solder (Nordberg et
    al., 1973). Recovery from acute poisoning appears to be rapid and
    complete. The amount of cadmium absorbed is probably very limited
    due to vomiting and the consequential short presence of cadmium in
    the gastrointestinal tract. However, no follow-up studies of people
    who have experienced acute cadmium poisoning have been reported.

    8.2  Chronic Effects

         Lower cadmium concentrations with longer periods of exposure
    than those described above will cause chronic cadmium poisoning.
    Fully developed poisoning among industrial workers shows two main
    effects: renal dysfunction and emphysema (Friberg, 1948a,b, 1950).
    The kidney is most frequently the critical organ, but under certain
    conditions (short-term peak exposures) it may be the lung (Bonnell,
    1955). For people in the general environment, exposure is usually by
    the oral route and the kidney is the critical organ.

    8.2.1  Renal effects and low molecular weight proteinuria

    8.2.1.1  In industry

         Renal dysfunction is one of the characteristic signs of cadmium
    poisoning, and many cadmium workers have developed proteinuria,
    renal glucosuria, and aminoaciduria. In working environments with
    high cadmium exposure levels, workers have also developed
    hypercalciuria, phosphaturia, and polyuria (Friberg, 1950; Clarkson
    & Kench, 1956; Kazantzis et al., 1963; Tsuchiya, 1967; Lauwerys et
    al., 1974a, 1979b), and some have suffered from renal colic due to
    recurrent stone formation (Friberg, 1950; Ahlmark et al., 1961;

    Adams et al., 1969; Scott et al., 1976; Kanzantzis, 1979). The
    polyuria is due to loss of urinary concentrating ability (Kazantzis,
    1979), and, in addition, the kidneys of cadmium-poisoned workers
    lose their ability to handle an acid load after a standard
    NH4Cl-loading test. These are signs of distal tubular damage, and
    in a few severe cases, the renal damage progresses to a reduction in
    glomerular filtrations (see section 8.2.1.5).

         Renal function, as measured by inulin or creatinine clearance
    and urine concentrating capacity, was depressed in several poisoning
    cases (Friberg, 1950; Bonnell, 1955; Bernard et al., 1979). Thus, in
    the more advanced cases, there is a combination of tubular and
    glomerular effects. In most of the early cases, only proteinuria,
    mild in comparison with the proteinuria in many other renal
    disorders, has been reported as a sign of renal dysfunction, and
    other signs of kidney dysfunction were not evident (Piscator,
    1966a,b).

         Since Friberg first observed the urinary proteins of cadmium
    workers (Friberg, 1950), the proteinuria has proved to involve
    proteins with a molecular weight of 10 000 to 40 000 and is the
    so-called tubular proteinuria (Butler & Flynn, 1958). Table 15
    contains data on proteins in urine useful for the diagnosis of
    cadmium-induced proteinuria. The increased excretion of low
    molecular weight proteins in urine from cadmium-exposed workers has
    been found to apply to ß2-microglobulin, lysozyme (muramidase),
    ribonuclease, immunoglobin chains, retinol-binding protein, and
    alpha1-microglobulin (Piscator, 1966a; Peterson et al., 1969;
    Peterson & Berggård, 1971; Lauwerys et al., 1974a; Bernard et al.,
    1976, 1982b). In groups of exposed and unexposed workers, the
    urinary ß2-microglobulin concentrations follow log-normal
    distributions, and an operational definition for what is an
    "increased" level should be established for each population studied
    (Kjellström et al., 1977a).

         Proteinuria is known to be an early sign of cadmium poisoning,
    but the degree of proteinuria varies with time. In a group of 40
    workers with heavy exposure to cadmium, it was found that
    proteinuria was persistent and even increased several years after
    cessation of exposure, as evaluated by qualitative methods (Friberg
    & Nystrom, 1952; Piscator, 1966a). Tsuchiya (1976) examined five
    cadmium-exposed workers who showed proteinuria. Ten years after
    cessation of exposure, three of them no longer revealed proteinuria,
    but two of these showed a high urinary ß2-microglobulin level, as
    did the two workers with persistent total proteinuria. Four workers
    in a British pigment factory still had grossly elevated
    ß2-microglobulin levels despite removal from exposure many years
    earlier (Stewart & Hughes, 1980).


        Table 15.  Excretion of urinary proteins in healthy people and in cases of glomerular and tubular disorders
                                                                                                                                          

    Protein type      Normal plasma   Normal filtered           Urinary excretion (mg/24 h)             Reference
                      concentration   amount in primary    Healthy      Glomerular         Tubular
                      (mg/ml)         urine (mg/24 h)      people       disorders          disorders
                                                                                                                                          

    Total protein                                          43-127      310-54 100         129-1570        Peterson et al. (1969)

    Albumin               50              500              3.9-24       88-48 800         13.8-578        Mogensen & Solling (1977)

    Retinol-binding                                         0.11                           20-150         Peterson & Beggard (1971)
    protein
                                                            0.04            3                 45          Kanai et al. (1971)

    ß2-microglobulin     0.002            300             0.06-0.21     0.06-4.7           1.1-105        Peterson (1971)
                                                            0.073                                               Evrin et al. (1971)

    Lysozyme                                                0-2a                                                Prockop & Davidson (1964)
                                                          0.07-1.1a                        47-130a              Harrison et al. (1968)

    Ribonuclease                                          0.24-1.5a                        1.9-10a              Harrison et al. (1968)
                                                                                                                                          

    a    Values reported as mg/litre

    

         According to recent observations using quantitative proteinuria
    methods (Roels et al., 1982), total proteinuria in 19 workers had
    not changed 4 years after exposure ceased. In those 11 workers for
    whom urinary ß2-microglobulin was measured before and after
    cessation of exposure, an increase was invariably seen. Eight of the
    workers had abnormal ß2-microglobulin levels before exposure
    ceased, whereas three had normal levels before and developed
    abnormal levels after cessation. It can be concluded that
    cadmium-induced tubular proteinuria is irreversible in most workers,
    at least for several years.

         A marked increase in urine cadmium level may reflect
    cadmium-induced nephropathy if exposure has been chronic and
    correlates with low molecular weight proteinuria (section 6.5.1.2).
    Lauwerys et al. (1979b) proposed a biological threshold of 10 µg
    cadmium/µg urinary creatinine for males occupationally exposed to
    cadmium. Smith et al. (1980) found that workers with low exposure to
    airborne cadmium had an average urinary cadmium level of
    13.1 µg/litre, whereas workers with long histories of work in areas
    with substantial airborne cadmium had an average level of
    45.7 µg/litre. The high-exposure group showed a significant
    reduction in urinary clearance and increased ß2-microglobulin
    excretion. Buchet et al. (1980) found increased excretion of both
    low and high molecular weight proteins and tubular enzymes in
    workers excreting more than 10 µg cadmium/g creatinine or with a
    blood cadmium level above 10 µg cadmium per litre.

         Retinol binding protein (RBP) has been shown to correlate well
    with ß2-microglobulin in urine with a pH value greater than 5.5.
    and is equally sensitive for detection of tubular proteinuria
    (Bernard et al., 1982a,b). This protein occurs in serum complexed to
    prealbumin and retinol, but, after retinol is delivered to target
    cells, RBP rapidly dissociates from prealbumin, is filtered through
    the glomerulus, and is reabsorbed by the tubule (Peterson, 1971).

         Renal tubular brush border enzymes may also be excreted in
    chronic cadmium poisoning. In patients with Itai-itai disease,
    urinary trehalase activity correlates inversely with tubular
    resorption of phosphorus (Nakano et al., 1987) and there is a
    statistical correlation between urinary trehalase and other urinary
    indicators of renal tubular dysfunction, such as glucose,
    ß2-microglobulin, cadmium, and alpha-amino nitrogen, in
    inhabitants of chronic cadmium-polluted areas in Japan (Nogawa et
    al., 1980).

         Other renal effects in cadmium workers include glucosuria,
    aminoaciduria, impaired concentrating abilities, and hypercalciuria
    (Kazantzis et al., 1963; Scott et al., 1976), which may cause
    disturbances in bone and calcium metabolism (section 8.2.2). The

    hypercalciuria leads to renal stone formation in some workers
    (section 8.2.2.1). An increased excretion of amino acids,
    particularly of serine and threonine, has been shown in industrial
    workers (Clarkson & Kench, 1956), but the amino acid excretion
    pattern was not consistent. In a cadmium worker with osteomalacia
    (Kazantzis, 1979), there was an increase excretion of
    hydroxyproline, which could be an effect of changes in collagen
    metabolism related to the bone disorder (section 7.2.4).

         The renal effects of cadmium that lead to proteinuria may
    progress and, in some cases, with high exposures, lead to an
    increase in blood creatinine. This has contributed to a
    higher-than-expected mortality rate among highly exposed workers
    (Kjellström et al., l979). In a Swedish battery factory, there were
    four deaths from nephritis or nephrosis among 185 workers, all of
    whom had been exposed to cadmium for more than 15 years. The
    expected number of deaths due to these causes in this group of
    workers was 0.4 (P = 0.05) (Andersson et al., l984). In a study of
    about 6995 cadmium-exposed British workers (Armstrong & Kazantzis,
    1983), there were 10 deaths due to nephritis or nephrosis, whereas
    15.3 deaths were expected. In the subgroup with the highest exposure
    (211 workers), one death occurred (0.3 expected). A 5-year follow-up
    of this study (Kazantzis et al., 1988) confirmed no excess mortality
    from nephritis and nephrosis (ICD 580-584), the number of observed
    deaths now having increased to 16 (18.9 expected). Armstrong &
    Kazantzis (1985) conducted a case control study of this cohort in
    which a more detailed assessment of the past exposure of workers was
    obtained. There was a marginally increased, but not statistically
    significant, risk from nephritis and nephrosis (ICD 580-584) in
    workers with "ever high" or "ever medium" exposure to cadmium.

         Existing studies of mortality from nephritis/nephrosis have
    been based upon epidemiological studies of renal failure given as
    the underlying cause of death on death certificates. With the advent
    of kidney dialysis and transplantation, patients with kidney failure
    frequently survive and die of other causes. If kidney failure is
    indicated at all on their death certificates, it is frequently given
    as a contributing rather than underlying cause of death.

         No studies on the contribution of cadmium-induced renal effects
    to morbidity, absence from work, etc., have been published, although
    one study (Vorobjeva & Eremeeva, 1980) reported increased
    cardiovascular disease and related increased work absence among
    cadmium workers (section 8.2.4).

    8.2.1.2  In the general environment

         In Japanese cadmium-polluted areas, signs of renal dysfunction
    very similar to those in cadmium-exposed industrial workers have
    been found. Proteinuria and glucosuria were found to be common
    (30-80%) among the exposed people in one area (Ishizaki, 1969) and
    less common among people living in control areas and areas bordering
    a polluted area. In the exposed groups, a positive correlation
    between age and the prevalence of signs was also seen (section
    8.3.2). Due to the cumulative nature of cadmium, the total dose is
    directly correlated to age.

         With the large number of elderly people and women included in
    the groups exposed in the general environment, factors other than
    cadmium that can affect renal function may make direct comparisons
    with industrial workers difficult. Nevertheless, the tubular
    proteinuria (Shiroishi et al., 1977), aminoaciduria, and other signs
    of renal tubular damage (Saito et al., 1977; Nogawa et al. 1984)
    were very similar to the findings for industrial workers. In
    addition, as in the case of exposed workers, elevated urinary
    excretion of metallothionein occurs as a result of environmental
    cadmium exposure (Tohyama et al., 1981b).

         Among cadmium-exposed people in the general environment, the
    mean urine ß2-microglobulin excretion was highest (Shiroishi et
    al., 1977) in patients with Itai-itai disease (section 8.2.2.2).
    Many of the Itai-itai patients also have signs of decreased
    glomerular filtration, as indicated by decreased urea clearance
    (Nakagawa, 1960) and increased serum creatinine (Nogawa et al.,
    1979).

    8.2.1.3  Methods for detection of tubular proteinuria

         Determination of total protein and electrophoretic analysis of
    concentrated urinary protein were originally the common methods for
    the detection and diagnosis of tubular proteinuria. Quantitative
    immunological methods (detection limit, 0.002-0.003 mg/litre) for
    the measurement of ß2-microglobulin (Evrin et al., 1971) and RBP
    (Bernard et al., 1982b) in urine ("normal" level about 0.1 mg/litre)
    are available, and these methods facilitate the detection of tubular
    dysfunction. An electrophoretic method with reasonable sensitivity
    (0.8 mg/litre) for measuring specific proteins in the urine utilizes
    staining of proteins in sodium dodecyl sulfate acrylamide gel
    electrophoresis (Nomiyama et al., 1982b). More recently, radio-,
    latex-, and enzyme-linked immunoassays have been developed (Evrin et
    al., 1971; Bernard et al., 1982a; Carlier et al., 1981). However,
    the disadvantage with ß2-microglobulin as a marker for renal
    tubular dysfunction is that this protein is unstable if urinary pH
    is less than 5.5.

         RBP has an advantage over ß2-microglobulin, particularly for
    screening purposes, in that serum levels and, hence, excretion are
    not affected as readily by concomitant immunological disease and are
    more stable at an acidic pH (Bernard et al., 1982b). An enzyme-
    linked immunosorbent assay (ELISA) for urinary RBP has also been
    described (Topping et al., 1986).

         Common tests for qualitative determination of proteinuria, such
    as paper tests (dip sticks), the nitric acid test, and the boiling
    test, should not be used for screening cadmium-induced proteinuria,
    since positive readings will be obtained only at fairly high urine
    protein concentrations (Piscator, 1962). Trichloroacetic acid (TCA)
    or sulfosalicylic acid (SA) can be used for qualitative tests, but a
    negative result does not exclude a moderate increase in low
    molecular weight proteinuria.

    8.2.1.4  Significance of cadmium-induced proteinuria

         More than 70% of proteins with a molecular weight less than
    15 000 but less than 5% of those with a molecular weight greater
    than 40 000 pass through the glomerular membrane (Squire et al.,
    1962). The glomerular filtrate contains relatively large amounts of
    plasma proteins, which are normally almost completely reabsorbed in
    the proximal tubules and only small amounts are found in the urine.
    The increased excretion of tubular proteins in cadmium nephropathy
    is thought to be due mainly to a decreased tubular reabsorption
    capacity. This provides early evidence of renal tubular dysfunction.

         The concentration of albumin in normal serum is about 25 000
    times higher than the concentration of ß2-microglobulin (Table
    15). In spite of the fact that very little of the albumin but about
    80% of the ß2-microglobulin is filtered through the glomeruli
    (Maack et al., 1979), the filtered amount of albumin is still higher
    than the amount of ß2-microglobulin (Table 15).

         Only a small fraction of the albumin or the other proteins is
    excreted in normal urine due to the normally efficient (more than
    99%) tubular reabsorption of all proteins (Table 15). The urinary
    albumin excretion is about 100 times greater than the
    ß2-microglo-bulin excretion (Table 15).

         ß2-Microglobulin is a subunit of a major immunoglobulin
    complex with a molecular weight of 12 000 and normally occurs in
    serum at a concentration of approximately 2.0 mg/litre. In the case
    of a decreased glomerular filtration rate, the serum concentration
    of ß2-microglobulin will also increase. In certain conditions, for
    example, where excessive production occurs as in some cancers and
    autoimmune disorders, serum levels increase, the tubular capacity
    for reabsorption may be exceeded, and the concentration in the urine
    will rise. In tubular dysfunction, the capacity for absorption is

    impaired and, again, this is reflected by an increased excretion in
    the urine. Such renal disorders include the congenital and acquired
    Fanconi syndrome, diabetic nephropathy, certain cases of reflux
    nephropathy, and advanced glomerular disease (Squire et al., 1962).
    A raised urinary excretion of ß2-microglobulin or other low
    molecular weight protein is not, therefore, specific to renal
    dysfunction induced by cadmium, and a differential diagnosis should
    be considered in all cases where this occurs.

         The "normal" average urinary excretion of ß2-microglobulin
    measured in several populations was in the range 0.05-0.1 mg/24 h
    (or mg/litre or mg/g creatine) (Kjellström & Piscator, 1977). Below
    age 65, there was very little or no change with age in the urinary
    ß2-microglobulin (Kjellström & Piscator, 1977), a fact confirmed
    by later studies (Tsuchiya et al., 1979; Kowal & Kraemer, 1982). In
    all of the studies, some high individual values were found in the
    age group above 65 years, and the studies of Tsuchiya et al. (1979)
    and Kowal & Kraemer (1982) reported age-regression coefficients
    indicating an increase with age. However, there was wide variation
    with age and the average urinary ß2-microglobulin levels in the
    oldest age groups (above 65 years) were only 10-20% higher than in
    the other age groups (Kowal & Kraemer, 1982). The prevalence of
    increased low molecular weight proteinuria (above 0.5 mg/litre) was
    less than 5% in these studies, but in a control group of people
    above age 80 from a Japanese cadmium-polluted area (section 8.3.2.2)
    the prevalence was about 15%.

    8.2.1.5  Glomerular effects

         Although renal tubular dysfunction with its accompanying low
    molecular weight proteinuria is thought to be the most prominent
    renal effect of cadmium, the ß2-microglobulinuria is sometimes
    accompanied by the excretion of high molecular weight proteins such
    as albumin (molecular weight, 69 000). This albuminuria may
    occasionally occur as a result of cadmium exposure without any
    concomitant increase in the urinary excretion of low molecular
    weight proteins (Bernard et al., 1976, 1979); this indicates that
    cadmium, in some cases, may produce a change in the glomerular
    permeability to larger proteins.

         Cadmium may also affect the glomerular filtration rate (GFR).
    Friberg (1950) reported decreased inulin clearance in
    cadmium-exposed battery workers. Elinder et al. (1985a) measured GFR
    by chromium-EDTA in 17 workers previously exposed to cadmium fumes.
    They found a significant negative correlation between decreasing GFR
    and tubular reabsorption loss, and reported that GFR decreased with
    increasing cumulative exposure to cadmium fumes. The urinary
    clearance of ß2-microglobulin increased with decreasing GFR.

         Several other occupational studies have reported increased
    serum concentrations of creatinine and/or ß2-microglobulin,
    indicating reduced GFR, in cadmium-exposed workers (Thun et al.,
    1989; Roels et al., 1989).

         Thun et al. (1989) found a small increase in mean serum
    creatinine in a group of 45 cadmium-exposed workmen. Serum
    creatinine also increased with cadmium dose, suggesting decreased
    glomerular function. Cadmium dose remained the important predictor
    of serum creatinine even after controlling for age, blood pressure,
    body size, and other extraneous factors.

         Roels et al. (1989) measured the serum creatinine and serum
    ß2-microglobulin levels of 23 workers, removed from cadmium
    exposure, on several occasions over a period of six years. The
    average yearly decrease in GFR was estimated to be 6 ml/min per
    1.73 m2, which is considerably more than the normal value
    (< 1 ml/min per 1.73 m2) and significantly more than that of a
    control group examined at the same time.

         There is also evidence of glomerular effects in people exposed
    to cadmium in the environment. Nogawa et al. (1980) suggest that a
    reduction in creatinine clearance may be detected at the early stage
    of cadmium poisoning in a polluted area. In addition, Nogawa et al.
    (1984) reported a significant correlation between decreased tubular
    reabsorption of phosphate and decreased GFR in farmers living in a
    cadmium-polluted area.

         The mechanism for the glomerular effects from cadmium is
    uncertain. It has been suggested that cadmium-induced tubular damage
    leads to a certain degree of interstitial nephritis which in turn
    results in a decreased GFR (Elinder et al., 1985a). It has also been
    proposed that cadmium exerts a direct toxic effect on the glomerulus
    (Roels et al., 1989).

    8.2.1.6  Relationship between renal cadmium levels and the
             occurrence of effects

         The number of reports of renal pathology in autopsy cases and
    renal biopsies that contain data on kidney cortex concentrations of
    cadmium is small. Thus, it is difficult to establish a dose-response
    relationship between cadmium content and pathology or dysfunction.

         Nomiyama (1977) summarized data from 26 cadmium-exposed workers
    and 16 cadmium-exposed people from the general environment. The
    criteria for choosing the subjects were that they possessed high
    renal and/or high liver concentrations of cadmium, morphological
    studies on the kidney had been performed, and data were available on
    the occurrence of proteinuria while the person was alive. Among the

    42 cases reviewed, those exhibiting slight or no proteinuria and no
    morphological alterations had higher concentrations of cadmium in
    the renal cortex than non-exposed people. Most cases with
    morphological changes plus proteinuria had lower renal cadmium
    concentrations that those without proteinuria and/or morphological
    changes. In more recent studies, Ellis et al. (1985) found that in
    cases of renal dysfunction the mean liver and kidney cadmium values
    for retired workers were lower than those for active workers. These
    findings are similar to those from animal studies (section 6.5.1.2),
    where kidney concentrations levelled off or even declined in the
    presence of kidney damage.

         The use of  in vivo neutron activation analysis has
    facilitated the study of the relationship between renal cadmium
    levels and occurrence of effects (Ellis et al., 1981a; Roels et al.,
    1981b). However, the data must be assessed with caution as the
    accuracy of this method has not yet been fully determined. For
    instance, the exact location of the kidney needs to be known.
    Erroneously low renal cadmium levels were reported by Roels et al.
    (1981b) due to an error in adjusting for the distance between skin
    and kidney (Roels et al., 1983a). Data from Ellis et al. (1981a) and
    Roels et al. (1983a,b) have shown that few cases with increased
    urinary ß2-microglobulin concentrations are seen when the level of
    renal cortex cadmium is less than 150 mg/kg tissue and that of liver
    cadmium is less than 40 mg/kg. There is a pattern of liver and
    kidney cadmium levels increasing simultaneously until the average
    renal cortex cadmium concentration is about 300 mg/kg and the
    average liver level is about 60 mg/kg. At higher liver levels, the
    renal cortex level is disproportionately low in most cases, and, in
    addition, many of these workers have increased urinary
    ß2-microglobulin.

         Skerfving et al. (1987) measured kidney cortex cadmium levels
    by X-ray fluorescence in a group of 20 workers from a factory
    producing alkaline batteries and found an average value of 147 mg/kg
    (range 53-317). When compared to a control group, these workers had
    higher average urine levels of cadmium (5.4 vs 0.8 nmol/mmol
    creatinine) and ß2-microglobulin (14.6 vs 6.6 µg/mmol creatinine).
    Six workers had ß2-microglobulin levels exceeding 22 µg/mmol
    creatinine. Due to selection procedures the results are, however,
    not predictive for cadmium-exposed workers in general. Nevertheless,
    it is clear that there are no significant correlations between
    levels of cadmium or ß2-microglobulin in urine and cadmium levels
    in the kidney. These results suggest that there is a relationship
    between renal cadmium and occurrences of effects on a group basis
    but renal cadmium levels per se are not always predictive of
    pathological effects on an individual level.

    8.2.1.7  Reversibility of renal effects

         The potential for reversibility of renal effects has been
    studied in populations of workers with occupationally induced
    cadmium nephropathy as well as in residents of cadmium-polluted
    areas.

    a) Occupational exposures

         In a group of 40 workers heavily exposed to cadmium, it was
    found, using qualitative methods, that proteinuria was persistent
    and sometimes even increased several years after cessation of
    exposure (Friberg & Nystrom, 1952; Piscator, 1966a).

         Tsuchiya (1976) studied a group of 13 workers who had been
    exposed to cadmium fumes (133 µg/m3) and who had proteinuria
    (determined by the trichloroacetic acid method) and abnormal
    electrophoretic urine patterns (ß2-microglobulin levels above
    40 000 µg/litre). A 10-year follow-up study of five of these
    patients was carried out after improvements had been made in their
    working environment (cadmium fumes, 20 µg/m3). The proteinuria was
    reversed (measured using a single radial immuno-diffusion method) in
    three of the five patients: ß2-microglobulin values were 3500,
    2600 µg/litre, and not detectable (limit of detection
    2000 µg/litre), and retinol-binding proteins (RBP) were not
    detectable (limit of detection 500 µg/litre). In addition, there
    were improvements in the remaining two patients (ß2-microglobulin,
    9700 and 5500 µg/litre; RBP, 34 000 and 120 000 µg/litre). Tsuchiya
    (1976) suggested that the difference in the period of exposure to
    cadmium was the reason for this difference in the degree of recovery
    from the effects of cadmium.

         Stewart & Hughes (1981) reported on similar cases from a
    British pigment factory. Despite the fact that exposure ceased many
    years earlier, grossly elevated ß2-microglobulin levels were still
    detected.

         Using quantitative methods to detect proteinuria, Roels et al.
    (1982) found that total proteinuria in 19 workers was unchanged 4
    years after exposure had ceased. In those 11 workers for whom
    urinary ß2-microglobulin was measured before and after cessation
    of exposure, levels were invariably increased. Eight of the workers
    had abnormal levels of ß2-microglobulin even before cessation of
    exposure, whereas three had normal levels before cessation and
    developed abnormal levels afterwards.

         Roels et al. (1989) examined 23 workers once a year for 5 years
    after removal from exposure to cadmium. These workers had been
    exposed to cadmium for periods of 6 to 41.7 years (mean 25 years),
    and their first follow-up examination took place when they had been

    removed from exposure for an average of 6 years. Their mean age at
    that time was 58.6 years (range 45.5-68.1 years). Cadmiumuria in
    these workers had been assessed three years previously by measuring
    the cadmium levels in liver and kidney using neutron activation
    analysis. The cadmium concentrations (mg/kg wet weight) in the liver
    and kidney cortex ranged from 24 to 158 (mean 61) and from 133 to
    355 (mean 231), respectively. Although cadmium concentrations in the
    blood and urine decreased significantly over the five-year period,
    urine concentrations of albumin, ß2-microglobulin, and RBP did not
    change significantly.

         Harada (1987) conducted studies on the health status of seven
    workers exposed prior to 1972 to high cadmium levels in a cadmium
    sulfide dye manufacturing factory. These workers were examine for 15
    years, improvements having been made to working conditions in 1974
    which led to markedly decreased cadmium exposures. The cadmium
    content of the blood and urine declined after the improvements in
    working conditions but increased again when production rose. The
    working condition improvements resulted in a marked reduction in
    urine ß2-microglobulin level in five workers (e.g., from 1272 to
    520 µg/g creatinine in 1 year in one worker and from 2090 to
    503 µg/g creatinine in 6 months in another), but there was elevated
    urinary ß2-microglobulin excretion when production increased. One
    worker had fairly constant near-normal urinary levels of
    ß2-microglobulins (55 to 183 µg/g creatinine) regardless of
    workplace improvements or production levels. Initially, four workers
    had low GFR values, but none of the seven workers showed any
    decrease in glomerular filtration during the 15-year follow-up
    period. TRP rates decreased in three workers but remained relatively
    unchanged in the other four. These changes in GFR and TRP seemed to
    be independent of cadmium exposure levels.

         Elinder et al. (1985b) found that urine cadmium excretion
    decreased in 14 out of 19 workers re-examined at least once five
    years or more after exposure to cadmium, but renal tubular function,
    as measured by urinary ß2-microglobulin excretion, had
    deteriorated or not improved in nearly all of the workers. Thun et
    al. (1989) concluded that "time since last exposure to cadmium" was
    not an important determinant of renal outcome whether considered on
    its own or together with the cadmium dose. In their study of 45
    workers at a plant that recovered cadmium from industrial waste, 9
    out of 15 workers with the highest ß2-microglobulin excretion had
    not been exposed to cadmium for at least five years and one for 45
    years. This study suggested that if cadmium nephropathy is
    reversible, the recovery is so slow as to be indiscernible after
    decades of non-exposure.

         Ellis et al. (1985) showed that the liver cadmium levels in
    workers no longer exposed to cadmium gradually declines. Persistence
    of renal tubular dysfunction after cessation of exposure may reflect
    the level of body burden and the transfer of cadmium from liver to
    kidney.

    b) Residents of cadmium-polluted areas

         Reversibility of renal tubular dysfunction has been
    investigated in residents of cadmium-polluted areas in Japan. Kasuya
    et al. (1986) carried out a comparative study of urine
    ß2-microglobulin determinations made in 1975 and 1985 for 93
    people with Itai-itai disease and their family members. Urine
    ß2-microglobulin levels improved in the group with
    ß2-microglobulin levels of 1000 µg/g creatinine or less but
    worsened in the group with ß2-microglobulin levels of 3000 µg/g
    creatinine or more. Most of the people who recovered were aged 39
    years or less and had been resident for 30 years or less. It was
    considered that mild renal dysfunction among young individuals was
    reversible.

         Saito (1987) measured the urine ß2-microglobulin levels of
    residents of cadmium-polluted areas for 3 years after improvements
    had been made in the level of soil contamination and compared the
    results with determinations obtained 7 years previously. During this
    3-year period, the urine ß2-microglobulin levels tended to remain
    unchanged in people with a concentration of around 1000 µg/litre.

         The reversibility of ß2-microglobulinuria, glucosuria, and
    aminoaciduria was examined in 74 inhabitants (32 males and 42
    females) over 50 years of age who lived in a cadmium-polluted area.
    Examinations were conducted just after the cessation of cadmium
    exposure and 5 years later. The geometric mean concentrations of
    ß2-microglobulinuria, glucosuria, and aminoaciduria indicated a
    significant increase in excretion during the 5-year period. In cases
    where the level of ß2-microglobulinuria exceeded 1000 µg/g
    creatinine at the time cadmium exposure ceased, evidence was found
    indicating significant increases in proteinuria after 5 years,
    whereas in cases where the excretion of ß2-micro-globulin had been
    less than 1000 µg/g creatinine no significant changes were observed
    (Kido et al. 1988).

    8.2.2  Disorders of calcium metabolism and bone effects

    8.2.2.1  In industry

         Friberg (1950) observed 7 cases of renal stones among 43
    cadmium workers and drew attention to the possibility of renal
    stones being associated with exposure to cadmium. Ahlmark et al.
    (1961) found that 44% of a group of 39 cadmium workers exposed to

    cadmium oxide dust for more than 15 years had a history of renal
    stone formation. Nine stones from six workers were analysed, and in
    four workers the stones were composed of basic calcium phosphate
    (Axelsson, 1963). There was an increase in the mean calcium
    excretion rate in the cadmium-exposed group as compared to a control
    group. Kidney stones were also found in 12 out of 43 British workers
    at an accumulator factory (Adams et al., 1969). It is noteworthy
    that in both of these studies (Axelsson, 1963 and Adams et al.,
    l969) there was a higher prevalence of renal stones in workers
    without proteinuria than in those with proteinuria. The men with
    proteinuria had, as a group, increased urinary excretion of calcium
    and phosphate, whereas in the group without proteinuria there were a
    few cases with hypercalciuria. Hypercalciuria (81%) and renal stones
    (19%) were also reported among 27 coppersmiths exposed to cadmium
    (Scott et al., 1976, 1978).

         Elinder et al. (1985a) found an increased prevalence of renal
    stones among cadmium workers with tubular proteinuria, and Mason et
    al. (1988) observed decreased renal reabsorption of calcium among
    cadmium alloy workers.

         Seven of the 12 workers in a cadmium pigment factory
    investigated by Kazantzis et al. (1963) were found to have a urinary
    calcium excretion rate greater than 300 mg/day (at least in 1 of 2
    specimens). There was no evidence of excessive calcium intake in
    these men. Five of these seven workers had been exposed to cadmium
    compounds for more than 25 years and also had tubular proteinuria.
    The remaining two, who had been exposed for 2 and 12 years,
    respectively, had no other abnormality except for a urinary calcium
    excretion of 308 and 403 mg/day. Follow-up was possible with six of
    the twelve men, including all five with hypercalciuria and
    proteinuria (Kazantzis, 1979). Six of the seven who had
    hypercalciuria when first examined continued to have a raised
    urinary calcium excretion, and one further worker developed
    hypercalciuria during the follow-up period. All those with
    hypercalciuria also had tubular proteinuria, although this was
    marginal in one of the workers. Blood calcium levels remained within
    normal limits in all cases (Kazantzis, 1979). The occurrence of
    disordered calcium metabolism in all seven men followed-up for a
    number of years makes it very likely that a common environmental
    factor, such as occupational exposure to cadmium compounds, was
    causative.

         The data of Kazantzis (1979) agree with the findings of
    hypercalciuria among 27 coppersmiths with high cadmium exposure
    (Scott et al., 1976, 1978). Scott et al. (1980) reported that in 15
    cadmium-exposed men the amount of calcium in the whole body was
    lower than that of controls and decreased with duration of an
    increased exposure to cadmium. The cadmium-induced hypercalciuria
    could be reduced by thiazide treatment (Scott et al., l979).

         In a study by Thun et al. (1989) of workers at a plant that
    recovered cadmium from industrial waste, 8 of 45 exposed workers had
    experienced kidney stones, in contrast to one of 32 unexposed
    workers. Increase in the urinary excretion of ß2-microglobulin and
    RBP was accompanied by decreased renal tubular reabsorption of
    calcium and phosphates.

         In contrast to the above findings, a low urinary calcium
    excretion was detected in 47 out of 81 workers with exposure to a
    variety of cadmium compounds and also cadmium oxide fumes (Tarasenko
    & Vorobjeva, 1973; Tarasenko et al., 1975). The 24-h excretion of
    calcium in these workers was below 100 mg, compared with 115-210 mg
    in a control group of 21 people. Blood calcium values were within
    the normal range in all cases.

         Radiological examination was performed on 32 workers exposed
    for 4-20 years to cadmium compounds (concentrations ranging from 0.1
    to 5.5 mg/m3). All of them complained of pains in the bones.
    Pseudofractures suggestive of osteomalacia were seen in two workers
    exposed for 16 and 19 years, but no histological confirmation of
    osteomalacia was obtained. Radiological appearances described as
    enostosis were reported in five cases and periosteal proliferation
    and consolidation in a further three cases (Tarasenko & Vorobjeva,
    1973; Tarasenko et al., l975).

         Horstowa et al. (1966) performed radiological examination of
    the skeleton in 26 alkaline battery workers with signs of chronic
    cadmium intoxication out of 80 workers exposed to 0.13-1.17 mg
    cadmium/m3 for 1-12 years. Seven of these workers had proteinuria
    detected by sulfosalicyclic acid; pseudofractures were found in 3
    workers, sclerotic foci in 13, and osteoporosis in 10. In another
    alkaline battery factory, where a number of cases of severe cadmium
    poisoning were diagnosed (Friberg, 1950), X-ray examinations
    revealed no signs of bone disease.

         One of the workers with multiple tubular defects studied by
    Kazantzis et al. (1963) developed osteomalacia confirmed by
    histological examination 10 years after the initial investigation
    (Kazantzis, 1979). He previously displayed hypercalciuria but, at
    the time of diagnosis, his urinary calcium excretion was low.
    Extensive investigation failed to reveal any of the other generally
    accepted causes of osteomalacia such as malabsorption or nutritional
    deficiency.

         In a study of 43 workers at a battery plant, one worker
    developed osteomalacia without evidence of malabsorption or
    nutritional deficiency but with multiple renal tubular defects
    (Adams et al., 1969). Another case of osteomalacia from the same
    factory was subsequently detected in a man who had been a cadmium

    battery worker for 40 years (Adams, 1980). Eight years before
    retirement he had a partial gastrectomy due to a duodenal ulcer.
    Proteinuria was first diagnosed 6 years before retirement, but
    otherwise he was in "apparent good health" and "on a balanced diet"
    until 8 years after retirement. He was then frail, had pains in his
    legs, and a "waddling gait". His serum alkaline phosphatase level
    was increased, X-rays showed generalized osteoporosis, and a bone
    biopsy showed osteomalacia. After 1 year of treatment with large
    doses of vitamin D, he could walk well again.

         It also seems likely that the six workers exposed to cadmium
    oxide dust described by Nicaud et al. (1942), who had pains in the
    back and limbs and showed multiple pseudofractures on radiological
    examination, suffered from osteomalacia. More detailed data on these
    workers was presented by Valetas (1946), who also pointed out that
    "massive doses" of vitamin D were needed to improve the symptoms. It
    took several months for improvement to occur and the vitamin D
    treatment had to be maintained for several years to keep the workers
    in stable health. Valetas (1946) concluded that this bone disease
    was caused by occupational exposure to cadmium. Eight workers with
    8-30 years of exposure to lead dust and cadmium oxide fume and dust
    (Gervais & Delpech, 1963) were also found to have multiple
    pseudofractures and pains in the back, thorax, and legs. Very
    limited biochemical investigations were carried out, but in four
    cases proteinuria was found. The authors suspected that lead
    exposure led to the observed effects.

    8.2.2.2  In the general environment

         Bone disease and abnormalities of calcium metabolism from
    exposure to cadmium in the general environment have only been noted
    in people in Japan with the clinical syndrome referred to as
    Itai-itai disease. The main characteristics of the disease are
    osteomalacia1 and osteoporosis2 with a tendency to fractures
    accompanied by severe pain and renal tubular dysfunction. The
    results of epidemiological and clinical investigations indicate an
    association with cadmium exposure, although the Co-operative
    Research Committee on Itai-itai Disease (1967) stated that
    "malnutrition (low protein, low calcium diets) and multiple
    pregnancies may also be involved".

                 

    1 Osteomalacia is characterized by inadequate mineralization of
      bonematrix, resulting in an increase in the relative amount
      of osteoid tissue. It represents the adult counterpart of
      childhoodrickets (Robbins et al. 1984).

    2 Osteoporosis is defined as an excessive but proportional
      reduction in the amounts of both the mineral and matrix phases of
      bone unaccompanied by any abnormality in structure of the residual
      bone (Robbins et al., 1984).

         Itai-itai disease is an endemic bone disease prevalent in the
    basin of the Jinzu river, which runs through the central part of
    Toyama Prefecture in West-Central Japan (Kono et el., 1956). It is
    characterized by osteomalacia in combination with renal tubular
    dysfunction in most cases. Patients also have osteoporosis and one
    of the most characteristic symptoms is severe bone pain. Hagino &
    Yoshioka (1961) reported that high concentrations of cadmium, lead,
    and zinc were present in autopsy tissues from people with Itai-itai
    disease and in the everyday foods of the endemic area.

         Systematic epidemiological investigations, which included
    extensive mass health examinations as well as case control studies
    on both patients and controls, started in 1962 (Cooperative Research
    Committee on Itai-itai Disease, 1967). It was reported that
    Itai-itai disease in Toyama Prefecture was restricted to a limited
    area (Fuchu area) irrigated by the Jinzu river, the geographical
    distribution of the patients being consistent with the levels of
    cadmium concentration in the paddy fields, and that the
    concentrations of cadmium in urine were higher in patients than in
    controls. The total number of patients was estimated in 1955 by the
    Toyama Prefecture to be 41 out of a total of 1666 residents (849
    women) (Cooperative Research Committee on Itai-itai Disease, 1967).
    The major source of cadmium pollution in the area was a mine 50 km
    upstream from the endemic area (Japan Public Health Association,
    1968).

         The age and sex distribution of the patients displayed a very
    distinct pattern. Clinically apparent cases were limited to women
    over 40 years of age who had given birth to many children (6 on
    average) and had lived in the area for more than 30 years. No
    detailed data on past patients were available, but it was estimated
    that the age of onset of the disease was probably between 35 and 65
    years, and that almost 100 deaths had been reported up to the end of
    1966. The incidence was presumably very high from 1936 to 1950 and
    at its highest in 1946 and 1947, but decreased thereafter even
    though the same cadmium exposure levels had been maintained. By
    March 1989, 150 cases of Itai-itai disease had been officially
    recognized as pollution-related disease. Whereas all cases have been
    reported in the Fuchu area, there have been a few suspected cases in
    2 out of 12 cadmium-contaminated areas of Japan other than the Fuchu
    area (Table 7). Clinical features of five suspected cases from the
    Ikuno area matched those of Itai-itai disease and urine cadmium
    levels were very high (Nogawa et al., 1975). In one of these cases
    an autopsy was performed; the liver cadmium level was very high
    (75 mg/kg) but the renal cortex cadmium level was low (53 mg/kg)
    (Nogawa et al., 1975).

         Takebayashi (1980a,b, 1983a,b, 1984) and Takebayashi et al.
    (1985, 1987a,b,c, 1988a,b,c,d) reported pathological findings in
    kidney and bone from autopsies of eleven elderly men and women (3
    males and 8 females; 72-95 years of age) from Tsushima Island. The
    average levels of cadmium in the liver and kidney cortex were
    92.4 mg/kg and 44.0 mg/kg, respectively. The authors considered the
    histological osteomalacia and renal tubulopathy noted in eight cases
    (Takebayashi, 1980, 1983a, 1984, Takebayashi et al., 1985, 1987a,b,
    1988c,d) to be similar to Itai-itai disease from Toyama Prefecture.

         However the Japan Cadmium Research Committee (1989), supported
    by the Japanese Environment Agency, concluded, after these eight
    cases had been examined by the expert group, that it was clinically
    difficult to diagnose them as osteomalacia.

         According to the Japan Cadmium Research Committee (1989),
    diagnosed cases of Itai-itai disease were reported only in the Fuchu
    area of Japan. It denied the presence of osteomalacia in five cases
    in the Ikuno area, and stated that osteomalacia had not been
    observed "clinically" in Tsushima Island.

         A study by Kido et al. (1989) indicates that exposure to
    cadmium could cause osteopenia, particularly in women. Bone density
    was measured in 28 women with Itai-itai disease, 92 men and 114
    women with cadmium-induced renal dysfunctions, and 44 men and 66
    women living in three different non-polluted areas using a
    microdensitometer. The values of indices corresponding to both
    cortical width and bone mineral content were significantly lower in
    Itai-itai disease patients than in cadmium-exposed women with renal
    dysfunctions or in non-exposed subjects. The cadmium-exposed women
    also showed a decrease in bone density compared with the non-exposed
    subjects. A significant decrease in bone density was also observed
    in cadmium-exposed men compared with non-exposed subjects, although
    the difference was not as clear as it was in women.

         Reviews (in English) of Itai-itai disease have been produced by
    Tsuchiya (1969), Friberg et al. (1974), Tsuchiya (1978), and Nogawa
    (1981).

    8.2.2.3  Mechanism of cadmium-induced bone effects

         The available data show that cadmium can affect calcium,
    phosphorous, and bone metabolism in both industrial workers and
    people exposed in the general environment. These effects may be
    secondary to the cadmium effects on the kidneys but there have been
    few studies of calcium metabolism in people with excess exposure to
    cadmium. The increased prevalence of renal stones reported from
    certain industries is probably one manifestation of the
    cadmium-induced kidney effects. It is not known if factors other
    than cadmium play a role.

         Nogawa et al. (1987) reported that serum 1,25-dihydroxy-
    vitamin D levels were lower in Itai-itai disease patients and
    cadmium-exposed subjects with renal damage than in non-exposed
    subjects. The reduction in these levels was closely related to serum
    concentrations of parathyroid hormone and ß2-micro-globulin and to
    the percentage tubular reabsorption of phosphate (% TRP), suggesting
    that cadmium-induced bone effects were mainly due to a disturbance
    in vitamin D and parathyroid hormone metabolism.

         Osteomalacia has been reported in a few heavily exposed
    industrial workers and people with Itai-itai disease. The industrial
    cases are mainly male, whereas Itai-itai patients are almost
    exclusively female. However, the clinical features and biochemical
    findings are similar, except that Itai-itai patients may also suffer
    from ostoporosis.

         A possible mechanism for the development of osteomalacia has
    been proposed (Kjellström, 1986). It is known that normal calcium
    absorption in the intestines and normal bone mineralization is
    dependent upon 1,25-dihydroxycholecalciferol. Vitamin D3 taken
    into the body is converted to 25-hydroxy-vitamin D3 in the liver,
    and then to 1,25-dihydroxy-vitamin D3 in the mitochondria of renal
    proximal tubular cells, this being the biologically active species.
    Cadmium accumulates in the proximal tubular cells, depressing
    cellular functions, and this may result in reduced conversion of
    25-hydroxy-to 1,25-dihydroxy-vitamin D3. This is likely to lead to
    decreased calcium absorption and decreased mineralization of bone,
    which in turn may result in osteomalacia.

    8.2.3  Respiratory system effects

         Cadmium workers may develop chronic injury to the respiratory
    system, depending on the level and nature of exposure. The
    development of such effects is often quite slow, so that they are
    apparent only after several years of exposure. The rate of
    development and severity appear to be roughly proportional to the
    time and level of exposure.

    8.2.3.1  Upper respiratory system

         Chronic inflammation of the nose, pharynx, and larynx have been
    reported by Vorobjeva (1958) and Horstowa et al. (1966). Anosmia is
    a frequent symptom in cadmium workers after prolonged exposure. This
    has been reported by, for instance, Valetas (1946), Friberg (1950),
    Baader (1951), Vorobjeva (1958), Tarasenko & Vorobjeva (1973), and
    Apostolov (1979), but was not observed by Tsuchiya (1967) or Suzuki
    et al. (1965).

    8.2.3.2  Lower respiratory system

         Chronic obstructive lung disease of varying degrees of severity
    is frequently seen in cadmium workers. Friberg (1950) reported
    dyspnoea, impaired lung function with increased residual volume, and
    reduced working capacity in a group of 43 cadmium workers. Similar
    studies, which included the use of pulmonary function measurements,
    by Bonnell (1955), Buxton (1956), Kazantzis et al. (1963), and Adams
    et al. (1969) all showed impairment of respiratory function in
    groups of workers with prolonged exposure. The symptoms and findings
    were more suggestive of emphysema than bronchitis in these cases;
    they were commonly diagnosed as emphysema but pathological
    confirmation of this was rare (Smith et al., l960).

         Tarasenko & Vorobjeva (1973) reported the presence of increased
    lung markings in the chest X-rays of 17 out of 72 cadmium workers,
    which were interpreted as being due to diffuse interstitial
    fibrosis. Similar lung changes were observed in 21 out of 26 workers
    studied by Horstowa et al. (1966).

         The presence of chronic obstructive respiratory disease in
    cigarette smokers exposed to an additional harmful environmental
    agent presents difficulties in determining the contribution made by
    the latter. Studies on the chronic respiratory effects of cadmium in
    the past have not always been standardized for smoking. Lauwerys et
    al. (1974a) did take smoking habits into consideration by matching
    his cadmium-exposed and control groups for smoking habits. They
    reported the presence of impaired lung function in a group of
    cadmium workers exposed for over 20 years, but not in those with
    shorter exposure. The degree of lung impairment found was small.

         The effects on the lung increases the mortality of cadmium
    workers with high exposures (Kjellström et al., 1979; Armstrong &
    Kazantzis, 1983). In the latter study, the mortality for diseases
    coded as bronchitis (ICD 490-491) was related to the intensity of
    exposure, the group with the highest exposure having a highly
    significant (almost 4-fold) excess risk (observed 13 expected 3.4).
    A 5-year follow-up of this study (Kazantzis et al., 1988) confirmed
    the earlier finding, the marked excess mortality being related to
    both intensity and duration of exposure. The follow-up revealed an
    excess mortality from emphysema, but this was seen only in the
    low-exposure group.

    8.2.4  Hypertension and cardiovascular disease

         Despite the abundance of data showing that under certain
    exposure conditions cadmium induces hypertension in animals, there
    are very few results available from studies of cadmium-exposed
    workers. Friberg (1950) examined 43 workers with a mean period of

    exposure to cadmium oxide dust of 20 years (air concentration,
    3-15 mg/m3) and 15 workers with a mean exposure period of 2 years.
    The study included physical and roentgenological examinations of the
    heart, electrocardiographic examination at rest and after exercise,
    and measurement of blood pressure. No increased prevalence of
    cardiac disease or pathological electro-cardiographic changes were
    found. The majority of subjects had completely normal blood
    pressure, but since Friberg did not examine blood pressure in the
    control group, it is not possible to draw definite conclusions.

         Chest examination and blood pressure measurements have also
    been reported in other studies (Bonnell, 1955; Bonnell et al., 1959;
    Kazantzis et al., 1963; Holden, 1969), but in no cases were there
    findings of cardiac disease or hypertension due to cadmium exposure.
    Hammer et al. (1972) found no relationship between exposure to
    cadmium and blood pressure in superphosphate workers.

         Vorobjeva & Eremeeva (1980) examined 72 female and 20 male
    workers at a battery factory exposed to cadmium oxide dust at
    concentrations ranging from 0.04 to 0.5 mg/m3. Blood pressure was
    measured and electrocardiograms taken, but there was no control
    group. The authors reported increased prevalence of hypertension and
    absence from work due to hypertensive and ischaemic heart disease
    among the exposed workers compared to what was considered normal.
    Furthermore, several types of abnormalities in the electrocardiogram
    of the exposed workers were observed: 39% showed tachycardia,
    between 11 and 13% were regarded as normal, and 26% had changes in
    the "R" spike (compared to the normal 7-9%). Increased QRS period
    was observed in 45% of the workers compared to the normal values of
    14-16%. The data presented in this report are especially interesting
    in view of the evidence in rats (section 7.2.6) that suggests
    myocardial effects from cadmium exposure. The results of the study
    are, however, presented in a very condensed form and it is therefore
    difficult to draw clear-cut conclusions.

         In a retrospective study of 311 male workers in an alkaline
    battery factory it was found that hypertensive workers had a longer
    employment time than an age-matched control group from the same work
    environment (Engvall & Perk, 1985). Again it is difficult to draw
    conclusions from this study. In a study of cadmium-exposed workers
    in the United Kingdom (Kazantzis et al., 1988), mortality from
    hypertensive disease (ICD 400-404) over the total study period from
    1943 to 1988 was elevated but not significantly (49 deaths occurred
    as opposed to 41.3 expected). There was no relationship with
    intensity of exposure. However, mortality from cerebrovascular
    disease (ICD 430-438) was significantly lower (178 deaths occurred
    as opposed to 230.3 expected). These findings do not suggest any
    association between cadmium exposure and the development of
    hypertension.

         In contrast, Thun et al. (1989) found that mean systolic and
    diastolic blood pressures were higher in 45 cadmium workers (134 and
    80 mmHg, respectively) than in 32 male controls (120 and 73 mmHg
    respectively). Blood pressure was measured systematically by a
    single examiner on the right arm of subjects who had been seated for
    at least 15 min. Systolic but not diastolic blood pressure was
    significantly associated with cadmium dose in multivariate analyses.

         Schroeder (1965, 1967) observed that people in the general
    population dying from hypertensive and/or cardiovascular disease had
    somewhat higher cadmium concentrations in liver and kidney tissues
    than people dying from other causes. He suggested that cadmium could
    be a causative factor for these diseases. Unfortunately, smoking
    habits were not accounted for and it is likely that this was a
    confounding factor. The same problem exists with a number of
    subsequent studies on hypertension and cadmium in tissues, blood,
    and urine.

         A correlation between average air cadmium levels in cities in
    the USA and mortality associated with hypertension and heart disease
    has been reported (Carroll, 1966; Hickey et al., 1967). Again,
    several confounding factors such as smoking habits, air pollutants
    other than cadmium, and other environmental factors make it
    difficult to draw conclusions concerning the effects of cadmium. In
    a study by Staessen et al. (1984), the confounding variables age,
    sex, body weight, and cigarette smoking were considered in a
    multiple regression analysis of systolic and diastolic blood
    pressure and the urinary excretion of cadmium and
    ß2-micro-globulin. Negative correlations between blood pressure
    and urinary cadmium or ß2-microglobulin were found in some groups.
    As there was a very strong age effect on both blood pressure and
    urinary cadmium, the meaning of the negative correlations is not
    clear. In any case, these data do not support cadmium exposure as a
    cause of hypertension.

         Shigematsu et al. (1979) could find no evidence that blood
    pressure was higher in polluted areas (1611 people sampled) of Japan
    compared with control areas (1826 people). In a comparison of blood
    pressure by prefecture (13 570 in the cadmium-polluted areas and
    7196 in the control areas), the prevalence of hyper-tension was
    found to be high in the polluted area of one of the eight
    prefectures investigated. However, in the other seven prefectures,
    the prevalence of hypertension tended to be lower in the polluted
    areas (Japan Cadmium Research Committee, 1989).

         In a study on cadmium-polluted areas in Japan by Nogawa et al.
    (1981b), the cerebrovascular disease mortality rate among people who
    had had cadmium-induced proteinuria was twice as high as that of
    people in the same area without proteinuria. However, the difference
    was not statistically significant. The number of men in the cohort
    with proteinuria was 81 and the number without proteinuria was 1109.
    Another study comparing administrative units containing polluted
    areas with those without such areas (Shigematsu et al., 1981, 1982,
    1983) found no difference in the cerebrovascular disease mortality
    rates.

         Data on a total population of 333 000 from both
    cadmium-polluted and non-polluted areas were collected
    retrospectively for a period of 6-30 years, based on vital
    statistics or death certificates (Shigematsu et al., 1982). The
    mortalities from all causes, including cardiovascular disease such
    as cerebrovascular and hypertensive disease, in the general
    population in the cadmium-polluted areas were no higher than, or in
    some cases even lower than, those in the non-polluted areas.

         A mortality study of Shipham residents and of a nearby control
    village was reported by Inskip et al. (1982). The study population
    consisted of 501 Shipham residents of whom 278 had died over a
    40-year follow-up period. Overall mortality was low in both villages
    compared generally with England and Wales. There was a small but
    statistically significant excess mortality rate in Shipham from
    hypertensive and cerebrovascular disease. The highest ratio of all
    was for genito-urinary disease in Shipham men (but, with only eight
    observed deaths, the result was only significant at the 10% level).
    The Standardized Mortality Ratios (SMR) for nephritis and nephrosis
    in both sexes were also slightly elevated, but there were only two
    deaths for each sex from this cause. In men, the numbers of
    prostatic and lung cancer deaths were approximately equal to the
    expected numbers, and in neither case was the SMR in Shipham greatly
    different from that in the control village.

    8.2.5  Cancer

    8.2.5.1  In industry

         A number of epidemiological studies have been published. In
    order to facilitate the interpretation of published data on the
    relationship between cadmium exposure and cancer, the studies have
    been grouped according to the types of industrial plants in which
    they have been conducted. In some cases, more than one study has
    been conducted at the same plant.

    a) Nickel-cadmium battery plants

         In an early study, Potts (1965) found that three out of eight
    deaths in a small cohort of nickel-cadmium battery workers in the
    United Kingdom with at least 10 years of exposure to cadmium oxide
    dust were from carcinoma of the prostate. This study was extended by
    Kipling & Waterhouse (1967) to include 248 men with at least one
    year of exposure to cadmium oxide dust. Four deaths from carcinoma
    of the prostate, including the three cases previously reported by
    Potts (1965), were observed as opposed to an expected number of
    0.58.

         Sorahan & Waterhouse (1983) carried out a further investigation
    of the same plant using a cohort of 3025 employees who started work
    between 1923 and 1975 and had a minimum employment period of one
    month. The method of regression models in life tables was used to
    compare duration of exposed employment in those dying from relevant
    causes with that of matched survivors in the same year of follow-up.
    No new evidence of an association between occupational exposure to
    cadmium and cancer of the prostate was found. However, there was an
    excess mortality from cancer of the respiratory system significant
    at the 5% level (89 cases, SMR = 127). As in other studies, data on
    smoking habits were not available and confounding factors were
    present in the form of exposure to nickel hydroxide and welding
    fumes so that no firm conclusions about the pulmonary
    carcinogenicity of cadmium could be drawn from this study.

         Sorahan & Waterhouse (1983) reported on the incidence of
    prostatic cancer in a subgroup of 458 workers employed for at least
    1 year in a job involving high exposure to cadmium oxide dust. Eight
    cancers were observed compared to two expected (SMR 400, P < 0.01).
    However, exclusion of the four cases previously reported by Kipling
    & Waterhouse leaves a non-significant excess incidence (P = 0.21),
    from which the investigators concluded that if cadmium oxide is
    potentially carcinogenic current risks are likely to be small.

         In the most recent update of the nickel-cadmium battery plant
    workers (Sorahan, 1987), the earlier findings were confirmed and
    there was some evidence of an association between risk of death from
    lung cancer and duration of employment in jobs with high or moderate
    exposure among workers first employed in the period 1923-1946.
    However, among workers first employed from 1947 to 1975 (the group
    with the higher SMR for lung cancer), there was no evidence of such
    an association. The authors concluded that the findings do not
    suggest these nickel-cadmium battery workers had experienced an
    elevated lung cancer risk as a consequence of exposure to cadmium
    oxide dust.

         In Sweden, Kjellström (1979) investigated the incidence of
    cancer among 269 male nickel-cadmium battery workers. All workers
    had been heavily exposed (on average about 1 mg cadmium/m3) for
    five years or more to cadmium dust or fume, and were alive in 1959.
    Fifteen workers were found to have cancer between 1959 and 1975. It
    was calculated from national incidence rates that 16.4 new cases
    would have occurred; only 2 were prostatic cancers while 1.2 were
    expected. In a re-examination of the same cohort, there were 8
    deaths from lung cancer with a non-significantly raised SMR of 133.
    The SMRs increased progressively with increasing latent periods
    without reaching statistical significance (Elinder et al., 1985c).

    b) Copper-cadmium alloy plants

         Copper-cadmium alloy workers in the United Kingdom who had
    heavy past exposure to cadmium oxide fume on two sites, one urban
    the other rural, were studied by Holden (1980a). There was an
    increased lung cancer mortality at the urban site (8 observed versus
    4.5 expected) and a significant deficit at the rural site (2
    observed; 7.8 expected). Vicinity workers in the urban plant, where
    the mean cadmium concentration averaged no more than 60 µg/m3),
    also experienced a significantly increased lung and prostatic cancer
    mortality (36 observed; 26.1 expected).

         A case control study was performed (Kazantzis et al., 1989) in
    the same copper-cadmium alloy plants where workers had experienced
    heavy past exposure to cadmium oxide fume and dust, which had given
    rise to a number of deaths coded as chronic cadmium poisoning.
    Before and during the period 1939-1945, cadmium oxide fume levels
    had been estimated to be up to 4 mg/m3. Cases and controls were
    selected from the cohort previously studied by Holden (1980a).
    Personal interviews conducted with a small number of long-term
    employees revealed that arsenical copper had been additionally
    produced by adding bags of arsenic trioxide to the molten copper and
    stirring manually; this resulted in the evolution of dense white
    clouds of arsenic fume. The case control study showed no evidence of
    an increased risk of lung cancer associated with past cadmium
    exposure but an approximately two-fold excess risk associated with
    arsenic exposure.

         Kjellström (1979) also investigated a cadmium-copper alloy
    plant in Sweden where workers had been exposed to cadmium oxide
    fumes and included 94 workers employed in 1940 or who started work
    after that year. Four cases of prostatic cancer occurred as opposed
    to 2.7 expected.

    c) Cadmium recovery plant in the USA

         An increase in prostatic cancer incidence was also found by
    Lemen et al. (1976) in a study of 292 male smelter workers heavily
    exposed to cadmium oxide dust or fumes. Air cadmium concentrations
    in 1973 were up to 24 mg/m3 but generally below 1 mg/m3. There
    were four deaths from cancer of the prostate (1.15 expected). There
    were also 12 deaths from lung cancer (5.1 expected); the difference
    was statistically significant.

         Thun et al. (1985) expanded the Lemen et al. (1976) cohort to
    include 602 workers who had been employed at this cadmium production
    plant between 1940 and 1969 for at least 6 months. Exposure was to
    cadmium in baghouse dust, a by-product of zinc smelting which was
    processed to produce cadmium metal and cadmium oxide. The plant
    functioned as an arsenic smelter up to the end of 1925, and small
    quantities of lead, arsenic, thallium and indium were subsequently
    produced at intervals. The vital status of the workers was
    determined in 1978. A dose-response relationship was observed
    between lung cancer mortality and cumulative exposure and was
    statistically significant for workers whose exposure exceeded
    2920 mg/m3.days. The SMR for this group was 280. The lung tumours
    were, as far as can be determined, mostly of bronchogenic origin.
    The authors accounted for smoking habits by obtaining questionnaires
    from survivors or next-of-kin in 50% of the cohort members and for
    arsenic exposure by measuring arsenic in certain parts of the plant.

    d) Cadmium processing plants in the United Kingdom

         Kazantzis & Armstrong (1982) and Armstrong & Kazantzis (1983)
    investigated a large cohort of workers in England at 17 plants with
    processes using cadmium. The cohort comprised 6995 cadmium-exposed
    male workers born before 1940, first exposed before 1970, and not
    included in any previous mortality study. Jobs were assessed for
    each relevant year involving high, medium or low exposure to cadmium
    on the basis of discussions with hygienists and employees with
    knowledge of past working conditions, taking into account
    environmental and biological monitoring data (e.g., cadmium urine
    data > 20 mg/litre in the high-exposure group. The periods at risk
    of the study population were classified on the basis of these
    categories and recorded job histories into three groups: (i) those
    workers continuously employed for more than one year in a job
    assessed as entailing high exposure - "ever high"; (ii) those
    workers continuously employed for more than one year in a job
    assessed as entailing medium exposure, but who were never for more
    than one year in a high-exposure job - "ever medium", and (iii) all
    others. Actual deaths were compared with expected numbers calculated
    from mortality rates for the population of England and Wales
    corrected for regional variation. The 8th revision of ICD codes was
    used and results were expressed as SMRs.

         Only 3% of the workers (about 200) were assigned to the "ever
    high" category. The mean duration of exposure was 11 years and the
    mean interval from initial exposure to the end of the follow-up was
    27 years. The SMR (all causes) for the entire population was 97.
    There were no prostatic cancer deaths in the "ever high" and "ever
    medium" exposure categories (0.4 and 2.5, respectively, expected),
    and the number of deaths (23) in the "always low" group was close to
    the expected value. There was a small, but not statistically
    significant, excess of lung cancer in all categories, but in those
    with more than 10 years exposure in the "always low" category this
    excess was significant at the 5% level (100 observed, SMR 126).
    Since there was no correlation between increase in lung cancer risk
    and intensity of exposure, the authors concluded that it was
    unlikely that the excess in the "always low" group was due to
    cadmium.

         A 5-year update of this study (Kazantzis et al., 1988)
    confirmed no excess risk from prostatic cancer over the total study
    period from 1943 to 1984 and no cases of prostatic cancer in the
    medium- or high-exposure groups. The SMR was 99 as opposed to the
    value of 90 in the initial study. However, there was now a
    significant excess lung cancer mortality (277 observed deaths, 240.9
    expected), giving a SMR of 115 (95% confidence interval, 101-129).
    This excess risk was related to intensity of exposure, there being
    12 deaths in the small high-exposure group as opposed to 6.2
    expected (SMR, 194; 95% CI, 100-339), 41 deaths in the
    medium-exposure group and 224 deaths in the low-exposure group (SMR
    121 and 112, respectively; not significant). While there appeared to
    be evidence of a dose-response relationship, it was not
    statistically significant. The increased cancer risk mainly involved
    those employed before 1940, rising with length of employment and
    with length of follow-up.

         Further studies have been conducted on workers at these 17
    plants (Armstrong & Kazantzis, 1985; Ades & Kazantzis, 1988). A case
    control study on lung cancer was carried out on workers in a large
    lead-zinc-cadmium smelter. These workers formed 64% of the cohort of
    6995 men, and the study included 70% of the lung cancer deaths
    observed in the cohort as a whole (Ades & Kazantzis, 1988). There
    was a significant excess lung cancer risk among the smelter workers,
    and a significant trend with increasing duration of employment,
    particularly evident among those employed for more than 20 years.
    Quantitative estimates of exposure to cadmium and ordinal rankings
    for lead, arsenic, zinc, sulfur dioxide and dust were used to
    calculate cumulative exposures from job histories. However, matched
    logistic regression analysis showed that the increasing risk of lung
    cancer associated with increasing length of employment could not be
    accounted for by cadmium exposure and did not appear to be
    restricted to any particular process or department.

    e) Summary of industrial studies

         Increased mortality from lung cancer has been observed in
    several occupational cohorts exposed to cadmium, and there is some
    evidence of dose-response relationships in two of the examined
    populations. Case control studies have not given support for such a
    relationship. It is difficult to reach a firm conclusion about
    causality, because in all of the occupational cohorts there has been
    simultaneous exposure to other potential carcinogens (e.g., nickel,
    arsenic, polyaromatic hydrocarbons) or other environmental
    pollutants (e.g., sulfur dioxide). Information on tobacco smoking is
    inadequate or entirely absent in all except two studies.
    Investigations of the relationships between cadmium exposure and
    prostatic cancer are inconclusive.

    8.2.5.2  In the general environment

         Elevated cadmium levels have been found in the liver and
    kidneys of patients with bronchogenic carcinoma (Morgan, 1970;
    Morgan et al., 1971). However, the authors stressed the possibility
    that differences observed could reflect the effect of smoking
    (section 5.1.3) or could represent a non specific association.

         A study of the causes of death in areas of high cadmium
    exposures in Japan (Shigematsu et al., 1982) revealed no difference
    in age-adjusted cancer mortality rates between polluted and control
    areas of the same prefecture. The mortality rate due to prostatic
    cancer was elevated in two areas but only achieved statistical
    significance (P < .01) in one area. It was not significant in two
    areas including Toyama prefecture, which has the largest area of
    pollution.

    8.2.6  Mutagenic effects in human cells

         An increased frequency of chromosomal aberrations in somatic
    human cells is considered to be evidence of some exposure to
    mutagenic agents. Shiraishi (1975) noticed an increased frequency of
    chromosomal aberrations in lymphocytes obtained from 12 Itai-itai
    patients compared to 9 female controls. However, this observation
    was not confirmed by Bui et al. (1975) who examined cells from 4
    Itai-itai patients and 4 controls.

         Among cadmium workers, an increased prevalence of chromosomal
    aberrations, compared to controls, was reported by Deknudt & Leonard
    (1975) and by Bauchinger et al. (1976), whereas no such effect was
    seen by O'Riordan et al. (1978). In none of these occupational
    studies was the actual exposure to cadmium measured, and the
    possible confounding effect from other industrial chemicals and
    smoking was not considered.

         Nogawa et al. (1986) did not find evidence for increased sister
    chromatid exchange in people exposed to cadmium in the general
    environment. IARC (1987a,b) reviewed the available evidence for
    mutagenic and related effects and noted the differences in results
    reported from different industrial environments.

         In conclusion, it is not yet possible to say whether cadmium
    causes mutagenic effects in humans.

    8.2.7  Transplacental transport and fetal effects

         There have been few studies on the fetal toxicity of cadmium
    transported across the placenta. Maternal hypertension and decrease
    in birth weight have been associated with elevated levels of cadmium
    in the neonate (Huel et al., 1981). In addition, it is
    well-established that the babies of mothers who are cigarette
    smokers are smaller at birth than are those of non-smokers. The
    ratio of placental zinc to cadmium is positively related to infant
    birth weight in the case of pregnant smokers, and older pregnant
    smokers are at higher risk for impaired fetal growth than are
    younger ones (Cnattingius et al., 1985; Kuhnert et al., 1987a,
    Kuhnert et al., 1987b). Multiparity is related to an increased
    placental cadmium level in smokers and to a decreased placental zinc
    level in both smokers and non-smokers. These results have been
    interpreted as consistent with a depletion of zinc with increasing
    number of births and a progressive increase in cadmium in smokers
    because of the long half-life of cadmium (Kuhnert et al., 1988).

         The cellular mechanisms and factors that influence
    trans-placental transport of cadmium are not known. Metallothionein
    has been identified in the human placenta and in fetal membranes at
    term, and metallothionein synthesis is inducible in cultured
    trophoblasts by treatment with cadmium (Waalkes et al., 1984). This
    effect is seen with cadmium concentrations in the culture medium as
    low as 52.2 µg/litre (0.5 µmol/litre) (Lehman & Poisner, 1984).
    Higher levels of exposure to cadmium may have a direct toxic effect
    on the placenta. In a test system involving perfusion of maternal
    and fetal blood vessels in the isolated human placenta, it was shown
    that perfusion of the maternal circulation with cadmium at a
    concentration of 1.12 mg/litre (10 µmol/litre) resulted in the
    deposition of 2.5 µg cadmium per g placenta (22 nmoles/g), but very
    little of it was detectable in the fetal circulation. Perfusion of
    the maternal circulation with higher concentrations of cadmium
    produced placental cadmium concentrations of 11.2-16.8 µg/g
    (100-150 nmoles) with stromal oedema, syncytiotrophoblastic
    vesiculation and vacuolization of Hofbauer cells within 6-8 h,
    followed by placental necrosis. These changes were associated with a
    decrease in human chorionic gonadotropin release and decreased
    movement of zinc into the fetal circulation (Miller, 1986).

    8.2.8  Other effects

         Many other different symptoms and signs have been reported in
    humans exposed to cadmium. These include loss of appetite, loss of
    weight, fatigue, and increases in the erythrocyte sedimentation rate
    (ESR). Valetas (1946) reported details of the poisoning cases in a
    French accumulator factory, which were first described by Nicaud et
    al. (1942). In addition to the bone effects and the pains (section
    8.2.2.1), Valetas mentioned that several workers experienced
    paraesthesia and involuntary muscular contractions. This could be an
    effect resulting from abnormal changes in the levels of serum
    electrolytes, such as calcium or potassium, which may in turn be
    caused by severe kidney damage.

         Mild anaemia has been more frequently observed among
    cadmium-exposed workers than among controls (Friberg, 1950; Bonnell,
    1955; Bernard et al., 1979).

         More specific effects from cadmium are the yellow discoloration
    of the proximal part of the front teeth (Barthelemy & Moline, 1946;
    Valetas, 1946; Princi, 1947; Friberg, 1950; Apostolov, 1979) and
    anosmia (Friberg, 1950). Anosmia was found by Friberg (1950) in
    about one third of a group of workers with a mean exposure time to
    cadmium oxide dust of 20 years. Baader (1951) in Germany and
    Apostolov (1979) in Bulgaria also noted that anosmia was common
    among workers exposed to cadmium oxide dust for long periods of
    time. Suzuki et al. (1965) and Tsuchiya (1967) in Japan, found no
    increase in the prevalence of anosmia in workers exposed to cadmium
    stearate and cadmium oxide fumes.

         Nervous system symptoms were reported by Vorobjeva (1957), who
    investigated 160 workers at an accumulator factory in the USSR.
    Subjective symptoms included headache, vertigo, and sleep
    disturbance. Physical examination revealed increases in knee-joint
    reflexes, tremor, dermographia, and sweating.

         Cadmium sulfide is sometimes used as a yellow tattoo pigment,
    which is deposited intradermally. Local phototoxic reactions may
    take place when the skin is exposed to ultraviolet light and are
    probably connected with the marked photoconducting properties of
    cadmium sulfide. Of 24 patients with yellow tattoos who were
    examined by Bjornberg (1963), 18 experienced skin swelling when
    exposed to sunlight.

    8.3  Clinical and epidemiological studies with data on both exposure
         and effects

         There are several clinical and epidemiological studies with
    data on occupational or general environment exposure levels, but the
    data concerning effects are restricted to the lungs and kidneys.

    8.3.1  Studies on respiratory disorders

         Friberg (1950) studied 43 male workers exposed to cadmium oxide
    dust, with an average period of employment of 20 years (range 9-34
    years), and 15 workers who had been employed for only 1-4 years.
    They were compared with a group of 200 sawmill workers. Shortness of
    breath was the common symptom among the workers with long exposure,
    and an impairment of lung function (increased residual capacity in
    relation to total lung capacity and a decreased working capacity)
    was demonstrated. The lung function of the group with short exposure
    (less than 5 years) was found to be normal. The cadmium
    concentration in air varied from 3 to 15 mg/m3, measurements
    having been made at five places on only one occasion. In another
    battery factory (where air cadmium concentrations were
    0.05-5 mg/m3, Adams et al. (1969) found a slight average decrease
    in forced expiratory volume in a group of 27 male workers.

         Twelve out of 96 cadmium workers exposed for up to 27 years to
    cadmium oxide fume in two cadmium-copper alloy factories were found
    to suffer from emphysema, as evaluated from a comprehensive lung
    function test (Bonnell, 1955; Buxton, 1956; Kazantzis, 1956). These
    workers were compared with a similar size control group. The average
    air cadmium concentrations in the two factories were 40-50 µg/m3,
    and 90% of the particles were less than 0.5 µm in diameter (King,
    1955).

         Lauwerys et al. (1979a) studied pulmonary ventilatory function
    in three groups of workers exposed to cadmium oxide dust and in
    matched control groups (the matching included smoking habits). A
    slight but significant reduction in forced vital capacity, in forced
    expiratory volume in one second, and in peak expiratory flow rate
    was found in 22 men. These were all smokers and had been exposed for
    more than 20 years to a time-weighted average air concentration of
    66 µg/m3 (21 µg/m3 respirable cadmium). In another group of
    workers (smokers and non-smokers) exposed for 1-20 years to an
    average concentration of 134 µg/m3 (the respirable cadmium level
    at the most polluted work site was 88 µg/m3), the pulmonary
    indices were on average lower than in the control group, but the
    differences were not statistically significant. A more thorough
    examination of a subgroup of the workers with long exposures carried
    out by the same research group (Stanescu et al., 1977) found more
    respiratory symptoms in the cadmium-exposed group than in a control
    group and also impaired lung function (not statistically
    significant). However, Lauwerys et al. (1979a) reported more
    extensive data from the same plants and found that the workers with
    less than 20 years of exposure (average 7.5 years) showed
    significant effects in the lung function tests.

         Reduced forced vital capacity was also found at a cadmium
    production plant in the USA (where the air concentrations were
    "commonly greater than 200 µg Cd/m3") among 17 workers exposed for
    more than 6 years (Smith et al., 1976). De Silva & Donnan (1981)
    provided evidence that insoluble cadmium compounds may induce
    emphysematous changes after more than 7 years exposure to a
    time-weighted average cadmium concentration of 700 µg/m3.

         Edling et al. (1986) found no lung function differences between
    an exposed group of workers using cadmium-containing solders and a
    control group. The level of exposure, which lasted for several
    years, was estimated to be 0.05-0.5 mg cadmium/m3, but the workers
    had not been exposed to cadmium for several years. Of the 57 workers
    examined, 42% had cadmium-induced renal tubular dysfunction.

         Davison et al. (1988) examined 101 male workers, who had worked
    for 1 year or more manufacturing copper-cadmium alloys, and found,
    compared with a reference group, impaired lung function. They also
    compared certain parameters (transfer coefficient: KCO) with the
    estimated cumulative exposure index for cadmium workers with 95%
    confidence limits for the regression line. Among 35 workers exposed
    for more than five years and with a cumulative cadmium exposure
    index up to 14 mg/m3.years, there was no evidence of a threshold.
    The authors concluded that inhaled cadmium fumes caused changes in
    lung function and in chest radiographs consistent with emphysema.
    This could also explain the increased mortality reported. The
    impaired lung function was also related to liver cadmium levels as
    measured with neutron activation  in vivo.

         Some studies on respiratory disorders have yielded negative
    results. However, some of these studies did not use lung function
    tests (Hardy & Skinner, 1947; Princi, 1947; Tsuchiya, 1967; L'Epee
    et al., 1968) and another did not use a control group (Teculescu &
    Stanescu, 1970). Suzuki et al. (1965) examined a group of workers
    exposed for a short period (average 3.3 years) to 30-690 µg
    cadmium/m3 (as cadmium stearate) and found no changes in lung
    function when compared to a control group.

         In summary, it is clear that exposure to cadmium dust and fume
    over prolonged periods can give rise to impaired lung function and
    emphysema. Such effects have been seen predominantly at high air
    cadmium concentrations (above 100 µg/m3), but one study showed
    effects after more than 20 years of exposure to respirable cadmium
    oxide dust concentrations of 21 µg/m3.

         Cadmium workers sometimes suffered from symptoms such as
    coughing and throat irritation, but did not show abnormal chest
    X-ray findings when exposed to cadmium oxide fume at a concentration
    of 100 µg/m3 for 4-8 years (Hardy & Skinner, 1947) or
    40-1440 µg/m3 for 8 years (Princi, 1947), or to cadmium oxide dust
    at a concentration of 64-241 µg/m3 for up to 15 years (Tsuchiya,
    1967).

    8.3.2  Studies on renal disorders in industry

         Friberg (1950) reported that prolonged exposure gave rise to
    renal damage among a large group of workers exposed to cadmium oxide
    dust at concentrations of 3-15 mg/m3 in an accumulator factory. In
    one group of 43 workers with a mean exposure period of 20 years
    (range 9-34 years), a high prevalence of proteinuria was
    demonstrated by the nitric acid and trichloroacetic acid test. In
    several of the workers, the renal damage was also manifested by a
    decreased inulin clearance and decreased concentrating capacity.
    Another group of 15 workers with a mean exposure period of 2 years
    (range 1-4 years) showed no positive reactions.

         Since 1950, there have been many studies on proteinuria among
    workers in various industries. This type of proteinuria is
    characterized particularly by a great relative increase in the
    excretion of low molecular weight (LMW) proteins (section 8.2). In
    most of the early studies, qualitative tests for detecting
    proteinuria were used, but, more recently, specific methods for the
    quantitative determination of LMW proteins have been developed.

         Table 16 contains data on the prevalence of proteinuria from
    several epidemiological studies on cadmium workers. It must be
    recognized that, in most studies, the dose measurements are based on
    short sampling periods (hours or a few days), whereas exposure may
    have been for decades. Information on sampling method (static or
    personal) and the use of respirators is usually inadequate, which
    makes accurate dose estimates difficult (section 2.2.1).

         It is evident that the prevalence of proteinuria in cadmium
    workers increases with exposure intensity duration. The study by
    Kjellström et al. (1977a) presents frequency distributions of
    urinary ß2-microglobulin excretion for 240 exposed workers and a
    control group. There is a general shift to higher excretion levels
    among the exposed workers, and a large proportion of them have
    excretion levels far outside the control distribution. Any cut-off
    point (operational definition) for "abnormal" proteinuria is
    arbitrary. If a cut-off point of 290 µg/litre (corresponding to the
    97.5 percentile of the control group) is chosen, 26% of the whole
    group of exposed workers would be classified as having LMW
    proteinuria. If higher cut-off points are used, the prevalence of
    proteinuria will obviously be lower.

         Table 16 provides evidence of a dose-response relationship. The
    lowest "dose" that gave rise to a statistically significant increase
    in urinary ß2-microglobulin, as defined above, was a 6-to 12-year
    exposure to 50 µg cadmium/m3 (based on personal sampling)
    (Kjellström et al., 1977a).

         Järup et al. (1988) recently made a reassessment of
    dose-response in the same battery plant (Table 16). A pattern very
    similar to Kjellström et al. (1977a) was observed with a prevalence
    of ß2-microglobulinuria of 4% at a cumulative dose of 0.5 mg/m3
    (corresponding to 10 years of exposure to 50 µg cadmium/m3). 
    Lauwerys et al. (1979a,b) studied the prevalence of increased
    ß2-microglobulin clearance (cut-off point: 97.5 percentile of
    controls) and found a 21% prevalence after more than 20 years of
    exposure to 66 µg cadmium/m3 total dust (static samples) or 21 µg
    cadmium/m3 respirable dust (Table 16).

         Holden (1980b) measured urine levels of ß2-microglobulin and
    found dose-response relationships using cut-off points of
    200 µg/litre, 1000 µg/litre, or 10 000 µg/litre. The cut-off point
    of 200 µg/litre gave a 16% LMW proteinuria prevalence rate after
    6-10 years of exposure (Table 16).

         Table 16 also shows that an increased prevalence of total
    proteinuria, as measured by sulfosalicyclic acid, trichloroacetic
    acid, or quantitative determination of total proteinuria, occurs
    after 5-10 years exposure to approximately 100 µg cadmium/m3. An
    increased excretion of LMW protein (e.g., ß2-microglobulin) occurs
    at much lower doses.

         The  in vivo measurement of cadmium in the liver and kidneys
    of people with various levels of cadmium exposure provides a means
    for relating organ dose to effects and response rates (section
    6.4.2). Some questions still remain regarding the accuracy of the
    analytical method (section 2.2.3.4) and the mathematical-statistical
    methodology (Kjellström et al., 1984). Nevertheless, Roels et al.
    (1983a) and Ellis et al. (l984) suggested that renal tubular damage
    would be experienced by about 10% of people with a kidney cortex
    level of 200 mg cadmium/kg, and by about 50% of people with a kidney
    cortex level of 300 mg cadmium/kg.


        Table 16.  Prevalence of proteinuria in cadmium workers
                                                                                                                                               

    Cadmium            Estimated air        Exposure         No. of     Prevalence of    Proteinuria and           Reference
    compounds          concentrations       period           examinees  proteinuria (%)  characteristics of
                       (µg/m3)a             (years)b                                   detection
                                                                                             methode
                                                                                                                                               

    Cadmium oxide      40-50                 control           60           2             SA and TCA               Bonnell (1955); King (1955);
    fume                                       1-9             37          24                                      Bonnell et al. (1959)
                                               > 9             63          46

                       64-241c               control           11           0             TA                       Tsuchiya (1967)
                                               < 1              4           0             < 100 mg/litre
                                               1-4              4          50

                       123c                    > 5              4          100
                       (time-weighted
                       average

    Cadmium oxide      3000-15 000             1-4             15           0             nitric acid ("Hellers    Friberg (1950)
    dust                                      9-15             12          33             test"); positive in
                                              16-22            17          41             more than half the
                                              23-34            14          64             test

                       31 (1.4)c             control           31           0             Abnormal                 Lauwerys et al. (1974a)
                                            1-12 (4)           31           0             electrophoretic
                                             control           27           4             pattern as defined
                                                                                          by the authors;
                                                                                          ß2-microglobulin
                                                                                          clearance
                       134 (88)c          0.6-19.7 (9)         27          15
                                             control           22           0
                       66 (21)                21-40            22          68
                       66 (21)                > 20             42          21
                                                                                                                                               

    Table 16 (contd).
                                                                                                                                               

    Cadmium            Estimated air        Exposure         No. of     Prevalence of    Proteinuria and           Reference
    compounds          concentrations       period           examinees  proteinuria (%)  characteristics of
                       (µg/m3)a             (years)b                                     detection
                                                                                             methode
                                                                                                                                               

    Cadmium oxide
    dust
                                             control           87          3.4            ß2-microglobulin         Kjellström et al. (1977a)
                       50c                     0-3             50          6.0            (RIA)
                       50c                     3-6             30          6.6            > 290 µg/litre
                       50c                    6-12             21         19.0            (sg = 1.023)

    Cadmium stearate   30-690                control           24          17             TCA                      Suzuki et al. (1965)
    dust                                       (3)             19          58

    Cadmium sulfide    114d                   < 1-5            12          17             EP                       Harada (1987)
    dust                                      5-21              7          100
                                              < 1-5            12           8             TCA
                                              5-21             12          43
                                             control          203           1             ß2-microglobulin         Stewart & Hughes (1981)
                       80                      0-5            105           0             (RIA)
                       100                    6-11             41           0             > 765 µg/litre
                                                                                          (sg = 1.016)
                       100-600                11-19            13          7.7
                       100-600                 20+             14         57.0

    Mixed exposures;   not reported,        controls          642        0 (0.8)          ß2-microglobulin         Holden (1980b)f
    12 factories;      but mean blood      < 18 months        121        0 (10)           (RIA)
    mainly zinc        cadmium level    19 months-5 years     168       1.8 (8.3)         > 1000 µg/litre
    smelters           after 1 year           6-10            170       1.8 (16)          (or > 200 µg/litre)
                       exposure was           11-15            82       7.3 (22)
                       about                  16-20            33        24 (45)
                       15 µg/litre
                                               20+             68        25 (56)
                                                                                                                                               

    Table 16 (contd).
                                                                                                                                               

    Cadmium         Estimate of cumulative   Number of    Prevalence (%)   Proteinuria and                Reference
    compounds       dose (mg/m3.year)        examinees    of proteinuria   characteristics of
                                                                           detection method
                                                                                                                                               

    Cadmium fume          < 1                   16             18          ß2-microglobulin               Elinder et al. (1985b)
    (oxide)               1-2                   22             32          > 0.034 mg/mmol creatinine
                          2-3                    9             44
                          3-5                    8             62
                          > 5                    5            100

                         < 1 )                   6                                                        Mason et al. (1988)
                        1-15 )                  67
                        1.5-3)                  75             58
                         3-5 )                  86
                         > 5 )                 100

    Cadmium oxide        < 0.4                 264            1.1                                         Jarup et al. (1988)
                        0.4-1.7                 76            9.2
                        1.7-4.6                 43           23.3
                        4.6-9.6                 31           32.3
                        9.6-15                  16           32.2
                         > 15                   10             50
                                                                                                                                               

    a    Numbers in parentheses refer to average concentrations of the respirable particulates (< 5 µm) fraction
    b    Numbers in parentheses are average values
    c    Measured in breathing zone by personal sampler
    d    Calculated average exposure for the worker with the most pronounced effect
    e    SA = sulfosalicyclic acid method (qualitative); TCA = trichloroacetic acid method (qualitative);
         TA = tungstate method (quantitative); EP = electrophoresis; RIA = radioimmunoassay; sg = specific gravity
    f    Values for prevalence of proteinuria refer to a ß2-microglobulin level of > 1000 µg/litre.
         Values in parentheses refer to a level of > 200 µg/litre.

    

         Ellis et al. (1985) correlated time-weighted exposure indices
    (TWE), based on employment records, area monitoring techniques and
    personal sampling, with body burden of cadmium measured by
     in vivo neutron activation analysis of the liver and left kidney
    in 82 men exposed to cadmium dust in a smelter. The workers were
    grouped as follows: production workers (40 active, 21 retired);
    office and laboratory workers (8 active, 4 retired); and
    non-production workers (3 active, 6 retired). From these
    measurements the authors were able to estimate the probability of
    developing kidney dysfunction based on the workers' cumulative
    exposure index. When the exposure limit was 400-500 µg/m3.years,
    the prevalence for renal dysfunction was about 32%; it was 22-40%
    with a wider exposure index (300-600 µg/m3). Kjellström et al.
    (1977a) reported a prevalence of 19% at a battery factory at a level
    of 50 µg Cd/m3, which resulted in a similar exposure index.
    Lauwerys et al. (1974a) observed proteinuria in 68% of workers with
    long-term exposure (20 years at 66 µg/m3), whereas the logistic
    model developed by Ellis et al. (l985) would have predicted 65%
    under these exposure conditions.

         For exposures of 250 µg/m3.years there is a 19% probability
    of experiencing renal dysfunction. In the case of workers with
    normal renal function, an exposure index of 400 µg/m3 predicts a
    mean cadmium concentration of 28 mg/kg in liver and 288 mg/kg of
    renal cortex. The model would predict that a 10-year exposure to
    25 µg/m3 would result in a mean renal cortex concentration of
    252 mg/kg, which is similar to the critical concentration defined by
    Friberg.

         Thun et al. (1989) assessed the quantitative relationship
    between exposure to airborne cadmium and various markers of renal
    tubular and glomerular function in 45 male workers at a plant that
    recovered cadmium from industrial waste. The dose was estimated from
    historical air sampling data. In this study, the "critical dose" of
    cadmium necessary to induce nephropathy was based on the 5th or 95th
    percentile of test results in the unexposed population. Using this
    definition, renal tubular dysfunction sharply increased as
    cumulative exposure to cadmium rose above 300 mg/m3.days
    (corresponding to about 0.8 mg/m3.years). Very similar
    dose-response curves with an increased prevalence of
    ß2-microglobulinuria at cumulative exposure levels exceeding about
    0.5-1 mg cadmium/m3.year have been reported from examinations of
    workers exposed to cadmium fumes (Elinder et al., 1985b; Mason et
    al., 1988). These findings are consistent with the recommendations
    by a working group of the World Health Organization (WHO, l980) to
    limit workplace exposures to 10 µg/m3 in order to prevent tubular
    proteinuria after life-time occupational exposure to cadmium.

         Cumulative cadmium exposure indices have been calculated for 75
    cadmium alloy workers employed for periods of up to 39 years,
    together with the  in vivo liver and kidney cadmium burden (Mason
    et al., 1988). Several indicators of both tubular and glomerular
    dysfunction correlated significantly with both cumulative exposure
    index and liver cadmium burden. Using these estimates of dose, a
    two-phase linear regression model was applied to identify an
    inflection point of the order of 1100 µg/m3.years above which
    changes in renal function occurred. A number of biochemical
    variables fitted this model, including total protein, albumin, and
    ß2-microglobulin. Simple dose-response analysis showed a greatly
    increased incidence of tubular proteinuria when the cumulative
    cadmium exposure index was greater than this value. The cumulative
    exposure index was equated to about 20 to 22 years of exposure to a
    cadmium level of 50 µg/m3.

         Evidence of tubular damage was investigated in a group of 91
    cadmium workers subjected to yearly estimation of cadmium
    concentration in blood and urine over a period of eight years. In
    workers with blood and urine cadmium levels constantly below the
    Biological Limit Value of 10 µg/litre, the prevalence of tubular
    damage, as indicated by an increased excretion of ß2-microglobulin
    above 260 µg/litre, was below 3%. RBP excretion confirmed this
    pattern.

    8.3.3  Studies on renal disorders in the general environment

    8.3.3.1  Health surveys in Japan

         Following the recognition of the association between Itai-itai
    disease and exposure to cadmium (Japanese Ministry of Health and
    Welfare, 1968), additional general surveys of cadmium pollution were
    performed in Japan, and further areas were found to be involved.
    Health effects were studied first among the population in the area
    where Itai-itai cases had occurred and later in other areas found to
    be contaminated. The original studies were designed to find cases of
    Itai-itai disease, but it was possible also to estimate the
    prevalence of proteinuria and glucosuria in the examined population.
    A detailed description of the methods used in these cadmium
    pollution surveillance programmes has been reported by Shigematsu et
    al. (1979).

         At the time of the first surveillance programmes (1969-71),
    methods were developed for estimating the degree of contamination
    with cadmium and the total daily intake. At the early stage of the
    investigations, the most common index of cadmium intake measured in
    all areas was the cadmium concentration in rice. From data of the
    Japan Public Health Association (1970), it was estimated that, in
    areas with different exposure levels, an average of almost 50%
    (range 14-71) of the daily cadmium intake came from rice. In one
    area, the proportion was estimated to be 85% (Kawano & Kato, 1978).

         The average cadmium concentration in rice from non-polluted
    areas has been reported to be 0.066 mg/kg in polished rice
    (Moritsugi & Kobayashi, 1964) and 0.09 mg/kg in unpolished rice
    (Japanese Ministry of Agriculture and Forestry, 1973) (section
    5.2.1). The national average consumption of rice was 364 g per
    person in 1961, 308 g in 1971, and 222 g in 1981 (Japanese Ministry
    of Health and Welfare, 1983).

         Proteinuria was generally estimated with qualitative methods
    such as the sulfosalicylic acid method or the trichloracetic acid
    method according to standardized techniques (Japanese Ministry of
    Health and Welfare, 1971). More recently, emphasis has been placed
    on the identification of the urinary protein pattern, in particular
    to detect early evidence of tubular dysfunction. The methods
    currently used are electrophoresis and the quantitative
    determination of lysozyme, RBP, and ß2-microglobulin. Several
    studies have been published, and there are extensive reviews in
    English (Tsuchiya, 1969; Yamagata & Shigematsu, 1970; Friberg et
    al., 1974; Tsuchiya, 1978; Shigematsu et al., 1979, l980).

         From 1976 to 1984, epidemiological health surveys of residents
    in areas with environmental cadmium pollution were performed by the
    Japan Environment Agency using methods including immunological tests
    for the detection of low molecular weight proteinuria in eight
    prefectures (Akita, Fukushisuma, Gunma, Toyama, Ishikawa, Hyogo,
    Nagasaki, Oita). More than 13 000 inhabitants of polluted areas and
    more than 7000 inhabitants of non-polluted areas, aged 50 years or
    more in both areas, were subjected to these surveys.

         The following screening method was adopted for health
    examinations. The urine of those people with proteinuria
    (demonstrated by a semiquantitative method) and/or glucosuria (by a
    paper test) was analysed for ß2-microglobulin (> 10 mg/litre),
    RBP (> 4 mg/litre), lysozyme (> 2 mg/litre), total amino acid
    nitrogen (> 20 mmol/litre), and cadmium (> 30 µg/litre). Those
    who exceeded the above levels in more than one item were tested for
    renal function by urine and blood analysis. Finally those for whom
    the TRP was less than 80% were subjected to detailed health
    examination, including skeletal radiography, in order to make a
    clinical diagnosis (Fig. 7).

         With the exception of Oita prefecture, the number of
    individuals who had or were suspected of having proximal renal
    tubular dysfunction (as defined by the Japanese Cadmium Research
    Committee) or related findings tended to be greater in the polluted
    areas than in the non-polluted areas, and this was often
    significantly related to the degree of pollution (see Table 16).
    This suggests that environmental cadmium pollution is associated
    with the occurrence of proximal renal tubular dysfunction.

    FIGURE 7

         Five areas in which significantly increased
    ß2-microglobulinuria was found are reviewed in detail below. In
    addition there is a description of some other Japanese polluted
    areas and three European polluted areas.

    8.3.3.2  Toyama prefecture (Fuchu area)

         This is the area where the Itai-itai disease was first
    described (Kono et al., 1956). Exposure levels in polluted villages,
    as measured by cadmium concentrations in rice during the 1960s,
    varied greatly but in some villages the level was as high as 2 mg/kg
    (Ishizaki et al., 1969). A zinc and lead mine was the major source
    of pollution, and cadmium concentrations in soil were elevated
    (Japan Public Health Association, 1968). Many studies have been
    performed with sulfosalicyclic acid and trichloroacetic acid for the
    identification of proteinuria. Both proteinuria and glucosuria were
    common findings in the polluted area (Ishizaki et al., 1969;
    Fukushima et al., 1974). There was a strong relationship between the
    degree of proteinuria and age, and a greatly increased prevalence in
    the older age groups compared with controls. The proteinuria was
    similar to that seen in cadmium workers as evaluated by
    electrophoresis (Piscator & Tsuchiya, 1971) or gel filtration
    (Fukuyama, 1972). Quantitative estimation of the LMW urinary
    proteins ß2-microglobulin (Shiroishi et al., 1975, 1977) and
    retinol-binding protein (Kanai et al., 1971) confirmed that the
    proteinuria was tubular.

         Fukushima et al. (1973) reported on the cadmium concentration
    in rice and the prevalence of renal effects in various hamlets in
    the Fuchu and control areas. In control hamlets situated outside the
    Jinzu river basin, the cadmium concentration in rice varied between
    0.05 and 0.2 mg/kg wet weight, and the prevalence of concurrent
    proteinuria and glycosuria varied between 0 and 9%. In the polluted
    villages, where cadmium levels in polished rice were 0.5-1.0 mg/kg,
    the prevalence was 15-20%, and, in all the 20 hamlets, the
    correlation coefficient between cadmium in rice and prevalence of
    renal effects was 0.68 (P < 0.05) (Fukushima et al., 1973). The
    prevalence had a tendency to be somewhat higher in the hamlets where
    Itai-itai disease was endemic, as compared with the hamlets where it
    did not occur, even though the latter hamlets had similar cadmium
    concentrations in rice.

         Using a disc electrophoresis technique (Shiroishi et al., 1972)
    in the age groups over 40 years, a tubular urinary protein pattern
    was found in about 25% of exposed persons but not found at all in
    the control group. Quantitative determination of ß2-microglobulin
    in the urine of patients with Itai-itai disease and so-called
    observation patients (people in polluted areas with likely
    cadmium-induced renal damage) showed a marked difference between the
    exposed and control groups (Shiroishi et al., 1977).

         The level of urinary ß2-microglobulin in patients with
    Itai-itai disease was on average 43 mg/litre, i.e. 100 times higher
    than in the controls, and the level in observation patients was on
    average 65 times higher than it was in the controls.

         A comparison by Kjellström et al. (1977b) of 138 cadmium-
    exposed women in the age-group 51-60 and 40 controls revealed
    large differences. The exposed women were selected on the
    basis of their consumption of polluted rice (average cadmium
    concentration above 0.7 mg/kg); no health data influenced the
    selection. On average, the urinary ß2-microglobulin excretion was
    10 times greater among the exposed women than among the controls,
    and the individual urinary levels increased as a function of the
    cadmium dose. Additional data from the same area for women in the
    age-group 40-45 (Kjellström, 1977) also showed an increase
    prevalence of high ß2-microglobulin levels in urine.

         Nogawa & Ishizaki (1979) reported a significant increase in the
    prevalence of both proteinuria and concurrent proteinuria and
    glucosuria at an average rice cadmium level of 0.41 mg/kg. In a
    further study (Nogawa et al., 1979), the prevalence of proteinuria
    was analysed as a function of urinary cadmium levels. The
    correlation between the two variables was good, but urinary cadmium
    may not be a suitable measure of dose as it also increases as a
    consequence of renal damage (section 8.2.1).

         A mathematical dose-response analysis was carried out by Hutton
    (1983) based on the data of Shiroishi et al. (1977) on urinary
    ß2-microglobulin excretion. For each individual the cadmium dose
    index (µg/day.years) was based on the estimated daily cadmium intake
    via rice and other foodstuffs and the number of years the person had
    lived in the polluted area. The age-groups 51-60 and 40-45 were both
    divided into three sub-groups with different dose index levels. In
    the analysis of Hutton (1983), three groups from Kosaka area were
    included (section 8.3.3.4) for whom the same type of data was
    available (Kojima et al., 1977). Fig. 8 shows that the prevalence of
    increased LMW proteinuria (response rate) increased with dose. These
    prevalences were adjusted for a control group prevalence of 2.5%
    (Kjellström, 1977), giving an expected "background" prevalence
    without cadmium exposure of 0%. The 95% fiducial limits were quite
    wide. For instance, at a cadmium intake of 55 µg/day (95% fiducial
    limits 25-123), there would be a 1% increase of proteinuria in the
    population. At a dose index of 5000 µg/day.years (or 50 years at
    100 µg cadmium/day intake), the expected response rate was within
    the range 2-12%.

    FIGURE 8

    8.3.3.3  Hyogo prefecture (Ikuno area)

         In the Ikuno area of Hyogo prefecture, an inactive zinc and
    copper mine is the probable source of pollution of the Ichi river
    basin. The average cadmium concentration in rice in the most
    polluted part was found to be 0.69 mg/kg in one study and 1.10 mg/kg
    in another (Hyogo Prefectural Government, 1972).

         In 1972, urine from 1560 people (of both sexes, over 30 years
    of age) from the polluted area and groups of 1574, 2002, and 638
    people (over 30) from three control areas were examined (Tsuchiya,
    1978). The prevalence of proteinuria, as measured by the
    sulfosalicyclic acid methods was 58% and 33%, respectively, a
    statistically significant difference. The reason for the high
    prevalence in the control area is not known.

         In a study by Watanabe & Murayama (1975), a search was made for
    LMW proteins among 39 people in a polluted area and 56 in a control
    area (all the people were above 70 years of age). Urinary
    ß2-microglobulin excretion exceeding 10 000 µg/litre was found in
    41% of the examined people in the polluted area and 4% of those in
    the control area.

         Kitamura & Koizumi (1975) used disc electrophoresis to study
    tubular-type proteinuria among 224 people (above 50 years of age)
    from a polluted area and compared the results with those from a
    study of old bedridden people. Fig. 9 demonstrates the considerably
    higher prevalence of tubular proteinuria among people from the
    polluted area. There was also a definite increase in the occurrence
    of tubular proteinuria with age in the exposed and bedridden control
    groups.

    8.3.3.4  Ishikawa prefecture (Kakehashi area)

         In the Kakahaski river basin of Ishikawa prefecture, several
    mines had polluted the river with cadmium and copper (Tsuchiya,
    1978). Rice samples were studied in a number of villages along the
    river, and village-average levels of up to about 0.7 g/kg were
    found. Values were higher in paddy fields on the shores of a narrow
    river valley close to the mine.

         In 1974-1976, health examinations of 2805 inhabitants over the
    age of 50 were carried out using test tape for proteinuria and
    glucosuria examination as well as single radial immunodiffusion
    analysis for RBP in urine (Tsuchiya, 1978). Based on the findings,
    some people were selected for secondary and tertiary examinations,
    and 39 were considered to require consultation for renal tubular
    dysfunction. However, no cases with severe bone disease were found
    at that time.

         This area is the only one where quantitative measurement of LMW
    protein in urine was carried out in the first screening (Nogawa et
    al., 1978). The prevalence data in Table 17 are therefore of
    particular interest. None of the other LMW proteinuria studies
    mentioned in Table 16 were carried out on such a large group using a
    broad epidemiological approach. A scatter in the prevalence values
    among the villages is seen in Fig. 10, but there is no doubt that
    the villages with the highest rice cadmium values had an increased
    prevalence of high urinary RBP. This is also evident when the data
    from different villages with the same rice cadmium levels are
    combined (Table 17). In all of the exposed groups with different
    rice cadmium levels (Table 17), the prevalence of tubular
    proteinuria increases with age, but that is not seen in the control
    group. It is not known whether the age effect reflects increased
    cadmium dose rather than age itself.

         Further analysis of these data using a mathematical
    dose-response approach (Hutton, 1983) clearly showed the effect of
    calculated cadmium intake on the prevalence of proteinuria
    (Fig. 11). The fiducial limits are narrower than in Fig. 8 because
    of the larger number of people studied.


    FIGURE 9

         In a study by Nogawa et al. (1978), laboratory determinations
    related to proximal renal tubular function, etc., were compared by
    age group. The findings in the most polluted areas hardly differed
    from those in the non-polluted areas in the age-group 50-59
    (Table 17). At age 60 and over, however, the frequency of findings
    tended to increase with age, except in the case of total
    aminoaciduria. The difference in the age-adjusted rates for these
    determinations between the polluted and non-polluted areas tended to
    be enhanced by aging. Table 18 shows how the prevalence of tubular
    proteinuria varies according to age and average rice cadmium
    concentration. Of the 438 participants in the final detailed
    examinations (426 in the polluted areas and 12 in the non-polluted
    areas), findings of "possible proximal renal tubular dysfunction"
    were noted in 334 people (333 in the polluted areas and 1 in the
    non-polluted areas). Among these cases, 202 in the polluted areas
    were determined to have proximal renal tubular dysfunction and 116
    of them were considered to require medical supervision in view of
    the severity of the dysfunction. The urinary ß2-microglobulin
    level in Itai-itai disease patients was on average 43 mg/litre, 100
    times higher than that in the controls, and the patients
    investigated by Nogawa et al. (1978) had an average urinary level of
    ß2-microglobulin 65 times the controls.


        Table 17.  Age-adjusted prevalence rate (%) of renal tubular dysfunction and related conditionsa
                                                                                                                                             

    Prefecture         Year of        Polluted (P) or  No. of examinees     ß2-Microglobulinuria     Decreased TRP         Tubular dysfunction
    studiedb           investigation  non-polluted     male       female      (> 10 mg/litre)         (< 80%)              male       female
                                      (NP) areac                            male     female        male       female
                                                                                                                                             

    Toyama             1979-1984          P           3432        4099      6.5      10.8          4.6         5.5         1.4         3.3
     (Fuchu area)                        NP            944        1205      0.4d      0.5d         0.6d        0.2d        0.0d        0.0d

    Hyogo                1977             P            230         280     12.8      16.8          4.4         6.8         2.0         3.5
     (Ikuno area)                        NP            212         251      2.7d      1.9d         0.9e        0.4d        0.0         0.0e

    Ishikawa             1976             P            260         306      7.6      10.9          6.9         5.7         2.4         3.2
     (Kakehashi area)                    NP            200         275      1.1d      1.5d         0.5d        0.0d        0.0         0.0d

    Akita                1976             P            179         247      6.4       5.0          2.3         0.7         0.0         0.0
     (Kosaka area)                       NP            168         234      0.0d      0.0d         0.0         0.0         0.0         0.0

    Nagasaki             1976             P            143         191      3.4      10.6          4.6         9.1         1.7         6.2
     (Tsushima area)                     NP            210         291      1.9       0.3d         1.5         0.0d        0.0         0.0d

    Fukushima            1977             P            307         425      0.4       0.5          0.6         0.5         0.0         0.3
                                         NP            246         396      0.0       0.0          0.4         0.0         0.0         0.0

    Gunma              1976-1978          P            937        1160      1.6       0.6          1.6         0.5         0.0         0.0
                                         NP            620         786      0.8       0.1          0.6         0.3         0.0         0.0
                                                                                                                                             

    Table 17 (cont'd).
                                                                                                                                             

    Prefecture         Year of        Polluted (P) or  No. of examinees     ß2-Microglobulinuria     Decreased TRP         Tubular dysfunction
    studiedb           investigation  non-polluted     male       female      (> 10 mg/litre)         (< 80%)              male       female
                                      (NP) areac                            male     female        male       female
                                                                                                                                             

    Oita                 1978             P            169         194      1.7       1.5          1.1         0.5         0.0         0.0
                                         NP            182         215      1.7       1.0          1.2         0.0         0.0         0.0
                                                                                                                                             

    a    From: Japan Cadmium Research Committee (1989). The response rates for these studies were greater than 90% of the target
         population. The age composition (50-59, 60-69, 70-79, and 80+) in each prefecture was adjusted to the Japanese population
         in 1980. The criteria for renal tubular dysfunction were: one out of three signs (low molecular weight proteinuria, glucosuria,
         and generalized aminoaciduria), %TRP < 80% and acidosis (blood hydrogen carbonate below 23 mEq/litre).
    b    The total number of people living in polluted areas in each prefecture is shown in Table 7.
    c    Total number of people examined was 5657 males and 6902 females in polluted areas and 2782 males and 3653 females in non-polluted areas.
    d    Significant difference (P < 0.01)
    e    Significant difference (P < 0.05)

    Table 18.  Prevalence (%) of tubular proteinuriaa in relation to age (age-groups 50-59, 60-69, and > 69) and
               village-average rice cadmium concentrationsb
                                                                                                                                             

    Rice cadmium                 50-59                                  60-69                             > 69
    concentration
    (µg/g)              No.      A (%)        B (%)          No.        A (%)      B (%)        No.       A (%)       B (%)
                                                                                                                                             

    Control (< 0.1)    104       0.96         0              80         2.50       1.25         64         0           0

    0.19-0.29          477       0.84         0.42          377         2.65       0.80        268        13.81c       4.48

    0.30-0.39          184       3.26         2.72          138         5.07       0.72         91        17.58c       7.69d

    0.40-0.49          295       1.69         0.34          204         6.86       2.94        117        14.53c       8.55c

    0.50-0.59          140       0.71         0             120        10.83d      5.00         93        34.41c      25.81c

    0.60-0.69           60      18.33c        5.00d          57        24.56c     12.28c        23        73.91c      43.48c
                                                                                                                                             

    a    Prevalence of increased RBP in Ishikawa prefecture only
    b    From: Nogawa et al. (1978); No. = number of people examined; RBP was measured by a semiquantitative method; values in column A refer
         to the prevalence of RBP in urine at levels above 4 mg/litre; values in column B refer to the prevalence at values above 16 mg/litre
    c    Significant difference (P < 0.01) compared with control
    d    Significant difference (P < 0.05) compared with control

    

    FIGURE 10


    FIGURE 11

         In a later epidemiological study, Nogawa et al. (1989)
    investigated the dose-response relationship in 1850 cadmium-exposed
    and 294 non-exposed inhabitants of the Kakehashi River basin. Using
    a urine concentration of 1000 µg ß2-microglobulin/g creatinine as
    an index of renal tubular dysfunction, and the average rice cadmium
    concentration as an index of cadmium exposure, the authors
    determined linear regression equations for men and women. These are
    related to the prevalence of ß2-microglobulinuria and total
    cadmium intake and are shown in Table 19. The authors concluded that
    the total cadmium intake that produced an adverse effect on health
    was approximately 2000 mg for both men and women. On the basis of
    the linear regression equations shown in Table 19, an average daily
    cadmium intake of 440 µg/day in men and 350 µg/day in women would
    be expected to cause a 50% response rate (> 1000 µg 
    ß2-microglobulin/litre urine). Response rates of 20, 10 and 5%
    would occur at daily intakes of 220, 150, and 110 µg/day for men and
    200, 150, and 120 µg/day for women. The authors indicated that these
    data are in general agreement with results from other studies
    involving the consumption of various levels of cadmium in rice.

    8.3.3.5  Akita prefecture (Kosaka area)

         Around Kosaka mine and refinery areas, increased cadmium levels
    in rice were first reported by the Akita Prefectural Government
    (1973). Kojima et al. (1976) gave further data from the Kosaka area,
    where the reported average cadmium level in rice varied between 0.26
    and 0.56 mg/kg. The latter average was based on 41 samples where one
    was reported to contain 4.81 mg/kg. In the exposed area, the
    weighted average of cadmium levels in rice in each district
    according to the number of examinees was calculated by Kojima et al.
    (1976) to be 0.57 mg/kg in 1973 and 0.50 mg/kg in 1974. These
    values, according to Kojima et al. (1976), represented the level of
    cadmium exposure in this study and were considered more accurate
    than the general average given above.

         In an epidemiological investigation of the total population in
    the age-group 50-69 of defined geographical areas (93 out of 98 in
    the control area and 156 out of 190 in the exposed area
    participated), Kojima et al. (1976, 1977) obtained data on faecal
    excretion of cadmium. The cadmium level in 24-h faeces samples was
    analysed only for those participants who said that they defaecated
    once a day (64 in the control area and 118 in the polluted area).
    Average rates were 51 µg/day and 177 µg/day for the control and
    exposed groups, respectively (Kojima et al., 1976). The prevalence
    of proteinuria exceeding 150 mg/litre (using the Tsuchiya biuret
    method) and of combined proteinuria and glucosuria (test tape) was
    significantly higher in the exposed group than in the control group
    (Kojima et al., 1976).


        Table 19.  Linear regression equations relating total cadmium intake and prevalence of ß2-microglobulinuriaa
                                                                                                                       

    Sex       ß2-microglobulinuria        Linear regression        Prevalence of                Total cadmium intake
                                          equationb                ß2-microglobulinuria               (mg)c
                                                                   in the control group (%)
                                                                                                                       

    Male      > 1000 µg/litre             Y = 0.0076X - 10.33             5.3                          2057

              > 1000 µg/g creatinine      Y = 0.0083X - 7.93              6.0                          1678

    Female    > 1000 µg/litre             Y = 0.011X - 19.61              3.1                          2065

              > 1000 µg/g creatinine      Y = 0.012X - 16.16              5.0                          1763
                                                                                                                       

    a    From: Nogawa et al. (1989)
    b    Y = prevalence of ß2-microglobulinuria (%); X = total cadmium intake (mg)
    c    Total cadmium intake yielding a ß2-microglobulinuria prevalence equivalent to the control group

    

         Quantitative analysis of urinary ß2-microglobulin with
    radioimmunoassay (RIA) was performed on the same population (Kojima
    et al., 1977). The frequency distributions were log-normal, as for
    occupationally exposed people, and the prevalence of
    ß2-microglobulin excretion was 15% in the whole exposed group and
    3% in the control group. The exposed and control groups showed
    average faecal cadmium excretion rates of 139 and 41 µg per day,
    respectively (Kojima et al., 1977).

         The ß2-microglobulin data and cadmium intake data in the
    study by Kojima et al. (1977) were divided into three dose groups
    (Kjellström et al., 1977b) and analysed for a dose-response
    relationship by Hutton (1983).

         Further studies of urinary ß2-microglobulin over the age
    range 5-90 years were reported by Saito et al. (1981). The RIA
    method was used, and a control area in Akita prefecture was compared
    with cadmium-polluted areas in Akita prefecture (Kosakai), Ishikawa
    prefecture (Kakehashi) (section 8.3.3.3), and Nagasaki prefecture
    (Tsushima) (section 8.3.3.5). For people over the age of 40, there
    were significant increases in average urinary ß2-microglobulin
    excretion in all the polluted areas. In the older age-groups, the
    increase was 10-100 times above control values.

         In the first comprehensive study of proximal renal tubular
    functions performed on a population living in a cadmium-polluted
    area, Saito et al. (1977) conducted health examinations within Akita
    prefecture. Renal tubular function tests consisted of renal
    glucosuria, uric acid clearance, low molecular weight proteinuria,
    tubular reabsorption of phosphate, hydrogen carbonate threshold,
    acid-base balance, concentrating and acidifying ability of urine,
    endogenous creatinine clearance, and renal plasma flow. Of the 147
    residents (97% of target population) examined, 33 (22%) had some
    indications of proximal renal tubular dysfunction, such as renal
    glucosuria and low molecular weight proteinuria. In addition, 10
    subjects (7%) were diagnosed as having multiple proximal renal
    tubular dysfunctions. Detailed examinations revealed that none of
    these 10 subjects had experienced any other environmental exposures
    or diseases that could have caused the renal dysfunction. They were
    therefore diagnosed as suffering from the effects of chronic cadmium
    poisoning (Saito et al., 1977).

    8.3.3.6  Nagasaki prefecture (Tsushima area)

         This area has been a lead and zinc mining district from ancient
    times (Takabatake, 1978b). Modern operations started in 1948, and
    mining wastes have been scattered throughout the local area. In
    1952, local farmers complained about the poor growth of crops. In
    the 1960s, studies of cadmium pollution were carried out. Health
    examinations for cadmium effects have been conducted since 1966
    (Takabatake, 1978b).

         Early studies showed an increased prevalence of proteinuria in
    the most polluted village, and an average rice cadmium level of
    0.75 mg/kg was reported (Takabatake, 1978b).

         The study of urinary ß2-microglobulin according to age
    referred to in section 8.3.3.4 (Saito et al., 1981) included an
    exposed group of people from Tsushima. The age-specific average
    urinary excretions were much higher than the control values and
    similar to those found in the Kakehashi and Kosaka areas. For women,
    the Tsushima values appear higher than those of the other two
    polluted areas (Table 17), which may reflect the higher estimated
    average cadmium intake in the Tsushima area.

    8.3.3.7  Other Japanese areas

         As shown in Table 7, health surveys have been performed in
    areas other than Fuchu, Ikuno, Kakehashi, Kosaka, and Tsushima.
    According to the Japanese Cadmium Research Committee (1989), it
    should be emphasized, however, that no cadmium health effects,
    including elevated prevalence of ß2-microglobulinuria, were
    observed in some areas with higher levels of cadmium (daily intakes
    of 180-309 µg in Bandai, Fukushima; 180-380 µg in Annaka, Gunma; and
    222-391 µg in Okutake river basin, Oita) even than Kosaka and
    Kakehashi (cadmium in rice = 0.16-0.58 mg/kg, daily intake of
    cadmium = 139-177 µg in Kosaka, Akita; cadmium in rice =
    0.2-0.8 mg/kg, daily intake of cadmium = 160-190 µg in the Kakehashi
    river basin, Ishikawa). Also, no health effects were found in the
    Uguisuzawa river basin, Miyagi (cadmium in rice = 0.6-0.7 mg/kg),
    Watarase river basin, Gunma (0.32 mg/kg), Shimoda, Shizuoka
    (0.4-1.1 mg/kg), and Ohmuta, Fukuoka (0.72 mg/kg), even though
    residents consumed rice heavily contaminated with cadmium.

    8.3.3.8  Belgium

         The Liege area of Belgium is known to be polluted by cadmium,
    mainly due to the activities of non-ferrous smelters since the end
    of the 19th century (Kretzschmar et al., 1980; Lauwerys et al.,
    1980a).

         A pilot study was performed in 1979 on a group of 60 elderly
    non-smoking women who had spent most of their lives in the Liege
    area and had never been occupationally exposed to cadmium (Roels et
    al., 1981a). Daily intakes of cadmium ranged from 2-88 µg/day with
    an average of 15 µg/day. Their average blood cadmium level
    (1.6 µg/litre) and their urinary excretion rates of cadmium
    (0.093 µg/h), total protein (17.3 mg/h), amino acids (5.45 mg amino
    acid N/h), and albumin (1.54 mg/h) were higher than those found in a

    group of 70 women of the same age and socio-economic status who
    lived in another industrial area (Charleroi) less polluted by
    cadmium. Although the average excretion rate of ß2-microglobulin
    was greater in Liege (93.6 µg/h) than in Charleroi (22 µg/h), the
    difference between the geometric means was not statistically
    significant. The two areas were well matched with respect to their
    environmental pollution by sulfur dioxide, fume, suspended
    particles, and various metals, including lead, vanadium, nickel,
    chromium, and iron.

         Following these observations, a mortality study and a
    preliminary autopsy study were undertaken (Lauwerys & De Wals, 1981;
    Lauwerys et al., 1984a). It was found that, although the overall
    mortality was not markedly different, the standard mortality ratio
    (SMR) and proportional mortality rate (PMR) from nephritis and
    nephrosis for the years 1967-1976 were higher in Liege than in
    Charleroi or in Belgium as a whole (SMR: Belgium, 100; Charleroi,
    102; Liege, 196; PMR: Belgium, 3.3; Charleroi, 3.0; Liege, 6.0).
    Since the increased mortality rate for renal diseases was observed
    in both males and females, the influence of environmental factors
    other than occupation is probable.

         The results of the preliminary autopsy study indicated that, in
    the age-group 40-60, the average body burden of cadmium was
    approximately twice as high in people autopsied in Liege as it was
    in those autopsied in a city (Brussels) less polluted by cadmium
    (Lauwerys et al., 1984a). The geometric mean values of cadmium
    concentration in the kidney cortex were 38.3 and 22.8 mg/kg wet
    weight in Liege and Brussels, respectively.

         According to the authors of these reports, the studies
    performed so far in the Liege area do not refute the hypothesis that
    environmental pollution by cadmium in the area has increased the
    body burden of cadmium of the inhabitants and has affected their
    renal function. A large-scale morbidity and autopsy study is at
    present underway (Braux et al., 1987).

    8.3.3.9  Shipham area in the United Kingdom

         The village of Shipham is located on the slag heaps of an old
    zinc mine and high levels of cadmium have been found in soil and
    dust (section 3.4.3).

         The exposed population has been studied using both mortality
    and morbidity end-points. A census in 1979 identified 1092
    residents, of whom 64% had resided in the village for more than 5
    years, and 548 participated in a health study coordinated by the
    United Kingdom Department of the Environment (Barltrop & Strehlow,
    1982a). A similar study of 543 age-and sex-matched individuals was
    performed in a nearby control village (Barltrop & Strehlow, 1982b).
    The daily intake of cadmium in Shipham was an average of 35 µg/day
    (section 4.2.4), which is about twice as high as the estimated
    United Kingdom national average but much lower than in polluted
    areas of Japan (section 5.2.4).

         A health inventory was compiled by means of a questionnaire,
    which included information on smoking habits, alcohol consumption,
    medication, and occupation. Blood samples were analysed for
    haemoglobin, haematocrit, serum protein, ß2-microglobulin,
    creatinine, erythrocyte protoporphyrin, lead, and cadmium. Urine
    samples were analysed for total protein, creatinine, ß2-micro-
    globulin, and cadmium.

         The mean 24-h urinary concentration of cadmium for Shipham
    residents was 0.68 µg cadmium/g creatinine and, in the control area,
    0.60 µg cadmium/g creatinine with 97.7% of values less than 3.4 µg
    cadmium/litre. The difference was statistically significant
    (P < 0.03) (Barltrop & Strehlow, 1982b), but the similarity of the
    values for average urinary cadmium concentrations between the two
    areas and the generally low levels of cadmium in Shipham suggest a
    rather low daily cadmium intake.

         However, there are data showing that some individuals in
    Shipham had high cadmium exposures. Liver cadmium concentrations,
    measured by means of  in vivo neutron activation analysis, were
    determine for 21 adult volunteers living in the most heavily
    contaminated areas of Shipham (Harvey et al., 1979). Their age range
    was 40-62 years (mean, 53 years) and, with one exception, they had
    lived in Shipham for 9-50 years (mean, 23 years). On average, half
    of their vegetable consumption was of local origin. The mean liver
    cadmium concentration was 11.0 (+ 2.0) mg/kg, compared with 2.2
    (+ 2.0) mg/kg in 20 age-matched, non-Shipham controls (P < 0.001).
    The maximum concentration in the Shipham group was 28 mg/kg, which
    would correspond to levels in the kidney cortex of at least
    200-300 mg/kg (Friberg, 1979) (section 6.4). Health effects were not
    studied in this investigation.

         In the health study by the Department of the Environment
    (Barltrop & Strehlow, 1982a), the comparison of ß2-microglobulin
    data from the two villages showed similar distributions, and all
    other laboratory data, including blood pressure levels, were

    distributed within the normal range. However, the poor participation
    rate in this health study (50%), makes it difficult to interpret the
    findings. Another study of 31 volunteers from Shipham (Carruthers &
    Smith, 1979) reported a high prevalence of hypertension and LMW
    proteinuria, but the methodology of the study has been criticized
    (Hughes & Stewart, 1979; Kraemer et al., 1979).

         Examination of the data in relation to soil cadmium levels
    showed no evidence of an increased mortality from any cause in those
    living in the most polluted areas. It was concluded from this study
    that, if cadmium contamination had any effect on the mortality
    pattern in Shipham, this effect was only slight and did not present
    a serious health hazard to residents. No case resembling Itai-itai
    disease has at any time been reported in Shipham. All the authors
    involved in the health studies in Shipham pointed to the possible
    protective effect of high levels of zinc also present in soil, and
    Kraemer et al. (1979) pointed to the need to assess dietary zinc and
    the intake of nutrients other than cadmium.

    8.3.3.10  USSR

         Screening of populations, both environmentally and
    occupationally exposed, which included measurements of urinary
    ß2-microglobulin, has been carried out within the USSR (Likutova,
    1989). Increased prevalence (up to 6%) of ß2-micro-globulinuria
    (> 280 µg/g creatinine) was observed in females (20-50 years old)
    in some of the most heavily polluted cities, i.e. Odjonikidze and
    Kursk. The air cadmium concentrations in these two cities were
    0.085 µg/m3 and 0.005-0.027 µg/m3, respectively. The examination
    of workers (50-300 µg/m3) exposed to cadmium also revealed an
    increased prevalence of ß2-microglobulinuria (up to 19% in the
    most heavily exposed group). The findings are in good agreement with
    the data presented in Table 15.

    8.4  Conclusions

         High inhalation exposure to cadmium oxide fume results in acute
    pneumonitis with pulmonary oedema, which may be lethal. High
    ingestion exposure of soluble cadmium salts causes acute
    gastroenteritis.

         Long-term occupational exposure to cadmium has caused severe
    chronic effects, predominantly in the lungs and kidneys. Chronic
    renal effects have also been seen among the general population.

         Following high occupational exposure, lung changes are
    primarily characterized by chronic obstructive airway disease. Early
    minor changes in ventilatory function tests may progress, with
    continued cadmium exposure, to respiratory insufficiency. An
    increased mortality rate from obstructive lung disease has been seen
    in workers with high exposure, as has occurred in the past.

         The accumulation of cadmium in the renal cortex leads to renal
    tubular dysfunction with impaired reabsorption of, for instance,
    proteins, glucose, and amino acids. A characteristic sign of tubular
    dysfunction is an increased excretion of low molecular weight
    proteins in urine. In some cases, the glomerular filtration rate
    decreases. Increase in urine cadmium correlates with low molecular
    weight proteinuria and in the absence of acute exposure to cadmium
    may serve as an indicator of renal effect. In more severe cases
    there is a combination of tubular and glomerular effects, which may
    progress in some cases to decreased glomerular filtration. For most
    workers and people in the general environment, cadmium-induced
    proteinuria is irreversible.

         Among other effects are disturbances in calcium metabolism,
    hypercalciuria, and formation of renal stones. High exposure to
    cadmium, most probably in combination with other factors such as
    nutritional deficiencies, may lead to the development of
    osteoporosis and/or osteomalacia.

         There is evidence that long-term occupational exposure to
    cadmium may contribute to the development of cancer of the lung but
    observations from exposed workers have been difficult to interpret
    because of confounding factors. For prostatic cancer, evidence to
    date is inconclusive but does not support the suggestion from
    earlier studies of a causal relationship.

         At present, there is no convincing evidence for cadmium being
    an etiological agent of essential hypertension. Most data speak
    against a blood pressure increase due to cadmium and there is no
    evidence of an increased mortality due to cardiovascular or
    cerebrovascular disease.

         Data from studies on groups of occupationally exposed workers
    and on groups exposed in the general environment show that there is
    a relationship between exposure levels, exposure durations, and the
    prevalence of renal effects.

         An increased prevalence of low molecular weight proteinuria in
    cadmium workers after 10-20 years of exposure to cadmium levels of
    about 20-50 µg/m3 has been reported.

         In polluted areas of the general environment, where the
    estimated cadmium intake has been 140-260 µg/day, effects in the
    form of increased low molecular weight proteinuria have been seen in
    some individuals following long-term exposure.

    9.  EVALUATION OF HUMAN HEALTH RISKS

    9.1  Exposure assessment

    9.1.1  General population exposure

         In the ambient air, cadmium concentrations based on long-term
    sampling periods indicate, in most cases, a range of
    0.001-0.015 µg/m3 in rural areas, 0.005-0.05 µg/m3 in urban
    areas, and up to 0.6 µg/m3 near sources of pollution (section
    5.1.1).

         One cigarette usually contains 1-2 µg cadmium, of which about
    10% may be inhaled (section 5.1.3).

         Among staple foods, rice and wheat usually contain less than
    0.1 mg/kg and other foods usually less than 0.05 mg/kg wet weight,
    but liver and kidney may contain 1-2 mg/kg wet weight and certain
    sea-foods as much as 10 mg/kg wet weight (section 5.2). Certain
    animals, e.g., the horse, may accumulate considerably higher
    concentrations in the liver and kidney. In polluted areas, these
    levels are further increased.

         The content of natural waters is usually less than 1 µg/litre,
    but higher levels may be found near sources of pollution.

         The total daily intake in non-polluted areas of most countries
    from food, water and air is estimated to be approximately
    10-40 µg/day (food, 10-40 µg/day; water, < 1 µg; and air,
    < 0.5 µg/day for non-smokers).

         Twenty cigarettes per day would contribute a further 2-4 µg. In
    polluted areas, the daily intake may be much higher, and intakes of
    several hundred µg/day have been reported (section 5.3.2).

    9.1.2  Occupational exposure

         Air is the main source of additional cadmium exposure for
    industrial workers. In many countries such exposures have now been
    reduced considerably. In the past, levels of several mg/m3 were
    recorded in workplaces. Now, with proper industrial hygiene
    practices, levels of 0.02-0.05 mg/m3 would be more typical
    (section 5.1.2).

    9.1.3  Amounts absorbed from air, food, and water

         The proportion of cadmium from food and water that is absorbed
    will depend on the chemical nature of the cadmium compounds, but
    estimates based on the available data indicate that gastrointestinal
    absorption is approximately 5%, with considerable individual

    variation (section 6.1.2). Similarly, the amount absorbed from the
    air will depend on the chemical nature and the particle size of the
    inhaled material. The absorption varies between 25 and 50% depending
    on particle size and solubility (section 6.1.1). About 10% of the
    cadmium inhaled in cigarette smoke is absorbed.

         Thus, the average amount absorbed from food and water in a
    person from a non-polluted area would be about 0.5-1.3 µg/day. The
    absorbed amount from smoking 20 cigarettes per day would be
    1-2 µg/day and that from workroom air could be many times greater
    (section 5.3).

    9.2  Dose-effect relationships

    9.2.1  Renal effects

         Long-term exposure to cadmium causes renal tubular dysfunction
    with proteinuria, glucosuria, and aminoaciduria, as well as
    histopathological changes, in both experimental animals and humans
    (sections 7.2.1.4 and 8.2.1, respectively). These are usually the
    first effects to occur after ingestion or inhalation exposure. As
    the renal dysfunction progresses in severity, the glomeruli may also
    be affected and, in a few cases, the cadmium-induced damage may lead
    to renal failure (section 8.2.1). Daily cadmium intakes in food of
    140-260 µg/day for more than 50 years or workplace air exposures of
    50 µg/m3 for more than 10 years have produced an increase in renal
    tubular dysfunction in some exposed popu-lations (section 8.3.3.2).

    9.2.2  Bone effects

         Cadmium may produce bone effects in both humans and animals.
    The most notable clinical entity in these cases is osteomalacia, but
    many subjects also show osteoporosis. Animal experiments show that
    both can be produced by long-term cadmium exposure (section 7.2.4).
    In animals and humans, osteomalacia has been seen in combination
    with cadmium-induced renal damage. The bone effects may be linked to
    cadmium effects on calcium and vitamin D metabolism in the kidney.
    The daily intakes via food and exposure levels in air at which the
    bone effects occur are uncertain, but they must be higher than those
    causing renal effects. Bone effects have been seen among both the
    general population and industrial workers in the past when exposure
    levels were very high. Host and nutritional factors influence the
    development and severity of cadmium-induced bone effects.

    9.2.3  Pulmonary effects

         Chronic obstructive airway disease has been reported in a
    number of studies of cadmium workers (section 8.2.3). This has, in
    severe cases, led to an increased mortality. The dose needed to
    produce these effects is uncertain, but it is higher than the dose
    needed to produce renal effects, as most workers reported to have
    lung effects also had renal effects. On the other hand, many workers
    with renal effects, who had been exposed to cadmium oxide dust and
    fume, had no lung effects.

    9.2.4  Cardiovascular effects

         Some animal studies have shown that, under certain exposure
    conditions, increased blood pressure and effects on the myocardium
    occur. Studies of cadmium-exposed workers and people in the general
    environment have been carried out, but most data do not support the
    animal findings.

    9.2.5  Cancer

         There is evidence that cadmium chloride, sulfate, sulfide and
    oxide give rise to injection site sarcomata in the rat and that the
    chloride and sulfate induce interstitial cell tumours of the testis
    in rats and mice.

         Long-term inhalation studies in rats exposed to aerosols of
    cadmium chloride, sulfate, and oxide fume and dust at low
    concentrations demonstrated a high incidence of primary lung cancer
    with evidence of a dose-response relationship. This has not so far
    been shown in other animals.

         There is evidence that long-term occupational exposure to
    cadmium may contribute to the development of cancer of the lung, but
    observations from exposed workers have been difficult to interpret
    because of inadequate exposure data and confounding factors. The
    evidence to date is inconclusive, but does not support the
    suggestion from earlier studies that cadmium can cause prostatic
    cancer.

         IARC (1987a) considered that there was sufficient evidence for
    the carcinogenicity of specified cadmium compounds in experimental
    animals and limited evidence for carcinogenicity in humans exposed
    to cadmium. A combined evaluation of human and animal data by IARC
    (1987b) classified cadmium as a probable human carcinogen (IARC
    group 2A). The IPCS Task Group found no reason to deviate from this
    IARC evaluation.

    9.2.6  Critical organ and critical effect

         The kidney is the critical organ for chronic cadmium poisoning.
    Within the kidney, the cortex is the site where the first adverse
    effect occurs. Therefore, in assessing dose-response relationships,
    the cadmium concentration in the kidney cortex is of prime
    importance.

         The critical effect is renal tubular dysfunction, which is most
    often manifested as low molecular weight proteinuria. Animal studies
    indicate that histological changes in the renal tubules occur at a
    dose level lower than that needed to produce low molecular weight
    proteinuria.

    9.3  Critical concentration in the kidneys

    9.3.1  In animals

         Several studies with data on both cadmium concentrations in the
    renal cortex and the occurrence of tubular damage were discussed in
    section 7.2.1. The findings were summarized in Table 12. They showed
    that histological tubular lesions or proteinuria was usually seen at
    cadmium renal cortex levels of 200-300 mg/kg wet weight. In some
    studies on rats, monkeys, horses, and birds, certain effects were
    seen at lower levels.

         As no dose-response data are given in most animal studies, it
    may be assumed that these renal cortex levels correspond to a 50%
    response rate (CC50). Naturally, the cadmium levels at which lower
    response rates occur would be lower.

         In studies on monkeys conducted in Japan, kidney cadmium levels
    were related to dose and duration of exposure. At the two highest
    dose levels, acute liver effects occurred. If one wishes to
    establish a range of values for the critical concentration in
    individuals at which a small but significant part of an exposed
    population will show effects, animal studies indicate that a renal
    cortex level of about 100-200 mg/kg is likely to coincide with such
    a range. There is some evidence that the average critical
    concentration (CC50) could be as high as 300 or 400 mg/kg for the
    more severe signs of renal tubular damage, but such high levels
    should not be used as a starting point for calculations of
    "acceptable daily exposures".

    9.3.2  In humans

         Section 8.2.1.5 reviewed all available data from cases in which
    both renal cortex cadmium levels and renal effects were measured.
    Data from autopsies or biopsies have mainly been cross-sectional,
    i.e. the renal cadmium concentrations and the effects were measured
    more or less simultaneously. This has made it difficult to interpret
    the data from a critical concentration point-of-view, as the cases
    with the most severe cadmium-induced kidney dysfunction had the
    lowest renal cadmium levels. Cadmium is lost from the kidney when
    the damage progresses (section 6.5.1.2).

          In vivo neutron activation analysis has provided a new tool
    for establishing the human critical concentration of cadmium in the
    renal cortex. Longitudinal studies measuring the renal cortex
    cadmium concentration several times during continued exposure can
    now be carried out. The cadmium level at which the first measurable
    signs of renal tubular dysfunction occurs can be estimated. However,
    only two studies using  in vivo neutron activation have been
    published to date, and both of them are cross-sectional.

         The renal cadmium concentrations are disproportionately low
    when the liver cadmium concentrations are high and renal effects
    have developed. Of the several methods available to estimate the
    average critical kidney concentration in these groups of exposed
    workers, the method of preference assumes that the peak for renal
    cortex cadmium level, plotted against liver cadmium, is equivalent
    to the point where renal tubular dysfunction occurs. This results in
    a value of 319 mg/kg tissue (based on a ratio of renal cortex
    cadmium to whole kidney cadmium of 1.5). There is considerable
    variance in the individual values, the 95% tolerance (which
    corresponds to a confidence interval) being in the range ± 90 mg/kg
    from the mean. Other studies, using similar assumptions, have
    reported a value of 332 mg/kg, 10% of the workers having a peak
    cadmium level of about 216 mg/kg tissue. A re-evaluation of the
    original study resulted in a calculated cadmium level of about
    200 mg/kg. It was concluded that for the purposes of dose-response
    calculations, using a metabolic model, this concentration could be
    used as a starting point for renal effects occurring in an exposed
    population.

    9.4  Dose-response relationships for renal effects

         Two approaches can be used to estimate dose-response
    relationships. One employs epidemiological data from industry and
    the general environment studying associations between exposure and
    response. The other begins with a critical concentration in the
    kidney cortex and employs a metabolic model to calculate, on the
    basis of certain given assumptions, the exposure that is required to
    reach a critical concentration.

    9.4.1  Evaluation based on data on industrial workers

         Table 16 contains data from various group studies on cadmium
    workers. In most of these studies, the dose measurements were based
    on short sampling periods (hours or a few days). However, exposure
    may have lasted for decades, levels usually being higher in the
    past. The use of protective devices may also confound the picture.

         As discussed in section 8.3.2, there are now several reports
    available that show a clear exposure-response relationship between
    cadmium in workplace air and the prevalence of proteinuria.

         An increased prevalence of overt proteinuria, as measured by
    sulfosalicylic acid, trichloroacetic acid, or quantitative
    determination of total proteinuria, can occur after only 5-10 years
    of exposure to approximately 100 µg cadmium/m3. If instead, the
    increased excretion of low molecular weight proteins (more than 97.5
    percentile of control group) is used as the critical effect, 10-20%
    of workers would have this effect after a cumulative dose
    corresponding to 10-20 years of exposure to 50 µg cadmium/m3.
    These evaluations are all based on levels of total cadmium in
    inhaled dust or air.

    9.4.2  Evaluation based on data on the general population

         As indicated in chapter 8, there exists a considerable amount
    of information from epidemiological studies carried out on the
    general population in Japan. It was shown that in some areas of high
    cadmium exposure the prevalence of low molecular weight proteinuria
    was significantly higher than in control areas. This may be
    considered in relation to the known cadmium concentrations in rice
    and the daily cadmium intakes in the affected areas (Tables 7 and
    17). Contamination of drinking-water in some areas may be a
    complicating factor (section 8.3.3).

         Taking all of the data in section 8.3.3 together, it seems
    that, when the most sensitive method for diagnosis of low molecular
    weight proteinuria is applied, there is an association between
    cadmium exposure and increased excretion of low molecular weight
    proteins among some people over 50 years of age at a daily intake of
    about 140-260 µg cadmium or a cumulative cadmium intake of about
    2000 mg or more (for both men and women).

    9.4.3  Evaluation based on a metabolic model and critical
           concentrations

         Using the data on critical concentrations and kinetic models of
    cadmium metabolism, attempts have been made to calculate the
    dose-response relationship for cadmium. Assuming that cadmium in the
    kidney is accumulated in accordance with a one-compartment model and
    that a third or a quarter of the body burden of cadmium is in the

    kidney (and making certain other assumptions indicated in Tables 20
    and 21), the daily cadmium intake via food and the occupational air
    concentrations needed to reach the critical concentration have been
    calculated (Tables 20 and 21).

         As the values calculated in Tables 20 and 21 are for an average
    person, not all of those exposed to these levels would have reached
    the renal cortex cadmium concentration of 200 mg/kg tissue or their
    individual critical concentration. Nevertheless, these calculations
    produce values that are similar to the levels at which effects have
    been observed, and the model approach may be a useful way to
    quantify the response rates at levels lower than those easily
    measurable.

         Calculations have been reported of the relationship between
    intake and response rates using the observed frequency distributions
    of daily intake and renal cortex cadmium concentrations, and
    utilizing multi-compartment metabolic model values in the same range
    as those given in Tables 20 and 21. Further development of these
    modelling techniques would be of value.

         Using a single-compartment model for the accumulation of
    cadmium in the kidney, the average daily intake that would give rise
    to an average concentration of 200 mg/kg wet weight in the kidney
    cortex at age 50 would be 260-480 µg/day, assuming 5%
    gastrointestinal absorption, various biological half-times, and
    different proportions of the body burden in the kidneys (Table 19).
    Assuming a 10% absorption rate, the intake needed would be
    140-260 µg per day. These estimates will vary depending on the body
    weight estimates for different populations.


        Table 20.  Calculated daily cadmium intake via ingestion required by a
               non-smoker to reach a kidney cortex concentration of 200 mg/kg
               at age 50 (using a one-compartment model)a
                                                                                   

    Gastrointestinal   Proportion of body    Estimated half-time in kidney cortexb
    absorption rate    burden in kidney
         (%)                                    17 years           30 years
                                                                                   

          5            one-third              365 µg (286 µg)    265 µg (208 µg)
         10                                   182 µg (143 µg)    133 µg (104 µg)

          5            one-quarter            486 µg (382 µg)    353 µg (277 µg)
         10                                   243 µg (191 µg)    177 µg (139 µg)
                                                                                   

    a The data in the table are based on the following assumptions:

      gastrointestinal absorption, either 5% or 10%;
      half-time in kidney cortex, either 17 years or 30 years (as reported in
      section 6.6.2);
      one-third or one-quarter of body burden in the kidneys; 
      cadmium concentration in renal cortex 25% higher than renal average;
      average weight of both kidneys at age 50 of 300 g for a 70-kg person
      or 235 g for a 55-kg person;
      average cadmium concentration in foodstuffs constant during
      the last 50 years;
      variation of daily intake with age has been disregarded since such
      variation would influence the values by less than 10%.

    b Data have been calculated for a 70-kg person; values in parentheses
      are for a 55-kg person.


    Table 21.  Calculated concentration of cadmium in industrial air required
               for a kidney cortex concentration of 200 mg/kg to be reacheda
                                                                                   

    Proportion of body burden     Estimated half-time in kidney cortexb
         in kidney
                                      17 years                30 years
                                                                                   

         one-third                16 µg/m3 (13 µg/m3)    14 µg/m3 (11 µg/m3)
         one-quarter              21 µg/m3 (17 µg/m3)    19 µg/m3 (15 µg/m3)
                                                                                   

    a The data in the table are based on the following assumptions:

      those assumptions given in Table 20;
      exposure time of 25 years;
      225 working days per year;
      10 m3 of air inhaled per day;
      25% pulmonary absorption

    b Data have been calculated for a 70-kg worker; values in parentheses
      are for an average 55-kg person
        10.  CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF
         HUMAN HEALTH

    10.1  Conclusions

         The kidney is considered the critical target organ for the
    general population as well as for occupationally exposed
    populations. Chronic obstructive airway disease is associated with
    long-term high-level occupational exposure by inhalation. There is
    some evidence that such exposure to cadmium may contribute to the
    development of cancer of the lung but observations from exposed
    workers have been difficult to interpret because of confounding
    factors.

    10.1.1  General population

         Food-borne cadmium is the major source of exposure for most
    people. Average daily intakes from food in most areas not polluted
    with cadmium are 10-40 µg. In polluted areas the value has been
    found to be several hundred µg per day. In non-polluted areas,
    uptake from heavy smoking may equal cadmium intake from food.

         An association between cadmium exposure and increased urinary
    excretion of low molecular weight proteins has been noted in humans
    with a life-long daily intake of about 140-260 µg cadmium, or a
    cumulative intake of about 2000 mg or more.

    10.1.2  Occupationally exposed population

         Occupational exposure to cadmium is mainly by inhalation but
    includes additional intakes through food and tobacco. The total
    cadmium level in air varies according to industrial hygiene
    practices and type of workplace. There is an exposure-response
    relationship between airborne cadmium levels and proteinuria. An
    increase in the prevalence of low molecular weight proteinuria may
    occur in workers after 10-20 years of exposure to cadmium levels of
    about 20-50 µg/m3.  In vivo measurement of cadmium in the liver
    and kidneys of people with different levels of cadmium exposure have
    shown that about 10% of workers with a kidney cortex level of
    200 mg/kg and about 50% of people with a kidney cortex level of
    300 mg/kg would have renal tubular proteinuria.

    10.2  Recommendations for protection of human health

         a)  Measures to increase recycling of cadmium should be 
             systematically examined and promising ideas encouraged.

         b)  Information on the importance of minimizing waste discharge 
             of cadmium, particularly into surface waters, should be 
             supplied to countries.

         c)  Public health measures for protection from cadmium 
             exposures would be improved by:

             i)    collection of more data from countries on cadmium  
                   levels in foodstuffs and the environment;

             ii)   determination of tissue cadmium levels and
                   monitoring of health parameters in non-exposed
                   populations and in those living near mines or
                   smelters or exposed to elevated levels of the metal
                   in foodstuffs;

             iii)  technical assistance to developing countries for
                   the training of staff, particularly for cadmium
                   analysis;

             iv)   development of means of reducing cadmium exposure
                   by, for instance, improved working conditions and
                   the dissemination of information on the proper use
                   of fertilizers (which sometimes contain high levels
                   of cadmium), techniques for the disposal of
                   cadmium-containing wastes, etc.

    11.  FURTHER RESEARCH

    a)   There is a need for improved analytical techniques for
         measuring cadmium species and biological indicators of cadmium
         exposure/toxicity, such as ß2-microglobulin, in various
         matrices, and for international centres for quality assurance
         and training.

    b)   The assessment of human exposure to cadmium from all media
         needs to be improved by increased monitoring of cadmium levels
         in the environment. Changes in cadmium levels with time are of
         particular importance.

    c)   Populations with ß2-microglobinuria (both those in the 
         workplace and in the general environment) should be
         longitudinally investigated to determine the nature, severity,
         and prognosis of adverse health effects associated with this
         finding. Further research is needed on ß2-microglobulin as a
         biological indicator of exposure and effect.

    d)   International collaborative efforts should be encouraged to
         examine further the role of cadmium in the development of human
         cancer. Both the general population and industrial workers
         should be studied with special emphasis on the development of a
         common format for analysing and presenting data and the
         collection of additional information on exposure to cadmium,
         tobacco, and other confounding factors. Multiple exposures must
         be considered. It is proposed that a collaborative study
         coordinated by an international body (e.g., IARC) should
         include the existing cohorts in order to obtain better exposure
         data. It should also collect both exposure and effects data in
         a standardized manner, so that the results of different studies
         may be more readily compared. A further approach would be to
         perform a collaborative prospective study identifying all those
         workers who have shown evidence of an effect of cadmium on the
         kidney and who would therefore be considered to have had
         unusually heavy exposure. In such a study, both morbidity and
         mortality data would be collected. Outcome would be studied not
         only for cancer but also for sequelae to renal dysfunction.

    e)   Existing occupational cohorts should be linked, where 
         possible, to regional cancer registers to determine the 
         incidence of prostatic cancer (morbidity) in relation to 
         cadmium exposure.

    f)   To understand the mechanism(s) of cancer induction,
         experimental studies on the bioavailability of cadmium at the
         target site and the interactions between zinc and cadmium would
         be of value. The role of metallothionein induction in the
         target cells of the respiratory tract and its relationship to
         such phenomena as DNA damage and repair and oncogene protein
         structure would be of interest.

    g)   Further information on the long-term health consequences of
         cadmium exposures in the general environment is essential, with
         emphasis on renal dysfunction and other end-points such as
         neurotoxicity and immunotoxicity.

    h)   Studies of the effects of cadmium on calcium-phosphorus
         metabolism and bone density should be conducted on female
         workers to clarify whether these workers are at special risk in
         the occupational setting. The effect of cadmium on the placenta
         and subsequent effects on the fetus, especially in multiple
         pregnancies, need further study.

    i)   The effects of various nutritional deficiencies and of exposure
         to other metals on the transport, accumulation, and toxicity of
         cadmium should be investigated with special reference to bone
         toxicity. These studies should be conducted in humans and
         experimental animals with respect to age, sex, dose-dependence,
         biological half-time, and estimation of critical concentration.

    j)   To provide additional scientific support for the assessment of
         human health risks from cadmium exposure, studies in
         experimental animals addressing the following issues should be
         initiated:

         *    mechanism of cadmium transport into the cell and factors
              controlling the process;

         *    mechanism of cadmium-induced toxicity with particular
              emphasis on kidney and bone and the role(s) of
              non-metallothionein-bound cadmium in these processes;

         *    mechanisms of cadmium-induced calcuria and the
              relationship of this phenomenon to tubular proteinuria and
              osteomalacia.

    12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         The carcinogenic potential of cadmium was evaluated in 1976 by
    the International Agency for Research on Cancer (IARC, 1976) and
    re-evaluated in 1987 (IARC, 1987a). It was concluded in the
    re-evaluation that there was limited evidence that cadmium and
    cadmium compounds are carcinogenic in humans. Sufficient evidence
    was available to show that cadmium and specified cadmium compounds
    cause cancer in experimental animals. Cadmium was classified as a
    probable human carcinogen (group 2A) (IARC, 1987a,b).

         To prevent adverse pulmonary and renal effects the following
    health-based limits for occupational exposure to cadmium fumes and
    respirable dust were proposed by WHO (WHO, 1980): 250 µg Cd/m3 for
    short-term exposures provided the recommended time-weighted average
    (40 h/week) of 10 µg Cd/m3 is respected. It was further
    recommended that control measures be applied when cadmium levels in
    urine and blood of individuals exceed 5 µg Cd/g creatinine and
    5 µg Cd/litre of whole blood, respectively.

         A drinking-water guideline value of 0.005 mg/litre has been set
    for cadmium by the World Health Organization (WHO, 1984).

         Cadmium was evaluated by a WHO Working Group developing air
    quality guidelines (WHO, 1987). Based on non-carcinogenic effects,
    the following recommendations were made:

    a)   in rural areas, levels of < 1-5 ng/m3 should not be allowed
         to  increase, and

    b)   in urban and industrialized areas without agricultural 
         activities, levels of 10-20 ng/m3 may be tolerable. However, 
         increases in the present levels of airborne cadmium should not 
         be permitted (WHO, 1987).

         At the thirty-third meeting of the Joint FAO/WHO Expert
    Committee on Food Additives and Food Contaminants, the previous
    recommendation was reaffirmed, i.e. the provisional tolerable weekly
    cadmium intake of 400-500 µg for an adult should not be exceeded
    (WHO, 1989).

         Regulatory standards established by national bodies in several
    countries and the EEC are summarized in the legal file of the
    International Register of Potentially Toxic Chemicals (IRPTC, 1987).

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    RESUME ET CONCLUSIONS

    1.  Identité, propriétés physiques et chimiques et méthodes
        d'analyse

         Il existe plusieurs méthodes pour le dosage du cadmium dans les
    échantillons biologiques. La plus utilisée est la spectrométrie
    d'absorption atomique, mais elle nécessite un traitement minutieux
    de la prise d'essai et une correction pour tenir compte des
    interférences lorsqu'elle est appliquée à des échantillons de faible
    teneur en cadmium. Il est tout à fait souhaitable que l'analyse
    s'accompagne d'un programme d'assurance de la qualité. A l'heure
    actuelle, il est possible, dans des conditions optimales, de doser
    environ 0,1 µg/litre dans l'urine et le sang et de 1 à 10 µg/litre
    dans les aliments et les tissus.

    2.  Sources d'exposition humaine et environnementale

         Le cadmium est un élément relativement rare et les méthodes
    actuelles d'analyse indiquent, dans les divers compartiments de
    l'environnement, des concentrations beaucoup plus faibles que les
    mesures antérieures. Pour l'instant, il n'est pas possible de
    déterminer si l'activité humaine est à l'origine d'un accroissement
    de la teneur des calottes polaires en cadmium à l'échelle des temps
    historiques.

         La production commerciale de cadmium a commencé au tournant du
    siècle. La consommation a changé de caractère ces dernières années
    avec un recul sensible de la galvanoplastie et une utilisation
    accrue dans la fabrication de batteries et de composants
    électroniques spéciaux. Dans la plupart des cas, le cadmium est
    utilisé sous la forme de dérivés peu concentrés, ce qui rend le
    recyclage indispensable. Les restrictions à l'usage du cadmium
    imposées par certains pays pourraient avoir des répercussions
    importantes sur ces applications.

         Les activités humaines entraînent la libération de cadmium dans
    l'air, le sol et l'eau. D'une façon générale, les deux principales
    sources de contamination sont la production et la consommation de
    cadmium et d'autres métaux non ferreux ainsi que le rejet de déchets
    contenant du cadmium. Dans les zones proches de mines ou de
    fonderies de métaux non ferreux, la contamination par le cadmium est
    souvent importante.

         Plus le sol contient de cadmium, plus la quantité fixée par les
    plantes est importante. L'exposition humaine par l'intermédiaire des
    cultures sera donc sensible à toute augmentation de la teneur du sol
    en cadmium. La fixation par les plantes est plus importante dans les
    sols de faible pH. Les processus qui acidifient le sol (pluies
    acides, par exemple) sont donc susceptibles de provoquer une

    augmentation de la concentration moyenne du cadmium dans les denrées
    alimentaires. Dans certaines régions du monde, l'utilisation
    d'engrais phosphatés et les dépôts d'origine atmosphérique
    constituent une source non négligeable de contamination des terres
    arables; les boues d'égout peuvent aussi, localement, entraîner une
    forte pollution. A l'avenir, ces sources risquent d'accroître la
    contamination du sol et celle des cultures, ce qui débouchera sur
    une exposition plus importante au cadmium par la voie alimentaire.
    Dans certaines régions, on peut constater une augmentation de la
    teneur des aliments en cadmium.

         Les animaux et les plantes comestibles qui vivent à l'état
    sauvage, comme les coquillages, les crustacés et les champignons
    accumulent naturellement le cadmium. Comme chez l'homme, on constate
    une augmentation de la concentration en cadmium dans le foie et les
    reins des chevaux et de certains animaux terrestres vivant à l'état
    sauvage. La consommation régulière de ces abats peut entraîner une
    exposition accrue. Dans les reins de certains vertébrés marins on
    trouve des concentrations assez fortes en cadmium, qui, même si
    elles sont d'origine naturelle, n'en provoquent pas moins des
    lésions au niveau de ces organes.

    3.  Concentrations dans l'environnement et exposition humaine

         La principale voie d'exposition au cadmium des non fumeurs est
    la voie alimentaire. Les autres voies sont peu importantes. Chez les
    fumeurs, l'apport de cadmium par le tabac est notable. Dans les
    zones contaminées, l'exposition d'origine alimentaire peut atteindre
    plusieurs centaines de microgrammes par jour. Chez les travailleurs
    exposés, la principale voie de pénétration est la voie pulmonaire,
    après inhalation d'air contaminé sur le lieu de travail. Le
    tabagisme et la consommation d'aliments contaminés ajoutent encore à
    la charge de cadmium de l'organisme.

    4.  Cinétique et métabolisme chez les animaux de laboratoire et
        chez l'homme

         Les données tirées de l'expérimentation animale et humaine
    montrent que l'absorption est plus importante au niveau des poumons
    qu'au niveau des voies digestives. Selon l'espèce chimique en cause,
    la granulométrie et la solubilité dans les liquides biologiques, le
    taux d'absorption peut atteindre 50% après inhalation. L'absorption
    gastro-intestinale dépend du régime alimentaire et de l'état
    nutritionnel. En particulier, le bilan martial est particulièrement
    important. En moyenne, le cadmium total contenu dans les aliments
    est absorbé à hauteur de 5%, avec un intervalle de variation de
    1%-20% selon les individus. Il existe un gradient materno-foetal de
    cadmium. Le cadmium peut également parvenir jusqu'au foetus, mais en
    faibles quantités malgré son accumulation dans le placenta.

         Le cadmium absorbé au niveau des poumons ou des voies
    digestives s'accumule principalement dans le foie et les reins où il
    représente plus de la moitié de la charge totale de l'organisme.
    Plus l'exposition est intense, plus l'accumulation du cadmium dans
    le foie est importante. En principe, l'excrétion est lente et la
    période biologique du cadmium dans les muscles, les reins, le foie
    et l'organisme dans son ensemble, est très longue, de l'ordre de
    plusieurs décennies. La teneur en cadmium de la plupart des tissus
    augmente avec l'âge. C'est en général dans le cortex rénal que la
    concentration est la plus élevée, mais en cas d'exposition
    excessive, elle peut l'être encore plus dans le foie. Chez les
    personnes exposées atteintes de lésions rénales, il y a augmentation
    de l'excrétion urinaire du cadmium de sorte que la période
    biologique pour l'ensemble de l'organisme est raccourcie. Du fait
    des lésions, le rein perd son cadmium et ces malades finissent par
    présenter une concentration rénale de cadmium plus faible que les
    individus en bonne santé soumis à la même exposition.

         La métallothionéine est une protéine qui joue un rôle important
    dans le transport et le stockage du cadmium et d'autres métaux. Le
    cadmium est capable d'induire la synthèse de cette protéine dans de
    nombreux organes, notamment le foie et le rein. En fixant le cadmium
    intracellulaire, la métallothionéine protège les tissus contre les
    effets toxiques de ce métal. Il est possible, par conséquent, que le
    cadmium non lié à la métallothionéine ait une responsabilité dans
    les lésions tissulaires. On ignore quels peuvent être les autres
    complexes du cadmium présents dans les liquides biologiques.

         L'excrétion urinaire du cadmium dépend de divers facteurs:
    charge totale de l'organisme, exposition récente et lésions rénales.
    Chez les individus peu exposés, la concentration urinaire du cadmium
    dépend principalement de la charge de l'organisme. En cas de lésions
    rénales dues au cadmium, ou même sans lésions de ce genre mais en
    présence d'une exposition excessive, il y a augmentation de
    l'excrétion urinaire. Les individus exposés au cadmium en excrètent
    davantage dans leurs urines lorsqu'ils présentent une protéinurie.
    Après cessation d'une exposition intense, le taux urinaire décroît,
    même s'il y a persistance des lésions rénales. Il faut donc prendre
    plusieurs facteurs en considération pour interpréter le cadmium
    urinaire. L'excrétion par la voie digestive est sensiblement
    équivalente à l'excrétion urinaire mais elle est difficile à
    mesurer. L'excrétion par d'autres voies (lactation, sueur ou passage
    transplacentaire) est négligeable.

         La teneur des matières fécales en cadmium est un bon indicateur
    d'une ingestion récente en l'absence d'exposition par la voie
    respiratoire. Le cadmium sanguin est présent principalement dans les
    hématies, la concentration plasmatique étant très faible. Il existe
    au moins deux compartiments dans le sang, l'un qui correspond à une
    exposition récente, avec une demi-vie de 2-3 mois et l'autre, qui
    est probablement lié à la charge totale de l'organisme et se
    caractérise par une demi-vie de plusieurs années.

    5.  Effets sur les animaux de laboratoire

         Une forte exposition par la voie respiratoire entraîne un
    oedème mortel du poumon. Après injection d'une seule dose,
    apparaissent des lésions testiculaires, une nécrose ovarienne, des
    lésions hépatiques et une atteinte des petits vaisseaux. L'ingestion
    de fortes doses provoque des lésions de la muqueuse gastrique et
    intestinale.

         Une exposition prolongée par la voie respiratoire ou une
    administration intratrachéenne entraîne des altérations pulmonaires
    de nature inflammatoire ainsi qu'une fibrose et donne au tissu
    pulmonaire un aspect qui évoque l'emphysème. L'administration
    prolongée par voie orale ou parentérale affecte principalement le
    rein mais elle a aussi des effets sur le foie et les systèmes
    hématopoiétique, immunitaire et cardio-vasculaire ainsi que sur le
    squelette. Chez certaines espèces et dans des conditions
    déterminées, on a provoqué une hypertension et constaté des effets
    sur le squelette. C'est le stade de la gestation où se produit
    l'exposition qui conditionne les effets tératogènes et les lésions
    placentaires et il peut y avoir interaction avec le zinc.

         Ce sont les effets aigus produits par l'inhalation du cadmium
    ainsi que sa néphrotoxicité chronique qui sont les plus importants
    du point de vue de l'exposition humaine. En cas d'exposition
    prolongée, c'est le rein qui est l'organe critique. Les effets sont
    caractérisés par une lésion des cellules tubulaires entraînant une
    insuffisance tubulaire parfois accompagnée d'insuffisance
    glomérulaire. L'insuffisance tubulaire a pour conséquence une
    perturbation du métabolisme du calcium et de la vitamine D. Selon
    certains travaux, ces troubles pourraient provoquer une ostéomalacie
    ou une ostéoporose. Cependant ces résultats n'ont pas été confirmés
    par d'autres études. On ne peut exclure un effet direct du cadmium
    sur la minéralisation de l'os. Chez l'animal de laboratoire, les
    effets toxiques du cadmium dépendent de certains facteurs génétiques
    et nutritionnels, des interactions avec d'autres métaux, en
    particulier le zinc, et d'un premier traitement éventuel par le
    cadmium susceptible d'avoir stimulé la synthèse de métallothionéine.

         En 1976 et 1987, le Centre international de recherche sur le
    cancer a admis posséder suffisamment de preuves que l'injection de
    chlorure, de sulfate, de sulfure et d'oxyde de cadmium pouvait
    entraîner l'apparition d'un sarcome local chez le rat et, dans le
    cas des deux premiers composés, de tumeurs testiculaires
    interstitielles chez ce même animal et chez la souris. Toutefois, il
    a considéré que les études basées sur l'administration par voie
    orale ne permettaient pas de procéder à une évaluation. Lors
    d'études au cours desquelles on a fait respirer à des rats des
    aérosols de sulfate de cadmium, des vapeurs d'oxyde de cadmium et de
    la poussière de sulfate de cadmium, on a observé une forte incidence
    de cancers primitifs du poumon, avec probablement une relation entre
    la dose et la réponse. Toutefois, ces résultats n'ont pu être
    reproduits chez d'autres espèces. Les travaux relatifs aux effets
    génotoxiques du cadmium ont donné des résultats contradictoires.

    6.  Effets sur l'homme

         Une forte exposition à des vapeurs d'oxyde de cadmium par la
    voie respiratoire entraîne une pneumopathie aiguë, accompagnée d'un
    oedème du poumon qui peut être mortel. L'ingestion de grandes
    quantités de sels solubles de cadmium provoque une gastro-entérite
    aiguë.

         A la suite d'une exposition professionnelle prolongée au
    cadmium, on a observé de graves effets chroniques, principalement au
    niveau des poumons et des reins. On a également observé une
    néphrotoxicité chronique dans la population générale.

         Les altérations pulmonaires consécutives à une exposition
    professionnelle intense sont essentiellement caractérisées par une
    obstruction des voies aériennes. Si l'exposition se poursuit, les
    légers troubles ventilatoires initiaux peuvent déboucher sur une
    insuffisance respiratoire. On a observé un accroissement de la
    mortalité par pneumopathie obstructive chez des travailleurs
    fortement exposés, comme cela se produisait auparavant.

         L'accumulation de cadmium dans le cortex rénal entraîne des
    troubles de la fonction tubulaire et une réabsorption insuffisante,
    par exemple, des protéines, du glucose et des acides aminés.
    L'accroissement de l'excrétion urinaire des protéines de faible
    masse moléculaire est un signe caractéristique de l'insuffisance
    tubulaire. Parfois il y a aussi baisse du taux de filtration
    glomérulaire. L'augmentation du cadmium urinaire est corrélée avec
    une protéinurie de faible masse moléculaire et, en l'absence
    d'exposition, peut servir d'indicateur de l'atteinte rénale. Dans
    les cas graves, les effets tubulaires et glomérulaires s'ajoutent
    s'accompagnant parfois d'une élévation du taux sanguin de
    créatinine. Chez la plupart des travailleurs et autres personnes, la
    protéinurie due à une néphropathie cadmique est irréversible.

         Parmi les autres effets, on peut citer les troubles du
    métabolisme calcique, l'hypercalciurie et la formation de calculs
    rénaux. Une exposition intense au cadmium peut, selon toute
    probabilité lorsqu'elle s'accompagne d'autres facteurs comme une
    carence nutritionnelle, provoquer l'apparition d'une ostéoporose
    et/ou d'une ostéomalacie.

         On est fondé à penser qu'une exposition professionnelle
    prolongée au cadmium peut favoriser l'apparition d'un cancer du
    poumon, mais la présence de facteurs de confusion ne facilite pas
    l'interprétation des observations effectuées sur les travailleurs
    exposés. En ce qui concerne le cancer de la prostate, les données ne
    sont pas concluantes et ne confirment pas, en tout cas, l'hypothèse
    antérieure d'une relation de cause à effet.

         A l'heure actuelle, on ne possède pas de preuve convaincante
    que le cadmium provoque une hypertension essentielle. La plupart des
    données contredisent cette hypothèse et rien n'indique un
    accroissement de la mortalité par maladie cardio-vasculaire ou
    accident vasculaire cérébral chez les personnes exposées.

         D'après les résultats d'études relatives à des groupes exposés
    de par leur profession ou simplement du fait de leur environnement
    général, il semble que la prévalence des effets néphrotoxiques soit
    liée à la durée et à l'intensité de l'exposition.

         Chez des ouvriers de l'industrie du cadmium, on a signalé,
    après 10 à 20 ans d'exposition à des concentrations de l'ordre de
    20-50 µg par mètre cube, une augmentation de la prévalence des cas
    de protéinurie à faible masse moléculaire.

         Dans des zones polluées, où l'on évalue l'apport de cadmium par
    voie orale à environ 140-260 µg/jour, on a observé des effets du
    genre protéinurie à faible masse moléculaire chez des sujets exposés
    pendant une longue période. On trouvera à la section 8 une
    estimation plus précise de la relation dose-réponse.

    7.  Evaluation des risques pour la santé humaine

    7.1  Conclusions

         On estime que le rein est l'organe cible tant dans la
    population générale que chez les groupes professionnellement
    exposés. Une exposition prolongée par inhalation entraîne
    l'apparition d'un syndrome respiratoire obstructif chez certains
    groupes professionnels. Certains détails incitent à penser que cette
    exposition au cadmium pourrait favoriser l'apparition d'un cancer du
    poumon, mais les observations effectuées sur des travailleurs
    exposés sont difficiles à interpréter en raison de la présence de
    facteurs de confusion.

    7.1.1  Population générale

         Pour la plupart des individus, les aliments constituent la
    principale voie d'exposition au cadmium. Dans la plupart des régions
    non polluées par ce métal, l'apport alimentaire journalier est de
    l'ordre de 10-40 µg. Dans les zones polluées, il peut atteindre
    plusieurs centaines de microgrammes par jour. Dans les zones non
    polluées, l'apport dû au tabac peut être égal à l'apport alimentaire
    chez les gros fumeurs.

         D'après un modele biologique, on estime qu'il existe une
    association entre l'exposition au cadmium et l'excrétion urinaire de
    protéines de faible masse moléculaire chez les sujets qui absorbent
    pendant toute leur vie une dose journalière d'environ 140-260 µg de
    cadmium, ce qui correspond à une dose cumulée d'environ 2000 mg ou
    davantage.

    7.1.2  Groupes professionnellement exposés

         Dans ce cas, l'exposition est essentiellement respiratoire,
    mais il s'y ajoute l'apport alimentaire et tabagique. La teneur
    totale de l'air en cadmium varie selon les pratiques en matière
    d'hygiène industrielle et selon le lieu de travail. Il existe une
    relation de type exposition-réponse entre la teneur de l'air en
    cadmium et la protéinurie de faible masse moléculaire. La prévalence
    de cette protéinurie peut augmenter après 10 à 20 ans d'exposition à
    des concentrations de cadmium de l'ordre de 20-50 µg par mètre cube.
     In vivo, le dosage du cadmium dans les reins et le foie de sujets
    plus ou moins exposés a montré que 10 % environ des travailleurs
    dont le cortex rénal contenait 200 mg/kg de cadmium et 50 % de ceux
    chez qui cette concentration atteignait 300 mg/kg, feraient un jour
    ou l'autre une protéinurie par insuffisance tubulaire.

    RESUMEN Y CONCLUSIONES

    1.  Identidad, propiedades físicas y químicas, y métodos analíticos

         Se dispone de varios métodos para determinar el cadmio presente
    en el material biológico. El más utilizado es la espectrometría de
    absorción atómica, aunque el análisis de muestras con
    concentraciones bajas de cadmio exige un tratamiento cuidadoso de
    las muestras y correcciones para tener en cuenta la interferencia.
    Se recomienda encarecidamente acompañar el análisis con un programa
    de garantía de la calidad. Actualmente, en circunstancias ideales
    pueden determinarse concentraciones de alrededor de 0,1 µg/litro en
    la orina y la sangre y de 1-10 µg/kg en alimentos y muestras de
    tejidos.

    2.  Fuentes de exposición humana y ambiental

         El cadmio es un elemento relativamente raro; los procedimientos
    analíticos actuales indican que las concentraciones del metal en el
    medio ambiente son mucho más bajas que las obtenidas en medidas
    anteriores. Hoy en día no es posible determinar si la actividad
    humana ha provocado un aumento histórico de los niveles de cadmio en
    los casquetes polares.

         La producción comercial de cadmio comenzó a principios de este
    siglo. La pauta de consumo de cadmio se ha modificado en los últimos
    años debido al notable descenso del uso de la galvano-plastia y al
    importante aumento de la producción de baterías y de las
    aplicaciones electrónicas especializadas. En las principales
    aplicaciones del cadmio éste se utiliza en forma de compuestos que
    se hallan presentes en bajas concentraciones; ello obstaculiza el
    reciclaje del metal. Las restricciones impuestas por algunos países
    a ciertas aplicaciones del cadmio pueden tener un efecto
    generalizado en esas aplicaciones.

         El cadmio se libera al aire, los suelos y las aguas debido a la
    actividad humana. En general, las dos fuentes principales de
    contaminación son la producción y el consumo de cadmio y de otros
    metales no ferrosos y la evacuación de desechos que contienen
    cadmio. Las zonas próximas a minas no ferrosas y fundiciones suelen
    estar muy contaminadas por cadmio.

         Al aumentar el contenido de cadmio del suelo, aumenta la
    absorción del metal por las plantas; la exposición humana a partir
    de las cosechas agrícolas está por tanto sometida a los aumentos del
    contenido de cadmio del suelo. Dado que la absorción por las plantas
    desde el suelo es mayor cuando el pH de éste es bajo, los procesos
    que acidifican el suelo (por ejemplo, las lluvias ácidas) pueden
    aumentar las concentraciones medias de cadmio en los alimentos. La

    aplicación de fertilizantes a base de fosfato y la deposición
    atmosférica son fuentes importantes de aportación de cadmio a las
    tierras cultivables en ciertas zonas del mundo; los fangos de
    alcantarillado también pueden ser una fuente de importancia a nivel
    local. Estas fuentes pueden, en el futuro, aumentar los niveles de
    cadmio en el suelo y con ello en las cosechas, lo que a su vez puede
    acrecentar la exposición al cadmio en la dieta. En ciertas zonas, se
    ha demostrado que está aumentando el contenido de cadmio en los
    alimentos.

         Ciertos organismos comestibles de vida libre como los mariscos,
    los crustáceos y los hongos son acumuladores naturales de cadmio.
    Como en el caso del ser humano, se observan niveles mayores de
    cadmio en el hígado y el riñón de los caballos y de algunos animales
    terrestres silvestres. El consumo habitual de estos alimentos puede
    aumentar la exposición. Ciertos vertebrados marinos contienen
    concentraciones notablemente elevadas de cadmio en el riñón,
    fenómeno que, aunque se considera de origen natural, se ha vinculado
    a signos de lesiones renales en esos organismos.

    3.  Niveles ambientales y exposición humana

         La principal fuente de exposición al cadmio en la población
    general no fumadora son los alimentos; la proporción de cadmio que
    se absorbe por otras vías es pequeña. El tabaco es una importante
    fuente de absorción de cadmio en los fumadores. En las zonas
    contaminadas, la exposición al cadmio por los alimentos puede
    alcanzar varios cientos de µg/día. En los trabajadores expuestos, la
    absorción pulmonar de cadmio por inhalación en el lugar de trabajo
    es la principal vía de exposición. También puede aumentar la
    absorción por la contaminación de los alimentos y por el consumo de
    tabaco.

    4.  Cinética y metabolismo en animales de experimentación y en
        el ser humano

         Los datos obtenidos en animales de experimentación y en el ser
    humano han demostrado que la absorción pulmonar es mayor que la
    gastrointestinal. Atendiendo a la especiación química, el tamaño de
    las partículas y la solubilidad en fluidos biológicos, puede
    absorberse hasta el 50% del compuesto de cadmio inhalado. La
    absorción gastrointestinal de cadmio depende del tipo de dieta y del
    estado nutricional. El estado nutricional respecto del hierro parece
    revestir particular importancia. Aunque en promedio se absorbe el 5%
    de la ingesta oral total de cadmio, los valores individuales varían
    entre menos del 1% hasta más del 20%. Existe un gradiente
    maternofetal de cadmio. Aunque se acumula en la placenta, la
    transferencia al feto es baja.

         El cadmio absorbido en los pulmones o el tracto
    gastrointestinal se almacena principalmente en el hígado y el riñón,
    donde se deposita más de la mitad de la carga corporal. Al aumentar
    la intensidad de la exposición, aumenta la proporción del cadmio
    absorbido que se almacena en el hígado. En el ser humano la
    excreción suele ser lenta y la semivida biológica es muy larga
    (decenios) en el músculo, el riñón, el hígado y el organismo entero.
    Las concentraciones de cadmio en la mayoría de los tejidos aumentan
    con la edad. Aunque las concentraciones más elevadas suelen
    encontrarse en la corteza renal, con exposiciones excesivas pueden
    producirse concentraciones mayores en el hígado. En las personas
    expuestas que padecen lesiones renales, aumenta la excreción
    urinaria de cadmio con lo que se reduce la semivida en el organismo
    entero. Las lesiones renales producen pérdidas del cadmio contenido
    en el riñón, y las concentraciones renales acaban con el tiempo
    siendo inferiores a las observadas en personas con un grado de
    exposición similar pero sin lesiones renales.

         La metalotioneína es una importante proteína de transporte y
    almacenamiento de cadmio y otros metales. El cadmio puede inducir la
    síntesis de metalotioneína en muchos órganos, en particular el
    hígado y el riñón. La unión del cadmio intracelular a la
    metalotioneína en los tejidos protege contra la toxicidad del metal.
    El cadmio libre puede por tanto tener una función en la patogenia de
    las lesiones tisulares debidas a ese metal. Se desconoce la
    especiación de otros complejos de cadmio en los tejidos o en los
    fluidos biológicos.

         La excreción urinaria de cadmio guarda relación con la carga
    corporal, la exposición reciente y la lesión renal. En personas poco
    expuestas, el nivel de cadmio en la orina depende principalmente de
    la carga corporal. Una vez que se ha producido la lesión renal
    inducida por el cadmio, o incluso en ausencia de lesión renal si la
    exposición es excesiva, aumenta la excreción urinaria. En las
    personas expuestas al cadmio que padecen proteinuria la excreción de
    cadmio suele ser mayor que en las que no padecen proteinuria. Cuando
    cesa la exposición intensa, el nivel de cadmio en la orina desciende
    aunque persista la lesión renal. En la interpretación de la
    presencia de cadmio en la orina hay que tener en cuenta, pues,
    varios factores. La excreción gastrointestinal es aproximadamente
    igual a la urinaria pero no puede medirse fácilmente. Otras vías
    excretoras como la leche, el sudor o la transferencia placentaria
    son insignificantes.

         El nivel de cadmio en las heces es un buen indicador de la
    ingesta diaria reciente a partir de los alimentos en ausencia de
    exposición por inhalación. En la sangre, el cadmio aparece
    principalmente en los glóbulos rojos y las concentraciones en el
    plasma son muy bajas. Existen al menos dos compartimentos en la
    sangre, uno referido a la exposición reciente, con una semivida de
    alrededor de 2-3 meses, y otro probablemente relacionado con la
    carga corporal, con una semivida de varios años.

    5.  Efectos en mamíferos de laboratorio

         Las exposiciones elevadas por inhalación provocan edema
    pulmonar letal. La inyección de una sola dosis elevada produce
    necrosis en el testículo y en el ovario no ovulante, lesiones
    hepáticas y lesiones en los vasos de menor tamaño. La administración
    oral de dosis elevadas produce lesiones en la mucosa gástrica e
    intestinal.

         La exposición por inhalación prolongada y la administración
    intratraqueal producen modificaciones crónicas de tipo inflamatorio
    en los pulmones, fibrosis y fenómenos indicativos de enfisema. La
    administración parenteral u oral prolongada afecta principalmente al
    riñón aunque también al hígado y a los sistemas hematopoyético,
    inmunitario, esquelético y cardiovascular. En ciertas especies y en
    determinadas condiciones se han inducido efectos esqueléticos e
    hipertensión. La aparición de efectos teratogénicos y lesiones
    placentarias depende de la fase gestacional en que se produzca la
    exposición y puede entrañar interacción con el zinc.

         En cuanto a la exposición humana, lo más notable son los
    efectos agudos por inhalación en el pulmón y los efectos renales
    crónicos. Tras la exposición prolongada, el riñón es el órgano
    crítico. Los efectos en este órgano se caracterizan por disfunción
    tubular y lesiones en las células tubulares, si bien pueden
    producirse también disfunciones glomerulares. Una de las
    consecuencias de la disfunción tubular renal es la alteración del
    metabolismo del calcio y de la vitamina D. Según algunos estudios,
    ello ha producido casos de osteomalacia y/o osteoporosis, pero esos
    efectos no se han confirmado en otros estudios. No debe excluirse el
    efecto directo del cadmio en la mineralización ósea.

         Los efectos tóxicos del cadmio en animales de experimentación
    están sometidos a la influencia de factores genéticos y
    nutricionales, las interacciones con otros metales, en particular el
    zinc, y el pretratamiento con cadmio, que puede guardar relación con
    la inducción de la metalotioneína.

         En 1976 y 1987, el Centro Internacional de Investigaciones
    sobre el Cáncer consideró suficientes las pruebas de que el cloruro,
    el sulfato, el sulfuro y el óxido de cadmio pueden producir sarcomas
    en el lugar de inyección en la rata y, en el caso de los dos
    primeros compuestos, inducir tumores en las células intersticiales
    del testículo en la rata y el ratón, pero consideró que los estudios
    de administración oral eran insuficientes para la evaluación. En
    estudios de inhalación prolongada en ratas expuestas a aerosoles de
    sulfato de cadmio, vapores de óxido de cadmio y polvos de sulfato de
    cadmio se observó una elevada incidencia de cáncer primario del
    pulmón con pruebas de proporcionalidad entre la dosis y la
    respuesta. Hasta el momento, sin embargo, esa observación no se ha
    confirmado en otras especies. Los estudios de los efectos
    genotóxicos del cadmio han dado resultados discordantes.

    6.  Efectos en el ser humano

         La exposición intensa por inhalación de vapores de óxido de
    cadmio produce neumonitis aguda con edema pulmonar, que puede ser
    letal. La ingestión de dosis elevadas de sales solubles de cadmio
    produce gastroenteritis aguda.

         La exposición ocupacional prolongada al cadmio ha producido
    efectos crónicos graves, principalmente en el pulmón y el riñón.
    También se han observado efectos renales crónicos en la población
    general.

         Los cambios pulmonares observados tras una intensa exposición
    ocupacional se caracterizan principalmente por la aparición de
    afecciones crónicas obstructivas de las vías aéreas. Los primeros
    cambios leves en las pruebas de la función ventilatoria pueden
    avanzar, si prosigue la exposición al cadmio, hasta insuficiencia
    respiratoria. Se ha observado una mayor tasa de mortalidad por
    enfermedad pulmonar obstructiva en trabajadores sometidos a
    exposiciones intensas, al igual que en otras épocas.

         La acumulación de cadmio en la corteza renal produce disfunción
    tubulorrenal con trastornos de la reabsorción de proteínas, glucosa
    y aminoácidos, entre otros. Un signo característico de la disfunción
    tubular es la mayor excreción de proteínas de bajo peso molecular en
    la orina. En algunos casos, disminuye la tasa de filtración
    glomerular. El aumento de la concentración de cadmio en la orina
    está correlacionado con la presencia de proteínas de bajo peso
    molecular en la orina y, en ausencia de exposición aguda al cadmio,
    puede servir como indicador de efectos renales. En los casos más
    graves se combinan los efectos tubulares y glomerulares, con aumento
    del nivel de creatinina en la sangre en algunos casos. Para la
    mayoría de los trabajadores y de las personas expuestas al medio
    ambiente general, la proteinuria inducida por el cadmio es
    irreversible.

         Entre otros efectos figuran los trastornos del metabolismo del
    calcio, la hipercalciuria y la formación de cálculos renales. La
    exposición intensa al cadmio, con toda probabilidad combinado con
    otros factores como carencias nutricionales, puede llevar a la
    aparición de osteoporosis y/o osteomalacia.

         Hay pruebas de que la exposición profesional prolongada al
    cadmio puede contribuir a la aparición de cáncer del pulmón aunque
    las observaciones obtenidas en trabajadores expuestos han sido
    difíciles de interpretar a causa de factores que inducen a
    confusión. En el caso del cáncer de la próstata, las pruebas
    obtenidas hasta la fecha no son concluyentes pero no apoyan la
    existencia de una relación causal, indicada en estudios anteriores.

         Actualmente no hay pruebas convincentes de que el cadmio sea
    agente etiológico de la hipertensión esencial. La mayor parte de los
    datos indican que no se debe al cadmio el aumento de la tensión y no
    hay pruebas de que la mortalidad por enfermedades cardio-vasculares
    o cerebrovasculares sea mayor.

         Los datos obtenidos en estudios de grupos de trabajadores
    expuestos y de grupos expuestos en el medio ambiente general
    demuestran que existe una relación entre los niveles de exposición,
    la duración de ésta y la prevalencia de los efectos renales.

         Se ha comunicado una mayor prevalencia de la proteinuria de
    bajo peso molecular en trabajadores del cadmio tras 10-20 años de
    exposición a niveles del metal de aproximadamente 20-50 µg/m3. En
    zonas contaminadas del medio general, en las que la ingesta de
    cadmio estimada ha sido de 140-260 µg/día, se han observado efectos
    en forma de aumento de la cantidad de proteínas de bajo peso
    molecular en la orina en algunos individuos tras una exposición
    prolongada. En la sección 8 se dan estimaciones más precisas de la
    relación dosis-respuesta.

    7.  Evaluación de los riesgos para la salud humana

    7.1  Conclusiones

         Se considera que el riñón es el órgano diana crítico en la
    población general así como en las poblaciones expuestas
    profesionalmente. Las enfermedades crónicas obstructivas de las vías
    respiratorias están asociadas a la exposición profesional prolongada
    e intensa por inhalación. Hay pruebas de que esa exposición al
    cadmio puede contribuir al desarrollo de cáncer del pulmón aunque
    las observaciones en trabajadores expuestos han sido difíciles de
    interpretar a causa de la presencia de factores que inducen a
    confusión.

    7.1.1  Población general

         El cadmio presente en los alimentos es la principal fuente de
    exposición para la mayoría de las personas. En la mayoría de las
    zonas no contaminadas con cadmio las ingestas diarias medias con los
    alimentos se encuentran entre 10 y 40 µg. En zonas contaminadas se
    ha observado que alcanza varios cientos de µg al día. En zonas no
    contaminadas, la absorción debida al consumo de tabaco puede igualar
    la ingestión de cadmio a partir de los alimentos.

         Basandose en un modelo biologico, se ha estimado que con una
    ingesta diaria de 140-260 µg de cadmio durante toda la vida, o una
    ingesta acumulativa de unos 2000 mg o más, se produce en el ser
    humano una asociación entre la exposición al cadmio y una mayor
    excreción de proteínas de bajo peso molecular en la orina.

    7.1.2  Población expuesta profesionalmente

         La exposición ocupacional al cadmio se produce principalmente
    por inhalación aunque comprende ingestas suplementarias con los
    alimentos y el tabaco. El nivel total de cadmio en el aire varía
    según las prácticas de higiene industrial y el tipo de lugar de
    trabajo. Existe una relación exposición-respuesta entre los niveles
    de cadmio en el aire y la proteinuria. Puede aumentar la prevalencia
    de la proteinuria de bajo peso molecular en trabajadores a los 10-20
    años de exposición a niveles de cadmio de unos 20-50 µg/m3. La
    medida  in vivo del cadmio en el riñón y el hígado de personas con
    distintos niveles de exposición al metal ha demostrado que alrededor
    del 10% de los trabajadores con un nivel en la corteza renal de
    200 mg/kg y aproximadamente el 50% de las personas con un nivel en
    la corteza renal de 300 mg/kg tendrían proteinuria tubulorrenal.
    


See Also:
        Cadmium (ICSC)
        Cadmium (PIM 089)
        Cadmium - environmental aspects (EHC 135, 1992)