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    IPCS INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 17








    MANGANESE









    This report contains the collective views of an
    international group of experts and does not
    necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme,
    the International Labour Organisation, or the World
    Health Organization

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

    World Health Organization

    Geneva, 1981

    ISBN 92 4 154077 X

    (c) World Health Organization 1981

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    Organization, Geneva, Switzerland. The World Health Organization
    welcomes such applications.

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    this publication do not imply the expression of any opinion whatsoever
    on the part of the Secretariat of the World Health Organization
    concerning the legal status of any country, territory, city or area or
    of its authorities, or concerning the delimitation of its frontiers or
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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR MANGANESE

    1. SUMMARY AND RECOMMENDATIONS FOR FURTHER STUDIES

        1.1. Summary
              1.1.1. Analytical methods
              1.1.2. Sources and pathways of exposure
              1.1.3. Essentiality of manganese
              1.1.4. Magnitude of environmental exposure
              1.1.5. Metabolism
              1.1.6. Effects on experimental animals
              1.1.7. Effects on man
                      1.1.7.1   Occupational exposure
                      1.1.7.2   Community exposure
              1.1.8. Organomanganese compounds
        1.2. Recommendations for further studies
              1.2.1. Analytical methods
              1.2.2. Environmental exposure
              1.2.3. Metabolism
              1.2.4. Experimental animal studies
              1.2.5. Epidemiological and clinical studies
                      in man

    2. PROPERTIES AND ANALYTICAL METHODS

        2.1. Chemical and physical properties of manganese
              and its compounds
        2.2. Sampling and analysis
              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   Optical spectroscopy
                      2.2.3.2   Atomic absorption spectroscopy
                      2.2.3.3   Neutron-activation analysis
                      2.2.3.4   X-ray fluorescence
                      2.2.3.5   Other methods
                      2.2.3.6   Comparability of methods

    3. SOURCES OF MANGANESE IN THE ENVIRONMENT

        3.1. Natural occurrence
        3.2. Industrial production and consumption
              3.2.1. Uses
              3.2.2. Contamination by waste disposal
              3.2.3. Other sources of pollution

    4. ENVIRONMENTAL LEVELS AND EXPOSURE

        4.1. Air
              4.1.1. Ambient air
              4.1.2. Air in workplaces
        4.2. Water
        4.3. Soil
        4.4. Food
        4.5. Total exposure from environmental media

    5. TRANSPORT AND DISTRIBUTION IN ENVIRONMENTAL MEDIA

        5.1. Photochemical and thermal reactions in the lower atmosphere
        5.2. Decomposition in fresh water and seawater
        5.3. Atmospheric washout and rainfall
        5.4. Run-off into fresh water and sea water
        5.5. Microbiological utilization in soils
        5.6. Uptake by soil and plants
        5.7. Bioconcentration
        5.8. Organic manganese fuel additives

    6. METABOLISM OF MANGANESE

        6.1. Absorption
              6.1.1. Absorption by inhalation
              6.1.2. Absorption from the gastrointestinal tract
        6.2. Distribution
              6.2.1. Distribution in the human body
              6.2.2. Distribution in the animal body
              6.2.3. Transport mechanisms
        6.3. Biological indicators of manganese exposure
        6.4. Elimination
        6.5. Biological half-times
              6.5.1. Man
              6.5.2. Animals

    7. MANGANESE DEFICIENCY

        7.1. Metabolic role of manganese
        7.2. Manganese deficiency and requirements in man
        7.3. Manganese deficiency in animals

    8. EXPERIMENTAL STUDIES ON THE EFFECTS OF MANGANESE

        8.1. Median lethal dose
        8.2. Effects on specific organs and systems
              8.2.1. Central nervous system
              8.2.2. Respiratory system
              8.2.3. Liver
              8.2.4. Cardiovascular effects
              8.2.5. Haematological effects
        8.3. Effects on reproduction
        8.4. Carcinogenicity
        8.5. Mutagenicity and chromosomal abnormalities
        8.6. Miscellaneous effects
        8.7. Toxicity of organic manganese fuel additives
        8.8. Mechanisms and toxic effects

    9. HUMAN EPIDEMIOLOGICAL AND CLINICAL STUDIES

        9.1. Occupational exposure and health effects
        9.2. General population exposure and health effects
        9.3. Clinical studies
              9.3.1. Pathomorphological studies
              9.3.2. Therapeutic studies
        9.4. Susceptibility to manganese poisoning
        9.5. Interaction

    10. EVALUATION OF THE HEALTH RISKS TO MAN FROM EXPOSURE TO
        MANGANESE AND ITS COMPOUNDS

        10.1. Relative contributions of air, food and water to total
              intake
              10.1.1. General population
              10.1.2. Occupationally-exposed groups
        10.2. Manganese requirements and deficiency
        10.3. Effects in relation to exposure
              10.3.1. General population
              10.3.2. Occupationally-exposed groups
                      10.3.2.1  Effects on the central nervous system
                      10.3.2.2  Manganese pneumonia
                      10.3.2.3  Nonspecific effects on the respiratory
                                tract
                      10.3.2.4  Diagnosis of manganese poisoning and
                                indices of exposure
                      10.3.2.5  Susceptibility and interaction
        10.4. Organomanganese compounds
        10.5. Conclusions and recommendations
              10.5.1. Occupational exposure
              10.5.2. General population exposure

    REFERENCES
    

    NOTE TO READERS OF THE CRITERIA DOCUMENTS

        While every effort has been made to present information in the
    criteria documents as accurately as possible without unduly delaying
    their publication, mistakes might have occurred and are likely to
    occur in the future. In the interest of all users of the environmental
    health criteria documents, readers are kindly requested to communicate
    any errors found to the Division of Environmental Health, World Health
    Organization, Geneva, Switzerland, in order that they may be included
    in corrigenda which will appear in subsequent volumes.

        In addition, experts in any particular field dealt with in the
    criteria documents are kindly requested to make available to the WHO
    Secretariat any important published information that may have
    inadvertently been omitted and which may change the evaluation of
    health risks from exposure to the environmental agent under
    examination, so that the information may be considered in the event of
    updating and re-evaluation of the conclusions contained in the
    criteria documents.

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR MANGANESE

     Members

    Dr M. Cikrt, Institute of Hygiene and Epidemiology, Prague,
        Czechoslovakia

    Dr G J. van Esch, Toxicology and Food Chemistry, National Institute of
        Public Health, Bilthoven, Netherlands  (Chairman)

    Dr G. F. Hueter, Environmental Research Center, US Environmental
        Protection Agency, Research Triangle Park, NC, USA

    Dr I. C. Munro, Toxicology Research Division, Bureau of Chemical
        Safety, Department of National Health and Welfare, Ottawa,
        Ontario, Canada  (Rapporteur)

    Dr H. Oyanguren, Institute of Occupational Health and Air Pollution,
        National Health Service, Santiago, Chile

    Dr M. Saric, Institute of Medical Research and Occupational Health,
        Zagreb, Yugoslavia

    Dr S. Sigan, Sysin Institute of General and Community Hygiene, Moscow,
        USSR

    Dr N. Skvortsova, Laboratory for Air Pollution Control, Sysin
        Institute of General and Community Hygiene, Moscow, USSR

    Professor M. Tati, Department of Public Health, Gifu University
        Medical School, Gifu, Japan

    Dr I. Ulanova, Institute of Industrial Hygiene and Occupational
        Diseases, Moscow, USSR  (Vice-Chairman)

     Representatives of other agencies

    Dr H. M. Mollenhauer, Division of Geophysics, Global Pollution and
        Health, United Nations Environment Programme, Nairobi, Kenya

    Dr D. Djordjevic, Occupational Health and Safety Branch, International
        Labour Organisation

    Mrs M. Th. van der Venne, Health Protection Directorate, Commission of
        the European Communities, Luxembourg

     Secretariat

    Dr Y. Hasegawa, Medical Officer, Control of Environmental Pollution
        and Hazards, World Health Organization, Geneva, Switzerland

    Dr H. de Koning, Scientist, Control of Environmental Pollution and
        Hazards, World Health Organization, Geneva, Switzerland

    Dr J. E. Korneev, Scientist, Control of Environmental Pollution and
        Hazards, World Health Organization, Geneva, Switzerland

    Dr G. E. Lambert, Scientist, Occupational Health, World Health
        Organization, Geneva, Switzerland

    Dr B. Marschall, Medical Officer, Occupational Health, World Health
        Organization, Geneva, Switzerland

    Dr V. B. Vouk, Chief, Control of Environmental Pollution and Hazards,
        World Health Organization, Geneva, Switzerland  (Secretary)

    ENVIRONMENTAL HEALTH CRITERIA FOR MANGANESE

        A WHO Task Group on Environmental Health Criteria for Manganese
    met in Geneva from 22 to 26 September 1975. Dr B. H. Dieterich,
    Director, Division of Environmental Health, opened the meeting on
    behalf of the Director-General. The Task Group reviewed and revised
    the second draft Of the criteria document and made an evaluation of
    the health risks from exposure to manganese and its compounds.

        The first and second drafts of the criteria document were
    prepared by Dr P. S. Elias of the Department of Health and Social
    Security, London, England. The first draft was based on national
    reviews received from the national focal points for the WHO
    Environmental Health Criteria Programme in Bulgaria, Japan, New
    Zealand, the United Kingdom, the USA, and the USSR. The second draft
    was prepared according to comments received from national focal points
    in Canada, Chile, Czechoslovakia, Greece, Japan, Netherlands, New
    Zealand, Poland, Sweden, the USA, and the USSR; and from the
    Commission of the European Communities, the Food and Agriculture
    Organization of the United Nations, the Ethyl Corporation, the
    International Union of Biological Sciences, the International Union of
    Pure and Applied Chemistry, the United Nations Economic Commission for
    Europe, and the World Meteorological Organization. Dr P. S. Elias and
    Dr I. C. Munro, Bureau of Chemical Safety, Department of National
    Health and Welfare, Ontario, Canada, assisted the Secretariat in the
    preparation of a third draft, which was distributed for comments to
    the Task Group members. Additional comments on this draft were
    received from Dr R. J. M. Horton, US Environmental Protection Agency,
    Research Triangle Park, USA, and Professor M. Piscator, the Karolinska
    Institute, Stockholm, Sweden. Following the recommendations made by a
    WHO Consultative Group on the application of environmental health
    criteria, Bilthoven, Netherlands, 2-5 May 1977, a final draft was
    prepared by Dr H. Nordman, Institute of Occupational Health, Helsinki,
    Finland, taking into consideration the comments of members of the Task
    Group and of Professor P. S. Papavasiliou, the New York Hospital
    Centre-Cornell Medical Center, New York, USA, and Professor M.
    Piscator.

        The collaboration of these institutions, organizations, and
    individual experts is gratefully acknowledged. The Secretariat wishes
    to thank, in particular, Dr P. S. Elias, Dr. I. C. Munro, and Dr H.
    Nordman for their help in the various phases of preparation of the
    document.

        This document is based on original publications listed in the
    reference section but much valuable information was also obtained from
    publications reviewing and evaluating the essentiality and toxicity of
    manganese, including those by Cotzias (1958, 1962), Stokinger (1962),
    Schroeder et al. (1966), Suzuki et al. (1973a, 1973b, 1973c), WHO
    (1973), WHO Working Group (1973), US Environmental Protection Agency
    (1975), International Agency for Cancer Research (1976), and Saric
    (1978). Owing to unforseen circumstances, it has not been possible to
    update the document beyond 1978.

        Details of the WHO Environmental Health Criteria Programme,
    including some terms frequently used in the documents, can be found in
    the general introduction to the Environmental Health Criteria
    Programme published together with the environmental health criteria
    document on mercury (Environmental Health Criteria 1, Mercury, Geneva,
    World Health Organization, 1976) and now available as a reprint.

        Financial support for the publication of this criteria document
    was kindly provided by the Department of Health and Human Services
    through a contract from the National Institute of Environmental Health
    Sciences, Research Triangle Park, North Carolina, USA -- a WHO
    Collaborating Centre for Environmental Health Sciences.

    1.  SUMMARY AND RECOMMENDATIONS FOR FURTHER STUDIES

    1.1  Summary

    1.1.1  Analytical methods

        Numerous analytical methods are available for the quantitative
    determination of manganese in environmental media and biological
    samples. The method the most frequently used is atomic absorption
    spectroscopy, which appears to be sufficiently sensitive for most
    analytical purposes. The way in which biological and environmental
    samples are procured and stored, prior to analysis, has an important
    bearing on the accuracy and validity of the results. For example, in
    air sampling, it is important to ensure that respirable particulate
    matter is collected. In the collection of biological samples with a
    low manganese content, contamination may constitute a major
    difficulty.

    1.1.2  Sources and pathways of exposure

        Manganese is one of the more abundant elements in the earth's
    crust and is widely distributed in soils, sediments, rocks, water, and
    biological materials. The major sources of man-made environmental
    pollution by manganese arise in the manufacture of alloys, steel, and
    iron products. Other sources include mining operations, the production
    and use of fertilizers and fungicides, and the production of synthetic
    manganese oxide and dry-cell batteries. Organomanganese fuel
    additives, though only a minor source at present, could significantly
    increase exposure, if they come into widespread use. Average manganese
    concentrationsa in soils range from about 500 to 900 mg/kg and
    concentrations in sea water range from 0.1 to 5 g/litre. Surface
    waters may have a manganese content of 1-500 g/litre, but in areas
    where high concentrations of manganese occur naturally, levels may be
    considerably higher. Average manganese levels in drinking water range
    from 5 to 25 g/litre.

        Manganese is present in all foodstuffs, usually at concentrations
    below 5 mg/kg. However, concentrations in certain cereals, nuts, and
    shellfish can be much higher, exceeding 30 mg/kg in some cases. Levels
    in finished tea leaves may amount to several hundred mg/kg.

        Manganese has been found in measurable quantities in practically
    all air samples of suspended particulate matter. Annual average levels
    in ambient air in unpolluted urban and rural areas vary from 0.01 to
    0.07 g/m3. However, in areas associated with the manganese industry,

              

    a  Throughout the document, the term concentration refers to mass
       concentration, unless otherwise stated.

    annual averages may be higher than 0.5 g/m3, and have occasionally
    exceeded 8 g/m3. About 80% of the manganese in suspended particulate
    matter is associated with particles having a mass median equivalent
    diameter (MMED)b of less than 5 m, i.e., particles within the
    respirable range. This association with small particles favours the
    widespread airborne distribution of manganese.

    1.1.3  Essentiality of manganese

        Manganese is an essential trace element for both animals and man.
    It is necessary for the formation of connective tissue and bone, and
    for growth, carbohydrate and lipid metabolism, the embryonic
    development of the inner ear, and reproductive functions. Some
    specific biochemical functions of manganese have been discovered such
    as the catalysing of the glucosamine-serine linkages in the synthesis
    of the mucopolysaccharides of cartilage.

        Estimates from intake and balance studies in man show that the
    daily requirement for adults is 2-3 mg/day and that of pre-adolescent
    children, at least 1.25 mg/day. Manganese deficiency states, which
    have been detected in a wide variety of animals, have been described
    only once in man, in association with vitamin K deficiency and the
    accidental omission of manganese from the diet. A distinctly negative
    manganese balance is found in newborn infants, the metal being
    excreted from stores that have accumulated in the tissues during fetal
    life. However, deficiency symptoms have not been detected.

    1.1.4  Magnitude of environmental exposure

        Food is the major source of manganese for man. Daily intake
    ranges from 2 to 9 mg, depending on the relative consumption of foods
    with a high manganese content, especially cereals and tea. In young
    children and up to the age of adolescence, the daily intake is about
    0.06-0.08 mg/kg body weight; for breastfed and bottlefed infants, it
    is only about 0.002-0.004 mg/kg body weight. Daily intake with
    drinking water may range from a few micrograms to 200 g, the average
    intake being about 10-50 g/day.

              

    b  Mass median equivalent diameter: equivalent diameter above and
       below which the weights of all larger and smaller particles are
       equal.

        The daily intake of manganese in the air by the general
    population in areas without manganese emitting industries is below
    2 g/day. In areas with major foundry facilities, intake may rise to
    4-6 g/day and in areas associated with ferro- or silicomanganese
    industries it may be as high as 10 g, with 24-h peak values exceeding
    200 g/day.

    1.1.5  Metabolism

        The respiratory and gastrointestinal tracts constitute the major
    routes of absorption of manganese. Quantitative data are not
    available, but it seems unlikely that the skin is an important route
    of absorption for inorganic manganese compounds, although
    organomanganese compounds can be absorbed by this route.

        The extent of absorption of manganese following inhalation is
    unknown. A certain proportion of inhaled manganese particles is
    cleared by mucociliary action and swallowed, and is available for
    gastrointestinal absorption. The small amount of information available
    concerning the gastrointestinal absorption of manganese in man
    indicates that the absorption rate in healthy adults is below 5% but
    that it is higher in anaemic subjects. This is supported by data from
    studies on mice and rats. There is little information on
    gastrointestinal absorption in infants and children and not much is
    known about the mechanism of absorption from the gastrointestinal
    tract.

        In studies on experimental animals, preloading with high dietary
    levels of manganese caused a decrease in the rate of absorption and
    young rats appeared to have a considerably higher absorption rate than
    adult rats.

        The total manganese body burden for a man of 70 kg is about
    10-20 mg. It is transported in the plasma bound to a beta1-globulin,
    most likely transferrin, and is widely distributed throughout the
    body. Manganese concentrates in tissues rich in mitochondria, the
    highest concentrations being found in the liver, pancreas, kidney, and
    the intestines. It can also penetrate both the blood-brain barrier and
    the placenta. The disappearance half-time for manganese from the whole
    body is about 37 days and the half-time in the brain appears to be
    longer than that for the whole body. Tissue concentrations in man are
    remarkably stable throughout life. Variable excretion is known to play
    an important role in the homeostasis of manganese, but recent studies
    have shown that the variability of absorption is also important.

        Inorganic manganese is mainly eliminated in the faeces. The
    principal route of excretion is with the bile, part of which is
    reabsorbed in the enterohepatic circulation. To some extent, manganese
    is also excreted with the pancreatic juice and through the intestinal
    wall; the importance of these routes may increase under abnormal
    conditions such as biliary obstruction or increased manganese
    exposure. It has been shown that only about 0.1-1.3% of the daily
    intake of inorganic manganese is normally excreted in the urine.
    However, larger amounts are excreted through the kidney following
    exposure to organomanganese tricarbonyl compounds, indicating that
    these compounds, which are used as additives in gasoline, are
    metabolized in the body.

    1.1.6  Effects on experimental animals

        The toxic effects of manganese on the central nervous system have
    been induced in various animal species, including the rat and monkey,
    mainly by the administration of manganese dioxide or dichloride.
    Exposure of a monkey to manganese dioxide aerosol, by inhalation, at
    concentrations of 0.6-3.0 mg/m3, for 95 1-h periods over 4 months,
    induced typical signs of central nervous system effects. Parenteral
    administration of manganese dioxide or dichloride also induced signs
    of central nervous system disturbance but oral administration produced
    fewer effects, presumably because of poor gastrointestinal absorption.
    Histopathological lesions found in intoxicated animals included
    degenerative changes, primarily in the striatum and pallidum, but
    lesions in the subthalamic nucleus, cortex, cerebrum, cerebellum, and
    the brain stem have also been observed. It has been shown that
    manganese causes depletion of dopamine, and probably serotonin, in the
    basal ganglia of monkeys, rabbits, and rats. These biochemical
    findings may explain, at least in part, the neurotoxic effects of
    manganese.

        Inflammatory changes were produced in rats by intratracheal
    administration of manganese dioxide at concentration of 0.3 mg/m3 for
    5-6 h daily, over 4 months; mottling was seen on the pulmonary
    radiographs of monkeys exposed to the same compound by inhalation
    (0.7 mg/m3). Sulfur dioxide was found to act synergistically with
    manganese dioxide on the respiratory tract of guineapigs.

        Biochemical and histopathological changes have been reported in
    other organ systems, notably the liver. Testicular changes have been
    demonstrated in the rat after intravenous administration of
    permanganate at 50 mg/kg body weight and in the rabbit after
    administration of manganese dichloride at 3.5 mg/kg. Intraperitoneal
    injections of manganese(II) sulfate (10 mg/kg body weight, 15
    injections) in mice increased the incidence of lung rumours; however,
    the carcinogenic, mutagenic, and teratogenic potential of manganese
    needs further investigation.

    1.1.7  Effects on man

    1.1.7.1  Occupational exposure

        Chronic manganese poisoning is a hazard in the mining and
    processing of manganese ores, in the manganese alloy and dry-cell
    battery industries, and in welding. The disorder is characterized by
    psychological and neurological manifestations, the neurological signs
    closely resembling those that occur in other extrapyramidal disorders,
    notably parkinsonism. Autopsy reports on cases of chronic manganese
    poisoning have shown that lesions of the central nervous system are
    most severe in the striatum and pallidum, and may also be found in the
    substantia nigra. In one case, post-mortem analysis revealed a reduced
    concentration of dopamine. This finding combined with animal data and
    the fact that a precursor of dopamine, 3-hydroxy L-tyrosine (L-dopa),
    has been effective in the treatment of chronic manganese poisoning
    implicates the dopaminergic pathway in the etiology of extrapyramidal
    manifestations of the disease.

        Individual susceptibility to the adverse effects of manganese
    varies considerably. The minimum dose that produces effects in the
    central nervous system is not known, but signs of adverse effects may
    occur at manganese concentrations in air ranging from 2 to 5 mg/m3.

        Although an increased incidence of pneumonia has repeatedly been
    reported in manganese workers, it is not possible to establish any
    exposure-effect relationships from available data. It may be that
    particle size distribution and the type of manganese compound are more
    important than the mass concentration of manganese in air. This may
    also be true for the nonspecific effects on the respiratory tract
    reported in manganese workers. Smoking appears to act synergistically
    with manganese in causing such effects.

        The early diagnosis of manganese poisoning is difficult in the
    absence of reliable biological indicators of exposure. Repeated
    screening for subjective symptoms and thorough clinical examinations
    should be undertaken at regular intervals together with measurements
    of manganese in blood and urine. Measurement of manganese levels in
    faeces may serve as a useful guide to exposure.

        With better understanding of the pathophysiology of manganese
    poisoning, new drugs have been introduced for its treatment. In many
    cases, the use of the dopamine precursor L-dopa, has been successful.
    The use of chelating agents has also been reported to have a
    beneficial effect, although sometimes only temporarily and mainly in
    the early stages of poisoning. This treatment cannot be expected to
    bring about any improvement in cases where structural neurological
    injury has already occurred.

    1.1.7.2  Community exposure

        Adverse effects have been reported in populations, in areas
    associated with manganese-processing plants. In 1939, increased
    morbidity and mortality due to lobar pneumonia were reported from
    Sauda in Norway, where a ferro- and silicomanganese plant was
    operating. The mortality rate was positively correlated with the
    amount of manganese alloy produced. Manganese was reported to occur in
    the ambient air as Mn (II, III) oxide (Mn3O4) at manganese
    concentrations of up to 45 g/m3. In another study, a higher
    prevalence of nose and throat symptoms and lowered respiratory
    function were registered in schoolchildren exposed to manganese
    concentrations in air ranging from 4 to 7 g/m3 (5-day mean values)
    compared with an unexposed control group. However, short-time sampling
    (1-h) of the factory smoke, down-wind, yielded a maximum level of
    260 g/m3.

        A 4-year study performed in a population living in the vicinity
    of a ferromanganese plant indicated that even a manganese exposure of
    only 1 g/m3 might be connected with an increase in the rate of acute
    respiratory disease. However, it is possible that some other factors,
    which were not sufficiently controlled, might have influenced the
    results.

        In one study, the incidence of abortions and stillbirths was
    reported to be higher in wives of workers exposed to manganese for
    10-20 years than in a control group. The study is difficult to
    evaluate as factors such as the occupations of the wives were not
    reported.

    1.1.8  Organomanganese compounds

        There are two groups of organomanganese compounds of
    toxicological importance. Manganese ethylene-bis-dithiocarbamate
    (Maneb) is used as a fungicide on edible crops. Toxicologically, the
    manganese fraction is of little importance, whereas the organic
    portion is part of a larger problem concerning this type of fungicide.
    The manganese tricarbonyl compounds constitute the other group of
    organomanganese compounds of toxicological significance. These are
    used as additives in unleaded petrol (gasoline) and future widespread
    use seems likely. After combustion, only a small fraction of the
    compound is emitted and this undergoes rapid photodecomposition to
    form compounds that, so far, have not been satisfactorily identified.
    Exposure to manganese tricarbonyl compounds is therefore likely to
    constitute an occupational hazard but community exposure to the parent
    compound will remain very small, even if the use of these compounds
    increases. Nevertheless, widespread use would result in increased

    community exposure to inorganic manganese and to other possible
    combustion products. Rats, hamsters, and monkeys have been exposed
    experimentally to combusted methylcyclopentadienyl manganese
    tricarbonyl (MMT) at concentrations of manganese in air ranging from
    12 to 5000 g/m3 for various periods ranging up to 66 weeks without
    any adverse effects. However, tissue levels of manganese increased in
    monkeys exposed to a manganese concentration in air of 100 g/m3.

    1.2  Recommendations for Further Studies

    1.2.1  Analytical methods

        There is a need for interlaboratory comparison to determine the
    accuracy of methods available for the estimation of manganese.
    Additional studies are required to determine particle size in airborne
    manganese particulate matter, so that total intake through the
    respiratory pathway can be estimated more precisely.

    1.2.2  Environmental exposure

        More precise data are needed on manganese intake, especially by
    inhalation. A better understanding of the translocation of manganese
    in the environment and factors that affect this process is required
    and its potential for bioaccumulation in environmental compartments
    should be explored in more depth.

    1.2.3  Metabolism

        Chemobiokinetic studies are necessary to identify, more
    precisely, the mechanisms involved in the uptake and clearance of
    manganese from the gastrointestinal tract and the respiratory system
    in both experimental animals and exposed populations and to obtain a
    better understanding of factors that affect these processes. Tissue
    levels at which adverse effects are observed should be established and
    special attention should be paid to the role of nutritional status and
    age in the metabolism of manganese.

    1.2.4  Experimental animal studies

        More information is needed on the long-term, low-level effects of
    manganese in order to develop dose-response data. Further studies are
    also necessary on the neurotoxicity and potential carcinogenicity,
    teratogenicity, and mutagenicity of manganese and on factors that
    might affect toxicity such as nutrition, age, disease state, and the
    presence of other pollutants.

        Not enough is known about the essentiality of manganese as a
    nutrient and more studies are needed on the biochemical role of this
    metal to obtain a better understanding of toxic mechanisms and to
    develop a rational basis for the treatment of manganese intoxication.

    1.2.5  Epidemiological and clinical studies in man

        Studies are required to elucidate the dose-effect and
    dose-response characteristics of manganese with particular emphasis on
    the effects of long-term, low-level, inhalation exposure on the
    respiratory and central nervous systems. Interactions with other
    pollutants, diet, age, and general health status should be studied in
    more detail. The effects of manganese on the cardiovascular system,
    particularly its effects on blood pressure and the myocardium, need to
    be more fully understood. Reliable diagnostic procedures for manganese
    intoxication should be established, paying particular attention to the
    development of methods for its early detection. Additional studies are
    necessary to assess the embryotoxic potential of manganese and its
    compounds in communities exposed to elevated levels of manganese in
    air. Organomanganese compounds may come into widespread use as fuel
    additives. This would result in increased exposure of the general
    population to manganese and probably to other combustion products of
    the additive. Thus, the potential hazards to public health of the use
    of organomanganese fuel additives should be examined by means of
    carefully conducted controlled and epidemiological studies.

    2. PROPERTIES AND ANALYTICAL METHODS

    2.1  Chemical and Physical Properties of Manganese and its Compounds

        Manganese, Mn (atomic number Z = 25; relative atomic mass Ar =
    54.938) is an element of the VIIb group of the periodic table of
    elements, together with technetium and rhenium. It belongs to the
    first series of d-block transition elements which also contains
    titanium, vanadium, chromium, nickel, and copper. Because of their
    electron configuration, transition elements have some characteristic
    properties: they are all metals; they exist in a variety of oxidation
    states; and they form many coloured and paramagnetic compounds.
    Several transition elements have an important role in biological
    systems.

        In the elemental state, manganese is a white-grey, brittle, and
    reactive metal with a melting point of 1244C and a boiling point of
    1962C. It is the most common transition metal after iron and
    titanium. It can form compounds in a number of oxidation states, the
    most important being +2, +3, and +7.

        Manganous (Manganese(II), Mn2+) salts are mostly water-soluble,
    with the exception of the phosphate and carbonate, the solubilities of
    which are rather low. Dihalides of manganese include MnF2, MnCl2,
    MnBr2, and MnI2. Addition of OH- ion to the Mn2+ solutions gives
    the gelatinous white hydroxide Mn(OH)2. MnO and MnS are also known.
    The MnII complexes are generally weakly coloured (pale pink). Mn2+
    is in many ways similar to Mg2+, and can replace it in some
    biological molecules.

        Mn3O4 (hausmannite) contains both MnII and MnIII, i.e., MnII
    MnIII2O4. The manganic Mn(III) ion (Mn3+) easily hydrolyses in weak
    acid solutions into Mn2+ and MnO2. Manganese(III) and manganese(IV)
    complexes seem to be important in photosynthesis.

        Manganese dioxide (MnO2), found naturally as pyrolusite, is the
    most important manganese (II) compound. It is insoluble in water and
    in cold acids. The little-known manganese(IV) ion occurs in blue
    "hypomangamates".

        Manganese(VI) exists in the deep green manganate ion, MnO42-,
    which is stable only in very basic solutions. Otherwise, it breaks
    down to give the permanganate ion MnO4- and MnO2. The permanganate
    ion is the best known form of MnVII. Permanganate, which is a good
    oxidant in basic solutions, is reduced to Mn2+ in acid solutions.

        The properties of some inorganic manganese compounds are
    summarized in Table 1.


        Table 1.  Chemical and physical properties of manganese and some manganese compoundsa
                                                                                                                                                

                            Chemical         Relative atomic   Melting        Boiling
           Compound          formula          or molecular      point          point                Solubility
                                                  mass          (C)           (C)
                                                                                                                                                

      Manganese              Mn                   54.94         1244          1962          Decomposes in cold and hot
                                                                                            water; soluble in dilute acid.
        (II) acetate         Mn(C2H3O2)2         173.02                                     Soluble in cold water
                                                                                            (decomposes); soluble in
                                                                                            alcohol.
        (II) carbonate       MnCO3               114.95         decomposes                  Soluble in cold water;
                                                                                            soluble in dilute acids.
        dichloride           MnCl2               125.84         650           1190          Soluble In cold and hot water,
                                                                                            and in alcohol.
        (II) nitrate         Mn(NO3)2 . 4H2O     251.01         25.8          1294          Soluble in cold and hot water,
                                                                                            and in alcohol.
        (II, III) oxide      Mn3O4               228.81         1705                        Soluble In hydrochloric acid.
        dioxide              MnO2                 86.94         -0.535                      Soluble In hydrochloric acid.
        (III) oxide          Mn2O3               157.87         -0.1080                     Soluble In acid.
        (II) metasilicate    MnSiO3              131.02         1323                        Insoluble In water and
                                                                                            hydrochloric acid.
        (II) sulfate         MnSO4               151.00         700           850           Soluble in cold and hot water, and
                                                                              (decomposes)  in alcohol.

    Table 1.  (contd).
                                                                                                                                                

                            Chemical         Relative atomic   Melting        Boiling
           Compound          formula          or molecular      point          point                Solubility
                                                  mass          (C)           (C)
                                                                                                                                                

        (III) sulfate        Mn2(SO4)3           398.06         160                         Decomposes in water, soluble in
                                                                                            hydrochloric acid, and
                                                                                            dilute sulfuric acid.
        (II) sulfide         MnS                  87.00         decomposes                  Soluble In cold water, dilute
                                                                                            acid, and alcohol.
        (IV) sulfide         MnS2                119.07         decomposes                  Decomposes in hydrochloric acid.
      Potassium              KMnO4               158.00         decomposes    < 240         Soluble in cold and hot water,
      permanganateb                                                                         in sulfuric acid, alcohol, and
                                                                                            acetone. Decomposes in alcohol.
                                                                                                                                                

    a  From: Weest (1974).
    b  From: Stokinger (1962).
    

        Manganese may form a variety of complexes particularly in the +2
    state. The +1 state is present in hexacyano complexes such as
    K5Mn(CN)6, which exist also with manganese in the +3 state,
    K3Mn(CN)6.

        Manganese forms various organometallic compounds such as
    Mn2(CO)10, sodium pentacarbonylmanganate (NaMn (CO)5), and
    manganocene (C5H5)2Mn. However, of major practical interest is
    methylcyclopentadienyl manganese tricarbonyl (CH3C5H4Mn(Co)3),
    often referred to as MMT, Cl-2 or Ak-33X (antiknock 33X), which has
    been used as an additive in fuel oil, as a smoke inhibitor, and as an
    antiknock additive in petrol, usually as a supplement to
    tetraethyllead.

    2.2  Sampling and Analysis

    2.2.1  Collection and preparation of samples

        Nonmetallic sampling systems should be used for the collection of
    environmental materials, and suitable precautions should be taken to
    avoid contamination during the analytical process.

        Filters for ambient air particulates must be chosen with care so
    that trace amounts of manganese in the filter material do not distort
    the results. Generally the air sampling techniques chosen will depend
    on the purpose of the investigation. High-volume air samplers and
    centripeters are expensive, require power points, and are unsuitable
    for large-scale monitoring at multiple sites. The use of standard
    deposit gauges is limited to the collection of particles larger than
    5 m; particles with a smaller diameter are deposited only by
    impaction. In Japanese studies, a high-volume air sampler is used for
    suspended particulate matter, and a cyclone type low-volume air
    sampler for suspended particulate matter with a particle size of 10 m
    or less (Environment Agency, Japan, 1972).

        Sphagnum moss techniques are useful for comparing fallout in
    different areas or for studying seasonal variations in one area.
    Continuous sampling drawing measured air volumes through filter paper,
    or dry deposition on filter papers protected from the rain combined
    with rain water collecting, may also be used. According to normal
    practice in emission studies, sampling for manganese at stationary air
    pollution sources is carried out isokinetically, using a sampling
    train that will remove manganese efficiently. In the source sampling
    method used by the US Environmental Protection Agency (1971), it is
    possible to analyse the particulates collected in the probe, on the
    filter, and in the water impingers.

        Manganese is emitted in automobile exhaust in the form of
    particulate matter. Concentrations vary according to the natural
    manganese levels in the fuel and to the concentration of
    manganese-containing additives, if present. Exhaust particulates may
    be collected by total or proportional sampling of the hot exhaust or
    by proportional sampling of the exhaust mixed with air, which allows
    cooling and condensation of the compounds of greater relative atomic
    mass associated with short-time ambient exhaust particulates. The
    second method provides a more realistic assessment of the mass and
    composition of the primary exhaust particulates. Collection using this
    technique can be carried out using a single filter, multiple filter,
    beta gauge (Dresia & Spohr, 1971), or particulate-size-fractionating
    devices. Gaseous samples may be collected either by the cold-trap
    technique or on chromatographic columns.

        The following considerations are important in the sampling of
    water for manganese analysis:  (a) selection of sampling sites;  (b)
    frequency of sampling;  (c) sampling equipment; and  (d) sample
    preparation (Brown et al., 1970). Usually, little or no sample
    preparation is required but freeze-drying operations can be used.

        Aqueous samples should be filtered immediately on collection,
    using a membrane or other suitable filtering material if
    differentiation between soluble and particulate phases is to be
    attempted. Once the particulates are collected on a filter, the
    analytical problems are similar to those of air analysis. Special
    precautions are required in the handling and storage of solid and
    aqueous samples with regard to the choice of equipment and containers.

        Because of the extremely low concentration of manganese in some
    biological tissues and body fluids, contamination of the samples
    constitutes a major difficulty, a fact which is often overlooked or
    underestimated. It seems likely that the wide variation in manganese
    concentrations reported, for instance, in serum (section 6.2.1) can
    portly be explained by contamination.

        Steel equipment is considered unsuitable for tissue biopsy, and
    quartz or glass knives have been suggested as alternatives; the use of
    a laser beam has also been discussed (Becker & Maienthal, 1975).
    Versieck et al. (1973a) reported that the radioactivated Menghini
    needles used in liver biopsy could cause up to 30% manganese
    contamination. It has also been suggested that skin-pricking is
    inferior to venepuncture in the drawing of blood samples because of
    the possible introduction of tissue manganese into the sample
    (Papavasiliou & Cotzias, 1961). Single transfer of blood through
    conventional steel needles has caused serious contamination of samples
    (Cotzias et al., 1966), and the use of platinum-rhodium alloy needles
    with Kel-F hubs has been proposed to overcome this problem (Becker &
    Maienthal, 1975).

        A considerable contamination problem may arise in the presence of
    some anticoagulants. Bethard et al. (1964) reported a manganese
    concentration in heparin of 3.56 g/ml whereas acid-citrate-dextrose
    contained only 0.002 g/ml. Consequently, when heparin was used as an
    anticoagulant, the manganese concentration was 0.17  0.03 g/ml
    compared with 0.00014 g/ml when acid-citrate-dextrose was used.

        Sampling of hair may be complicated by the fact that manganese is
    associated with melanin-containing structures, black and brown hair
    containing much higher concentrations of manganese than white hair
    (Cotzias et al., 1964).

    2.2.2  Separation and concentration

        Special procedures are not normally necessary for the separation
    of manganese from other metals prior to the analysis or concentration
    of samples. Chromatographic methods for the determination of manganese
    have been reviewed by Fishbein (1973).

    2.2.3  Methods for quantitative determination

    2.2.3.1  Optical spectroscopy

        Trace metals, including manganese, have been determined
    spectroscopically by a number of research workers. With suitable
    variations in sample preparation, the available standard spectroscopic
    methods can be used equally well for mineral ores, air particulates,
    or biological samples (Cholak & Hubbard, 1960; Tipton, 1963;
    Angelieva, 1969, 1970, 1971; Bugaeva, 1969; Carlberg et al., 1971; El
    Alfy et al., 1973; Ppin et al., 1973). The advantages of spectroscopy
    are that it can be applied to most elements with a satisfactory
    specificity and sensitivity and that it can be used for the
    simultaneous determination of several elements (US Environmental
    Protection Agency, 1972, 1973). Drawbacks of the emission
    spectroscopic assay include the exacting nature of the method, which
    necessitates the use of highly qualified personnel, the cost of the
    instrument, the complexity of the method, and the detection limits,
    which are too high to detect metals occurring in low concentrations
    (Thompson et al., 1970).

    2.2.3.2  Atomic absorption spectroscopy

        This is the most commonly used method of determining manganese at
    present, because the procedure is relatively simple and fast and the
    sensitivity is high. The application to ambient air samples has been
    described by Thompson et al. (1970), Begak et al. (1972), and Muradov
    & Muradova (1972). The method is fairly free from interference except
    for possible matrix effects, which can generally be avoided. Any

    silica extracted from glass-fibre filters can cause interference
    unless removed by the addition of calcium to the solution, prior to
    analysis (Slavin, 1968). Atomic absorption methods have also been used
    to determine manganese in water and other materials. Little or no
    preparation of the sample solution is required (Thompson et al., 1970;
    Tichy et al., 1971; US Environmental Protection Agency, 1974).

        The advantage of flameless atomizers is that the determination
    can be carried out with high sensitivity using only a small sample.
    The method was initiated by L'vov (1961) to avoid interference caused
    by reactions in the flame. However, the precision of the results is
    not necessarily good since atomizing can easily be altered by various
    conditions such as the type of the sample which, for instance, may
    stick to the wall of the boat. These difficulties are especially
    significant when directly atomizing biological samples. Graphite
    furnace or carbon rod techniques can be used for the direct analysis
    of water samples, although matrix interference must be checked for and
    eliminated. Concentration of fresh water can be achieved simply by
    evaporation. Other variants have been developed for biological
    substrates, foodstuffs, soils, and plant materials (Ajemian & Whitman,
    1960; Suzuki, 1968; Suzuki et al., 1968; Obelanskaja et al., 1971; Bak
    et al., 1972; Van Ormer & Purdy, 1973).

        An atomic absorption assay using direct aspiration of the sample
    into the burner has been described for the determination of
    methylcyclopentadienyl manganese tricarbonyl (MMT) in gasoline. The
    drawback of this method is that it does not discriminate between MMT
    and other manganese compounds (Bartels & Wilson, 1969).

        Atomic absorption methods can be classified, according to the
    type of sample or sample solution to be applied to the atomizer, into
     (a) the direct method, in which the sample or sample solution is
    used directly; and  (b) the solvent-extraction method in which a
    clean-up and concentration process by solvent extraction is carried
    out before atomizing. The gross matrix effects of saline waters
    necessitate a preliminary extraction, which usually entails a
    concentration procedure. Chelating ion-exchange (Riley & Taylor, 1968)
    and solvent extraction are also often used (Hasegawa & Ijichi, 1973).

    2.2.3.3  Neutron-activation analysis

        This method has a high specificity and sensitivity for very low
    concentrations of manganese as well as several other elements (Dams et
    al., 1970). However, the user must be aware that neutron-activation of
    biological samples may result in the production of isotopes that
    interfere with the determination of manganese. Irradiated samples are
    treated by a chemical separation process with a certain amount of

    manganese carrier and then determined by gamma-spectroscopy. The
    1810.7 Kev gamma line of 56Mn is measured. This method can be used to
    check the accuracy of results obtained by other analytical methods and
    for the determination of manganese at very low concentrations in a
    small number of samples. It is essential to collect particulate matter
    on filters that have a very low trace element content (ashless filter
    paper). Variations of this method have been used for determining
    manganese concentrations in blood and serum (Cotzias et al., 1966) and
    in plants (Hatamov et al., 1972).

    2.2.3.4  X-ray fluorescence

        The use of X-ray fluorescence spectroscopy provides a means for
    the non-destructive analysis of elements in sediments and
    particulates.

        X-ray fluorescence can also be used to determine manganese in
    solutions, if the sample is prepared by freeze-drying. Birks et al.
    (1972) have made a complete elemental analysis with high sensitivity
    in 100 seconds using multichannel analysers with 14-24 crystals. The
    necessity of distinguishing unreactive, structurally incorporated
    manganese in particulates and sediments from the more reactive
    absorbed, biogenic, and hydrogenic phases was discussed in a paper by
    Chester & Hughes (1967), who proposed a selective acid-leaching
    technique for this purpose. Manganese in water was determined by
    Watanabe et al. (1972), using a nickel carrier, with a limit of
    detection of 0.03 g. Another method that has been developed for the
    analysis of various elements including manganese, is proton-induced
    X-ray emission analysis (Johansson et al., 1975). Manganese in dust
    samples collected by an impactor was detected at nanogram levels using
    this method.

    2.2.3.5  Other methods

        The periodate method is the classical wet chemical method of
    analysing air samples for manganese (American Conference of
    Governmental Industrial Hygienists, 1958). The advantage of this
    method is that it can be used in almost any chemical laboratory with
    relatively simple equipment, but the sensitivity (0.1 mg/m3) is
    rather poor in comparison with that of other methods (Peregud &
    Gernet, 1970). This technique has also been widely used for
    determining total manganese in the soil but it is considered to give a
    poor estimate of the manganese available to plants.

        The permanganate method is the most commonly used method for the
    analysis of manganese in water samples. Interference caused by
    manganese in the glassware has to be eliminated when the manganese
    level in the sample is low, and prior removal of organic material may
    be necessary. However, not all forms of manganese likely to occur in
    water can be measured by the permanganate method (e.g., the complexes
    of trivalent manganese and manganese dioxide), and an improved, simply
    performed formaldoxime method has been developed for the analysis of
    both water and soils (Samohvalov et al., 1971; Cheeseman & Wilson,
    1972).

        A rapid drop quantitative method, developed for determining
    manganese in the air of the working environment, is based on the
    colour reaction of manganese ions with potassium ferricyanide. The
    method is specific and results compare well with those obtained by
    emission spectroscopy (Muhtarova et al., 1969).

        A kinetic method based on the ability of manganese to catalyse
    the atmospheric oxidation of the morin-beryllium complex has been
    developed for the determination of manganese in atmospheric
    precipitates (Morgen et al., 1972). Polarography can be used for
    determining manganese in industrial waste waters with a sensitivity of
    0.05 mg/litre. Chromium interference can be removed by phosphate
    precipitation (Bertoglio-Riolo et al., 1972). A similar method for
    analysing animal foodstuffs, organs, and tissues has been developed
    for samples weighing only 2 g. Interference caused by iron can be
    avoided by precipitating it with a mixture of ammonium chloride and
    ammonium hydroxide (Usovic, 1967). An alternative method for the
    determination of manganese in biological material is electron
    paramagnetic resonance spectroscopy (Cohn & Townsend, 1954; Miller et
    al., 1968).

        Spark source mass spectroscopy is probably a suitable method for
    the determination of manganese in petrol (US Environmental Protection
    Agency, 1975). Cyclopentadienyl manganese tricarbonyl can be
    determined by treating the sample with nitric and sulfuric acid and
    subsequently converting the manganese to permanganate (Byhovskaja et
    al., 1966).

    2.2.3.6  Comparability of methods

        As already stated, atomic absorption spectroscopy combined, when
    necessary, with a separation solvent procedure, can be applied to most
    environmental samples. Each of the other methods described has its
    particular advantages and characteristics and can be used according to
    the need for sensitivity and to the type of sample. Studies such as
    that of Harms (1974) on the comparison of data from several different
    analytical methods are useful. The inter-comparison of analytical
    techniques carried out under the responsibility of EURATOMa also
    provides interesting information. In this study, good agreement was
    obtained when neutron-activation analysis, X-ray fluorescence,
    emission spectroscopy, and atomic absorption spectroscopy were
    compared for the determination of manganese.

              

    a  EURATOM (unpublished data, 1974) Chemical analysis of airborne
       particulates: intercomparison and evaluation of analytical
       techniques. In: Guzzi, G., ed.  Minutes of the Meeting held at
       Ispra, Italy, 8-9 July 1974, Ispra Establishment, Chemistry
       Division, Joint Research Centre of the European Communities,
       33 pp.

    3.  SOURCES OF MANGANESE IN THE ENVIRONMENT

    3.1  Natural Occurrence

        Manganese is widely distributed in nature but does not occur as
    the free metal. The most abundant compounds are the oxide (in
    pyrolusite, brannite, manganite, and hausmannite), sulfide (in
    manganese blonde and hauserite), carbonate (in manganesespar), and the
    silicate (in tephroite, knebelite, and rhodamite). It also occurs in
    most iron ores in concentrations ranging from 50-350 g/kg, and in many
    other minerals throughout the world.

        A rough estimate of the average concentration of manganese in the
    earth's crust is about 1000 mg/kg (NAS-NRC, 1973). Manganese
    concentrations in igneous rock may range from about 400 mg/kg in
    low-calcium granitic rock to 1600 mg/kg in ultrabasic rock and
    sedimentary rocks. Deep sea sediments contain concentrations of about
    1000 mg/kg (Turekian & Wedepohl, 1961). It has been reported that the
    manganese content of coal ranges from 6 to 100 mg/kg (Ruch et al.,
    1973) and that of crude oil from 0.001 to 0.15 mg/kg (Bryan, 1970).

        In soil, manganese concentrations depend primarily on the
    geothermal characteristics of the soil, but also on the environmental
    transformation of natural manganese compounds, the activity of soil
    microorganisms, and the uptake by plants.

        Although the principal ores are only slightly soluble in water,
    gradual weathering and conversion to soluble salts contribute to the
    manganese contents of river and sea water. Considerable amounts of
    manganese are present in deposits in large areas of the oceans in the
    form of nodules. These are formed continuously at a rate of several
    million tonnes per year (Schroeder et al., 1966). The average
    concentration of manganese in these nodules is about 200 mg/kg (Zajic,
    1969) with a range of about 150-500 mg/kg (Schroeder et al., 1966).

    3.2  Industrial Production and Consumption

        Elemental manganese was isolated in 1774, though the oxide has
    been used in the manufacture of glass since antiquity. The total world
    production of manganese, which was 18 million tonnes in 1969, rose to
    about 27 million tonnes in 1975. However, consumption, which had risen
    by 20% between 1970 and 1975, dropped by 3% in 1975 (Mineral Yearbook,
    1975, 1977).

        Fumes, dust, and aerosols from metallurgical processing, mining
    operations, steel casting (Mihajlov, 1969) and metal welding and
    cutting, (Erman, 1972), mainly in the form of manganese oxide are the
    principal sources of environmental pollution. Emissions into the
    atmosphere from blast and electric furnaces vary considerably
    depending on the process involved and the degree of control exercised.
    Dust from the handling of raw materials in metallurgical processing
    and other manufacturing activities probably makes only a small
    contribution to the atmospheric concentration of manganese. Calculated
    emission factors for manganese are given in Table 2.

        Table 2.  Emission factors for manganese
                                                                                   

    Mining                         0.09 kg/tonne of manganese mined

    Processing
        manganese metal           11.36 kg/tonne of manganese processed
        ferromanganese
           blast furnace           1.86 kg/tonne of ferromanganese produced
           electric furnace       10.86 kg/tonne of ferromanganese produced
        silicomanganese
           electric furnace       31.55 kg/tonne of silicomanganese produced

    Reprocessing
        carbon steel
           blast furnace          10.22 kg/1000 tonnes of pig iron produced
           open-hearthfurnace     23.18 kg/1000 tonnes of steel produced
           basic oxygen furnace   20.00 kg/1000 tonnes of steel produced
           electric furnace       35.45 kg/1000 tonnes of steel produced
        cast iron                150.00 kg/1000 tonnes of cast iron
        welding rods               7.27 kg/tonne of manganese processed
        nonferrous alloys          5.45 kg/tonne of manganese processed
        batteries                  4.54 kg/tonne of manganese processed
        chemicals                  4.54 kg/tonne of manganese processed

    Consumer uses
        coal                       3.50 kg/tonne of coal burned
                                                                                   

    From: Davis & Associates (1971).

    
    3.2.1  Uses

        Over 90% of the manganese produced in the world is used in the
    making of steel, either as ferromanganese, silicomanganese, or
    spiegeleisen. Manganese is also used in the production of nonferrous
    alloys, such as manganese bronze, for machinery requiring high
    strength and resistance to sea water, and in alloys with copper,
    nickel, or both in the electrical industry. In dry-cell batteries,
    manganese is used in the form of manganese dioxide, which is also used
    as an oxidizing agent in the chemical industry. Many manganese
    chemicals, eg., potassium permanganate, manganese(II) sulfate,
    manganese dichloride, and manganese dioxide are used in fertilizers,
    animal feeds, pharmaceutical products, dyes, paint dryers, catalysts,
    wood preservatives and, in small quantities, in glass and ceramics.
    Some of these uses contribute to environmental pollution.

    3.2.2  Contamination by waste disposal

        The disposal of liquid and solid waste products containing
    manganese may contribute to the contamination of land, water courses,
    and soil. For example, sludges and various waste waters containing
    manganese are used in the production of micronutrient fertilizers
    (Eliseeva, 1973) and manganese slurries have been used in the
    production of clay blocks for road construction. Information
    concerning the degree of pollution arising from the incineration of
    refuse containing manganese is not available.

    3.2.3  Other sources of pollution

        The emission of manganese from motor vehicles powered by petrol
    that does not contain manganese additives has been estimated to
    average 0.03-0.1 mg/km (Moran et al., 1972; Gentel et al., 1974a;
    Gentel et al., 1974b).

        Methylcyclopentadienyl manganese tricarbonyl (MMT) was initially
    marketed in the USA as a supplement to tetraethyl lead in an antiknock
    preparation. During the 1960s, it was introduced as a fuel-oil
    combustion improver and as a smoke suppressant for gas turbines using
    liquid fuels. In 1974, it came into commercial use as a fuel additive
    in unleaded petrol in the USA; in 1976 about 20% of the fuel was
    unleaded, and 40% of this amount contained MMT at an average
    concentration of 10.56 mg/litre (0.04 g/US gallon) (Ethyl Corporation,
    private communication). The use of MMT is likely to increase during
    the coming years. At the manufacturer's recommended maximum level of
    MMT (a manganese concentration of 33 mg/litre),a the emission of MMT
    is approximately 0.62-3.1 g/km (1-5 g/mile); levels of about
    0.62-1.55 g/km (1-2.5 g/mile) have been reported in lubrication oil
    (Hurn et al., 1974). This low emission rate together with the fact
    that MMT rapidly undergoes photochemical decomposition (section 5.8)
    suggests that exposure to the parent compound through the exhaust gas
    would be low.

        Taking data on lead emissions in exhaust gas as a model, it has
    been calculated that the use of MMT in petrol might result in the
    emission of 0-0.25 g of manganese per m3 of air, with a median of
    0.05 g/m3, and that the organic component of this would be about
    1.2  10-5 g/m3 (Ter Haar et al., 1975). This is not far from the
    estimate of 0.05-0.2 g/m3 made by Keane & Fisher, (1968). It has
    been reported that 50% of emitted manganese particles have a mass
    median diameter (MMD) of 0.5 m or less (Moran, 1975).

        At the 1975 SAE Automobile Engineering Meeting, it was claimed
    that the use of manganese in petrol resulted in increased total
    particulate emissions that could not be totally accounted for on the
    basis of increased manganese content (Moran, 1975). This was disputed
    at the same meeting by Desmond (1975), who argued that the figures
    presented by Moran (1975) for increased total particulate emissions
    were compatible with the theoretical maximum emissions of Mn3O4
    resulting from combustion of the manganese in the fuel.

        It appears that the use of MMT in petrol causes increased
    emission of hydrocarbons (Gentel et al., 1974b; Hurn et al., 1974;
    Kocmond et al., 1975). However, there is no conclusive evidence to
    indicate that MMT decreases the efficiency of catalysts (Faggan et
    al., 1975; Moran, 1975).

        It is possible that MMT in petrol increases aldehyde emissions,
    though the data so far available are conflicting (Ethyl Corporation,
    1974; Gentel et al., 1974b; Hurn et al., 1974). Too little information
    is available to draw any conclusions with regard to the effects of MMT
    in petrol on the emission of polynuclear aromatic hydrocarbons. Tests
    performed by the Ethyl Corporation (1974) showed a decrease in
    benzo(a)pyrene concentrations in exhaust gas. A similar decrease in
    benzo(a)pyrene concentrations was reported by Lerner (1974) using an
    analogous compound, cyclopentadienyl manganese tricarbonyl. In one
    study, it was shown that MMT in petrol could decrease atmospheric
    visibility (Kocmond et al., 1975). Results of other studies conducted
    by the Ethyl Corporation (1971) indicated that comparatively high
    concentrations of manganese in air were needed to influence the
    reaction converting sulfur dioxide to sulfuric acid and sulfates.
    Thus, the reaction rate was unchanged at a manganese concentration of
    4 g/m3 and no effect was detectable at a concentration of 36 g/m3,
    when the humidity was below 70%.

              

    a  In June 1977, the manufacturer reduced the recommended maximum
       level of manganese in petrol to 16 mg/litre, bringing about a
       corresponding cut in the estimated emission levels (Ethyl
       Corporation, private communition).

        The effects of MMT in petrol on the emission of carbon monoxide
    and oxides of nitrogen are not clear (Moran, 1975).

        Another organic manganese compound, manganese
    ethylene-bis-dithiocarbamate (Maneb), is used as a fungicide.

        A large-scale investigation was made in Japan using a pilot
    plant, equipped with a desulfurization device containing activated
    manganese dioxide, to explore its influence on manganese levels in the
    surrounding environment. The operation of the device increased the
    manganese level in air by an average value of 0.002 g/m3 (Ministry
    of International Trade and Industry & Ministry of Health and Welfare,
    1969).

        Minor uses of manganese compounds in the manufacture of linoleum
    and calico printing and in the manufacture of matches and fireworks
    may be an additional source of environmental contamination.

    4.  ENVIRONMENTAL LEVELS AND EXPOSURE

    4.1  Air

    4.1.1  Ambient air

        The natural level of manganese in air is low. A concentration in
    air of 0.006 g/m3 at a height of 2500 m and an annual average
    concentration of 0.027 g/m3 at 823 m were reported by Georgii et al.
    (1974). In rural areas, manganese levels in air may range from 0.01 to
    0.03 g/m3 (US Environmental Protection Agency, 1973).

        Because nearly all the manganese emitted into the atmosphere is
    in association with small particles, it may be distributed over
    considerable distances. According to Lee et al. (1972), about 80% of
    manganese emitted into the atmosphere is associated with particles
    with a mass median equivalent diameter of less than 5 m and about 50%
    with particles of less than 2 m. Thus, most of the particles are
    within the respirable range.

        A survey of manganese concentrations in suspended particulate
    matter, conducted during the period 1957-1969 at some 300 urban and
    300 nonurban sites in the USA, has been summarized by the US
    Environmental Protection Agency (1975). Annual average manganese
    concentrations ranged from less than 0.099 g/m3 for about 80% of the
    sites to more than 0.3 g/m3 for about 5% of the sites (Table 3). In
    areas associated with local ferromanganese or silicomanganese
    industries such as Johnstown, Charleston, and Niagara Falls, the
    annual average concentrations ranged upwards from 0.50 g/m3
    (Table 4). The average 24-h concentrations in such places can exceed
    10 g/m3 and may present an important health risk. Urban centres
    without major foundry facilities, such as New York, Los Angeles, and
    Chicago, exhibited annual average manganese concentrations in air
    ranging from 0.03 to 0.07 g/m3, whereas in cities with these
    facilities, such as Pittsburg, Birmingham, and East Chicago, values
    ranged from 0.22 to 0.30 g/m3 (US Environmental Protection Agency,
    1973). These concentrations are in agreement with those found in other
    studies from the USA (Brar et al., 1970; Lee et al., 1972). The
    highest reported annual average concentration of 8.3 g/m3, was
    measured in Kanawha Valley, West Virginia, during 1964-65. The major
    source of pollution was a ferromanganese plant situated in a nearby
    area (US Environmental Protection Agency, 1975).

        Manganese values from air sampling sites in the United Kingdom
    during 1971-1972 ranged from 0.004 to 0.049 g/m3; Keane & Fisher
    (1968) reported mean manganese concentrations of 0.013-0.033 g/m3 in
    relatively unpolluted areas of the United Kingdom.



        Table 3.  Number of National Air Surveillance Network (NASN) stations within selected
              annual average manganese concentration intervals, 1957--1969a
                                                                                                  

                                             Concentration interval (g/m3)
                                                                                      

    Year                         <0.099      0.100-0.199      0.200-0.299      >0.300      Total
                                                                                                  

    1957-     No. stations         76            29               10            13           128
    1963      %                    59.4          22.7              7.8          10.2         100
    1964      No. stations         68            12                6             7            93
              %                    73.1          12.9              6.5           7.5         100
    1965      No. stations        132            14                5             6           157
              %                    84.1           8.9              3.2           3.8         100
    1966      No. stations        113             8                4             3           128
              %                    88.3           6.3              3.1           2.3         100
    1967      No. stations        121            13                4             4           142
              %                    85.2           9.2              2.8           2.8         100
    1968      No. stations        126            11                2             6           145
              %                    86.9           7.6              1.4           4.1         100
    1969      No. stations        169            23                9             8           209
              %                    80.9          11.0              4.3           3.8         100
    1957-     No. stations        805           110               40            47          1002
    1969      %                    80.4          11.0              4.0           4.7         100
                                                                                                  

    a  From: US Environmental Protection Agency (1975).
    


        Table 4.  National Air Surveillance Network (NASN) stations with annual
              average manganese concentrations greater than 0.5 g/m3a
                                                                              

                                       Manganese concentration (g/m3)
                                                                              

    Year         Station            Average   Max. quarterly   Max. 24-h
                                                                              

    1958     Charleston, W.VA        0.61         1.10           7.10
    1959     Johnstown, PA           2.50         5.40           7.80
             Canton, OH              0.72         1.10           2.20
    1960     Gary, Ind.              0.97                        3.10
    1961     Canton, OH              0.57                        2.90
             Philadelphia, PA        0.70                      >10.00
    1963     Johnstown, PA           1.44                        6.90
             Philadelphia, PA        0.62                        3.70
    1964     Charleston, W.VA        1.33                      >10.00
    1965     Johnstown, PA           2.45         3.90
             Philadelphia, PA        0.72         1.70
             Lynchburg, VA           1.71         2.50
             Charleston, W.VA        0.60         1.70
    1966     Niagara Falls, NY       0.66         1.30
    1967     Knoxville, TN           0.81         1.50
    1968     Johnstown, PA           3.27                       14.00
    1969     Niagara Falls, NY       0.66         1.30
             Johnstown, PA           1.77         2.10
             Philadelphia, PA        0.50         1.30
                                                                              

    a  From: US Environmental Protection Agency (1975).
    
        In the Federal Republic of Germany, manganese concentrations were
    found to range from 0.08 to 0.16 g/m3 in different areas of
    Frankfurt, with a maximum 24-h concentration of 0.49 g/m3 (Georgii &
    Mller, 1974), whereas in a residential area of Munich levels of
    0.030-0.034 g/m3 were reported, with 0.06-0.27 g/m3 in a street
    with heavy traffic (Bouquiaux, 1974).

        The Environment Agency, Japan (1975) reported an annual mean
    manganese concentration in the air of Japanese cities of about
    0.02-0.80 g/m3 with maximum 24-h concentrations of 2-3 g/m3
    (Environment Agency, Japan, 1975). Studies are also available from a
    district in Kanazawa, Japan, close to a plant using electric furnaces
    for the production of manganese alloys. Average levels during 1970
    varied from 1.1 to 9.8 g/m3, when measured over 2-day periods at a
    point 300 m from the emitting source. Unpolluted areas of the same
    city showed average levels of 0.035 g/m3 during the period
    1968-1970 (Itakura & Tajima, 1972). When manganese concentrations were

    measured at underground shopping districts adjoining subway stations
    in Tokyo, Osaka, and Nagoya, open-air concentrations of
    0.042-0.074 g/m3 and subway concentrations of 0.040-0.353 g/m3
    were found, indicating that heavy subway traffic on railway lines
    containing manganese as a ferroalloy may increase manganese exposure
    (Japan Environmental Sanitation Centre, 1974).

        Thus, it can be concluded that annual average levels for
    manganese in ambient air in nonpolluted areas range from approximately
    0.01 to 0.03 g/m3, while in urban and rural areas without
    significant manganese pollution, annual averages are mainly in the
    range of 0.01-0.07 g/m3. With local pollution near foundries, this
    level can rise to an annual average of 0.2-0.3 g/m3 and in the
    presence of ferro- and silicomanganese industries, to over 0.5 g/m3.
    The data available are not adequate for drawing valid conclusions with
    respect to trends in ambient manganese concentrations.

    4.1.2  Air in workplaces

        In recent years, most of the industrialized countries have
    established occupational exposure limits for manganese. Thus, working
    conditions have improved and earlier reports of excessive exposure to
    manganese do not always represent more recent conditions. This should
    be borne in mind when considering the information presented in this
    section.

        According to one report (Ansola et al., 1944a), Chilean manganese
    miners were exposed to manganese concentrations in air of
    62.5-250 mg/m3. However in a later study in a Chilean mine, Schuler
    et al. (1957) reported a concentration range of 0.5-46 mg/m3, the
    highest levels being found in connection with the drilling of pure,
    dry ore and the drilling of manganese-bearing rock. Manganese
    concentrations of up to 926 mg/m3 of air were found in Moroccan mines
    (Rodier, 1955). Flinn et al. (1940) recorded a manganese concentration
    of 173 mg/m3 in an ore-crushing mill in the USA but a much later
    survey of dust levels in the air of a ferromanganese crushing plant in
    the United Kingdom (as measured by personal sampling devices) showed
    manganese concentrations of 0.8-8.6 mg/m3. The device of one man
    cleaning down the crusher showed an exceptionally high concentration
    of 44.1 mg/m3. When levels in air were measured at fixed sampling
    points, they ranged from 8.6 to 83.4 mg/m3 (Department of Health &
    Social Security, unpublished data).a

        In an electric steel foundry in Japan, manganese concentrations
    ranged from 4.0 to 38.2 mg/m3 around an electric furnace and from 4.9
    to 10.6 mg/m3 around the mouth of the kiln (Ueno & Ohara, 1958).

        In studies in the USSR reported by Mihajlov (1969), manganese
    concentrations in air of 0.3 mg/m3 or more were found in 98% of 1905
    samples collected in the furnace area of a steel shop, during the
    period 1948-1983. The levels reached 1.8-2.4 mg/m3 during melting
    operations and increased to as much as 10 mg/m3, when the molten
    steel was being poured. Additional data on manganese concentrations in
    air can be found in section 9.1.

        Few studies have included details of the size distribution of
    manganese dust, which is of importance in the evaluation of dust
    absorption following inhalation. Akselsson et al. (1975) reported
    manganese concentrations of up to 3 mg/m3 in the breathing zone of
    welders. The highest concentrations were associated with particles
    ranging in size from 0.1 to 1.0 m. This is in agreement with the
    finding that 80% of particles from a ferromanganese furnace ranged in
    size from 0.1 to 1.0 m (Sullivan, 1969). In studies by Smyth et al.
    (1973), more than 99% of the particles in airborne fume around a blast
    furnace were smaller than 2 m and 95% of airborne dust particles at a
    crushing and screening plant were smaller than 5 m.

    4.2  Water

        Manganese may be present in fresh water in both soluble and
    suspended forms. However, in most reported studies, only total
    manganese has been determined.

        Surface waters of various American lakes were found to contain
    from 0.02 to 87.5 g of manganese per litre with a mean of
    3.8 g/litre (Kleinkopf, 1960). In two other studies the contents of
    large rivers in the USA ranged from below the detection limit to
    185 g/litre (Durum & Haffty, 1961; Kroner & Kopp, 1965). A range of
    0.8-28.0 g/litre was found in Welsh rivers (Abdullah & Royle, 1972).
    Manganese concentrations at 37 river sampling sites in the United
    Kingdom (Department of Health and Social Security, 1975 --
    unpublished) and in the Rhine and the Maas and their tributaries
    (Bouquiaux, 1974) ranged from 1 to 530 g/litre. There are some
    reports indicating a seasonal variation in the manganese contents of
    rivers (Bescetnova et al., 1968; Kolesnikova et al., 1973) and inshore
    waters, manganese levels being lowest during the winter months
    (Morris, 1974). High manganese concentrations reaching several
    mg/litre have been found in waters draining mineralized areas
    (Kolomijeeva, 1970; Department of Health and Social Security, 1975 --
    unpublished) and in water contaminated by industrial discharges
    (Kozuka et al., 1971).

              

    a  Department of Health and Social Security (1975)  Environmental
        health criteria for manganese and its compounds: Review of work
        in the United Kingdom, 1967-1973. 

        In the USSR, groundwater not associated with manganese-bearing
    rock, contained manganese concentrations ranging from 1 to
    250 g/litre (Kolomijeeva, 1970). A comparatively high average
    concentration of 0.55 mg/litre was reported in a study of 6329
    untreated samples of groundwater in Japan (Kimura et al., 1069) and
    concentrations ranging from 0.22 to 2.76 mg/litre were found in deep
    well water in the Takamatsu City area (Itoyama, 1971).

        An average concentration of manganese in seawater of 0.4 g/litre
    was reported by Turekian (1969). In other studies on the manganese
    contents of sea water in the North Sea, the Northeast Atlantic, the
    English Channel, and the Indian Ocean, concentrations ranged from 0.03
    to 4.0 g/litre with mean values of 0.06-1.2 g/litre. In estuarine
    and coastal waters of the Irish Sea and in waters along the North Sea
    shores of the United Kingdom, values ranging from 0.2 to 25.5 g/litre
    have been reported with mean values of 1.5-6.1 g/litre (Topping,
    1969; Preston et al., 1972; Jones et al., 1973; Bouquiaux, 1974).

        Manganese concentrations in treated drinking-water supplies in
    100 large cities in the USA ranged from undetectable to 1.1 mg/litre,
    with a median level of 5 g/litre; 97% of the supplies contained
    concentrations below 100 g/litre (Durfor & Becker, 1964). According
    to a US Public Health Service survey quoted by Schroeder (1966),
    manganese levels in tap water from 148 municipal supplies ranged from
    0.002 to 1.0 mg/litre, with a median level of 10 g/litre. Mean
    concentrations of manganese in drinking-water in the Federal Republic
    of Germany were reported to range from 1 to 63 g/litre (Bouquiaux,
    1974).

    4.3  Soil

        The average concentration of manganese in soils is probably about
    500-900 mg/kg (NAS/NRC, 1973). Earlier analyses are of doubtful value,
    as errors arising from contamination and interference with other
    substances were not fully appreciated (Mitchell, 1964). The
    significance of manganese levels in soils depends largely on the type
    of compounds present and on the characteristics of the soil such as
    the pH and the redox potential. Accumulation usually occurs in the
    subsoil and not in the surface, 60-90% of manganese being found in the
    sand fraction of the soil. In well-drained areas, the manganese
    contents of stream sediments and of parent rocks and soils have been
    found to be comparable. In areas of poorly-drained, peaty gleys and
    podzols, stream sediments may be greatly enriched. For example, stream
    sediments from poorly drained Welsh moorlands with rock and soil
    concentrations of 540 mg/kg and 300 mg/kg, respectively, contained an
    excess of 1% manganese (Nichol et al., 1967).

        Soddy-podzolic soils in the USSR contained manganese
    concentrations of 21-200 mg/kg, chernozem soils, up to 6400 mg/kg, and
    boggy soils, 10-500 mg/kg. Mobile manganese in the USSR soils varied
    from 23 to 149 mg/kg (Vasilevskaja & Bogatyrev, 1970). In Belgium,
    loess formation in a forest region contained manganese concentrations
    of 113-450 mg/kg. In a semi-industrialized region, concentrations
    ranging from 135 to 320 mg/kg were found, while in sandy uncultivated
    soil, concentrations ranged from 30 to 43 mg/kg (Bouquiaux, 1974).

    4.4  Food

        The manganese contents of various foodstuffs vary markedly
    (Table 5).

        In cereal crops from the USSR, manganese concentrations varied
    from 2 to 100 mg/kg wet weight, concentrations in pulse crops ranged
    from 0.36 to 32 mg/kg, and those in root crops from 0.2 to 15 mg/kg;
    beet crops contained up to 37 mg/kg (Aljab'ev & Dmitrienko, 1971;
    Musaeva & Kozlova, 1973).

        The edible muscle tissue of 8 common commercial species of fish
    in New Zealand was reported by Brooks & Rumsey (1974) to have mean
    concentrations of manganese ranging from 0.08 to 1.15 mg/kg wet
    weight. Similar values (0.03-0.2 mg/kg wet weight) were found in North
    Sea fish. In cod and plaice, most values were lower than 0.1 mg/kg.
    Shellfish may concentrate manganese. Scallops, oysters, and mussels
    dredged from Tasman Bay contained average manganese levels of 111 mg,
    8 mg, and 27 mg/kg dry weight, respectively (Brooks & Rumsey, 1965).

        High concentrations of manganese have been found in tea including
    levels of 780-930 mg/kg in the finished leaves (Nakamura & Osada,
    1957) and 1.4-3.6 mg/litre in liquid tea (Nakagawa, 1968).

        In most human studies, the average daily intake of manganese, via
    food, by an adult has been reported to be between 2 and 9 mg/day.
    Values of about 2.3-2.4 mg/day have been reported from the Netherlands
    (Belz, 1960) and the USA (Schroeder et al., 1966). North et al. (1960)
    obtained an average daily intake of 3.7 mg for 9 American college
    women, and Tipton et al. (1969), using the duplicate portion method,
    reported 50-week, mean daily intakes of 3.3 and 5.5 mg, respectively,
    for two American adult males. Similarly, an average intake of
    4.1 mg/day was reported from a Canadian composite diet (Mranger &
    Smith, 1972). In a study by Soman et al. (1969), also using the
    duplicate portion method, the average manganese intake for Indian
    adults was 8.3 mg/day, while the intake from drinking-water ranged
    from 0.004 to 0.24 mg/day. These results agree well with previously
    reported values for Indian adults on a rice diet (9.81 mg of
    manganese/day) and on a wheat diet (9.61 mg of manganese/day) (De,
    1949).

    Table 5.  Manganese levels in some foodstuffs
                                                                    

    Category                     Manganese (mg/kg wet weight)
                                                                    

                          Shroeder et al. (1966)    Guthrie (1975)
                                                                    

    Cereals
       barley, meal            17.8                     9.9
       corn                     2.1                     3.8
       rice, polished           1.5                     9.6
       unpolished               2.1                    32.5
       rye                     13.3                    34.6
       wheat                    5.2-11.3               13.7-40.3

    Meat and poultry          < 0.1-0.8               < 0.1-2.7

    Fish                      < 0.1                     0.1-0.5

    Dairy products
       milk                     0.2                     0.5
       butter                   1.0                     0.1

    Eggs                        0.5                     0.3

    Vegetables
       beans                    0.2                     1.8
       peas                     0.6                     2.6
       cabbage                  1.1                     0.8
       spinach                  7.8                     1.8
       tomatoes                 0.3                     0.2-0.6

    Fruit
       apples                   0.3                     0.2-0.3
       oranges                  0.4                     0.3
       pears                    0.3                     0.1-0.4

    Nuts
       walnuts                  7.5                    19.7

                                                                    

        The daily intake of manganese by bottlefed and breastfed infants
    is very low because of the low concentrations of manganese in cow's
    milk and, especially, in breast milk (McLeod & Robinson, 1972a).
    Widdowson (1969) reported a daily intake of 0.002 mg/kg body weight
    for 1-week-old babies. Values of a similar order of magnitude
    (0.002-0.004 mg/kg) have been reported for the first 3 months of life
    by Belz (1960) and McLeod & Robinson (1972a). When a child is
    established on a mixed food regimen after 3-4 months of age, the
    intake increases considerably (McLeod & Robinson, 1972a).

        Belz (1960) reported a daily intake of 1.7 mg for children aged
    7-9 years, and Schlage & Wortberg (1972) reported intakes of
    1.4 mg/day for 6 children aged 3-5 years, and 2.2 mg/day for 5
    children aged 9-13 years, corresponding to 0.08 mg and 0.06 mg/kg body
    weight, respectively. Day-to-day intake varied considerably, the
    maximum intake being 10 times the minimum. Similar values for daily
    intake were obtained by Alexander et al. (1974) for 8 children aged
    between 3 months and 8 years; the mean intake was 0.06 mg/kg body
    weight.

    4.5  Total Exposure from Environmental Media

        Based on annual average air concentrations and a respiratory rate
    of 20 m3/day, an estimate of the daily exposure to manganese of
    populations living in areas without manganese-emitting industries
    would be less than 2 g/day. For populations living in areas with
    major foundry facilities, the value is likely to be about 4-6 g,
    while in areas associated with ferromanganese or silicomanganese
    industries, the exposure may rise to 10 g, and 24-peak values may
    exceed 200 g.

        Considering the manganese concentrations in the vast majority of
    drinking-water supplies, and assuming a water intake of 2 litres per
    day, the average daily intake of manganese with drinking-water would
    be about 10-50 g with a range of about 2-200 g. Although the
    variation is considerable, an intake exceeding 1.0 mg/day would be
    exceptional.

        The daily intake of manganese from food appears to be 2-9 mg.
    Some European and American studies suggest a likely range of 2-5 mg,
    while in countries where grain and rice make up a major portion of the
    diet, the intake is more likely to be in the range of 5-9 mg. The
    consumption of tea may substantially add to the daily intake.

        The average intake for children from a very early age up to
    adolescence is about 0.06-0.08 mg/kg body weight whereas for breastfed
    or bottlefed infants intake is only about 0.002-0.004 mg/kg body
    weight.

    5.  TRANSPORT AND DISTRIBUTION IN ENVIRONMENTAL MEDIA

    5.1  Photochemical and Thermal Reactions in the Lower Atmosphere

        Atmospheric manganese compounds seem to promote the conversion of
    sulfur dioxide to sulfuric acid (Coughanowr & Krause, 1965; Matteson
    et al., 1969; Ethyl Corporation, 1971; McKay, 1971). However, the
    concentration of manganese required to achieve this conversion and the
    significance of its effect remain unknown. The available evidence
    seems to indicate that a higher concentration of atmospheric manganese
    than is normally observed would be necessary.

        Manganese dioxide reacts with nitrogen dioxide, in the
    laboratory, to form manganous nitrate (Schroeder, 1970). There is the
    possibility that such a reaction might occur in the atmosphere but
    further studies are needed before any conclusion can be reached.

    5.2  Decomposition in Fresh Water and Seawater

        All water contains manganese derived from soil and rocks.
    Manganese in seawater is found mostly as manganese dioxide (MnO2),
    some of which is produced from manganese salts by several species of
    bacteria common to soils and ocean muds. The aqueous chemistry of
    manganese is complex. Mobilization of manganese is favoured by low Eh
    and/or pH conditions. Thus acid mine-drainage waters can give rise to
    high environmental concentrations of dissolved manganese. Mitchell
    (1971) showed that mobilization was greatly enhanced in acid, poorly
    drained podzolic soils and groundwaters. It was suggested by Nichol et
    al., (1967) that, in acid waterlogged soils, manganese passes freely
    into solution and circulates in the groundwaters but that it is
    precipitated on entering stream waters with average pH and Eh, thus
    giving rise to stream sediments enriched with manganese.

        Particulate material suspended in natural waters may contain an
    appreciable proportion of manganese. Preston et al., (1972) found that
    67-84% of the total manganese in shoreline and offshore areas of the
    British Isles was associated with particulate matter that contained
    manganese levels of several hundred mg/kg. Levels of particulate
    manganese present in ocean waters are low in comparison with levels of
    dissolved manganese. However, much larger amounts of particulate
    manganese occur in estuarine and river waters, where resuspension of
    bottom material may occur. Spencer & Sachs (1970) found that organic
    particulate matter in the Gulf of Maine was predominantly regenerated
    in the water column and that the amount of manganese transported to
    the sediments in this way was negligible.

        In deep-sea sediments, manganese is concentrated in the form of
    both crustal material and coastal and shelf sediments. The composition
    of manganese nodules on the ocean floors is related to factors such as
    water composition, sedimentation rates, volcanic influences, and
    organic productivity. Regional variations have also been observed,
    especially in the Atlantic Ocean (Elderfield, 1972).

    5.3  Atmospheric Washout and Rainfall

        On the basis of samples taken at 32 stations in the USA, Lazrus
    et al., (1970) concluded that the manganese in atmospheric
    precipitation was derived mainly from human activity. The average
    manganese concentration in the samples was 0.012 mg/kg. These data do
    not show the immediate influence of major sources of industrial
    emissions.

    5.4  Run-off into Fresh Water and Seawater

        Aerosols, pesticides, limestone and phosphate fertilizers,
    manures, sewage sludge, and mine wastes have all been identified as
    possible sources of soil contamination that can add to the manganese
    burden of fresh water and seawater (Lagerwerff, 1967). The
    concentrations of trace elements in soil additives are generally low
    and do not significantly affect the total manganese content of soil
    (Swaine, 1962; Mitchell, 1971).

    5.5  Microbiological Utilization in Soils

        Manganese cycles in the soil have been proposed involving di-,
    tri-, and tetravalent manganese. Divalent manganese is transformed
    through biological oxidation to the less available trivalent form and
    later, through dismutation, the Mn+++ form is biologically reduced
    to Mn++. A dynamic equilibrium may exist between all forms. The
    oxidizing power of higher oxides increases with acidity and thus
    reduction by organic matter is more likely at low pH values. If the
    oxygen tension is low, biological reduction can take place at any pH
    value. Bacterial oxidation is very slow or absent in very acid soils
    and Mn++ predominates; organic matter can reduce the higher oxides.
    In alkaline soils, the divalent form nearly disappears bacterial
    oxidation is rapid and reduction by organic matter is slow. In
    well-aerated soils with a pH of more than 5.5, soil microorganisms can
    oxidize the divalent form rapidly. The rates of exchange between the
    various forms are not known at the present time but there is a very
    pronounced seasonal variation. This is probably due to oxidation and
    reduction induced by microbial action. The manganous form predominates
    in summer and the manganic form in winter, though the opposite is said
    to be true for alkaline soils (Zajic, 1969).

    5.6  Uptake by Soil and Plants

        It appears that plants mainly absorb manganese in the divalent
    state and that the availability of soil manganese is closely
    influenced by the activity of microorganisms that can alter pH and
    oxidation reduction potentials. Reducing the soil pH or the soil
    aeration by flooding or compaction favours the reduction of manganese
    to the Mn++ form and thereby increases its solubility and
    availability to plants. Heavy fertilization of acid soils without
    liming (particularly with materials containing chlorides, nitrates, or
    sulfates) may also increase manganese solubility and availability.
    Under some conditions of pH and aeration, the addition of organic
    compounds to soil can increase the chemical reduction of manganese and
    its uptake by plants. In a study by NAS/NRC (1973), it was shown that
    the capacity of plants to absorb manganese varied according to
    species. For example, in 20 different species of flowering plants, the
    absorption capacity of some species was 20-60 times greater than that
    of the species with the lowest capacity for absorbing the element
    (NAS/NRC, 1973).

        Areas with low manganese concentrations in the soil (below
    500 mg/kg) are associated with low manganese levels in the herbage
    (30-70 mg/kg dry weight) (Department of Health & Social Security, 1975
    -- unpublished). Liming has been shown to reduce the availability of
    manganese in soils; on plots with pH values ranging from 5.0 to 7.0,
    the average manganese content of clover fell from 55 to 12 mg/kg and
    that of rye grass from 104 to 13 mg/kg, alter liming (Reith, 1970).
    Nitrogen applications consistently reduce the availability of
    manganese. Organic material associated with a high pH can produce
    organic complexes of divalent manganese leading to insufficient
    available manganese for susceptible plants such as peas or cereals.
    Aging of manganese oxides reduces their availability. Manganese
    toxicity in plants may occur in soils containing manganese levels
    exceeding 1000 mg/kg dry weight; this generally occurs in very acid
    soils and can usually be remedied by liming (Mitchell, 1971). It
    should be noted that the total manganese content of soil is of little
    biological significance, since only a small amount is present in an
    available form.

        The uptake of manganese by barley p.!ants is stimulated by the
    presence of microorganisms, which also appear to break down
    EDTA-manganese chelates (Barber & Lee, 1974). On a dry-weight basis,
    perennial rye and timothy grass have been shown to have about three
    times the manganese content of lucerne, and rather more than
    tetraploid red clover. Under deficiency conditions, plants destined
    for herbage contained manganese concentrations of less than 10 mg/kg
    dry weight (Fleming, 1974).

    5.7  Bioconcentration

        Terrestrial mammals may concentrate available manganese up to a
    factor of 10, whereas fish and marine plants concentrate it by factors
    of 100 and 100 000, respectively.  Porphyra spp. in the Irish Sea
    contained 13-93 mg/kg dry weight and  Fucus spp. from British coasts
    contained 33-190 mg/kg dry weight (Preston et al., 1972).

        All vegetation appears to concentrate manganese to some extent,
    the greatest degree of concentration taking place. in new growth and
    seeds. Surface enrichment occurs through plant uptake and leaf
    shedding.

        Aquatic and terrestrial food chains have not been fully
    determined for manganese. Variations reported in manganese
    concentrations in foods may be caused by a number of factors, such as
    the level and availability of manganese in the soil and water, the use
    of agricultural chemicals, species differences in uptake, and
    variations in sampling techniques and analyses.

        The form in which manganese exists in animal and plant tissues is
    not known.

    5.8  Organic manganese fuel additives

        In the petrol engine, over 99% of the methylcyclopentadienyl
    manganese tricarbonyl (MMT) is combusted, the principal combustion
    product being Mn3O4 (Ethyl Corporation, 1974; Moran, 1975).
    According to available studies, less than 0.5% of MMT itself is likely
    to be emitted with the exhaust gas (Ethyl Corporation, 1974; Hurn et
    al., 1974). The emitted MMT is rapidly decomposed photochemically and
    has an atmospheric half-time of only a few minutes, at the most (Ter
    Haar et al., 1975). The photolytic decomposition products of MMT are
    not well known. Nearly all the manganese in this compound is converted
    by photochemical decomposition to a mixture of solid manganese oxides
    and carbonates; manganese carbonyl compounds do not appear to be
    formed (Ter Haar et al., 1975).

    6.  METABOLISM OF MANGANESE

    6.1  Absorption

        The main routes of absorption of manganese are the respiratory
    and gastrointestinal tracts. Absorption through the skin is not
    considered to occur to any great extent (Rodier, 1955).

    6.1.1  Absorption by inhalation

        Little is known about the absorption of manganese through the
    respiratory system. The absorption of some metals and metallic
    compounds was considered by the Task Group on Metal Accumulation
    (1973) and certain of the basic principles outlined in that group's
    report can be applied to inhaled metals in general. Particles small
    enough to reach the alveolar lining of the lung (less than a few
    tenths of a micrometre in diameter) are eventually absorbed into the
    blood. Mucociliary clearance, which differs with each individual,
    affects the degree of particle deposition in the lung. Furthermore, in
    studies by Hubutija (1972), it was shown that deposition of inhaled
    manganese oxide dust depended on the electrical charge carried, up to
    33% more positively charged dust being deposited than negatively
    charged dust. As a certain percentage of inhaled manganese particles
    cleared by mucociliary action may be swallowed (Mena et al., 1969),
    absorption from the gastrointestinal tract should also be considered
    (Mouri, 1973).

    6.1.2  Absorption from the gastrointestinal tract

        Not much is known about the mechanisms of absorption of manganese
    from the gastrointestinal tract. From  in vitro studies using the
    everted sac method, it would seem that manganese may be actively
    transported across the duodenal and ileal segments of the small
    intestine (Cikrt & Vostal, 1969). Results of studies in man and the
    rat on the interrelationship between manganese and iron absorption
    have indicated that intestinal absorption of manganese takes place by
    diffusion in iron-overload states and by active transport in the
    duodenum and jejunum in iron-deficiency states (Thomson et al., 1971).

        Few quantitative data are available concerning absorption from
    the gastrointestinal tract in man. Mena et al. (1969) studied
    gastrointestinal absorption in 11 healthy, human subjects, each of
    whom received 100 c (3.7 MBq) of radioactive manganese dichloride
    (54MnCl2) using 200 g of manganese dichloride (55MnCl2) as a
    carrier. About 3  0.5% of the amount administered was found to be
    absorbed. There were individual variations showing a five-fold
    difference between the lowest and highest values of absorption. The
    reported rate of absorption did not take into account reabsorption
    into the enterohepatic circulation, but the authors considered this
    underestimation to be small.

        The rate of absorption may be influenced by such factors as
    dietary levels of manganese and iron, the type of the manganese
    compound, iron deficiency, and age. Thus, in the study just described,
    Mena et al., found an absorption of 7.5  2.0% in 13 patients with
    iron-deficiency anaemia. They also found that, in 6 miners with high
    tissue levels of manganese, an increase in the rate of excretion of
    manganese was accompanied by an increase in iron excretion. This
    interrelationship may further aggravate a pre-existing anaemia, thus
    increasing the rate of manganese absorption and may be a relevant
    factor in occupational exposure to manganese. Similarly, Thomson et
    al. (1971), using duodenal perfusion with a manganese dichloride
    solution containing a manganese concentration of 0.5 g/ml, noted an
    increased rate of absorption in iron-deficient patients that could be
    inhibited by adding iron to the solution.

        Figures for gastrointestinal absorption in infants and young
    children are not available.

        Most studies on animals have indicated a gastrointestinal
    absorption of less than 4%. Suzuki (1974) reported an intestinal
    absorption of only 0.5-2.0% in mice fed dietary levelsa of manganese
    dichloride of 20-2000 mg/kg.

        However, when rats were given 0.1 mg of radioactive manganese
    orally, 3-4% of the dose was absorbed (Greenberg et al., 1943).
    Similar results were obtained by Pollack et al. (1965), who reported
    an absorption of 2.5-3.5% in rats given an oral dose of radioactive
    manganese dichloride (54MnCl2). Thus, absorption data for the adult
    rat agree with the figure obtained for the absorption of manganese
    dichloride in man. However, Mena (1974) reported that intestinal
    absorption in the young rat was of the order of 70% compared with 1-2%
    in the adult rat.

        In a study by Abrams et al. (1976), rats were given dietary
    levels of manganese ranging from 4 to 2000 mg/kg for about 2 weeks,
    followed by a single oral dose of radioactive manganese (54Mn).
    Absorption of 54Mn was significantly lower in rats receiving high
    dietary levels (1000-2000 mg/kg) than in animals receiving the lowest
    level (4 mg/kg).

        Ethanol given to fasting rats in doses of 4 g/kg body weight
    increased absorption of manganese from the gastrointestinal tract and
    resulted in a two-fold increase in uptake of manganese in the liver.
    Furthermore,  in vitro experiments indicated a four-fold increase in
    the transmural migration of manganese (Schafer et al., 1974). It has
    long been known that calcium in the diet can reduce the amount of
    manganese absorbed by poultry, probably by reducing the amount of
    manganese available for absorption (Wilgus & Patton, 1939).

        However, recent studies suggest that calcium may, under certain
    circumstances, enhance gastrointestinal absorption of manganese.
    Lassiter et al. (1970) noted a higher rate of absorption in rats fed a
    dietary level of calcium of 6 g/kg for 21 days before oral dosing with
    54Mn, compared with rats receiving a level of only 1 g/kg. In studies
    on sheep, the same authors found that phosphoric acid, mixed into the
    ground hay at a concentration of 15 g/kg, decreased gastrointestinal
    absorption of the stable manganese in the hay.

        In rats, the enterohepatic circulation appears to be of
    importance. Intraduodenal administration of manganese that had been
    excreted into the bile resulted in about 35% absorption, whereas only
    15% of an equivalent dose of manganese dichloride administered
    intraduodenally was absorbed (Cikrt, 1973). This indicates that
    manganese present in bile is in a form that is more easily absorbed
    than manganese dichloride.

    6.2  Distribution

    6.2.1  Distribution in the human body

        Manganese is an essential element for man and animals and thus
    occurs in the cells of all living organisms. Concentrations of
    manganese present in individual tissues, particularly in the blood,
    remain constant, in spite of some rapid phases in transport,
    indicating that such amounts may be considered characteristic for
    these particular organs irrespective of the animal species (Cotzias,
    1958).

        The total manganese body burden of a standard man of 70 kg has
    been estimated to be about 10-20 mg (Underwood, 1971; WHO Working
    Group, 1973; Kitamura et al., 1974). Thus, tissue concentrations will
    frequently be below the g/kg level. In general, higher manganese
    concentrations can be expected in tissues with a high mitochondria
    content (Maynard & Cotzias, 1955; Thiers & Vallee, 1957), with the
    exception of the brain which contains only low concentrations (Maynard
    & Cotzias, 1955). There also appears to be a tendency towards higher
    concentrations in pigmented tissues such as dark hair or pigmented
    skin (van Koetsveld, 1958; Cotzias et al., 1964).

              

    a  The approximate relation between concentration in diet in mg/kg
       (ppm) and mg per kg body weight per day is given for a number of
       animal species in Nelson (1954).

        Table 6.  Manganese in human tissues (mg/kg wet weight)
                                                                                             

    Tissue       Kehoe et al. (1940)        Tipton & Cook (1963)a      Kitamura (1974)
                 (emission spectroscopy)   (emission spectroscopy)   (atomic absorption)
                                                                                             

    aorta             --                         0.11                     --
    brain             0.30                       0.27                     0.25
    fat               --                         --                       0.07
    heart             0.32                       0.22                     0.19
    intestine         0.35                       --                       --
    kidney            0.60                       0.90                     0.58
    liver             2.05                       1.30                     1.20
    lung              0.22                       0.19                     0.21
    muscle            --                         0.06                     0.08
    ovary             --                         0.16                     0.19
    pancreas          --                         1.18                     0.74
    spleen            --                         0.13                     0.08
    testis            --                         0.13                     0.20
    trachea           --                         0.19                     0.22
    rib               --                         --                       0.06
                                                                                             

    a   Values calculated using the given ash percentage wet weight
        and the median value of manganese in tissue ash.

    

        Table 6 gives the results of 3 studies on the manganese contents
    of various tissues in people without any known occupational or other
    additional exposure to manganese. Two are studies on adults from the
    USA (Kehoe et al., 1940; Tipton & Cook, 1963). In a study by Kitamura
    (1974) performed on 15 Japanese males and 15 females who had died in
    accidents, the highest concentrations of manganese were found in the
    liver, pancreas, kidney, and intestines. Comparatively high
    concentrations were also found in the suprarenal glands.

        From birth to 6 weeks, infants have relatively higher tissue
    concentrations of manganese than older children, especially in tissues
    normally associated with low manganese levels. However, after about 6
    weeks of age, no accumulation of manganese appears to take place with
    increasing age (Schroeder et al., 1966). This is in agreement with the
    study of Dobrynina & Davidjan (1969), who reported that manganese did
    not accumulate with age, and that the manganese content of the lung

    actually decreased with increasing age. Anke & Schneider (1974) also
    found a statistically significant decrease in the kidney content of
    manganese beginning at about 60 years of age; they reported a slightly
    higher mean concentration in females (4.4 mg/kg) than in males
    (3.8 mg/kg). With respect to manganese concentrations in the liver,
    Widdowson et al. (1972) reported that there was no consistent change
    with age in 30 fetuses from 20 weeks' gestation to full-term, but
    that, generally, manganese concentrations in full-term livers were
    7-9% higher than concentrations in adult livers. Studies by Schroeder
    et al. (1966) and Widdowson et al. (1972) confirmed that human
    placental transfer of manganese takes place.


        Table 7.  Concentrations of manganese in the whole blood of people without occupational
              exposure to manganese
                                                                                                  

    Number of       Mean            Range
    subjects     (g/100 ml)     (g/100 ml)       Method                Reference
                                                                                                  

    14            0.844            n.r.a          neutron            Cotzias et al.
                                                  activation         (1966)
    19            n.r.             0.86-1.45      neutron            Cotzias & Papavasiliou
                                                  activation         (1962)
    7             1.16             0.90-1.45      neutron            Papavasiliou & Cotzias
                                                  activation         (1961)
    18            2.4              n.r.           neutron            Bowen (1956)
                                                  activation
    232           3.47b            n.r.           spectrographic     Horiuchi et al.
                                                                     (1967)
    47            4.0              n.r.           spectrographic     Butt et al. (1964)
    12            4.6              2.2-7.9        spectrographic     Cholak & Hubbard (1960)
    13            7.6              4.0-15.0       colorimetric       Barborik & Sehnalova
                                                                     (1967)
    30           12.0              n.r.           spectrographic     Kehoe et al. (1940)
                                                                                                  

    a  n.r. = not reported.
    b  median.

    Table 8.  Concentrations of manganese in the plasma and serum of people without occupational
              exposure.
                                                                                                       

    Number of         Mean           Range           Method                       Reference
    subjects       (g/100 ml)    (g/100 ml)
                                                                                                       

    12 (S)a         n.r.c         0.036-0.090     colorimetric              Fernandez et al. (1963)
    14 (P)b         0.059            n.r.         neutron activation        Cotzias et al. (1966)
    25 (S) (F)d     0.055         0.038-0.104     neutron activation        Versieck et al. (1974a)
    25 (S) (M)e     0.059         0.045-0.101     neutron activation        Versieck et al. (1974a)
    19 (P)          n.r.          0.183-0.310     neutron activation        Cotzias & Papavasiliou
                                                                            (1962)
    7 (P)           0.269         0.210-0.302     neutron activation        Papavasiliou & Cotzias
                                                                            (1961)
    16 (S)          0.250         0.205-0.297     neutron activation        Papavasiliou & Cotzias
                                                                            (1961)
    7 (P)           0.18f            n.r.         neutron activation        Hagenfeldt et al. (1973)
    --              0.32g            n.r.         neutron activation        Hagenfeldt et al. (1973)
    15 (P)          0.43             n.r.         neutron activation        Olehy et al. (1966)
    90 (S) (F)      1.05             n.r.         spectrographic            Zernakova (1967)
    60 (S) (M)      0.96             n.r.         spectrographic            Zernakova (1967)
    48 (S)          1.3              n.r.         spectrographic            Butt et al. (1964)
    30 (S)h         1.3             0.9-1.9       neutron activation        Kanabrocki et al. (1964)
    40 (S)          2.4             1.2-3.8       atomic absorption         Mahoney et al. (1969)
                                                                                                       

    a  (S) = serum,               e  (M) = male.
    b  (P) = plasma,              f  sampled at days 16-18 of a menstrual cycle.
    c  n.r. = not reported.       g  sampled at days 6-8 of a menstrual cycle.
    d  (F) = female,              h  non-dialysable serum.

    
        Some reports on the manganese contents of whole blood, plasma,
    and serum have been summarized in Tables 7 and 8. All studies were on
    subjects without any occupational exposure to manganese. The
    concentrations of manganese are low in blood and still lower in plasma
    and serum, thus increasing the vulnerability of sampling and
    analytical procedures to the possibilities of contamination (section
    2.2.1). This may partly explain the wide range of manganese
    concentrations found in the literature. Support for this theory comes
    from Cotzias et al. (1966), who considered that systematic
    contamination was responsible for the fact that previous plasma levels
    obtained by this group (Papavasiliou & Cotzias, 1961; Cotzias &
    Papavasiliou, 1962) were 4 times higher than those obtained in the
    1966 study (Table 8). A low order of magnitude of manganese levels in
    plasma and serum was reported by Fernandez et al. (1963) and more
    recently by Versieck et al. (1973b, 1974a).

        The concentrations of manganese in blood and serum appear to be
    fairly stable over long periods of time (Cotzias et al., 1966; Mahoney
    et al., 1969). A slight seasonal variation in blood manganese
    concentration, has been reported, the levels being somewhat lower
    during the summer and autumn months (Horiuchi et al., 1967). In this
    study, manganese concentrations in blood did not differ between age
    groups. Diurnal variations were reported by Sabadas (1969), the
    concentrations in blood being higher during the day than during the
    night. There do not appear to be any differences in the concentrations
    of manganese in the blood of men and women (Horiuchi et al., 1967;
    Zernakova, 1967; Mahoney et al., 1969; Versieck et al., 1974a).

        Hegde et al. (1961) claimed that manganese concentrations in
    serum increased following myocardial infarction, but, in more recent
    studies, Versieck et al. (1975) were unable to detect such a
    relationship. However, during the active phase of hepatitis, serum
    concentrations of manganese were invariably elevated (Versieck et al.,
    1974b).

        The mean concentration of manganese in the urine of unexposed
    people has been reported to be in the range of 3-21 g/litre (Kehoe et
    al., 1940; Cholak & Hubbard, 1960; Horiuchi et al., 1967; Tichy et
    al., 1971; McLeod & Robinson, 1972b).

    6.2.2  Distribution in the animal body

        Average levels of manganese in unexposed rabbit tissues were
    reported to be: 2.1 mg/kg wet weight in the liver; 2.4 mg/kg in the
    pituitary; 1.6 mg/kg in the pancreas; and 1.2 mg/kg in the kidney. The
    brain has a relatively low average content of 0.4 mg/kg wet weight
    (Fore & Morton, 1952). The lowest levels occur in bone marrow
    (0.04 mg/kg wet weight), blood (0.03 mg/kg wet weight) and lung
    (0.01 mg/kg wet weight) (Cotzias, 1958). According to Suzuki (1974),
    when aqueous solutions of manganese dichloride at concentrations
    ranging from 20 to 2000 mg/litre were given to mice, concentrations
    below 500 mg/litre did not result in accumulation in the organs.
    However, there was distinct accumulation at doses exceeding
    1000 mg/litre. When mice were exposed through inhalation to manganese
    dioxide concentrations of 5.6 and 8.9 mg/m3 (particle size 3 m)
    every 2 h, for 8 and 15 days, respectively, the highest concentrations
    of manganese were found in the kidney (10.8 and 8.4 mg/kg dry weight),
    liver (9.0 and 7.1 mg/kg), pancreas (8.4 and 8.2 mg/kg), and brain
    (5.9 mg/kg). Because of the route of administration, even higher
    concentrations were observed in the lungs, trachea, and
    gastrointestinal tract (Mouri, 1973).

        In a study in which monkeys were given a subcutaneous injection
    or a suspension of manganese dioxide once a week, for 9 weeks, the
    manganese concentration increased markedly in the tissues of the endo-
    and exocrine glands and of the cerebral basal ganglion, the
    accumulation rate being proportional to the dose administered (Suzuki
    et al., 1975).

        After intraperitoneal administration of radioactive manganese to
    rats, the highest concentrations were found in the suprarenal,
    pituitary, liver, and kidney tissues (Dastur et al., 1969). The uptake
    by glandular structures was also high in monkeys after intraperitoneal
    injection of radioactive manganese (Dastur et al., 1971).

        Several experimental studies have shown that manganese penetrates
    the placental barrier of various species (Koshida et al., 1963;
    Jrvinen & Ahlstrm, 1975; Miller et al., 1975). It has been reported
    that manganese is more uniformly distributed in the fetal tissues of
    the mouse than in adult tissues. The main differences were seen in the
    concentrations in kidney and liver tissues, which were lower in the
    fetuses than in the adults. At a later embryonic stage, manganese
    accumulation in the bone took place parallel with the process of
    ossification (Koshida et al., 1963; 1965). Miller et at. (1975) showed
    that, in contrast to adult animals and man, neonatal mice did not
    excrete manganese during the first 17-18 days of life, despite
    vigorous absorption of the radioactive metal (54Mn) with accumulation
    in both mitochondria and tissues, notably in the brain. This suggested
    an initial accumulation of the essential micronutrient, supplied in
    trace amounts in mouse milk (54 g/litre) by mothers consuming much
    higher dietary concentrations (50 mg/kg). In subsequent experiments,
    the same authors noted an absence of manganese excretion during the
    first 18 days of life in neonatal rats and kittens. Moreover, when
    lactating mothers were fed diets containing concentrations of
    manganese ranging from 40 to 40 000 mg/litre, the lactation barrier
    appeared to give adequate protection to the young. However, when the
    dietary level exceeded 280 mg/litre, the newborn initiated excretion
    before the 16th day of life. The neonates showed a greater
    accumulation than their mothers, whereas the increase in liver
    concentrations was proportional to concentrations found in the
    mother's liver. The findings suggest that the neonatal brain may be at
    higher risk of reaching abnormal concentrations than other tissues. In
    the Syrian hamster, manganese was found in embryonic tissues 24 h
    after intravenously injecting the mother with radioactive manganese at
    1.36 mg/kg body weight (Hanlon et al., 1975).

        After a single intragastric dose of 0.5 or 2.5 mg of
    methylcyclopentadienyl manganese tricarbonyl MMT) labelled with 54Mn,
    rat tissue and organs showed a distribution characteristic of
    inorganic manganese, i.e., the highest concentrations were found in
    the liver, kidney, and pancreas. However, high concentrations were
    also found in the lungs and to lesser degree in abdominal fat (Moore
    et al., 1974).

    6.2.3  Transport mechanisms

        Absorbed manganese is concentrated in the liver and it has been
    suggested that it forms complexes with bile components (Tichy & Cikrt,
    1972). It has also been suggested that manganese is transported
    directly into the bile (Klaassen, 1974). At one time, it was thought
    to be transported in the plasma in its trivalent form by a
    beta1-globulin other than transferrin, called transmanganin (Cotzias,
    1962), but the results of later  in vitro studies on the serum of
    cows and human serum and  in vivo studies on rabbit and rat blood
    have refuted this theory (Panic, 1967, Hancock et al., 1973). At
    present, it is largely accepted that manganese and iron are both
    transported by the transferrin in the plasma (Panic, 1967; Mena et
    al., 1974). It has already been pointed out that mitochondria have
    been shown to contain a non-dialysable fraction of manganese (Fore &
    Morton, 1952). Studies using radioactive manganese (56Mn) indicated
    that newly deposited 56Mn was easily removed from mitochondria
    whereas older, stable manganese was not, suggesting different types of
    bonding with mitochondria (Cotzias, 1958).

    6.3  Biological Indicators of Manganese Exposure

        Estimation of manganese exposure in man by examination of
    biological fluids or tissues has not proved to be a reliable index.
    Analyses of blood or urine samples from persons with signs and
    symptoms of manganese poisoning do not usually reveal high levels of
    manganese. However, a rough correlation between urine levels and
    average air concentrations seems to exist (Tanaka & Lieben, 1969).
    There is also some evidence that manganese may concentrate in hair
    following exposure to high concentrations (Rosenstock et al., 1971).
    Because of the short biological half-time, manganese levels in tissues
    and organs can only be related to recent exposure. At present, no
    specific diagnostic biological materials are known that could be used
    to monitor manganese exposure in epidemiological studies or for
    clinical diagnosis.

    6.4  Elimination

        It has already been pointed out that tissue concentrations of
    manganese are remarkably constant without any tendency to accumulate
    with age, after the first few weeks of life. From earlier studies, it
    was considered that variable excretion rather than variable absorption
    played an important role in manganese homeostasis (Britton & Cotzias,
    1966). However some later results, from studies using oral dosing in
    rats, have indicated that variable absorption is also an important
    factor (Abrams et al., 1976).

        The manganese absorbed in the body, whatever the route of
    absorption, is eliminated almost exclusively in the faeces. At
    ordinary exposure levels, manganese is mainly excreted into the bile
    (Papavasiliou et al., 1966). Quantitative data concerning excretion in
    man are not available. After intravenous injection of 0.6 g of
    manganese dichloride (MnCl24H2O) in rats, 12% of the injected dose
    was excreted into the bile within 3 h (Tichy et al., 1973), and 27%
    within 24 h (Cikrt, 1972). Intraperitoneal administration of 0.01 mg
    of manganese to rats resulted in the biliary excretion of 26% of the
    dose within 48 h; at a dose of 0.1 mg, the fraction appearing in the
    bile was 37% (Greenberg et al., 1943). Manganese excreted with the
    bile flow into the intestine is partly reabsorbed (section 6.1.2). In
    the rat, there is some evidence of the excretion of manganese through
    the intestinal wall into the duodenum, jejunum and, to a lesser
    extent, the terminal ileum (Bertinchamps et al., 1966; Cikrt, 1972).

        In dogs, some manganese is also excreted with the pancreatic
    juice (Burnett et al., 1952). It has been shown that, while excretion
    by the biliary route predominates under normal conditions, excretion
    by the auxiliary gastrointestinal routes may increase in significance
    in the presence of biliary obstruction or with overloading with
    manganese (Bertinchamps et al., 1966; Papavasiliou et al., 1966).
    Results of human studies have shown that only a small amount of
    manganese (about 0.1-1.3% of the daily intake) is excreted through the
    kidneys into the urine (Maynard & Fink, 1956; Tipton et al., 1969;
    McLeod & Robinson, 1972b). Urinary excretion is not increased by
    biliary obstruction or by overloading (Papavasiliou et al., 1966), but
    in rats it was increased many times by the administration of
    ethylenediamine tetraacetic acid (EDTA), urine becoming the
    predominant excretory route for 24 h, after which time faecal
    elimination was resumed (Kosai & Boyle, 1956; Maynard & Fink, 1956).

        Following intravenous administration of radiolabelled
    methylcyclopentadienyl manganese tricarbonyl (MMT) and manganese
    dichloride to rats, retention of 54Mn was similar, but the route of
    excretion was different. After intravenous administration of

    radioactive manganese chloride, only a trace was detected in urine,
    54Mn being excreted in the faeces. However, both oral and intravenous
    administration of MMT resulted in excretion in both faeces and urine.
    With oral administration of MMT, the urine/faeces ratio of manganese
    varied from 0.68 to 0.25. No MMT was detectable in the faeces,
    indicating a biotransformation of MMT.  In vitro experiments showed
    that MMT was metabolized in the liver, lung and kidney and to a small
    extent in the brain. Biotransformation of MMT by kidney homogenate may
    explain the high concentrations of manganese found in the urine of the
    rats (Moore et al., 1974).

        Insufficient data are available on dermal losses of manganese. An
    average excretion in human sweat was given as 60 g/litre by Mitchell
    & Hamilton (1949). Although sweat volumes are known to vary over a
    wide range (International Commission on Radiological Protection,
    1975), the average daily excretion of manganese with sweat is probably
    in the range of 30-120 g, assuming a sweat volume of 0.5-2 litre/day.
    This is in good agreement with a study by Conzolazio et al. (1964),
    who found a daily mean excretion of about 100 g (corresponding to
    2.3% of the total daily intake of manganese) in 3 men exposed to
    37.8C for 7.5-h periods. The loss of manganese with human hair and
    nails has been estimated to about 2 g/day (International Commission
    on Radiological Protection, 1975), although allowance must be made for
    the considerable variation of manganese concentrations in hair
    (Cotzias et al., 1964). Small quantities of manganese are also
    transferred through the placenta (section 6) and the excretion with
    breast milk is about 10-20 g/day (McLeod & Robinson, 1972a).

    6.5  Biological Half-times

        A few studies have been performed on animals and man in order to
    assess the biological half-times of inorganic manganese. However,
    half-times for organic forms of manganese have only been studied in
    animals. When considering biological half-times of trace elements in
    living organisms, the following factors should be taken into account:

        (a)  type of exposure (oral or parenteral, single or multiple);

        (b)  type of metabolic model (single compartment or
             multi-compartment);

        (c)  inter- and intraspecies variations; and

        (d)  the rates of phases of excretion (rapid and slow
             components).

    6.5.1  Man

        Mahoney & Small (1968) used single injections of radiolabelled
    manganese dichloride on 6 human volunteers to study the biological
    half-time of manganese in man. They found 2 phases in the elimination
    of manganese from the body, one of which was slow and the other fast.
    The mean biological half-time for the 3 "normal" adults was about 4
    days for the fast phase and 39 days for the slow phase. About 60-65%
    of elimination occurred during the slow phase, although in one subject
    90% was eliminated during this phase. In subjects with a high oral
    intake of manganese, elimination from the body took place at an
    increased rate. Iron reserves may also influence the retention of
    manganese dichloride.

        Cotzias et al. (1968) studied the tissue clearance of manganese
    in 19 healthy "normal" volunteers after a single injection of 54Mn.
    Clearance half-time of 54Mn was 37.5 days for the whole body, 25 days
    for the liver, 57 days for the thigh, and 54 days for the head. The
    clearance half-time from blood and plasma was less than 1.5 minutes.

        A clearance half-time for the whole body of 37 days was reported
    by Mena et al. (1969) in healthy subjects, compared with a half-time
    of 23 days in iron-deficient, anaemic patients. They also reported a
    half-time of 34 days in miners suffering from chronic manganese
    intoxication, while healthy miners exhibited a fast turnover of only
    15 days. This finding may have a bearing on the question of individual
    susceptibility to manganese intoxication.

    6.5.2  Animals

        Britton & Cotzias (1966) reported a two-component whole-body
    clearance of manganese in mice comparable with that reported by
    Mahoney & Small (1968) in man. The half-time of the slow component was
    given as 50 days and that of the fast component as 10 days. The
    fraction eliminated with the slow component was lower in mice than in
    man, i.e., approximately 35%. However, on a low-manganese diet, it
    increased to about 95% and the half-time for this component decreased
    from 50 to about 35 days. With a high-manganese diet, the half-time
    for the fast component decreased from 10 to 2 days.

        The effect of dietary manganese levels on the biological
    half-time of manganese was studied in mice by Suzuki (1974). The
    animals received an aqueous solution of manganese dichloride in
    concentrations ranging from 20 to 2000 mg/litre for 26-30 days, after
    which radioactive manganese was administered. The whole body clearance
    half-time was about 6 days in the 20 mg/litre group, about 3 days in
    the 100 mg/litre group, and 1-1.5 days in the group that had received
    2000 mg/litre, i.e., the heavier the preloading, the more rapid was
    elimination from the whole body. The half-time in the brain was longer
    than that in the whole body.

        Chemobiokinetic studies on 54Mn in monkeys disclosed a half-time
    of 95 days for whole-body elimination. Brain levels did not decrease
    significantly over the experimental period of 278 days, suggesting
    that the clearance half-time in the brain was longer than that for the
    whole body (Dastur et al., 1871).

        Adrenal glucocorticoids accelerated the total body clearance of
    manganese in mice (Hughes & Cotzias, 1960), and later studies using
    ACTH stimulation suggested the existence of an adrenal regulatory
    mechanism for the metabolism of manganese (Hughes et al., 1966).

        The whole-body retention curve for methylcyclopentadienyl
    manganese tricarbonyl (MMT) in rats was similar to that for manganese
    dichloride (section 6.4). The authors considered that this was due to
    the rapid metabolism of MMT and that the retention curve only
    reflected the metabolism of the labelled manganese (54Mn) (Moore et
    al., 1974).

    7.  MANGANESE DEFICIENCY

    7.1  Metabolic Role of Manganese

        The essential role of manganese as a trace metal nutrient for
    mammals was discovered mainly through experimental and epidemiological
    studies of deficiency states in animals. Thus, manganese has been
    shown to be associated with the formation of connective tissue and
    bone, with growth, carbohydrate and lipid metabolism, the embryonic
    development of the inner ear, reproductive function, and, probably,
    brain function (Underwood, 1971; NAS/NRC, 1973).

        The biochemical background of the metabolic defects that have
    been observed is poorly understood, though a few specific biochemical
    properties of manganese have been discovered. One is that manganese
    catalyses the formation of glucosamine-serine linkages in the
    synthesis of the mucopolysaccharides of cartilage; another, that the
    mitochondrial enzyme pyruvate carboxylase (EC 6.4.1.1) is a manganese
    metalloenzyme, thus, manganese is linked with carbohydrate metabolism.
    It has also been discovered that the digestive enzymes prolidase (EC
    3.4.13.9) and succinic dehydrogenase (EC 1.3.99.1) are
    manganese-dependent and that,  in vitro, manganese can substitute for
    other metals, especially magnesium, in various biological reactions
    (Underwood, 1971; NAS/NRC, 1973). Lindberg & Ernster (1954) performed
     in vitro experiments on rat liver mitochondria that demonstrated
    that manganese was required as a co-factor in oxidative
    phosphorylation. Manganese deficiency in mice was reported by Hurley
    (1968) to be associated with a decreased oxygen uptake by the liver
    mitochondria. However, the relationship between these findings and
    defects due to manganese deficiency remains obscure.

    7.2  Manganese Deficiency and Requirements in Man

        No definite syndrome of manganese deficiency has been described
    in man. However, in a human subject with experimentally induced
    vitamin K deficiency, a sequence of signs was attributed to the
    accidental omission of manganese from the diet during 1 week; the
    daily intake during 16 subsequent weeks was retrospectively calculated
    to have been about 0.35 mg. The subject was unable to elevate the
    depressed clotting proteins in response to vitamin K and this finding
    was experimentally reproduced in the chick. Moreover, marked
    hypocholesterolaemia, retarded growth of hair and nails, mild
    dermatitis, pigment changes in hair and beard, and moderate weight
    loss were present (Doisy, 1973).

        It has been difficult to estimate the minimum physiological
    requirements of manganese for man. On the basis of existing data on
    the daily manganese intake and manganese balance in man, a WHO Expert
    Committee concluded that an intake of 2-3 mg/day was adequate for
    adults (WHO, 1973). This is compatible with the figures quoted in
    section 4.5 and also agrees with the estimate of 2.7 mg made by De
    (1949) on the basis of balance studies on male subjects. A negative
    manganese balance was recorded by De in subjects with a mean manganese
    intake of 0.71 mg per day.

        Engel et al. (1967) measured the daily intake of manganese in 6
    to 10-year-old girls and estimated that 1 mg per day was needed to
    maintain the balance. Taking into account growth needs, integumental
    losses, and a reasonable safety margin, they suggested a required
    daily intake of 1.25 mg (0.045 mg/kg body weight). This also agrees
    well with the data presented in section 4.5, which show that healthy
    children within the age ranges of 9-13 and 3-5 years had daily intakes
    of 0.06 and 0.08 mg/kg body weight, respectively (Schlage & Wortberg,
    1972). A positive manganese balance was observed in girls, aged 7-9
    years, with a daily intake of 2.1-2.4 mg of manganese (Price et al.,
    1970). Breastfed infants may have a daily intake as low as
    0.002-0.003 mg/kg (Widdowson, 1969; McLeod & Robinson, 1972b) and may
    exhibit a distinctly negative manganese balance during the first week
    of life. Widdowson (1969) reported that the amount excreted in the
    faeces during the first week amounted to 3-5 times the amount ingested
    daily with breast milk, indicating the excretion of manganese from
    tissue reserves that had accumulated during fetal life (section
    6.2.1). This is in agreement with the observation of Schroeder et al.
    (1966) that tissue levels decreased during the first 45 days of life.

        An association has been suggested between manganese deficiency
    and lupus erythematosus found in patients following treatment with
    hydralazine. This is based on the fact that administration of
    manganese(II) salts improved the condition of such patients and of
    patients suffering from the spontaneous variety of disseminated lupus
    erythematosus (Comens, 1956).

    7.3  Manganese Deficiency in Animals

        Defects due to manganese deficiency have been shown
    experimentally in a variety of laboratory animals. The best-documented
    manifestations are those associated with skeletal abnormalities and
    impaired growth. Abnormally fragile bones that are shorter than
    normal, and bowed forelegs resulting from these changes have
    frequently been reported in mice, rats, and rabbits (Amdur et al.,
    1945; Ellis et al, 1947; Plumlee et al., 1956). Perosis with deformity
    of bones and dislocation of the achilles tendon ("slipped tendon") has
    long been known in young chickens (Wilgus & Patton, 1939). Early

    changes observed in chick embryos include nutritional
    chondrodystrophy, retarded growth, and shortening of the lower
    mandible (Lyons & Insko, 1937). In his review of manganese deficiency,
    Underwood (1971) quotes crooked and shortened legs and enlarged hock
    joints in pigs, leg deformities with "overknuckling" in cattle, joint
    pains in sheep, and tarsal joint excrescences in goats.

        Ataxia with loss of equilibrium and altered postural reactions to
    stimuli, without histological changes in the brain tissue have been
    reported in rats (Hill et al., 1950). It is likely that ataxia is due
    to the impaired development of the inner ear, where the otoliths
    appear to be absent or defective in several species of laboratory
    animals (NAS/NRC, 1973).

        Manganese deficiency can induce congenital malformations,
    stillbirths, and neonatal deaths in rats and guineapigs and seminal
    tubular degeneration and aspermia have been observed in rats and
    rabbits (NAS/NRC, 1973). In manganese-deficient female rats, estrous
    cycles may be absent or irregular, and the rats may be sterile; in
    severe deficiency states, the animals will not mate (Underwood, 1971).

        A decreased tolerance to orally administered glucose and an
    impaired peripheral use of parenterally administered glucose have been
    reported in guineapigs (Everson & Shrader, 1968). Newborn offspring of
    manganese-deficient guineapigs displayed aplasia or distinct
    hypoplasia of all cellular components of the pancreas; islets
    contained a reduced number of beta cells, which were also less
    intensely granulated (Shrader & Everson, 1968).

        There have been some reports relating manganese to lipid
    metabolism. Interaction between choline and manganese has long been
    recognized (Underwood, 1971). Pigs, fed manganese-deficient food,
    showed a statistically significant increase in fat deposits, measured
    as back-fat thickness (Plumlee et al., 1956). Curran (1954) reported
    that manganese stimulated the synthesis of fatty acids and cholesterol
    in the rat liver. Although the biological implications of these
    findings are not clear, it has been suggested that a decrease in the
    synthesis of cholesterol and its precursors due to manganese
    deficiency might limit the synthesis of sex hormones. This could
    explain the sterility of manganese-deficient animals (Doisy, 1972).

        A reduction in liver arginase (EC 3.5.3.1) activity in
    manganese-deficient rats and rabbits has been reported, but the
    importance of this remains to be assessed (Underwood, 1971).

        Table 9.  The acute toxicity of various forms of manganese

                                                                                              

                                    Administration       LD50
    Compound        Animal                route          (mg/kg)            Reference
                                                                                              

    manganese       mouse            subcutaneous         550b         Date (1960)
    dioxide
    manganese       mouse            oral               275-450        Sigan & Vitvickaja (1971)
    chloride        rat              oral               250-275        Hazaradze (1961)
    guineapig       oral                                400-810        Hazaradze (1961)
    manganese       mouse            intraperitoneal       64          Yamamoto & Suzuki,
    sulfate                                                            (1969)
                    mouse            subcutaneous         146b         Date (1960)
                    mouse            oral                 305b         Date (1960)
    manganese       mouse            intraperitoneal       56          Yamamoto & Suzuki
    nitrate                                                            (1969)
    potassium       mouse            subcutaneous         500b         Date (1960)
    permanganate    mouse            oral                  750         Sigan & Vitvickaja (1971)
                    rat              oral                  750         Sigan & Vitvickaja (1971)
                    guineapig        oral                  810         Sigan & Vitvickaia (1971)
    DAP-Mn          mouse            oral                 >8000        Suzuki et al. (1972)
    cakea           mouse            intraperitoneal      >1200        Suzuki et al. (1972)
    DAP-Mn          mouse, male      oral                 2790         Suzuki et al. (1972)
    dusta           mouse, female    oral                 2570         Suzuki et al. (1972)
                    mouse, male      intraperitoneal       378         Suzuki et al. (1972)
                    mouse, female    intraperitoneal       352         Suzuki et al. (1972)
                                                                                              

    a   DAP refers to a process for the removal of sulfur dioxide from flue gas. DAP-Mn cake:
        manganese oxides used in the desulfurization process. DAP-Mn dust: exhaust gas and dust
        from the desulfurization process in a plant.
    b   Lethal dose (LD100).

    
    8.  EXPERIMENTAL ANIMAL STUDIES ON THE EFFECTS OF MANGANESE

    8.1  Median Lethal Dose

        The toxicity of manganese varies according to the chemical form
    administered. Divalent manganese has been shown to be 2.5-3 times more
    toxic than the trivalent form. The median lethal doses (LD50) of
    various forms of manganese are listed in Table 9.

    8.2  Effects on Specific Organs and Systems

    8.2.1  Central nervous system

        Attempts to induce brain damage characteristic of manganese
    intoxication by feeding manganese compounds to experimental animals
    have not been completely successful (van Bogaert & Dallemagne, 1946).
    This may partly be due to the low absorption of orally administered
    manganese. Sigan & Vitvickaja (1971) showed that potassium
    permanganate altered conditioned reflex activity in rats, when
    administered orally at 10 mg/kg body weight per day for 9 months, and
    to a lesser extent when administered at a dose of 1 mg/kg.

        Exposure of a monkey to manganese dioxide aerosol at
    concentrations of 0.6-3.0 mg/m3 for 95 1-h periods during 4 months,
    initially produced alternating periods of sudden movement and torpor,
    nervousness, severe tremor, flexion-extension movements of upper
    limbs, yawning, and cyanosis. Sequelae after 5 months included gross
    tremors, uncertain gait, and paresis. Histological examination of the
    brain revealed atrophy of the cerebellar cortex, whereas the putamen,
    caudate, and pallidum did not exhibit any clear changes (van Bogaert &
    Dallemagne, 1946). Intraperitoneal administration of manganese
    dichloride to 4 monkeys on alternate days for up to 18 months,
    starting with a dose of 5 mg and increasing the dose to between 15 and
    25 mg, resulted in the characteristic lesions of the basal ganglia
    associated with choreiform movements and muscular rigidity, tremors,
    and limb contractions. Histologically, lesions with shrunken and
    pyknotic cells were detected in the putamen, caudate, and the
    pallidum. Demyelinized fibres were found in these areas. A slight
    chromatolysis was found in the cortex of  Macacus rhesus (Mella,
    1924). In studies on monkeys by Osipova et al. (1968), a clinical
    picture suggesting extrapyramidal dysfunction was obtained in animals
    given manganese dichloride subarachnoideally at 1-2 mg/kg body weight,
    in 3-8 doses. Similar effects were produced in 5 monkeys given
    repeated intramuscular administrations of manganese dioxide at several
    injection sites (Pentschew et al., 1963). In this study, the doses
    administrated (2000 and 3500 mg injected with an interval of 3 months)
    were reported for only one monkey, which was sacrificed 14 months
    after the first injection. The histopathological findings in the

    monkey mainly involved the subthalamic nucleus and the medial and
    lateral pallidum and were characterized by proliferation of bizarre
    cells and by extensive loss of neurons. Diffuse alterations were
    reported in the cerebrum, brainstem, and cerebellum. A study on early
    brain lesions in rats was reported by Chandra & Srivastava (1970).
    Animals which had received intraperitoneal administrations of
    manganese dichloride (8 mg/kg body weight) were sacrificed at 30-day
    intervals. The first histological changes, seen at 120 days, consisted
    of neuronal degeneration in the cerebellar and cerebral cortex. The
    extent of brain lesions increased in intensity up to 180 days and was
    directly related to the amount of manganese present in the brain
    tissue.

        When monkeys were given subcutaneous injections of a suspension
    of manganese dioxide, once a week for 9 weeks, at doses of 0.25-1.0 g,
    the typical extrapyramidal symptoms that appeared after 3-4 weeks were
    not proportional to the dose administered. However, the time of
    appearance of the symptoms was dose-related (Suzuki et al., 1975).
    Symptoms such as muscular rigidity and tremor were induced in squirrel
    monkeys by subcutaneous injection of a total of 400 mg of manganese
    dioxide divided into 2 doses, administered with a 5-week interval.
    These animals did not show any histologica] abnormalities of the
    brain, when sacrificed 3 months after the first injection, indicating
    that symptoms and signs as well as biochemical changes may appear
    before histological alterations can be found (Neff et al., 1969).

    8.2.2  Respiratory system

        "Manganese pneumonitis" is associated with inhalation of fine
    dust containing a relatively low concentration of manganese dioxide
    and probably other oxides of manganese, and does not lead to permanent
    pulmonary changes or fibrosis. Acute pneumonitis can be induced in
    rats by intratracheal administration of manganese dioxide dust or a
    solution of manganese dichloride. Characteristically, shedding of
    bronchial and alveolar epithelium is seen with intense mononuclear
    cell infiltration of the alveolar walls and alveoli. In a study on
    rats by Lloyd Davies & Harding (1949), intratracheal administration of
    manganese dioxide solutions produced intense mononuclear infiltration
    of the alveolar walls and alveoli, followed by granulomatous and giant
    cell formation. The changes disappeared within a year. Pulmonary
    congestion and oedema were observed after intratracheal injection of
    manganese dichloride. Similar intense mononuclear infiltration of the
    alveolar walls was produced in young rats by intratracheal
    administration of suspensions of various manganese compounds (particle
    size less than 3 m). The higher oxides of manganese and freshly
    prepared solutions were more toxic (Levina & Robacevskaja, 1955).

        Peribronchial and perivascular sclerosis and the appearance of
    collagenic threads were observed in rats after intratracheal
    administration of either 25 mg of ferromanganese dust containing 10 mg
    of manganese dioxide once a month for 4 months, or 10-30 mg of
    manganese dioxide in 6-10 doses over a period of 7 months (Levina &
    Robacevskaja, 1955). Similarly, peribronchial and perivascular
    sclerosis and inflammatory changes were seen in 15 out of 15 female
    rats exposed by inhalation to manganese dioxide at a mean
    concentration in air of 0.3 mg/m3, for 5-6 h daily, for 6 months but
    not in rats exposed to 0.033 mg/m3 for 5-6 daily for 7 months
    (Dokucaeva & Skvortsova, 1966).

        Nishiyama et al. (1975) exposed groups of 3 and 2 monkeys, 20
    rats, and 70 mice to air concentrations of manganese dioxide of
    3 mg/m3 and/or 0.7 mg/m3 (particle size less than 1 m), for 22 h
    daily, over a period of 5 months. Thorax X-rays appeared mottled in
    both groups of monkeys after 2-4 months of exposure. In 2 monkeys
    exposed to 3 mg/m3, the mottled picture appeared after 2 months, the
    patches growing larger and increasingly confluent at 3-5 months. The
    X-rays of these monkeys showed accentuation of blood vessels,
    indicating pulmonary congestion. The third monkey in this group and 2
    control animals did not show any signs of adverse effects. The 2
    monkeys exposed to a level of 0.7 mg/m3 showed abnormal findings that
    were less severe and appeared at a later stage, i.e., at 3-4 months.
    Mice showed inflammatory changes after 2 weeks at both levels of
    exposure. The inflammation disappeared after 2 months, at which time
    desquamation of bronchial epithelium was observed.

        Maigretter et al. (1976) exposed mice to aerosols containing a
    manganese dioxide concentration of 109 mg/m3 for one or more 3-h
    periods, after which the animals where challenged with  Klebsiella
     pneumoniae or influenza A virus. A decrease in resistance to
    infection was observed, even after a single exposure to the manganese
    aerosol. The authors discussed the possible causal association between
    the reduced resistance to infection and  in vitro observations
    showing that manganese dioxide reduced the number and viability of
    alveolar macrophages (Walters et al., 1975), and also impaired the
    phagocytic activity of these cells (Graham et al., 1975).

        Studies have been reported indicating the possibility of a
    synergistic effect of manganese dioxide and sulfur dioxide on the
    lungs of guineapigs (Rylander et al., 1971; Rylander & Bergstrm,
    1973). The ability to clear inert particles was lower in guineapigs
    exposed for 4 weeks (6 h per day, 5 days per week) to manganese
    dioxide (5.9 mg/m3) + sulfur dioxide (14.2 mg/m3) than in control

    animals or animals exposed to either of the two compounds singly
    (Rylander et al., 1971). Exposure of guineapigs to a combination of
    manganese dioxide at 20 mg/m3 and sulfur dioxide at 56.8 mg/m3
    resulted in a marked increase in leukocytes in the lungs, and a
    histological evaluation of the tracheal epithelium gave an "irritation
    score" of 3.0 for exposed animals compared with 1.8 for controls.
    Animals exposed to sulfur dioxide alone had a score of 1.9, while the
    score was 2.3 for those exposed to manganese dioxide only (Rylander &
    Bergstrm, 1973).

    8.2.3  Liver

        Rats given an intravenous dose of manganese at a concentration of
    55-60 mg/kg body weight showed a marked decrease in the ability of the
    liver to clear bilirubin from the bile. This was associated
    histologically with cholestatic changes. Reduction in bile flow
    occurred within 4 h (Witzleben, 1969). However, no decrease in bile
    flow was noted in rats 24 h after an intravenous dose of manganese
    dichloride of 30 g (Cikrt, 1972).

        A subcutaneous dose of 170 mg/kg body weight produced hepatic
    necrosis in rats within 18 h (Baxter et al., 1965). The metabolism of
    thiamine appears to be linked with that of manganese, the storage of
    manganese in the liver being related to the level of thiamine in the
    diet (Hill & Holtkamp, 1954). Subcutaneous injection of 1.5 and
    25 mg/kg body weight of manganese sulfate produced a decrease in
    monoamine oxidase (EC 1.4.3.4.) activity in rat liver. The reduction
    in activity was more pronounced after repeated injections of 5 and
    25 mg/kg for 10 and 5 days, respectively (Levina & Tcekunova, 1969).

        Rats exposed to manganese dioxide by inhalation for 5-6 h daily,
    6 times a week for 7 months, displayed a decreased serum
    albumen/globulin ration, which might have been a result of liver
    effects (Dokucaeva & Skvorcova, 1966).

        Ultrastructural alterations were found in the liver cells of rats
    after administration of manganese dichloride in the drinking-water at
    200 mg/litre for 10 weeks. The treated animals exhibited an increased
    amount of rough endoplasmic reticulum, a proliferated smooth
    endoplasmic reticulum in the centrolobular area, prominent Golgi
    apparatus in the biliary area, numerous mitochondria which were
    sometimes polymorphous and frequently had an electron-dense matrix.
    The changes suggested a process of adaptation to increased exposure to
    manganese dichloride (Wassermann & Wassermann, 1977).

        Rabbits given 3.5 mg per day of manganese dichloride
    intravenously, for 32 days, developed hepatic congestion, central vein
    thrombosis, and focal necrosis with leukocyte infiltration (Jonderko &
    Szczurek, 1967).

        Other effects of manganese possibly associated with the liver
    metabolism that have been observed include an increase in cholesterol
    synthesis in the rat (Curran, 1954), a disturbance in lipid and
    carbohydrate metabolism with lipid deposition in the liver and
    adrenals (Roscin, 1971), and an enhancement of the coagulating
    activity of the blood (Cereteli & Kipiani, 1971).

    8.2.4  Cardiovascular effects

        As early as 1883, Kobert noted that manganese could produce a
    reduction in blood pressure. Antihypertensive effects in the rat and
    the cat were also reported by Schroeder et al. (1955) and Kostial et
    al. (1974). Mjacina (1972) found an increase in the activity of
    monoamine oxidase (EC 1.4.3.4) in the cardiac tissue of rats following
    subcutaneous injection of manganese dichloride at 10 mg/kg body
    weight.

    8.2.5  Haematological effects

        Rats given manganese dichloride in doses of 50-1500 mg/kg body
    weight showed an increase in haemoglobin and haematocrit, mean
    corpuscular volume, and serum chloride, phosphate, and magnesium after
    4 h (Baxter et al., 1965). In anaemic lambs, manganese levels in diet
    of 1000-2000 mg/kg caused a retardation in haemoglobin regeneration
    and a decrease in serum iron concentrations (Hartman et al., 1955). At
    a dietary level of 2000 mg/kg, haemoglobin formation was also
    depressed in anaemic rabbits and baby pigs. The effect in pigs was
    reversed by a dietary supplement of iron of 400 mg/kg (Matrone et al.,
    1959). Dietary levels of manganese ranging from 50 to 125 mg/kg were
    found to be the minimum levels that would interfere with the
    formulation of haemoglobin in the baby pigs. The minimum level for
    lambs was 45 mg/kg (Hartman et al., 1955).

    8.3   Effects on Reproduction

        Disturbances in sex function and testicular changes have been
    noted in rats following exposure to potassium permanganate. Animals
    exposed orally or by inhalation to doses of 50 mg/kg body weight for
    various periods of time exhibited changes in spermatogenesis.
    Embryogenesis was also adversely affected (Mandzgaladze, 1966b, 1967).

        In studies on rabbits, intravenous administration of manganese
    dichloride at 3.5 mg/kg body weight was reported to produce
    histochemically detectable alterations in the testes, confirmed by
    decreases in NADH diaphorase, succinic dehydrogenase (1.3.99.1), and
    glucose-6-phosphate-dehydrogenase (1.1.1.49) activities. These changes
    affected germinal activity (Iman & Chandra, 1975).

    8.4  Carcinogenicity

        Few experimental studies have been conducted on the
    carcinogenicity of manganese and its compounds. In one recent study,
    manganese(II) sulfate was administered intraperitoneally to mice over
    a period of 30 weeks. The highest dose of 10 mg/kg body weight (15
    injections) produced a statistically significant (p < 0.05) increase
    in the incidence of lung tumours in treated animals compared with
    controls (Stoner et al., 1976). There are no other available studies
    indicating that inorganic manganese compounds are carcinogenic.

        A commercial fungicide containing manganese
    ethylene-bis-dithiocarbamate was evaluated for carcinogenicity by the
    International Agency for Research on Cancer (IARC Working Group,
    1976). Mice of 4 different strains were given 6 weekly doses of the
    compound at the rate of 500 mg/kg body weight. An increase in lung
    adenomas after 9 months was seen in only one of the 4 strains. It was
    concluded that the data available were too meagre to allow an
    evaluation of the carcinogenicity of this organomanganese compound.

    8.5  Mutagenicity and Chromosomal Abnormalities

        There is little information concerning the mutagenicity of
    manganese. Processes such as genetic recombination might be affected
    by manganese through its influence on enzymes that control DNA
    structure and metabolism. Manganese can be substituted for magnesium
    in the binding of the two ribosomal subunits as well as in the binding
    of M-RNA to the whole ribosome (Buttin & Kornberg, 1966). The
    bone-marrow cells of rats given manganese dichloride at 50 mg/kg body
    weight, orally, showed an unusual incidence of chromosome aberrations
    (30.9%) compared with those of control animals (8.5%) (Mandzgaladze,
    1966 a,b,c; Mandzgaladze & Vasakidze, 1966). Permanganate given to
    rats in daily doses of 10 mg/kg body weight, for 9 months, produced an
    increase in the mitotic activity of bone-marrow cells (Shigan &
    Vitvitskaja, 1971). Manganous chloride has been reported to be
    mutagenic for  Escherichia coli (Demerec et al., 1951; Durham & Wyss,
    1957) and  Serretia marcescens (Kaplan, 1962). Studies on
    manganese(II,III) oxide (Mn3O4) and methylcyclopentadienyl manganese
    tricarbonyl revealed that neither compound was mutagenic for
     Salmonella typhimurium or  Saccharomyces cerevisiae (Simmon &
    Ligon, 1977).

    8.6  Miscellaneous Effects

        Rats given doses of manganese sulfate of the order of 0.7-2.0 mg
    showed depressed thyroid activity accompanied by reduced thyroid
    weight, thinning of follicular epithelium, and smaller follicles
    (Hakimova et al., 1969). Observations over 6-12 months on rabbits
    injected with manganese dichloride at 3.5 mg of manganese per kg body
    weight showed an increase in serum calcium and decreases in serum
    magnesium and inorganic phosphorus (Jonderko, 1965). Other effects of
    manganese that have been observed include alterations in immunological
    activity (Antonova, 1968), disturbance of nitrogen metabolism,
    (Slavnov & Mandadziev, 1968), and a depression by manganous chloride
    of the acetylcholine output in the myenteric plexus of guineapigs
    (Kosterlitz & Waterfield, 1972).

        Table 10.  Acute toxicity of methylcyclopentadienyl manganese tricarbonyl (MMT) and
               cyclopentadienyl manganese tricarbonyl (CMT) following a single administration
                                                                                                  

                Administration                     LD50        LC50
    Compound        route           Animal        (mg/kg)     (mg/m3)          Reference
                                                                                                  

    MMT         oral              mouse             352                    Pfitzer at el. (1972)
                                  rat (male)        175
                                  rat (male)         58                    Hysell et el. (1974)
                                  rat (female)       89                    Pfitzer at al. (1972)
                                  guineapig         905                    Pfitzer at al. (1972)
                                  rabbit             95                    Pfitzer et al. (1972)
                intravenous       rabbit              6.6                  Pfitzer et al. (1972)
                percutaneous      rat               665                    Pfitzer at el. (1972)
                (6 h, 10%
                peanut oil)
                (24 h, 10%        rabbit           1350                    Pfitzer et el. (1972)
                kerosene)
    CMT         oral              mouse             150                    Arhipova (1963)
                                  rat                80                    Arhipova (1963)
                inhalation        rat                           120        Arhipova et al. (1965)
                (2 h)                                           (LD80)

                                                                                                  
    
    8.7  Toxicity of Organomanganese Fuel Additives

        There are two organomanganese carbonyl compounds that have been
    considered as gasoline (petrol) additives. In the USSR,
    cyclopentadienyl manganese tricarbonyl (CMT) has been studied for use
    as an additive, while, in the USA, the methylated homologue
    methylcyclopentadienyl manganese tricarbonyl (MMT) has been
    introduced. In assessing the potential toxicity of the two compounds,
    both occupational exposure to the parent compounds and exposure of the
    general population to the combustion products should be considered.
    Studies on acute toxicity in a number of animal species, following
    single administrations of MMT and CMT have been summarized in Table
    10.

        Following oral administration of MMT, rats developed huddling,
    roughened hair coats, tremors, progressive weakness, laboured
    respiration, serosanguineous nasal discharge, and terminal coma. All
    deaths occurred within 6 days. Survivors appeared normal 14 days after
    exposure. Necropsy findings consisted of saccular atonic stomachs,
    severe congestion of the liver and lungs, and tubular degeneration in
    the kidney. The picture differed from acute manganese toxicity, the
    dose administered being smaller than is needed for acute manganese
    poisoning in rats, and the liver lesions progressing from acute
    centrolobular congestion to parenchymal necrosis and, later, extensive
    cytoplasmic vacuolar changes. Whether the MMT itself or one of its
    metabolic products was responsible for the toxic effects, could not be
    assessed (Hysell et al., 1974).

        Rats appeared to be more sensitive to MMT and CMT than mice,
    guineapigs and rabbits, and males seemed more sensitive than females
    (Arhipova et al., 1963; Pfizer et al., 1972).

        Eight out of 20 mice died after 20 days of oral administration of
    CMT in oil at 25 mg/kg body weight, 6 times weekly. Daily oral
    administration of 5 mg/kg body weight to rats, for 2 months, only
    resulted in decreased osmotic resistance of the erythrocytes (Arhipova
    et al., 1963).

        Prolonged inhalation of MMT at a concentration of 15 mg/m3 for
    7 h daily, for 150 days, was lethal to mice and rats, whereas a
    concentration of 6 mg/m3 did not cause any deaths (Pfitzer et al.,
    1972). Repeated inhalation of CMT at a concentration of 20-40 mg/m3
    caused 50% mortality in rats. Prolonged inhalation (10 months) of
    concentrations of 0.7-1 mg/m3 by rabbits, guineapigs and rats
    resulted in muscarine effects on the central nervous system, a
    decrease in diuresis together with an increase in the urinary albumen
    content, and decreased resistance to infection (Arhipova, 1963).

        Three studies have been conducted on the effects of prolonged
    exposure to the combustion products of MMT. Moore et al. (1975)
    exposed rats and hamsters for 8 h daily for 56 days to mean
    concentrations of manganese in air of 131 and 117 g/m3 in
    non-irradiated and irradiated exposure chambers, respectively. The
    general condition and appearance of the experimental animals was not
    affected during the experiment and no histopathological lesions
    attributable to manganese exposure were found. However, an increase
    was noted in manganese tissue concentrations in the exposed rats
    compared with control rats. In another experiment, rats and monkeys
    were exposed for 24 h per day over 9 months to combustion products
    produced by burning MMT vapours in a propane flame. The exposure
    levels measured as inorganic manganese were 11.6, 112.5, and
    1152 g/m3. Clinical and histopathological investigations performed
    during, at the end of, and 6 months after the exposure period failed
    to reveal any adverse effects (Huntingdon Research Center, 1975). In a
    study by Coulston & Griffin (1976), monkeys were exposed to
    concentrations of manganese in air of 100 g/m3 for periods up to 66
    weeks without any signs of toxicity. However, manganese levels in
    tissues increased, particularly in the lungs and pons. Rats exposed in
    a similar way for periods up to 3 weeks also showed increased
    manganese concentrations in lung and brain tissue. Two monkeys exposed
    to about 5000 g/m3 for 23 weeks failed to exhibit any neurological
    or behavioural disorders during the exposure period and the following
    10-month observation period.

    8.8  Mechanisms and Toxic Effects

        At present, the relationship between a large number of  in vivo
    and  in vitro effects of manganese cannot be explained in terms of
    biochemical mechanisms. However, effects on the central nervous system
    may, to some extent, be explained by recent pathophysiological
    findings in the brain. Because of its clinical and histochemical
    resemblance to parkinsonism, it has been possible to associate
    alterations of the catecholamine metabolism in the brain with
    extrapyramidal manifestations of manganese poisoning. In parkinsonism,
    the most constantly affected area of the brain is the substantia
    nigra, whereas the striatum and pallidum show little damage (Faurbye,
    1970; Barbeau et al, 1976). It has been repeatedly shown that the
    dopamine concentration in the striatum and pallidum is reduced in
    patients with parkinsonism (Faurbye, 1970), and a causal relationship
    between cellular loss of the pars compacta of the substantia nigra and
    depletion of dopamine in the ipsilateral striatum and pallidum has
    been experimentally demonstrated in monkeys (Poirier & Sourkes, 1965;
    Sharman et al., 1967; Goldstein et al, 1969), cats (Poirier et al,
    1967a), and rats (Faull & Laverty, 1969). In monkeys, this type of

    brain damage resulted in abnormal motor function on the contralateral
    side. There was also an ipsilateral decrease in the synthesis of
    dopamine from the precursor 3,4-dihydroxyphenylalanine (L-dopa)
    (Poirier et al., 1967b; 1969), the rate-limiting factor of which may
    be the decreased activity of tyrosine 3-hydroxylase (EC 1.14.16.2)
    (Levitt et al., 1965; Goldstein et al., 1966). Similarly, it has been
    shown that lesions at the midbrain level in monkeys were associated
    with contralateral choreiform movements and depletion of striatal
    serotonin (Sourkes & Poirier, 1966; Goldstein et al., 1969). In
    manganese poisoning, the characteristic brain lesions, unlike the
    lesions in parkinsonism, are in the striatum and pallidum, with little
    alteration in the substantia nigra (section 9.3.1); nevertheless, in
    experimental studies on monkeys (Neff et al., 1969) rabbits (Mustafa &
    Chandra, 1971) and rats (Bonilla & Diez-Ewald, 1974), it was shown
    that manganese caused depletion of dopamine in the basal ganglia,
    especially in the striatum. In the study on monkeys, depletion of
    serotonin was also noted. Moreover, post-mortem biochemical analysis
    of the brain of a patient suffering from chronic manganese poisoning
    showed a reduced concentration of dopamine in the striatum and also in
    the substantia nigra (Bernheimer et al., 1973). These findings
    implicate the dopaminergic system in the extrapyramidal manifestations
    of chronic manganese poisoning and this is further supported by the
    fact that a remarkable improvement in the central nervous system
    symptoms can be achieved by the administration of L-dopa, a precursor
    of dopamine (section 9.3.2).

        Oxidative enzymes, which are abundant in the pallidum and
    striatum (Shimizu & Morikawa, 1957), are probably located within the
    mitochondria (Maynard & Cotzias, 1955) and, thus, are liable to be
    affected by the accumulation of manganese at these sites. Intact
    oxidative enzyme systems are needed to supply the energy for the
    degradation and synthesis of catecholamines involved in synaptic
    transmission. Any changes in these systems may affect behaviour and
    could be related to the initial psychiatric phase of chronic manganese
    poisoning (Mandell & Spooner, 1968). Similarly, tyrosine 3-hydroxylase
    and other enzymes in the biosynthetic pathway of catecholamines
    require oxygen (von Euler, 1965), and energy from ATP is needed to
    transport and compartmentalize essential compounds and to maintain the
    appropriate membrane and action potentials necessary for neuronal
    transmission. Any degeneration of neuronal cells would profoundly
    alter the neural mechanism with consequent clinical effects.

        Manganese may also be involved in the interrelationship between
    biogenic amines and adenosine 3',5'-monophosphate (cyclic AMP).
    Inhibition by manganese of adenyl cyclase (EC 4.6.1.1) in the membrane
    of the receptor cell may lead to decreased formation of cyclic AMP and
    thus uncouple processes that link the interaction of neurohypophyseal
    hormones with the formation of cyclic AMP. As a result, hormonal
    action may be inhibited (Bentley, 1967; Cotzias, 1969; Sutherland et
    al., 1968).

        Because of the involvement of metal ions in the neural
    transmission processes related to neurohormones, manganese
    concentrations have been determined in various regions of the rat
    brain. The hypothalamus contained the highest concentration and this
    may be related to the neuroendocrine function and oestrus disorders
    observed as a result of manganese deficiency in some species. It may
    also be required for the proper functioning of glycosyltransferases in
    the central nervous system (Donaldson et al., 1973).

    9.  HUMAN EPIDEMIOLOGICAL AND CLINICAL STUDIES

    9.1  Occupational Exposure and Health Effects

        Manganese exposure is a health hazard in the mining and
    processing of manganese ores and in the use of manganese alloys in the
    steel and chemical industries. The majority of cases of manganese
    poisoning that have been reported have been associated with a
    combination of high-speed drilling, which produces large amounts of
    manganese dust, and poor ventilation. However, manganese poisoning can
    also occur in other types of industry, such as in the production of
    dry-cell batteries (Emara et al., 1971). Chronic manganese poisoning
    can result from exposure to high concentrations of manganese dusts.
    Onset of the disease may occur after only a few months or several
    years according to the severity of exposure (Ansola et al., 1944b;
    Rodier, 1955). Damage is reversible, if the patient is removed from
    exposure at an early stage. However, apparently a sensitivity can
    develop, since a person who has recovered seems to be prone to
    contract the illness again.

        The signs and symptoms of chronic manganese poisoning have been
    described in detail by several authors (Flinn et al., 1940; Ansola et
    al., 1944b; Rodier, 1955; Pealver, 1955; Schuler et al., 1957; Mena
    et al., 1967; Letavet, 1973).

        According to the severity of the signs and symptoms, poisoning
    may be divided into 3 stages:  (a) A prodromal stage including the
    generally insidious beginning of the disease, with rather vague
    symptoms such as anorexia, asthenia, somnolence, insomnia,
    hyposexuality, and headache;  (b) An early clinical stage, when the
    onset of extrapyramidal manifestations occurs. Speech disturbances are
    early symptoms in this phase, sometimes leading to muteness. An
    increased tone of facial muscles results in a mask-like facies and
    there is also decreased ability to perform skilled movements.
    Hyperemotionalism is frequent and tendon reflexes in the lower limbs
    may be exaggerated;  (c) Established chronic manganese poisoning,
    which is characterized by psychomotor disturbances and neurological
    signs and symptoms. Marked rigidity due to muscular hypertonia, the
    most conspicuous sign, is most pronounced in the lower limbs and the
    face. Asthenia, adynamia, muscle pain, paraesthesia, speech
    disturbances, and disturbances of the libido are typical. The
    extrapyramidal dysfunction appearing clearly at this stage results in
    a close resemblance to parkinsonism. However, the tremor is frequently
    an intention tremor and not resting tremor that is typical of
    parkinsonism (Klawans et al., 1970). It has been pointed out that,

    contrary to parkinsonism, manganese intoxication is frequently
    associated with some degree of dystonia, defined as a postural
    instability of complementary muscle groups (Barbeau et al., 1976).
    Psychological signs and symptoms include apathy, unmotivated laughter,
    a tendency to weep, irritability, restlessness, and hallucinations.
    Increased salivation and sweating indicate that an autonomic
    disturbance is also present.

        Although manganese levels are elevated in most tissues in chronic
    manganese poisoning, studies of individuals with well-developed
    neurological signs and symptoms have revealed serum and blood
    manganese levels within the normal range. In contrast, healthy miners
    may have elevated blood manganese levels, suggesting that these
    indices are of limited value in the diagnosis of chronic intoxication
    (Mena & Cotzias, 1970).

        Another significant aspect of chronic manganese poisoning is
    marked individual susceptibility (section 9.4), since many miners are
    exposed to manganese dust but only a small percentage develop
    manifestations of poisoning (Rodier, 1955; Smyth et al., 1973).

        The possible toxic effects of manganese on the lungs were
    overshadowed during the earlier years by the effects on the central
    nervous system. It was only after a high death rate from pneumonia in
    a pyrolusite mill was reported that this association was suspected
    (Baader, 1932). The cases of pneumonia described by Lloyd Davies
    (1946) occurred in workers employed in the manufacture of potassium
    permanganate and exposed to manganese dioxide and, to a lesser extent,
    to the higher oxides of manganese. The incidence of cases diagnosed as
    pneumonia over the period 1938-1945 among the men employed (from 40 to
    124 men over the 8-year period) averaged 26 per 1000 workers (range
    15-63 per 1000) compared with an average of 0.73 per 1000 in a control
    group. Analysis of dust was performed on 2 days in 1944. Manganese
    concentrations in air, calculated from the manganese dioxide content
    of dust, displayed a range, for 6 measurements of 0.1-13.7 mg/m3. In
    general, particles were small, 80% being below 0.2 m. No case of
    chronic manganese poisoning was detected over the 8-year period. The
    clinical features of the pneumonia did not differ from conventional
    pneumonia with the exception that the response to sulfonamide was slow
    and that the entire respiratory tract from the nose, through the

    nasopharynx to the alveoli was involved. Permanent pulmonary changes
    including fibrosis were not observed. As in other workers exposed to
    chemical irritants in air, pharyngitis was a frequent finding. Mice
    exposed to dust from the milling room did not show any increased
    susceptibility to pneumococci types II and IV or to streptococci. The
    high incidence of pneumonia continued during the period 1946-1948
    (Lloyd Davies & Harding, 1949). The primary change was suggested to be
    an oedematous reaction of the respiratory epithelium resembling
    chemical pneumonitis, whereas manganese pneumonia was referred to by
    Rodier (1955) as a condition of acute alveolar inflammation with
    marked dyspnoea, shallow respiration, and cyanosis.

        Suzuki (1970) reported that the incidence of pneumonia in workers
    in a ferromanganase plant was twice as high as that in another plant
    situated in the same area.

        The laboratory diagnosis of chronic manganese poisoning is
    nonspecific and, at present, there is no adequate diagnostic test,
    although urinary manganese concentrations may have some value. This
    measurement, however, does not correlate well with the severity of the
    clinical signs. Blood levels of manganese provide little clinical
    information and blood urea nitrogen, fasting blood sugar, enzymes, and
    electrolytes are usually normal. Rodier (1955) mentions a reduction in
    excretion of 17-ketosteroids in 81% of his patients, a relative
    increase in lymphocytes and a decrease in polymorphonuclear leukocytes
    in 52%, and an increased basal metabolic rate in 57% of patients.
    Increased haemoglobin values and erythrocyte counts and decreased
    monocyte counts were reported by Kesic & Husler (1954) and an
    increased serum calcium level was observed by Chandra et al., (1974)
    in 12 cases of manganese poisoning. In mild cases of intoxication,
    serum adenosine deaminase levels were also elevated. Cotzias (1966)
    reported that cerebrospinal fluid findings were nonspecific but tended
    to show slightly increased cell and protein contents.

        Most of the cases of manganese poisoning described have occurred
    in manganese mines. Rodier (1955) reported on 150 cases from Moroccan
    mines with a total of about 4000 employees. Underground workers
    engaged in drilling blast holes ran a high risk of developing
    manganese poisoning; 132 out of 150 cases occurred among such workers.
    The concentration of manganese in air in the immediate vicinity of
    rock drilling was reported in one mine to be about 450 mg/m3 and in
    another, 250 mg/m3.

        In a study on 72 Chilean miners exposed to manganese
    concentrations in air of 62.5-250 mg/m3, 12(16.5%) were found to have
    neurological disorders. The average exposure time was 178 days, with a
    range of 49-480 days (Ansola et al., 1944a). A further study on 370
    miners exposed to manganese concentrations in air of 0.5-46 mg/m3
    showed that 15 workers (4%) had contracted typical manganese
    intoxication. In these workers, the average time of exposure was 8
    years, 2 months, with a range of 9 months-16 years (Schuler et al.,
    1957).

        Flinn et al. (1940) detected 11 cases of manganese poisoning
    among 34 workers in 2 manganese ore-crushing mills. The highest
    recorded concentration of manganese in air was 173 mg/m3. The
    prevalence of manganese poisoning was correlated with both manganese
    concentrations in air and the duration of employment. No cases were
    found among 9 workers exposed to concentrations of less than
    30 mg/m3. Five out of 6 men exposed for more than 3 years to
    concentrations exceeding 90 mg/m3 had chronic manganese poisoning.

        An occupational health investigation was carried out in Japan in
    3 types of industry: a crushing and refining factory, a dry-cell
    manufacturing plant, and a welding-rod manufacturing plant (Horiguchi
    et al., 1966; Horiuchi et al., 1970). The results of medical
    examinations of 134 workers from the 3 establishments were summarized
    as follows: On neurological examination, signs of disturbances of the
    central nervous system were clearly observed in 4 refinery workers,
    and 11 out of 47 refinery workers were suspected of having some
    neurological disturbances. Four out of 32 persons in the electric
    welding-rod plant, and 7 out of 55 persons from the dry-cell factory
    were also suspected of having some form of neurological disturbance
    (Horiguchi et al., 1966). Horiuchi et al. (1970) reported that a
    statistically significant correlation existed between the neurological
    findings and the levels of manganese in the urine of these workers.

        The concentrations of manganese in the blood and urine of these
    workers are shown in Table 11 together with the concentrations in the
    air of the work area.

        No significant relationship between the length of employment and
    the concentrations of manganese in blood and urine was found. The
    manganese concentrations in the blood and urine were higher in the
    manganese-refining workers than in workers in the other 2 industries,
    and neurological observations differed significantly. The coefficient
    of correlation between the manganese quantities in the blood and urine
    was +0.283 (Horiuchi et al., 1970).


        Table 11.  Manganese concentrations in the blood and urine of mangenese workers in relation to air
               concentrations in the work areaa
                                                                                                                  

                                           Mn in whole                            Statistical significance
    Type of work            Mn in air          blood        Mn in urine                                           
                             (mg/m3)        (mcg/100 g)       (mcg/1)          Mn in whole     Mn in urine
                                                                                  blood
                                                                                                                  

    crushing               2.3-17.1         4-54            8-165
    manganese ore          median = 8.4     median = 9.5    median = 68.5
    manufacturing          1.9-21.1         4-20            1-42               P = 0.0113b      P = 0.00049b
    dry-cell batteries     median = 4.3     median = 8      median = 6
    manufacturing          3.8-8.1          4-17            3-19
    electrodes             median = 4.9     median = 6      median = 5
                                                                                                                  

    a  From: Horiuchi et al. (1970).
    b  Statistically significant.

    

        Suzuki et al. (1973a, 1973b) carried out an investigation in 2
    ferromanganese factories (factories A and B). The manganese
    concentrations in air were 4.86 mg/m3 in the mixing and sintering
    plant and less than 1-2 mg/m3 in other places in factory A. Medical
    examination of 160 persons revealed that 27 were not healthy, as
    assessed by a screening questionnaire. More than a third of the 160
    workers examined complained of such symptoms as failing memory,
    fatigue, increased perspiration, and hyposexuality. Thirty-four out of
    144 male workers, (24%) exhibited tremor in the fingers, 5 (3,5%),
    displayed muscle rigidity, 7 (5%), adiadochokinesis and 19 (13%),
    disturbed balance. The geometric mean manganese concentrations in the
    blood and urine of 144 out of a total of 160 subjects were
    18.4 g/100 ml and 46 g/litre, respectively (Suzuki et al., 1973a;
    1973c).

        In the group of workers that had a blood level of manganese of
    more than 32.7/g/100 ml (=geometric mean + 1 standard deviation),
    reduced specific gravity of the whole blood, reduced haemoglobin and
    haematocrit values, and increased blood pressure, serum GOT, and
    urinary urobilinogen levels were observed. In the group in which the
    levels of manganese in the urine exceeded 75 g/litre (= geometric
    mean + 1 standard deviation), the specific gravity of the whole blood
    and haemoglobin values were comparatively high (Suzuki et al., 1973c).

        The ratio of the concentrations of manganese in urine and blood
    was positively correlated with both the specific gravity of the whole
    blood and the haemoglobin value. A negative correlation was found
    between the urine/blood ratio and the length of a worker's service,
    the diastolic blood pressure, and serum GOT. In the groups with a low
    urine/blood ratio, there were many cases of symptoms such as dynamia,
    failing memory, and hyposexuality (Suzuki et al., 1973c).

        In factory B, the concentration of manganese in the air near the
    electric furnace was 0.6 mg/m3 before tap, rising to 3.2-8.6 mg/m3,
    at tap. An occasional value of 24.3 mg/m3 was recorded under the
    conveyor belt, when the crusher was operating. During the medical
    examinations of 100 electric furnace workers, more than 40% complained
    of increased perspiration, failing memory, lumbago, footsores,
    headache, and sleepiness. Furthermore, 8% of the subjects exhibited
    adiadochokinesis, 10%, finger tremor, and 8%, acceleration of the
    patellar reflex. However, muscular force, whole blood gravity, and
    haematocrit values were within the normal range. The geometric means
    of the concentrations of manganese were 11 g/100 ml in blood and
    45 g/litre in urine (Suzuki et al., 1973b).

        Two investigations of 34 and 199 workers in a manganese steel
    mill exposed to concentrations of manganese in air in the range of
    0.4-15 mg/m3 showed that manganese levels in blood exceeding
    20 g/100 ml were accompanied by rises in blood cholesterol, total
    serum lipids, lipoproteins, serum bilirubin, calcium, aminolevulinic

    acid, and asparagine aminotransferase and decreases in magnesium,
    haemoglobin, serum proteins, and the glutathione contents of red
    cells. A review of morbidity and sickness records for a period of 6
    years showed a higher incidence of absenteeism and atherosclerosis in
    exposed workers (Jonderko et al., 1971, 1973a, 1973b, 1974).

        A recent epidemiological study of 369 male workers employed in
    the production of manganese alloys was reported by Saric et al.
    (1974). The mean concentration of manganese in air ranged from 0.39 to
    16.35 mg/m3 for the exposed population, while 2 control groups were
    exposed to concentrations of 4-40 g/m3 and 0.05-0.07 g/m3
    respectively. The data from this study suggest that manganese may
    contribute to the development of a chronic lung disease. Individuals
    with a history of smoking appeared to be more affected than nonsmokers
    and there was a relationship between the degree of smoking and the
    prevalence of respiratory tract symptoms in the manganese-exposed
    workers suggesting that smoking may act synergistically with manganese
    (Saric & Lucic-Palaic, 1977). A retrospective analysis of absenteeism
    due to pneumonia and bronchitis, in the same group of workers,
    revealed that those who were occupationally exposed to manganese were
    affected by these diseases more frequently than the controls. Data for
    this study were obtained from medical files covering a 13-year period.
    Bronchitis was classified into 2 categories:  (a) acute and not
    specifically defined, and  (b) chronic (Saric, 1972; 1978). During
    the epidemiological study, it was noted that manganese-exposed
    workers, particularly those involved in the production of alloys, had
    a lower mean systolic blood pressure than the controls. Diastolic
    pressure was not affected and the lowest mean diastolic pressure was
    observed in the controls. Factors such as age, body weight, and
    smoking habits, which may have influenced the results, were taken into
    account in their interpretation (Saric & Hrustic, 1975). A
    neurological examination performed in the same group of ferromanganese
    workers showed that 62 out of 369 workers (16.8%) had some
    neurological signs (Saric et al., 1977). In most cases, the sign was
    only a tremor of the fingers (47 workers); 11 workers had pathological
    reflexes with or without tremor and in 4 workers, cogwheel phenomenon
    was present as an isolated finding or combined with tremor or
    pathological reflexes.

        Whitlock et al. (1966) reported 2 cases of chronic manganese
    poisoning, which occurred in a ferromanganese plant where the
    concentrations of manganese in air were in the range of
    0.1-4.7 mg/m3. Examination 4 years later (Tanaka & Lieben, 1969),
    showed little improvement in one of the cases, the neurological
    manifestations being unchanged. The other case had improved but
    walking backward was still a little difficult. His face lacked
    expression to some extent but was no longer mask-like and the Babinski
    reflex was unilaterally positive.

        In studies by Sabnis et al. (1966), the daily weighted average
    exposure to manganese was estimated in a ferromanganese plant with
    1000 workers. No worker had a weighted average exposure exceeding
    2.3 mg/m3. During one year of weekly measurement, the highest
    recorded manganese concentration in air was 10 mg/m3 and the mean
    concentrations for various operations ranged from 0.5 to 5 mg/m3. No
    cases of manganese poisoning were detected in this plant, and when
    screening for symptoms and signs associated with early manifestation
    of manganese intoxication, all findings were "almost negative with
    respect to most of the symptoms".

        Weighted average concentrations were also estimated by Smyth et
    al., (1973), who discovered 5 cases of manganese poisoning among 71
    workers studied in a ferromanganese plant. No members of a control
    group of 71 unexposed workers displayed similar signs and symptoms.
    Three out of the 5 cases were exposed to manganese fumes and 2 to
    manganese dust; exposure times varied from 8 to 23 years. One case
    with 10 years of exposure to fumes, mainly of Mn(II,III) oxide, was
    exposed at the time of the investigations to a weighted average
    concentration of only 0.33 mg/m3, as calculated from 13 air
    measurements, each sampling period extending over 30 minutes; the
    highest recorded level was 5.9 mg/m3 and the other 12 measurements
    were below 5 mg/m3. The patient exhibited facial masking, reduced
    blinking reflex, micrographia, loss of associated arm movements on the
    right, tremor of the right hand and some cogwheel rigidity of the
    right extremities. A high degree of individual susceptibility or
    additional exposure to manganese seemed to be the likely explanation
    for this case of poisoning. However, the time of onset of the symptoms
    in this patient was not discussed, and the beginning of the disease
    may have been associated with the higher concentrations that prevailed
    earlier at this plant.

    9.2  General Population Exposure and Health Effects

        Only one epidemiological report is available on adverse effects
    from drinking-water contaminated with manganese. Kawamura et al.
    (1941) studied 16 cases of manganese poisoning, 3 of which were fatal
    (including one suicide), in a small Japanese community. About 400
    dry-cell batteries were found buried within 2 m of a well used as a
    water supply. The manganese content of the water was about 14 mg/litre
    and concentrations of 8 and 11 mg/litre were found in 2 other wells.
    All 16 intoxicated subjects drank water from these wells. The subjects
    exhibited psychological and neurological disorders associated with
    manganese poisoning, and high manganese and zinc levels were found in
    organs at autopsy.

        With the introduction of a ferro- and silicomanganese plant in
    Sauda (Norway), an increase was reported in the incidence of lobar
    pneumonia in the population living in the vicinity of the plant
    (Elstad, 1939a; 1939b). During the period 1924-1937; mortality due to
    lobar pneumonia was 8 times that in the whole country and morbidity
    was four times higher. Mortality due to lobar pneumonia in the age
    group 15-39 years was about 20 times that in the whole country and the
    course of the disease was more severe in Sauda (lethality 35.6%) than
    in the rest of Norway (lethality 20.3%). The following factors
    implicated manganese in the etiology of the disease:  (a) men working
    at the factory had a 50% higher mortality due to lobar pneumonia than
    men employed elsewhere (Elstad, 1939b);  (b) there was a positive
    correlation between morbidity and mortality and the amount of metal
    produced; and  (c) the occurrence and types of pneumococci in Sauda
    did not differ from the rest of the country (Elstad, 1939a; Riddervold
    & Halvorsen, 1943). Air analyses were performed in 1930 at a sampling
    site 3 km downwind from the factory, using a colorimetric assay which
    involved oxidation of manganese to permanganate. Air was found to
    contain Mn(II,III) oxide at 30-64 g/m3 and silica (SiO2) at
    6.4-8.9 mg/m3. However, the author stated that the oxidation of
    manganese to permanganate may have been incomplete, thus yielding
    rather low results (Bockman, 1939). Elstad (1939a) reported that air
    samples taken at various places contained levels of manganese oxides
    ranging from 45 to 64 g/m3. Thus, both reports indicate that
    manganese levels expressed as the metal may have been about 45 g/m3,
    at least. Exposure to manganese was further confirmed by the finding
    of a manganese concentration of more than 150 mg/kg dry weight in the
    lungs of a woman, who was not working in the factory (Bockman, 1939).
    Povoleri (1947) also noted that the prevalence of respiratory diseases
    among the inhabitants of Aosta (Italy) increased with the production
    of ferromanganese by a plant in that town, but no detailed study of
    the situation was conducted.

        Investigations in Japan include those of Nogawa et al. (1973) and
    Kagamimori et al. (1973), who studied the health of people living in
    the vicinity of a ferromanganese plant. The amount of manganese in
    dustfall that was collected in 4 places in Kanazawa city, far from the
    factory, averaged 8 kg/km2 per month. However, in 3 places, 200-300 m
    from the factory, the average manganese level was 200 kg/km2 per
    month. There was no difference in the quantities of dustfall and
    sulfur dioxide in the 2 areas. The 5-day mean concentration of
    manganese in suspended particulates was 4.04 g/m3 at a point 100 m
    away from the factory, and 6.70 g/m3 at a distance of 300 m.
    However, following the smoke downwind, a range of 1-h manganese
    concentrations of 4.5-260 g/m3 was measured at a distance of
    50-700 m from the chimney (Itakura & Tajima, 1972). A comparative
    study of junior high school students (1258) housed in a school 100 m

    away from the plant and a similar group (648) housed 7 km away
    produced the following findings: students in the school 100 m from the
    factory had a higher prevalence of nose and throat symptoms, a higher
    prevalence of past-history pneumonia, and a lower pulmonary function
    (as assessed by measuring the forced expiratory volume, one second
    capacity, one second ratio, and maximum expiratory flow) than students
    in the control school. Among the exposed schoolchildren, pulmonary
    function was lowest in those who had lived in the area longest and in
    those who lived closest to the factory. A follow-up study, conducted 1
    year after a dust collector had been established, showed that the
    manganese concentrations in suspended particulate matter had decreased
    by about half at 200-300 m distance from the factory. Furthermore, no
    differences were found in the symptoms or pulmonary function between
    exposed and control groups except in third-grade students, who had,
    presumably, been subjected to long-term exposure and whose lung
    function showed some deficit. Suzuki (1970) also made observations on
    pneumonia morbidity in the same area. He found a history of higher
    rates of pneumonia in schoolchildren and their families near the
    factory than in a control group.

        A 4-year study of the incidence of acute bronchitis,
    peribronchitis, and pneumonia was carried out on 31 000 inhabitants of
    a town on the coast of Dalmatia, Yugoslavia, where the atmosphere was
    polluted by the emissions from a manganese alloy plant. The
    concentrations of both manganese and sulfur dioxide in the atmosphere
    were monitored. According to the annual mean concentions of manganese
    in air, the town was divided into the following 3 zones: Zone I,
    0.27-0.44 g/m3; Zone II, 0.17-0.25 g/m3; Zone III,
    0.05-0.07 g/m3. Since a low-volume sampling technique was used, the
    particles collected were mainly of respirable size. The concentrations
    of sulfur dioxide were permanently low, with annual mean levels below
    30 g/m3. The incidence of respiratory diseases was analysed
    according to zones of manganese exposure and age, sex, and seasonal
    factors (manganese concentrations usually being higher in the summer
    than in winter) were taken into consideration. In residential zones,
    the incidence of acute bronchitis for both sexes was lowest in the
    zone with the lowest manganese concentration, but the highest
    incidence did not occur in the zone nearest the factory; however, the
    concentrations of manganese did not significantly differ in zones I
    and II. The incidence of pneumonia did not seem to exceed expected
    values and did not differ significantly in relation to sex, zone, or
    season. Thus, the expected higher rate of pneumonia in the winter
    failed to occur, and the authors raised the question as to whether

    this might be associated with higher summer concentrations of
    manganese (Saric, 1978; Saric et al., 1975). In the evaluation of the
    study, allowance should be made for the fact that 2-6 times higher
    concentrations were obtained using a high-volume technique than with a
    low-volume sampling technique (Saric, 1978) and that, apart from
    measuring sulfur dioxide levels, environmental and socioeconomic
    factors associated with the occurrence of respiratory illness were not
    taken into consideration.

        A study in the USSR carried out on 928 wives of workers employed
    in various manganese-processing plants showed that 13.8% had
    spontaneous abortions and 3.2% had stillbirths, while in a matched
    control group the incidence of these disorders was 8.1% and 1.7%,
    respectively. The rate of spontaneous abortion appeared to increase
    with the duration of exposure of the workers. Thus, the wives of
    workers employed for 10-20 years had a spontaneous abortion rate of
    15.4%, while the wives of workers exposed for 5-10 years had a
    spontaneous abortion rate of 11.7% (Mandzgaladze, 1967). No
    information regarding the type of work of the wives was given.

    9.3  Clinical Studies

    9.3.1  Pathomorphological studies

        There have been relatively few documented autopsy reports
    concerning pathological changes in man related to manganese poisoning
    (Casamajor, 1913; Ashizawa, 1927; Canavan & Drinker, 1934; Stadler,
    1936; Voss, 1939, 1941; Flinn et al., 1940; Kawamura et al., 1941;
    Parnitzke & Peiffer, 1954). In the central nervous system, the most
    extensive changes have been found in the striatum (caudate nucleus and
    putamen) and pallidum. Ashizawa (1927) noted a loss of ganglion cells
    in the pallidum and marked degeneration of the putamen and caudate
    nucleus; he also reported slight changes in the substantia nigra.
    Brain atrophy over the vertex and lateral aspects was reported by
    Canavan & Drinker (1934) in a patient who died 14 years after the
    onset of symptoms. On the frontal section, the atrophy was conspicuous
    and dilatation of the lateral ventricles with shrinking of the basal
    ganglia was found. Degeneration of nerve cells was seen in the basal
    ganglia together with gliosis and satellitosis. The caudate nucleus,
    putamen, globus pallidus, and thalamus were equally affected. Only
    diffuse cellular changes were seen in the cerebral cortex and
    cerebellum. Kawamura et al. (1941) reported that a 46-year-old patient
    died one month after the onset of an illness contracted from
    drinking-water heavily contaminated with manganese. Moderate
    congestion was noted in the brain, spinal cord, and meninges, with
    meningeal oedema most prominent in the occipital part. Severe
    degeneration was found in the globus pallidus, whereas the thalamus,

    caudate nucleus, and Louis' body were histologically normal and no
    increase in glial cells was found. The most pronounced changes found
    by Stadler (1936) were in the striatum and pallidum which were equally
    affected. Perivascular degeneration with loss of ganglion cells and
    proliferation of glial cells were typical findings in the putamen and
    the caudate nucleus. Less severe changes were found in the cortex and
    only slight changes in thalamus, hypothalamus, and cerebellum.

        Generalized atrophy of the liver cell cords, most marked at the  
    centre of the lobules, was found by Flinn et al. (1940). However,
    because of post-mortem changes, the findings on examination of the
    brain remained obscure. The 2 cases described by Voss (1939, 1941)
    both displayed degenerative changes of the pyramidal tract, whereas
    histopathological autopsy findings in the striatum, pallidum, caudate
    nucleus, putamen, and the cortex were minimal. Degeneration of
    peripheral nerves was present in both cases: however, one of the
    patients suffered also from amyotrophic lateral sclerosis (Voss,
    1939). According to Parnitzke & Peiffer (1954), a 19-year-old
    manganese miller, who developed symptoms and signs after 1 year of
    exposure, died 24 years later after progressive impairment of
    neurological function. The total exposure time was approximately 2
    years. A loss of ganglia cells in the pallidum with glial cell
    proliferation and high concentrations of manganese, lead, and iron in
    the plexus chorioideus were the major findings at autopsy.

        Bernheimer et al. (1973) described morphological findings in a
    woman with chronic manganese encephalopathy, who died with the
    clinical picture of a rigid-akinetic parkinsonian syndrome. She had
    been working for many years in a battery factory, and, 10 years after
    giving up this work, she had blood manganese levels 10 times higher
    than reference values. Generalized astroglial proliferation was found
    with a preference for certain cortical areas, the putamen, pallidum,
    and red nucleus. There was also mild pallidal atrophy and marked
    degeneration in the zona compacta of the substantia nigra. An
    interesting finding was the low concentrations of dopamine in the
    striatum and of noradrenaline in the hypothalamus; however, serotonin
    levels were considered to be normal.

    9.3.2  Therapeutic studies

        Treatment of chronic manganese poisoning has recently undergone a
    basic change reflecting a better understanding of the pathophysiology
    of the condition. Early attempts using various chelating agents,
    particularly EDTA, were of conflicting benefit but did seem to produce
    some improvement in the condition, if applied in its early phase, when
    presumably neuronal destruction had not yet occurred. No improvement
    could be expected after structural neurological injury had occurred.
    The results of Penalver (1955) and Tepper (1961) confirmed this and
    they regarded the treatment as ineffective. Whitlock et al. (1966)
    reported that treatment with intravenous calcium EDTA mobilized body
    deposits of manganese (as evidenced by increased levels of manganese
    in the urine) and led to improvement in muscle strength and
    coordination within 2-3 months of treatment; however, a follow-up of
    the 2 cases, 4 years later, revealed that the improvement was
    persistent in only one case and that the other had deteriorated
    (Tanaka & Lieben, 1969). That the improvement following EDTA treatment
    might be temporary was also reported by Cook et al. (1974). Successful
    treatment has been reported, particularly for early manifestations of
    manganese poisoning, using calcium EDTA and other chelating agents
    derived from polyamino-polyphosphoric acid (Mihajlov et al., 1967;
    Arhipova et al., 1968). Wynter (1962) reported poor results with EDTA
    in 7 cases in the advanced phase but encouraging results in one
    patient with early signs and symptoms. Similarly, Smyth et al. (1973)
    found EDTA treatment successful in 2 cases, both of which displayed
    loss of associated arm movement as the only neurological sign, but no
    improvement in 3 cases with more advanced neurological signs.

        The essentially negative results with chelating agents may be
    explained by the fact that increased levels of tissue manganese, that
    would be amenable to such treatment, were found only in healthy,
    actively working miners. Apparently, crippled ex-miners had cleared
    the manganese loads they once had, but did not show any improvement in
    their neurological picture, indicating that neurological signs can
    persist in the absence of elevated tissue concentrations (Cotzias et
    al., 1968). Thus, chelating agents can hardly be expected to have
    beneficial effects except in early cases, as no tissue concentrations
    remain to be cleared in the later stages of the disease.

        Recognizing that a similar biochemical defect was present in
    parkinsonism (section 8.6), Mena et al. (1970) used oral doses
    increasing up to 8.0 gm per day of the dopamine precursor
    3-hydroxy-L-tyrosine (L-dopa) in 6 patients. Five subjects showed
    reduction or disappearance of rigidity and hypokinesia, and regained
    their sense of balance. The sixth patient displayed aggravation of
    neurological signs during L-dopa treatment but responded favourably to
    a daily dose of 3 gm of 5-hydroxytryptophane, a precursor of
    serotonin. The rational basis for the use of 5-hydroxytryptophane was

    that muscle hypotonia, sometimes present in chronic manganese
    poisoning, but hardly ever present in parkinsonism (Cotzias, 1969),
    was probably related to low striatal serotonin levels. This is the
    case of the hypotonia of Down's syndrome, which can be reversed by the
    administration of the serotonin precursor (Bazelon et al., 1967).
    Experimental support for the use of dopamine or serotonin precursors
    in manganese poisoning includes the fact that the administration of
    manganese to rats, rabbits, and monkeys was followed by depletion of
    striatal dopamine and serotonin (Neff et al., 1966; Mustafa & Chandra,
    1971; Bonilla & Diez-Ewald, 1974) and that administration of dopamine
    and serotonin precursors resulted in an increase in the striatal
    concentrations of both dopamine and serotonin (Poirier et al., 1967b;
    Goldstein et al., 1969; Neff et al., 1969; Bonilla & Diez-Ewald,
    1974). However, data on the depletion of serotonin are still
    conflicting (Goldstein et al., 1969). A favourable result using L-dopa
    in one case of chronic manganese poisoning was also obtained by
    Rosenstock et al. (1971), but the beneficial response to L-dopa could
    not be confirmed by Cook et al. (1974), who treated 3 patients with
    the drug. It has been proposed that the beneficial therapeutic effect
    of L-dopa depends on the dopaminergic fibres not being completely
    degenerated (Goldstein et al., 1969; Mena et al., 1970). The
    therapeutic doses used in chronic manganese poisoning have generally
    been well tolerated, although doses of up to 12 g of L-dopa have been
    administered daily (Rosenstock et al., 1971). Considering the high
    doses needed, Cotzias (1969) drew attention to the possibility of
    choline or methionine deficiency resulting from the donation of their
    methyl groups, which are needed for the metabolism of L-dopa.

    9.4  Susceptibility to Manganese Poisoning

        Several authors have tried to explain the individual
    susceptibility of miners to chronic manganese poisoning on the basis
    of nutritional deficiencies and variations in intestinal absorption.
    Altstatt et al. (1968) showed that manganese and iron metabolism are
    closely related, and Mena et al. (1969) reported that individuals with
    increased intestinal iron absorption had an increased absorption of
    manganese as well. Thus, an intestinal absorption of manganese of 7.5%
    was found in anaemic subjects compared with 3% in healthy subjects.
    The accelerated turn-over of manganese with a concomitant increase in
    iron excretion found in heavily exposed workers with elevated tissue
    levels of manganese (Section 6.1.2.1) may further aggravate a
    pre-existing anaemia (Mena et al., 1969). Moreover, Mena et al. (1974)
    reported that the binding capacity of the plasma of anaemic rats was
    more than twice that of healthy rats. The authors considered that the
    increase in the transport capacity of the plasma to the blood-brain
    barrier was related to the finding of about 100% higher concentrations
    in the brain of anaemic rats.

        It was also found that the penetration of the blood-brain barrier
    in newborn and infant rats less than 18 days old was 4 times that of
    adult rats (Mena et al., 1974). According to Mena (1974), young rats
    had an intestinal absorption of 70% of manganese compared with 1-2% in
    the adult rat. Human data on these aspects are not available.

    9.5  Interaction

        Apart from individual susceptibility, some individuals may be at
    higher risk because of exposure to certain chemical or physical
    factors that may influence the toxicity of manganese. A recent study
    on occupationally exposed workers (section 9.1) indicated that smoking
    may act synergistically with manganese in the development of
    nonspecific respiratory disorders (Saric & Lucic-Palaic, 1977).
    Combined exposure to manganese and vibrations or X-rays increased the
    toxic effects of manganese, particularly in the central nervous system
    and the adreno-cortical system (Mihajlov et al., 1969; Levanovskaja &
    Neizvestnova, 1972; Neizvestnova, 1972a, b; Pocasev & Neizvestnova,
    1972). An increase in the toxicity of manganese compounds has been
    noted with exposure to chemicals such as carbon monoxide, silicon
    dioxide, sulfur dioxide, fluorine, copper, and lead (Belobragina &
    El'nicnyh, 1969; Belobragina et al., 1969; Davydova, 1969; El'nicnyh,
    1969; Mihajlov et al, 1969; Davydova et al, 1971; Rylander et al.,
    1971; Belobragina, 1972; Mavrinskaja et al., 1972; Rylander &
    Bergstrm, 1973).

        An inhibiting effect of manganese on muscle tumorigenesis caused
    by nickel subsulfide in rats was reported by Sunderman et al. (1974).
    Manganese ions were also found to antagonize the excitation of
    myocardial fibres in frogs caused by nickel ions (Babskiji & Donskih,
    1972; Donskih & Mukumov 1974).

    10.  EVALUATION OF HEALTH RISKS TO MAN FROM EXPOSURE TO MANGANESE
        AND ITS COMPOUNDS

    10.1  Relative Contributions of Air, Food, and Water to Total Intake

    10.1.1  General population

        In areas without manganese-emitting industries, the annual
    average concentrations of manganese in air are usually in the range of
    0.01-0.07 g/m3. In areas with major foundry facilities,
    concentrations of about 0.2-0.3 g/m3 can be expected. When
    ferromanganese or silicomanganese industries are present, the annual
    average concentration in the surrounding areas may increase to over
    0.5 g/m3; occasionally, annual values up to 8.3 g/m3 have been
    recorded. Assuming a standard respiration rate of 20 m3 per day, the
    daily intake of manganese through inhalation in unpolluted areas would
    be below 2 g/day, whereas in the presence of ferromanganese and
    silicomanganese industries, in extreme situations, the daily mean
    intake may increase to over 150 g/day. Thus, in most instances, the
    daily intake through inhalation constitutes less than 0.1% of the
    total daily intake, and rarely exceeds 1%, even in heavily polluted
    areas.

        There is no information on the rate of absorption of inhaled
    manganese particles. The particle size with which airborne manganese
    is associated is usually within the respirable range. Inhaled
    manganese particles are partly cleared through pulmonary defence
    mechanisms and swallowed. The small size of the particles favours a
    widespread airborne distribution of manganese, that reaches man
    indirectly, as a result of fallout on soil and water and through
    uptake by plants and animals.

        The mean levels of manganese in drinking-water are usually about
    5-25 g/litre, but individual samples from municipal supplies have
    shown concentrations ranging from trace levels to 100 g/litre. Values
    one order of magnitude higher have been determined in certain rivers.
    Assuming a standard daily water consumption of 500-2200 ml (ICRP,
    1975), the average daily intake of manganese with water is in the
    range of 2-55 g and is unlikely to constitute more than 1-2% of the
    total intake of manganese. Data on the form of manganese present in
    drinking-water and on the rate of absorption from the gastrointestinal
    tract of manganese in water are not available.

        Most foodstuffs contain manganese in concentrations below 5 mg/kg
    (wet weight). Grain, rice, and nuts may have manganese levels
    exceeding 10 mg/kg, whereas finished tealeaves contain several hundred
    mg/kg. The daily intake of manganese with food, by adults, is about
    2-9 mg. In young children and up to adolescence, the intake is about
    0.06-0.08 mg/kg body weight and in breastfed and bottlefed infants is

    as low as 0.002-0.004 mg/kg body weight. The small amount of
    information available indicates an absorption from the human
    gastrointestinal tract of less than 5% in healthy adults. The low
    absorption is supported by studies on mice and rats, in which
    absorption may range from 0.2 to 3%. There is no information available
    concerning absorption in infants and young children, but animal data
    indicate that it could be significantly higher than in adults. A
    gastrointestinal absorption of 5% would result in an absorbed dose of
    100-450 g/day for adults. The chemical forms and the possible
    differences in biological availability of manganese present in various
    foods are not known.

    10.1.2  Occupationally-exposed groups

        Recent data on the levels of manganese in air in manganese mines
    were not available to the Task Group, but most studies indicate that
    levels of several hundred milligrams per cubic metre may occur. Values
    ranging from 0.8 to 17 mg/m3 have been reported in ore-crushing
    plants. In steel plants, air concentrations are generally in the range
    of 0.1-5 mg/m3, only rarely exceeding 10 mg/m3. However, welders may
    be exposed to air concentrations exceeding 10 mg/m3. A major part of
    manganese present in the air in work areas is in the form of oxides,
    and data concerning other compounds are not available. Manganese in
    dust and fumes appears to be predominantly associated with particles
    below 5 m.

    10.2  Manganese Requirements and Deficiency

        The daily required intake of manganese for adult man appears to
    be 2-3 mg, and taking into account available data, an estimated
    minimum daily intake of 1.25 mg would seem adequate for pre-adolescent
    children. Although newborn infants display a negative manganese
    balance during the first weeks of life, as manganese is excreted from
    tissue stores accumulated during fetal life, signs of manganese
    deficiency have not been seen. Manganese deficiency has been described
    only once in man in connexion with experimentally induced vitamin-K
    deficiency and the accidental omission of manganese from the diet. All
    dietary studies on daily manganese intake have indicated that the
    daily requirements mentioned earlier are met. Furthermore, it seems
    that regulatory absorption and excretion mechanisms exist which make
    manganese deficiency unlikely in man.

    10.3  Effects in Relation to Exposure

        The primary target organs of inhaled manganese are the lungs and
    the central nervous system, although effects have occasionally been
    noted in other organs. The effects of manganese are not specific and a
    suitable biological indicator of the absorbed dose of manganese has
    not been identified, so far. In the measurement of inhalation
    exposures, personal samplers have rarely been used. Most data have
    been derived from occasional measurements at fixed sampling sites and
    do not necessarily represent actual exposure. Thus, exposure-effect
    and exposure-response relationships cannot be established for
    manganese on the basis of existing data. The scantiness of
    retrospective exposure data makes it difficult to associate effects
    with any long-term exposure levels.

    10.3.1  General population

        With a few exceptions, effects on the central nervous system have
    only been observed in occupationally exposed individuals. However, one
    incident involving 16 cases of severe manganese poisoning from
    drinking-water (manganese concentrations ranging from 8 to
    14 mg/litre) contaminated by discarded dry-cell batteries indicates
    the importance of ensuring the proper disposal of manganese-containing
    wastes.

        An increased incidence of pneumonia and nonspecific effects on
    the respiratory tract have been reported in populations living in
    areas associated with manganese alloy production. In Sauda, Norway, a
    4-fold increase in morbidity and an 8-fold increase in mortality due
    to lobar pneumonia were noted over a 14-year period, in a community
    living in the vicinity of a ferromanganese and silicomanganese plant.
    Moreover, the morbidity and mortality due to lobar pneumonia varied
    with the amount of manganese alloy produced by the plant. Results of
    bacteriological investigations in Sauda were similar to those in the
    rest of the country, which further indicates that manganese played at
    least some part in the etiology of the pneumonia. The actual exposure
    of the population to manganese oxide in air is uncertain in this case
    as only one value (64 g/m3) was given and it was later proved that
    the analytical method used gave rather low results. Another study,
    from Aosta, Italy, reporting an increase in mortality due to pneumonia
    as production of manganese alloys increased at the local
    ferromanganese plant is even more difficult to evaluate as no detailed
    investigations were carried out.

        A higher prevalence of nose and throat symptoms, anamnestic
    pneumonia, and decreases in pulmonary function were registered in a
    group of schoolchildren living about 100 m from a ferromanganese
    plant, compared with children attending a school 7 km away from the
    factory. The manganese concentrations in air in the polluted area
    ranged from 4.0 to 6.7 g/m3, (5-day mean values). However, on 3
    occasions, short-time samples (1-h) following the smoke downwind
    exceeded 100 g/m2 at distances of 50-700 m from the chimney, with a
    maximum value of 200 g/m3. The fact that a follow-up study, carried
    out after a dust collector 'had been in operation for 1 year, failed
    to show similar differences between more exposed and less exposed
    groups further incriminates manganese in the etiology of the
    respiratory findings.

        In a study in Yugoslavia, health effects in 2 populations (8700
    and 17 100 individuals), exposed to mean annual concentrations of
    manganese in air of about 0.27-0.44 and 0.10-0.24 g/m3,
    respectively, arising from a manganese alloy plant, were compared with
    those in a population exposed to concentrations below 0.1 g/m3. An
    increased incidence of bronchitis was noted in the exposed
    populations, but the incidence of pneumonia did not exceed expected
    values. The exposures may have been considerably higher owing to the
    low-volume sampling technique used. Although sulfur dioxide
    concentrations were measured, other environmental and socioeconomic
    factors, not considered, might have influenced the results.

    10.3.2  Occupationally-exposed groups

        Confounding factors have been reported in all the available
    studies relating effects to occupational manganese exposure. Some
    studies have related certain effects of manganese (including
    pneumonia, effects on the central nervous system, and subjective
    symptoms) to levels of exposure. As there are very few data concerning
    retrospective exposure, and subtle neurological and psychological
    symptoms and signs may have existed unrecognized for several years,
    the development of effects may, in fact, have been related to earlier,
    higher exposures. Moreover, the relationship between the development
    of signs and symptoms and short-term exposure to high concentrations
    is not known. Although these considerations should be borne in mind in
    the assessment of exposure-effect relationships, sufficient
    information exists to relate at least some effects to a range of
    manganese concentrations in air.

    10.3.2.1  Effects on the central nervous system

        Signs and symptoms of extrapyramidal disorders, characteristic of
    manganese poisoning, were reported in 2 manganese steel workers
    engaged in arc-burning. Measurements of manganese concentrations in
    air ranged up to 4.7 mg/m3. At re-examination 4 years later, one
    worker showed further neurological deterioration, and the other still
    displayed slight neurological signs.

        In a ferromanganese plant, manganese concentrations in air ranged
    from 1.9 to 4.9 mg/m3 in the sintering area and were below 2 mg/m3
    in other areas of the plant. Examination of 160 workers revealed
    symptoms such as failing memory, fatigue, increased perspiration, and
    hyposexuality in 30% of the subjects. Of 144 workers, 24% exhibited
    tremor of the fingers, 13% disturbed balance, 5%, adiadochokinesis,
    and 3.5%, muscular rigidity. In another ferromanganese plant, exposure
    levels were mainly below 1 mg/m3, and manganese concentrations up to
    3.2-8.6 mg/m3 were measured around the electric furnace at tap only
    (one value of 24.4 mg/m3 was measured under a conveyor belt that was
    in operation). Among the 100 workers, 40% complained of symptoms but
    not all the symptoms were necessarily due to manganese exposure.
    Adiadochokinesis was found in 8% of the workers, tremor of the fingers
    in 10%, and accelerated patellar reflex in 8%. Similarly, slight
    neurological signs were found in 7 out of 55 dry-cell battery plant
    workers exposed to a median manganese concentration in air of
    4.3 mg/m3 (range 1.9-21.1 mg/m3).

        One report from a ferromanganese plant with 1000 employees
    indicated annual mean concentrations for various operations ranging
    from 0.5 to 5 mg/m3; the highest concentration recorded was
    10 mg/m3, and the highest daily weighted average exposure for any
    worker was 2.3 mg/m3. The plant physician's register did not show any
    complaints that suggested manganese poisoning and a screening for
    subjective symptoms was negative. Unfortunately, clinical examinations
    were not carried out on the workers and reporting on symptoms was
    inadequate.

        In this context, it is pertinent to consider the fact that
    characteristic central nervous system signs were produced in monkeys
    exposed to 0.6-3.0 mg of manganese dioxide per m3 of air, for 1 h per
    day, over a 4-month period.

    10.3.2.2  Manganese pneumonia

        Considering that a causal connexion between exposure to manganese
    and pneumonia has been repeatedly suggested in the literature since
    1921, there have been surprisingly few studies concerned with the
    relationship between the incidence of pneumonia and the type and level
    of exposure. However, a 35-fold increase in the incidence of pneumonia
    was reported in workers engaged in the manufacture of potassium

    permanganate. The incidence was 26 per 1000 workers compared with 0.73
    in a control group. The manganese concentrations in air ranged up to
    14 mg/m3, as calculated from measurements of manganese dioxide in
    dust. Although measurements were scarce and higher concentrations may
    have existed in the beginning of the 8-year period of the study, the
    fact that no signs of chronic manganese poisoning were observed
    suggests that the exposure was comparatively low. It is not possible
    to conclude whether manganese exerts a direct chemical action on the
    lungs or causes an increased susceptibility to bacterial or viral
    agents.

    10.3.2.3  Nonspecific effects on the respiratory tract

        A recent epidemiological study of 367 male workers, exposed to a
    mean concentration of manganese in air of up to 16.4 mg/m3, indicated
    that manganese may contribute to the development of chronic
    bronchitis. The higher rate of symptoms related to the respiratory
    tract in smokers from the exposed group compared with smokers in the
    control group suggested that smoking may act synergistically with
    manganese. Retrospective studies of absenteeism because of respiratory
    disorders have also indicated that populations occupationally exposed
    to manganese are more frequently affected by these conditions than
    unexposed populations.

        In the assessment of exposure-effect levels in occupational
    health, it may be useful to consider that exposure of rats to
    manganese dioxide at 0.3 mg/m3, by inhalation, caused inflammatory
    changes in the respiratory tract of the animals, and that inhalation
    of the same compound at 0.7 mg/m3 and 3.0 mg/m3 caused mottling of
    the pulmonary X-rays of monkeys as well inflammatory alterations in
    the respiratory tract of mice.

    10.3.2.4  Diagnosis of manganese poisoning and indices of exposure

        The clinical diagnosis of manganese poisoning may be difficult,
    particularly in the early stages of the disease, since reliable
    diagnostic procedures are not available. Urine and blood manganese
    levels are only weakly correlated with the degree of exposure and with
    the severity of the toxic response. Pulmonary manifestations may be
    absent and when present in smokers, for instance, they may easily be
    ignored. The onset of psychological and neurological signs and
    symptoms is often insidious, and the manifestations nonspecific,
    whereas later stages resemble parkinsonism. Apart from the
    ascertainment of exposure, repeated screening for subjective symptoms
    and thorough neurological examinations, together with the
    determination of the manganese concentrations in urine and blood
    appear, at present, to be the only methods available for the detection
    of the disease. Since manganese is eliminated primarily in the faeces,
    the estimation of faeces manganese may serve as a useful guide to
    exposure, although this approach has rarely been applied.

    10.3.2.5  Susceptibility and interaction

        The incidence of chronic manganese poisoning among workers
    exposed to high manganese concentrations has shown highly variable
    individual susceptibility to the effects of manganese. The reasons for
    higher susceptibility in some individuals are not clear though the
    close relationship between manganese and iron metabolism may afford
    one explanation. The intestinal absorption of manganese in anaemic
    subjects is twice that of healthy individuals. Moreover, exposed
    workers with elevated tissue levels of manganese have an increased
    excretion of manganese combined with a concomitant increase in iron
    excretion, which may aggravate a pre-existing anaemia. Animal
    experiments have shown that the binding capacity of the plasma of
    anaemic rats is more than double that of healthy rats and that the
    entrance of manganese into brain is higher in anaemic rats.
    Penetration into the brain of newborn and infant rats is 4 times that
    of adult rats and the intestinal absorbtion of manganese in young rats
    may be up to 70%, compared with 1-2% in adult rats.

        There is little information on the interaction between manganese
    and other chemical and physical factors. However, some studies have
    indicated that manganese, smoking, and sulfur dioxide may produce
    synergistic effects on the respiratory tract. Vibration and X-rays
    have been reported to increase the toxic effects of manganese on the
    central nervous system and this may also be true of other chemicals
    such as carbon monoxide, silicon dioxide, fluorine, copper, and lead.

    10.4  Organomanganese Compounds

        Two classes of organomanganese compounds should be considered
    from the toxicological point of view. One includes manganese
    ethylene-bis-dithiocarbamate (Maneb), a fungicide used on edible
    crops. Here, the manganese entity is of little toxicological
    significance, while the organic fraction is part of a larger problem
    concerning the use of this class of fungicides. These fungicides have
    been considered by a joint FAO/WHO Meeting on Pesticide Residues in
    food (WHO, 1969). The International Agency for Research on Cancer
    recently considered data relevant to the carcinogenicity of manganese
    ethylene-bis-dithiocarbamate and concluded that the data available
    were too meagre for an evaluation of the carcinogenic risks of this
    compound man (IARC Working Group, 1976).

        The second class of organomanganese compounds of potential
    toxicological significance is constituted by the manganese tricarbonyl
    compounds used as additives in petrol. As only a small portion of the
    parent compound is emitted and this is rapidly photo-decomposed to
    mainly unknown compounds, exposure to manganese tricarbonyl compounds
    is more likely to constitute an occupational hazard than a public one.
    Widespread use of these compounds as petrol additives will, however,

    result in increased exposure of the general population to the
    combustion products, mainly inorganic manganese, and will especially
    affect urban environments. Animal experiments have not revealed any
    adverse effects from the long-term exposure (up to 66 meeks) of rats,
    hamsters, and monkeys to combustion products of
    methylcyclopentadienylmanganese tricarbonyl with manganese
    concentrations in air in the range of 12-5000 g/m3. However, at
    100 g/m3 for up to 66 weeks, the tissue levels of manganese
    increased significantly in monkeys. At present, data on the effects of
    prolonged exposure of man to low concentrations of manganese in air
    and on the effects of combined exposure to manganese and other
    pollutants are inadequate for an evaluation of the health risks, if
    any, that may arise from an substantial increase in the use of
    manganese tricarbonyl compounds in petrol. Studies on the effects on
    exhaust gas emissions of manganese tricarbonyl compounds as additives
    in petrol are also, in some respects, conflicting and further studies
    are needed.

    10.5  Conclusions and Recommendations

        Manganese is an essential trace metal for both man and animals.
    Manganese deficiency is extremely unlikely to occur in man because
    there is a sufficient supply of manganese in the diet and because of
    homeostatic mechanisms present in man.

        Systemic effects from over-exposure to manganese, which
    constitute an inhalation hazard for occupationally-exposed
    populations, may occur in other populations, but only in cases of
    accidental or intentional ingestion of exceptional amounts of the
    metal. Pneumonia and nonspecific effects on the respiratory tract may
    occur both in occupationally-exposed populations and in the general
    population, in areas associated with industrial emissions of
    manganese.

        The assessment of health risks related to both occupational and
    community exposure to manganese is made more difficult by the
    generally poor quality of available information particularly in the
    case of exposure data.

    10.5.1  Occupational exposure

        Signs and symptoms of effects on the central nervous system may
    already occur at air concentrations of manganese in the range of
    2-5 mg/m3. A minimum exposure-effect level cannot be assessed, but
    considering human and animal data as well as the highly variable
    individual susceptibility to manganese, it is probably less than
    1 mg/m3.

        Exposure-effect relationships for pneumonia and nonspecific
    respiratory effects cannot be established from available occupational
    data. Animal data indicate a local effect of manganese dioxide on the
    respiratory tract at concentrations ranging from 0.3 to 3.0 mg/m3. It
    seems possible that characteristics such as particle-size distribution
    and type of manganese compound are etiologically more important than
    mass concentrations of manganese. Special attention should be paid to
    the possibility of concomitant exposure to other pollutants which may
    act synergistically with manganese on the respiratory tract. There is
    a conspicuous discrepancy between, on the one hand, extremely low
    concentrations of manganese in the ambient air reported to cause
    effects on the respiratory tract, and, on the other hand, the
    scantiness of reports of similar effects in populations
    occupationally-exposed to about 100-1000 times these levels.

        Persons with psychological or neurological disorders are not
    suitable for work associated with exposure to manganese.

        Nutritional deficiency states may predispose to anaemia,
    increasing susceptibility to manganese; and subjects suffering from
    such deficiencies should be under surveillance.

        In the absence of specific diagnostic means, the worker should be
    screened for subjective symptoms and subjected to clinical
    examinations at regular and not too long intervals. A pre-employment
    examination is clearly needed.

    10.5.2  General population exposure

        At present, there is no evidence that the manganese
    concentrations of less than 0.1 g/m3 generally found in ambient
    rural and urban air are associated with any health risk to man.

        Annual mean concentrations of manganese in air exceeding
    0.1 g/m3 are invariably man-made and are found in areas associated
    with manganese-processing industries. Manganese compounds may be
    widely used as petrol additives in the future and may cause urban air
    concentrations of manganese to exceed this level.

        Increased morbidity and mortality due to pneumonia, and
    nonspecific effects on the respiratory tract in the general population
    have been related to increased exposure caused by nearby manganese
    alloy plant. The documentation available is inadequate for the
    establishment of guidelines with respect to manganese concentrations
    in ambient air.

        In view of existing data and considering the possibility of
    increasing use in the future of organomanganese compounds as petrol
    additives, it is recommended that epidemiological surveys be conducted
    in communities exposed to annual mean concentrations of manganese in
    air exceeding 1 g/m3.

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    See Also:
       Toxicological Abbreviations
       Manganese (ICSC)