Concise International Chemical Assessment Document 12


    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.

    Concise International Chemical Assessment Document 12


    First draft prepared by Dr Mildred Williams-Johnson, Division of
    Toxicology, Agency for Toxic Substances and Disease Registry, Atlanta,
    Georgia, USA

    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, and the
    World Health Organization, and produced within the framework of the
    Inter-Organization Programme for the Sound Management of Chemicals.

    World Health Organization
    Geneva, 1999

         The International Programme on Chemical Safety (IPCS),
    established in 1980, is a joint venture of the United Nations
    Environment Programme (UNEP), the International Labour Organisation
    (ILO), and the World Health Organization (WHO). The overall objectives
    of the IPCS are to establish the scientific basis for assessment of
    the risk to human health and the environment from exposure to
    chemicals, through international peer review processes, as a
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    technical assistance in strengthening national capacities for the
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    Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
    Agriculture Organization of the United Nations, WHO, the United
    Nations Industrial Development Organization, the United Nations
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    Co-operation and Development (Participating Organizations), following
    recommendations made by the 1992 UN Conference on Environment and
    Development to strengthen cooperation and increase coordination in the
    field of chemical safety. The purpose of the IOMC is to promote
    coordination of the policies and activities pursued by the
    Participating Organizations, jointly or separately, to achieve the
    sound management of chemicals in relation to human health and the

    WHO Library Cataloguing-in-Publication Data

    Manganese and its compounds.

         (Concise international chemical assessment document ; 12)

         1.Manganese - adverse effects   2.Manganese - toxicity
         3.Environmental exposure   4.Maximum permissible exposure level
         I.International Programme on Chemical Safety   II.Series

         ISBN 92 4 153012 X           (NLM classification: QV 290)
         ISSN 1020-6167

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    (c) World Health Organization 1999

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         The mention of specific companies or of certain manufacturers'
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    proprietary products are distinguished by initial capital letters.









              6.1. Environmental levels
              6.2. Human exposure



              8.1. Single exposure
              8.2. Irritation and sensitization
              8.3. Short-term exposure
              8.4. Long-term exposure
                   8.4.1. Subchronic exposure
                   8.4.2. Chronic exposure and carcinogenicity
              8.5. Genotoxicity and related end-points
              8.6. Reproductive and developmental toxicity
              8.7. Immunological and neurological effects


         9.1. Case reports
         9.2. Epidemiological studies


              10.1. Evaluation of health effects
                   10.1.1. Hazard identification and dose-response assessment
                   10.1.2. Criteria for setting guidance values for manganese
                   10.1.3. Sample risk characterization



              12.1. Human health hazards
              12.2. Advice to physicians
              12.3. Health surveillance programme











         Concise International Chemical Assessment Documents (CICADs) are
    the latest in a family of publications from the International
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    World Health Organization (WHO), the International Labour Organisation
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    relevant scientific information concerning the potential effects of
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         Risks to human health and the environment will vary considerably
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    advice on the derivation of health-based guidance values.

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    current status of knowledge, new information is being developed
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    In the event that a reader becomes aware of new information that would
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    contact IPCS to inform it of the new information.

    1 International Programme on Chemical Safety (1994)  Assessing
     human health risks of chemicals: deriviation of guidance values for
     health-based exposure limits. Geneva, World Health Organization
    (Environmental Health Criteria 170).


         The flow chart shows the procedures followed to produce a CICAD.
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    high-quality evaluations of toxicological, exposure, and other data
    that are necessary for assessing risks to human health and/or the

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    FIGURE 1


         This CICAD on manganese and its compounds was based principally
    on the report entitled  Toxicological profile for manganese (update),
     draft for public comment, prepared by the Agency for Toxic
    Substances and Disease Registry, US Department of Health and Human
    Services (ATSDR, 1996). Information contained in the Hazardous
    Substances Data Bank, developed and maintained by the National Library
    of Medicine, US Department of Health and Human Services, was also used
    (HSDB, 1998). Data identified as of November 1998 were considered in
    these source documents. Additional data came from other references,
    such as assessments prepared by the US Environmental Protection Agency
    (EPA) and the World Health Organization (WHO), as well as a variety of
    reports in the literature. The source documents used to develop this
    CICAD do not cover the effects of manganese on the ecological
    environment. No other sources (documents developed by a national
    organization and subject to rigorous scientific review) on this topic
    were identified. Therefore, this CICAD addresses environmental levels
    as a source of human exposure only. No attempt has been made in this
    document to assess effects on organisms in the environment.
    Information on the availability of the source documents is presented
    in Appendix 1. Information on the peer review of this CICAD is
    presented in Appendix 2. This CICAD was approved as an international
    assessment at a meeting of the Final Review Board, held in Berlin,
    Germany, on 26-28 November 1997. Participants at the Final Review
    Board meeting are presented in Appendix 3. The International Chemical
    Safety Card (ICSC 0174) for manganese, produced by the International
    Programme on Chemical Safety (IPCS, 1993), has also been reproduced in
    this document.

         Manganese (Mn) is a naturally occurring element that is found in
    rock, soil, water, and food. Thus, all humans are exposed to
    manganese, and it is a normal component of the human body. Food is
    usually the most important route of exposure for humans. Estimated
    Safe and Adequate Daily Intakes of 1-5 mg manganese have been
    established for children 1 year of age and older through to adults;
    these levels generally parallel amounts of the compound delivered via
    the diet.

         Manganese is released to air mainly as particulate matter, and
    the fate and transport of the particles depend on their size and
    density and on wind speed and direction. Some manganese compounds are
    readily soluble in water, so significant exposures can also occur by
    ingestion of contaminated drinking-water. Manganese in surface water
    can oxidize or adsorb to sediment particles and settle to the bottom.
    Manganese in soil can migrate as particulate matter to air or water,
    or soluble manganese compounds can be leached from the soil.

         Above-average exposures to manganese are most likely to occur in
    people who work at or live near a factory or other site where
    significant amounts of manganese dust are released into the air. In
    some regions, the general population can be exposed to manganese

    released into air by the combustion of unleaded gasoline containing
    the organomanganese compound methylcyclopentadienyl manganese
    tricarbonyl (MMT) as an antiknock ingredient. Some people can be
    exposed to excess manganese in drinking-water -- for example, when
    manganese from batteries or pesticides leaches into well-water.
    Children can be exposed to excess manganese in soils through
    hand-to-mouth behaviour.

         In humans, manganese is an essential nutrient that plays a role
    in bone mineralization, protein and energy metabolism, metabolic
    regulation, cellular protection from damaging free radical species,
    and the formation of glycosaminoglycans. However, exposure to high
    levels via inhalation or ingestion can cause adverse health effects.
    Given comparable doses, more manganese reaches the brain following
    inhalation than following ingestion, and most health effects are
    associated with chronic inhalation exposure. Little is known about the
    relative toxicity of different manganese compounds. However, available
    evidence indicates that various manganese compounds can induce
    neurological effects; these effects have been observed following
    chronic (365 days or more) inhalation exposures in humans and
    intermediate (15-364 days) and chronic oral exposures in animals.

         In general, the available data indicate that exposure to excess
    manganese for 14 days or less (acute duration) or up to a year
    (intermediate duration) has an effect on the respiratory system and
    the nervous system, with little to no effect on other organ systems.
    Acute inhalation exposure to high concentrations of manganese dusts
    (specifically manganese dioxide [MnO2] and manganese tetroxide
    [Mn3O4]) can cause an inflammatory response in the lung, which, over
    time, can result in impaired lung function. Lung toxicity is
    manifested as an increased susceptibility to infections such as
    bronchitis and can result in manganic pneumonia. Pneumonia has also
    been observed following acute inhalation exposures to particulates
    containing other metals. Thus, this effect might be characteristic of
    inhalable particulate matter and might not depend solely on the
    manganese content of the particle.

         There are a few reports suggesting that intermediate inhalation
    exposure to manganese compounds produces effects on the central
    nervous system, but reliable estimates of exposure levels are not
    available. Inhalation studies in animals resulted in biochemical,
    respiratory, and neurobehavioural effects. However, a threshold for
    these effects has not been identified, because the exposure levels
    associated with these effects range over an order of magnitude.

         In chronic inhalation exposure to manganese, the main organ
    systems affected are the lungs, nervous system, and reproductive
    system, although effects on other organ systems have also been
    observed. A recurring manganic pneumonia and acute respiratory effects
    have been associated with chronic inhalation exposures to manganese.
    Effects on the nervous system include neurological and
    neuropsychiatric symptoms that can culminate in a Parkinsonism-like

    disease known as manganism; evidence suggests that laboratory animals,
    especially rodents, are not as sensitive as humans, and possibly other
    primates, to the neurological effects of inhalation exposure to
    manganese. Reproductive effects of chronic inhalation exposure to
    manganese include decreased libido, impotence, and decreased fertility
    in men; information is not available on reproductive effects in women.
    Studies in animals indicate that manganese can cause direct damage to
    the testes and late resorptions. Data from animal studies on the
    effects of inhaled manganese on the immunological system and the
    developing fetus are too limited to make firm conclusions on the
    significance of these effects for humans.

         Information on the carcinogenic potential of manganese is
    limited, and the results are difficult to interpret with certainty. In
    rats, chronic oral studies with manganese sulfate (MnSO4) showed a
    small increase in the incidence of pancreatic tumours in males and a
    small increase in pituitary adenomas in females. In other studies with
    manganese sulfate, no evidence for cancer was noted in rats and a
    marginally increased incidence of thyroid gland follicular cell
    adenomas was observed in mice. The results of  in vitro studies show
    that at least some chemical forms of manganese have mutagenic
    potential. However, as the results of  in vivo studies in mammals are
    inconsistent, no overall conclusion can be made about the possible
    genotoxic hazard to humans from exposure to manganese compounds.

         Large oral doses of concentrated manganese salts given by gavage
    can cause death in animals, but oral exposures via food or water have
    not been found to cause significant toxicity over acute or short-term
    exposures. Similarly, parenteral administration of manganese salts can
    cause developmental toxicity, but effects were not found with oral
    exposure. Intermediate-duration oral exposure of humans to manganese
    has been reported to cause neurotoxicity in two cases, but the data
    are too limited to define the threshold or to judge if these effects
    were due entirely to the manganese exposure. Some data on neurological
    or other health effects in humans from chronic oral intake of
    manganese exist, but these studies are limited by uncertainties in the
    exposure routes and total exposure levels as well as by the existence
    of other confounding factors. The studies in humans and animals do not
    provide sufficient information to determine dose levels or effects of
    concern following chronic oral exposure. Thus, the available evidence
    for adverse effects associated with chronic ingestion of excess
    manganese is suggestive but inconclusive.

         The dermal route does not appear to be of significant concern and
    has not been investigated to any extent. Available information is
    limited to reports on the corrosive effects of potassium permanganate
    (KMnO4) and case reports of effects from dermal absorption of organic
    manganese compounds such as MMT.

         From these data, it is clear that adverse neurological and
    respiratory effects from manganese exposure can occur in occupational
    settings. Limited evidence also suggests that adverse neurological

    effects can be associated with ingestion of excess manganese in
    environmental settings. As a result of predisposing factors, certain
    individuals might be more susceptible to adverse effects from exposure
    to excess manganese. These might include people with lung disease,
    people who are exposed to other lung irritants, neonates, older
    people, individuals with iron deficiency, or people with liver

         There are several approaches to the development of a guidance
    value for manganese in air. A recently developed guidance value of
    0.15 µg manganese/m3 is highlighted here as one possible example;
    some additional approaches are also presented.


         Table 1 lists common synonyms and other relevant information on
    the chemical identity and properties of manganese and several of its
    most important compounds. Manganese is a naturally occurring element
    that is found in rock, soil, water, and food. Manganese can exist in a
    number of oxidation states. Manganese and its compounds can exist as
    solids in the soil and as solutes or small particles in water. Most
    manganese salts are readily soluble in water, with only the phosphate
    and the carbonate having low solubilities. The manganese oxides
    (manganese dioxide and manganese tetroxide) are poorly soluble in
    water. Manganese can also be present in small dust-like particles in
    the air. Additional physical/chemical properties are presented in the
    International Chemical Safety Card (ICSC 0174) reproduced in this

        Table 1: Chemical identity of manganese and its compounds.a

                    Manganese          Manganous        Manganese          Manganese                Manganese        potassium
                                       chloride         sulfate            (II, III) oxide          dioxide          permanganate

    Synonyms        Elemental          Manganese        Manganous          Trimanganese             Manganese        Permanganic acid;
                    manganese          chlorideb;       sulfate;           tetroxide;               peroxide;        potassium saltc;
                    colloidal          manganese        sulfuric acid      mangano-manganic         manganese        chameleon material
                    manganese;         dichloride       manganese          oxidec;                  binoxide;
                    cutavalb                                               manganese                manganese
                                                                           tetroxide                black;

    Chemical        Mn                 MnCl2            MnSO4              Mn3O4                    MnO2             KMnO4

    CAS             7439-96-5          7773-01-5        7785-87-7          1317-35-7                1313-13-9        7722-64-7

    Molecular       54.94c             125.85c          151.00c            228.81d                  86.94c           158.04c

    Colour          Grey-whited        Pinkd            Pale rose-red      Blackd                   Black            Purple

    Physical        Solid              Solid            Solid              Solid                    Solid            Solid

    Melting         1244 °Cd           650 °C           700 °C             1564 °C                  535 °Cd          <240 °C
    point                                                                                                            (decomposes)

    Boiling         1962 °Cd           1190 °Cd         Decomposes         No data                  No data          No data
    point                                               at 850 °C

    Table 1 (continued)

                    Manganese          Manganous        Manganese          Manganese                Manganese        potassium
                                       chloride         sulfate            (II, III) oxide          dioxide          permanganate


    Solubility      Dissolves in       Very soluble     Soluble in         Insoluble                Soluble in       Soluble in
                    dilute mineral     in water;        water and          in water;                hydrochloric     water, acetone
                    acidsd;            soluble in       alcohol            soluble in               acid; insoluble  and sulfuric
                    decomposes         alcohol                             hydrochloric             in water         acid
                    in water                                               acid

    a Adapted from ATSDR (1996). All information obtained from Sax & Lewis (1987), except where noted.
    b HSDB (1998).
    c Windholz (1983).
    d Lide (1993).

    Table 1a

                                Methylcyclo-                          Manganese                              Mancozebb
                                pentadienyl-                          ethylene-bis-
                                manganese                             dithiocarbamate

    Synonyms                    MMTc;                                 Trimangol 80; manebd                   Dithane M-45
                                methyl-cymantrene;                    ethylene-bis[dithiocarbamic            manganese
                                Antiknock-33;                         acid], manganous salt;                 ethylenebis
                                manganese                             Dithane                                (dithiocarbamate)
                                tricarbonyl                                                                  (polymeric);
                                methylcyclopentadienyl                                                       Manzate; Manzeb;

    Chemical                    C9H7MnO3                              C4H6MnN2S4                             C4H6MnN2S4.
    formula                                                                                                  C4H6N2S4Zn

    CAS                         12108-13-3                            12427-38-2                             12427-38-2

    Molecular                   218.10                                265.31                                 541.03

    Colour                      Dark orange-rede                      Yellow-brown                           Greyish-yellow

    Physical                    Liquide                               Powder                                 Powder

    Melting                     No data                               Decomposes on                          Decomposes
    point                                                             heating                                without melting

    Boiling                     232.8 °Ce                             No data                                No data

    Table 1a (continued)
                                Methylcyclo-                          Manganese                              Mancozebb
                                pentadienyl-                          ethylene-bis-
                                manganese                             dithiocarbamate

    Solubility                  Practically insoluble                 Slightly soluble                       Practically
                                in water (70 ppm at                   in water; soluble in                   insoluble in water
                                25 °C); completely                    chloroform                             as well as most organic
                                soluble in hydrocarbons                                                      solvents

    CAS = Chemical Abstracts Service

    a NTP (1999).
    b Hamilton (1995).
    c Zayed et al. (1994).
    d Ferraz et al. (1988).
    e Verschueren (1983).


         Atomic absorption spectrophotometric analysis is the most widely
    used method for determining manganese in biological materials and
    environmental samples. Fluorimetric, colorimetric, neutron activation
    analysis, and plasma atomic emission techniques are also recommended
    for measuring manganese in such samples. Most of these methods require
    wet digestion, derivatization, and/or extraction before detection. In
    most cases, distinguishing between different oxidation states of
    manganese is impossible, so total manganese is measured.

         The detection limits of these methods range from <0.01 to 0.2
    µg/g for biological tissues and fluids, from 5 to 10 µg/m3 for air,
    and from 0.01 to 50 µg/litre for water (Kucera et al., 1986; Abbasi,
    1988; Lavi et al., 1989; Mori et al., 1989; Chin et al., 1992; ATSDR,
    1996). Determination of manganese levels in soil, sludge, or other
    solid wastes requires an acid extraction/digestion step before
    analysis. The details vary with the specific characteristics of the
    sample, but treatment usually involves heating in nitric acid,
    oxidation with hydrogen peroxide, and filtration and/or centrifugation
    to remove insoluble matter (ATSDR, 1996).

         A nuclear magnetic resonance method (Kellar & Foster, 1991) and a
    method using on-line concentration analysis (Resing & Mottl, 1992)
    were used to determine both free and complexed manganese ions in
    aqueous media. The latter method was highly sensitive, with a
    detection limit of 36 pmol/litre (1.98 ng/litre when concentrating 15
    ml of seawater).


         Manganese is ubiquitous in the environment. It comprises about
    0.1% of the earth's crust (NAS, 1973; Graedel, 1978). Because
    manganese occurs in soil, air, water, and food, all humans are exposed
    to it. Manganese is a normal component of the human body, and food is
    usually the most important route of exposure for humans. Manganese
    does not occur naturally as a base metal but is a component of more
    than 100 minerals, including various sulfides, oxides, carbonates,
    silicates, phosphates, and borates (NAS, 1973). The most commonly
    occurring manganese-bearing minerals include pyrolusite (manganese
    dioxide), rhodocrosite (manganese carbonate), and rhodonite (manganese
    silicate) (NAS, 1973; Windholz, 1983; US EPA, 1984; HSDB, 1998).

         The manganese content in ore produced worldwide was estimated to
    be 8.8 million tonnes in 1986. Production levels of manganese ore and
    its total manganese metal content remained nearly the same through
    1990 (US Department of the Interior, 1993). Levels of ore produced
    worldwide in 1995, 1996, and 1997 declined slightly, with total
    manganese metal content declining proportionately to 8.0, 8.1, and 7.7
    million tonnes, respectively (US Department of the Interior, 1996,
    1998). Although modern steelmaking technologies call for lower unit
    consumption of manganese, worldwide demand for steel is projected to
    increase moderately in the future, particularly in developing
    countries (US Department of the Interior, 1995, 1998). Although
    manganese usage in other industries is increasing, this will have
    minor overall effect on manganese demand, and future trends for
    manganese are still expected to increase with demands for steel (EM,
    1993; US Department of the Interior, 1995, 1998). The demand for
    manganese in other industries (e.g., dry-cell battery manufacturing)
    might also increase, but the overall effect of these other uses on
    global trends in manganese production and use is minor (US Department
    of the Interior, 1995, 1998).

         Manganese compounds are produced from manganese ores or from
    manganese metal. The organomanganese compound MMT, an antiknock
    additive in unleaded gasoline, is produced by the reaction of
    manganese chloride (MnCl2), cyclopentadiene, and carbon monoxide in
    the presence of manganese carbonyl (NAS, 1973; US EPA, 1984; Sax &
    Lewis, 1987; HSDB, 1998). Metallic manganese (ferromanganese) is used
    principally in steel production along with cast iron and superalloys
    to improve hardness, stiffness, and strength (NAS, 1973; US EPA, 1984;
    HSDB, 1998). Manganese compounds have a variety of uses. Manganese
    dioxide is commonly used in the production of dry-cell batteries,
    matches, fireworks, porcelain and glass-bonding materials, and
    amethyst glass; it is also used as the starting material for the
    production of other manganese compounds (NAS, 1973; Venugopal &
    Luckey, 1978; US EPA, 1984). Manganese chloride is used as a precursor
    for other manganese compounds, as a catalyst in the chlorination of
    organic compounds, in animal feed to supply essential trace minerals,
    and in dry-cell batteries (US EPA, 1984; HSDB, 1998). Manganese

    sulfate is used primarily as a fertilizer and as a livestock
    supplement; it is also used in some glazes, varnishes, ceramics, and
    fungicides (Windholz, 1983; US EPA, 1984; HSDB, 1998). Manganese
    ethylene-bis-dithiocarbamate (maneb) is widely applied to edible crops
    as a fungicide and is therefore a potential source of manganese in
    soil and in food crops (Ferraz et al., 1988; Ruijten et al., 1994).
    Potassium permanganate is used as an oxidizing agent; as a
    disinfectant; as an antialgal agent; for metal cleaning, tanning, and
    bleaching; as a purifier in water and waste treatment plants; and as a
    preservative for fresh flowers and fruits (HSDB, 1998).

         The main sources of manganese releases to the air are industrial
    emissions, combustion of fossil fuels, and re-entrainment of
    manganese-containing soils (Lioy, 1983; US EPA, 1983, 1984, 1985a,
    1985b). Manganese can also be released to the air during other
    anthropogenic processes, such as welding and fungicide application
    (Ferraz et al., 1988; MAK, 1994; Ruijten et al., 1994). Total
    emissions to air from anthropogenic sources in the USA were estimated
    to be 16 400 t in 1978, with about 80% (13 200 t) from industrial
    facilities and 20% (3200 t) from fossil fuel combustion (US EPA,
    1983). Air emissions by US industrial sources reported for 1987
    totalled 1200 t (TRI87, 1989). In 1991, air emissions from facilities
    in the USA ranged from 0 to 74 t, with several US states reporting no
    emissions (TRI91, 1993). Air erosion of dusts and soils is also an
    important atmospheric source of manganese, but no quantitative
    estimates of manganese release to air from this source were identified
    (US EPA, 1984). Volcanic eruptions can also release manganese to the
    atmosphere (Schroeder et al., 1987).

         In some countries, combustion of gasoline containing MMT
    contributes approximately 8% to levels of manganese tetroxide in urban
    air (Loranger & Zayed, 1995). MMT was used as a gasoline additive in
    the USA for a number of years, resulting in manganese emissions.
    Analysis of manganese levels in the air indicated that vehicular
    emissions contributed an average of 13 ng manganese/m3 in southern
    California, whereas vehicular emissions were only about 3 ng/m3 in
    central and northern California (Davis et al., 1988). A ban on MMT use
    as a fuel additive was imposed for a period of time, then lifted by
    the US EPA in 1995.

         In Canada, MMT use as a fuel additive has gradually increased
    since 1976. Manganese emissions from gasoline combustion rose sharply
    from 1976 through the early 1980s, reaching an estimated 200.2 t by
    1985 (Jacques, 1984). In 1990, lead was completely replaced by MMT in
    gasoline in Canada (Loranger & Zayed, 1994). MMT use peaked in 1989 at
    over 400 t, which was more than twice the usage in 1983 and 1.5 times
    the usage in 1986. MMT use declined to about 300 t by 1992, owing to
    reductions in its concentration in gasoline. However, ambient
    monitoring data for manganese in Canadian cities without industrial
    sources for the 1989-1992 period did not reflect this peak in MMT use.
    Air manganese levels (PM2.5, or particulate matter with an aerodynamic
    diameter less than or equal to 2.5 µm) remained constant at 0.11-0.013

    µg/m3 for small cities and 0.020-0.025 µg/m3 for large cities
    (Health Canada, 1994; Egyed & Wood, 1996). Manganese emission levels
    can vary depending on the concentration of MMT in gasoline and
    gasoline usage patterns. One study reported a correlation between
    atmospheric manganese concentrations in 1990 air samples and traffic
    density in Montreal (Loranger et al., 1994). However, a later study by
    these investigators reported that atmospheric manganese concentrations
    in Montreal decreased in 1991 and 1992 despite an estimated 100%
    increase in manganese emission rates from MMT in gasoline (Loranger &
    Zayed, 1994). Another study suggested that the high manganese levels
    in Montreal were, in part, due to the presence of a silico- and
    ferro-manganese facility that ceased operation in 1991 (Egyed & Wood,

         Manganese can be released to water by discharge from industrial
    facilities or as leachate from landfills and soil (US EPA, 1979, 1984;
    Francis & White, 1987; TRI91, 1993). In the USA, reported industrial
    discharges in 1991 ranged from 0 to 17.2 t for surface water, from 0
    to 57.3 t for transfers to public sewage, and from 0 to 0.114 t for
    underground injection (TRI91, 1993). An estimated total of 58.6 t, or
    1% of the total environmental release of manganese in the USA, was
    discharged to water in 1991 (TRI91, 1993).

         Land disposal of manganese-containing wastes is the principal
    source of manganese releases to soil. In 1991, reported industrial
    releases to land in the USA ranged from 0 to 1000 t. More than 50% of
    the total environmental release of manganese (3753 t) was to land
    (TRI91, 1993).


         Elemental manganese and inorganic manganese compounds have
    negligible vapour pressures but can exist in air as suspended
    particulate matter derived from industrial emissions or the erosion of
    soils. Manganese-containing particles are removed from the atmosphere
    mainly by gravitational settling or by rain (US EPA, 1984).

         Soil particulate matter containing manganese can be transported
    in air. The fate and transport of manganese in air are largely
    determined by the size and density of the particle and wind speed and
    direction. An estimated 80% of the manganese in suspended particulate
    matter is associated with particles with a Mass Median Equivalent
    Diameter (MMED) of <5 µm, and 50% of this manganese is estimated to
    be associated with particles that are <2 µm in MMED. (Whether these
    data are for particles in urban or rural areas is unclear. However, it
    is known that the size of manganese particles in the air tends to vary
    by source; small particles dominate around ferromanganese and dry-cell
    battery plants, whereas large particles tend to predominate near
    mining operations [WHO, 1999].) Based on these data, manganese's small
    particle size is within the respirable range, and widespread airborne
    distribution would be expected (WHO, 1981). Very little information is
    available on atmospheric reactions of manganese (US EPA, 1984).
    Although manganese can react with sulfur dioxide and nitrogen dioxide,
    the occurrence of such reactions in the atmosphere has not been

         The transport and partitioning of manganese in water are
    controlled by the solubility of the specific manganese compound
    present. In most waters (pH 4-7), Mn(II) predominates and is
    associated principally with carbonate, which has relatively low
    solubility (US EPA, 1984; Schaanning et al., 1988). The solubility of
    Mn(II) can be controlled by manganese oxide equilibria (Ponnamperuma
    et al., 1969), with manganese being converted to other oxidation
    states (Rai et al., 1986). In extremely reduced water, the fate of
    manganese tends to be controlled by the formation of the poorly
    soluble sulfide (US EPA, 1984). In groundwater with low oxygen levels,
    Mn(IV) can be reduced both chemically and bacterially to the Mn(II)
    oxidation state (Jaudon et al., 1989). MMT has been found to be
    persistent in natural aquatic and soil environments in the absence of
    sunlight, with a tendency to sorb to soil and sediment particles
    (Garrison et al., 1995). In the presence of light, photodegradation of
    MMT is rapid, with identified products including a manganese carbonyl
    that readily oxidizes to manganese tetroxide (Garrison et al., 1995).

         Manganese is often transported in rivers adsorbed to suspended
    sediments. Most of the manganese from industrial sources found in a
    South American river was bound to suspended particles (Malm et al.,
    1988). The tendency of soluble manganese compounds to adsorb to soils
    and sediments can be highly variable, depending mainly on the cation

    exchange capacity and the organic composition of the soil (Hemstock &
    Low, 1953; Schnitzer, 1969; McBride, 1979; Curtin et al., 1980; Baes &
    Sharp, 1983; Kabata-Pendias & Pendias, 1984). The oxidation state of
    manganese in soils and sediments can be altered by microbial activity
    (Geering et al., 1969; Francis, 1985). 

         Manganese in water can be significantly bioconcentrated at lower
    trophic levels. Bioconcentration factors (BCFs) of 10 000-20 000 for
    marine and freshwater plants, 2500-6300 for phytoplankton, 300-5500
    for marine algae, 800-830 for intertidal mussels, and 35-930 for fish
    have been estimated (Folsom et al., 1963; Thompson et al., 1972). The
    high reported BCFs probably reflect the essentiality of manganese for
    a wide variety of organisms; specific uptake mechanisms exist for
    essential elements.


    6.1  Environmental levels

         Concentrations of manganese in seawater reportedly range from 0.4
    to 10 µg/litre (US EPA, 1984). In the North Sea, the northeast
    Atlantic Ocean, the English Channel, and the Indian Ocean, manganese
    content was reported to range from 0.03 to 4.0 µg/litre. Levels found
    in coastal waters of the Irish Sea and in the North Sea off the coast
    of the United Kingdom ranged from 0.2 to 25.5 µg/litre (Alessio &
    Lucchini, 1996). In a number of cases, higher levels in water (in
    excess of 1000 µg/litre) have been detected at US hazardous waste
    sites, suggesting that, in some instances, wastes from industrial
    sources can lead to significant contamination of water (ATSDR, 1996).

         In a 1974-1981 survey of 286 US river water samples,
    concentrations of dissolved manganese ranged from less than 11
    µg/litre (25th percentile) to more than 51 µg/litre (75th percentile)
    (Smith et al., 1987), with a median of 24 µg/litre. Mean groundwater
    concentrations were 20 and 90 µg/litre from two geological zones in
    California (Deverel & Millard, 1988). The surface waters of Welsh
    rivers were reported to contain from 0.8 to 28 µg manganese/litre.
    Concentrations of manganese ranged from 1 to 530 µg/litre in 37 rivers
    in the United Kingdom and in the Rhine and the Maas and their
    tributaries (Alessio & Lucchini, 1996).

         Concentrations of manganese in surface water are usually reported
    as dissolved manganese. Total manganese might be a better indicator,
    because manganese adsorbed to suspended solids can exceed dissolved
    manganese in many systems, and the bioavailability of manganese in
    this form has not been established (NAS, 1977; US EPA, 1984).

         Natural ("background") levels of manganese in soil range from 40
    to 900 mg/kg, with an estimated mean of 330 mg/kg (Cooper, 1984; US
    EPA, 1985a; Schroeder et al., 1987; Eckel & Langley, 1988; Rope et
    al., 1988). Accumulation of manganese in soil usually occurs in the
    subsoil and not on the soil surface (WHO, 1981).

         According to a National Research Council of Canada report (Stokes
    et al., 1988), manganese concentrations in air tend to be lowest in
    remote locations (about 0.5-14 ng/m3 on average), higher in rural
    areas (40 ng/m3 on average), and still higher in urban areas (about
    65-166 ng/m3 on average) (see Table 2). Similar concentrations have
    been reported elsewhere, leading to the conclusion that annual
    manganese concentrations average 10-30 ng/m3 in areas far from known
    sources and 10-70 ng/m3 in urban and rural areas without major point
    sources of manganese (WHO, 1999). Manganese concentrations in air tend
    to be highest in source-dominated areas (e.g., those with foundries),
    where values can reach 8000 ng/m3 (US EPA, 1984; Stokes et al.,
    1988). Annual averages of manganese concentrations in air near
    foundries may rise to 200-300 ng/m3 and to over 500 ng/m3 in air
    near ferro- and silicomanganese industries (WHO, 1999).

        Table 2: Average levels of manganese in air.
    a) Atmospheric air (worldwide)a:

    Type of location                   Average
                                       concentration (ng/m3)              Range(ng/m3)
      Continental                      3.4                                <0.18-9.30
      Oceanic                          14.2                                0.02-79
      Polar                            0.5                                 0.01-1.5

    Rural                              40                                   6.5-199

      Canada                           65                                  20.0-270
      USA                              93                                   5.0-390
      Europe                           166                                 23.0-850
      Other                            149                                 10.0-590

    b) US ambient airb:

    Type of
    location                                       Concentration (ng/m3)
                               1953-1957               1965-1967               1982
    Nonurban                   60                      12                      5
    Urban                      110                     73                      33
    Source dominated           No data                 250-8300                130-140
    a Adapted from Stokes et al. (1988).
    b Adapted from US EPA (1984).

         Manganese concentrations in air have been measured in many
    specific locations. In the Vancouver, Canada, area, for example,
    annual geometric mean concentrations of manganese ranged from <10 to
    30 ng/m3 in 1984 (Stokes et al., 1988). Over the period of 1981-1992,
    Loranger & Zayed (1994) found average manganese concentrations in
    Montreal, Canada, of 20 and 60 ng/m3 in areas of low and high traffic
    density, respectively. More recently, Loranger & Zayed (1997) found
    the average concentration of total manganese in an urban site in
    Montreal to be 27 ng/m3. In selected periods in the 1970s, annual
    mean concentrations of manganese were reported to range from 3 to 16
    ng/m3 in two German cities, from 42 to 455 ng/m3 in Belgium, and
    from 20 to 800 ng/m3 in Japanese cities (WHO, 1999).

         As Table 2 shows, manganese concentrations in air in the USA have
    decreased over the past three decades (Kleinman et al., 1980; US EPA,
    1984), a trend believed to be due primarily to the installation of
    industrial emission controls (US EPA, 1984, 1985b). In Ontario,
    Canada, as well, annual average manganese concentrations in air have
    decreased along with total suspended particulate levels (Stokes et
    al., 1988).

    6.2  Human exposure

         The most significant source of manganese exposure for the general
    population is food (Table 3). A summary of mean manganese
    concentrations in 234 foods analysed by the US Food and Drug
    Administration is presented in Table 4. Although wide ranges of
    manganese concentrations in foods have been reported, the highest
    manganese concentrations are found in nuts (up to 47 µg/g) and grains
    (up to 41 µg/g). Lower levels are found in milk products (0.02-0.49),
    meat, poultry, fish, and eggs (0.10-3.99 µg/g), and fruits (0.20-10.38
    µg/g). Tea and leafy green vegetables have also been found to be
    dietary sources of manganese (Davis et al., 1992). The US
    concentrations given in Table 4 are generally similar to
    concentrations reported from other countries. For example, during a
    1992 survey conducted by Canada's Department of Fisheries and Oceans,
    manganese was detected in muscle samples from bluefin tuna ( Thunnus
     thynnus) (Hellou et al., 1992); concentrations in 14 samples ranged
    from 0.16 to 0.31 µg/g dry weight, with a mean of 0.22 µg/g.

         Although manganese is considered an essential element, a
    Recommended Daily Allowance (RDA) has not been established in the USA
    because of insufficient data (NRC, 1989). However, the Food and
    Nutrition Board of the US National Research Council establishes
    Estimated Safe and Adequate Daily Dietary Intake (ESADDI) levels when
    data are insufficient to establish an RDA. These levels generally
    parallel amounts of the compound usually delivered via the diet,
    although some individuals consume greater or smaller amounts. The
    ESADDI levels for manganese are 0.3-0.6 mg/day for infants up to 6
    months old, 0.6-1.0 mg/day for infants 6 months to 1 year old, 1.0-1.5
    mg/day for children 1-3 years old, 1.0-2.0 mg/day for children 4-10
    years old, and 2.0-5.0 mg/day for people over 10 years old (NRC,

         Table 3 presents an example of manganese intake from foodstuffs
    based on estimated dietary patterns in the USA. Manganese intake among
    individuals varies greatly, however, depending upon dietary habits.
    For example, an average cup of tea contains 0.4-1.3 mg manganese, so
    individuals consuming three cups of tea per day can receive negligible
    amounts of manganese or up to 4 mg daily from this source alone
    (Schroeder et al., 1966; Pennington et al., 1986). Thus, some persons
    consume more or less than the estimated daily intakes noted above
    (NAS, 1980; Pennington et al., 1986; Davis et al., 1992). Indeed,
    estimates of daily intake for adults in the USA range from 2.0 to
    8.8 mg (NAS, 1977; Patterson et al., 1984; US EPA, 1984; WHO, 1984;
    Pennington et al., 1986).

         Although gastrointestinal absorption of manganese is only 3-5%
    (Mena et al., 1969; Davidsson et al., 1988) (see section 7), food is
    not only the largest source of manganese exposure in the general
    population, but also the primary source of absorbed manganese
    (Table 3). The bioavailability of manganese from vegetable sources is
    substantially decreased by dietary components such as fibre and
    phytates (US EPA, 1993). Individuals with iron deficiency exhibit
    increased rates of manganese absorption (Mena et al., 1969, 1974).

         In 1962, the public drinking-water supplies in 100 large cities
    in the USA were surveyed, and 97% contained less than 100 µg
    manganese/litre (Durfor & Becker, 1964). A 1969 survey of 969 systems
    reported that 91% contained less than 50 µg/litre, with a mean
    concentration of 22 µg/litre (ATSDR, 1996). In the Federal Republic of
    Germany, mean concentrations of manganese in drinking-water were
    reported to range from 1 to 63 µg/litre (Alessio & Lucchini, 1996).

         Certain groups are more highly exposed to manganese than the
    general population. Infants given prepared infant foods and formulas,
    for example, may be more highly exposed to manganese than adults in
    the general population. Collipp et al. (1983) reported that
    concentrations of manganese in infant formulas range from 34 to
    1000 µg/litre, compared with concentrations of 10 µg/litre in human
    milk and 30 µg/litre in cow's milk; Lavi et al. (1989) found an even
    lower concentration of manganese in market milk (16 + 2 µg/litre),
    suggesting that the difference between formula and milk could be even
    greater in some regions. Because of the high manganese levels in
    prepared infant foods and formulas, some infants might ingest more
    than the ESADDI for their age group (Pennington et al., 1986; NRC,

         In addition, people living in the vicinity of ferromanganese or
    iron and steel manufacturing facilities, coal-fired power plants, or
    hazardous waste sites can be exposed to elevated manganese particulate
    matter in air, although this exposure is likely to be much lower than
    in the workplace. Loranger & Zayed (1997) estimated average exposure
    doses of respirable manganese and total manganese in an urban site
    (botanical gardens) in Montreal, Canada, to be 0.005 and 0.008 µg/kg

        Table 3: Summary of typical human exposure to manganese.a

    Parameter                                     Exposure medium
                                  Water                   Air               Food

    Typical concentration         4 µg/litre              0.023 µg/m3       1.28 µg/calorie
    in medium

    Assumed daily                 2 litres                20 m3             3000 calories
    intake of medium
    by 70-kg adult

    Estimated average             8 µg                    0.46 µgb          3800 µg
    daily intake by
    70-kg adult

    Assumed                       0.03c                   1c                0.03d
    absorption fraction

    Approximate                   0.24 µg                 0.46 µg           114 µg
    absorbed dose
    a Adapted from US EPA (1984).
    b Assumes 100% deposition in the lungs.
    c No data; assumed value.
    d Davidsson et al. (1988).

    Table 4: Manganese concentrations in selected foods.a

    Type of food                      Range of mean concentrations
                                           (ppm; µg/g or mg/litre)

    Nuts and nut products                              18.21-46.83
    Grains and grain products                           0.42-40.70
    Legumes                                              2.24-6.73
    Fruits                                              0.20-10.38
    Fruit juices and drinks                             0.05-11.47
    Vegetables and vegetable products                    0.42-6.64
    Desserts                                             0.04-7.98
    Infant foods                                         0.17-4.83
    Meat, poultry, fish, and eggs                        0.10-3.99
    Mixed dishes                                         0.69-2.98
    Condiments, fats, and sweeteners                     0.04-1.45
    Beverages (including tea)                            0.00-2.09
    Soups                                                0.19-0.65
    Milk and milk products                               0.02-0.49

    a Adapted from Pennington et al. (1986).

    body weight per day (0.35 and 0.56 µg/day for a 70-kg person),
    respectively. Similarly, the daily intake of manganese in the air by
    the general US population was estimated to be less than 2 µg (WHO,
    1981). According to a study by Pellizari et al. (1992) and subsequent
    analyses by the US EPA (1994a, 1994b), measurements of personal
    exposure levels in an urban area in the USA (Riverside, California) in
    1990 indicated that about half the population had 24-h personal
    exposures to PM10 (particulate matter with an aerodynamic diameter
    less than or equal to 10 µm) manganese above 0.035 µg/m3 (0.7 µg/day,
    assuming a ventilation rate of 20 m3/day), while the highest 1% of
    the population had exposures above 0.223 µg/m3 (4.46 µg/day). By
    contrast, intakes in areas of the USA with ferro- or silicomanganese
    industries were as high as 10 µg/day, with 24-h peak values exceeding
    100 µg/day (WHO, 1981).

         People living in regions of natural manganese ore deposits or
    where manganese-containing materials (e.g., pesticides, batteries) are
    used or disposed of can also be exposed to elevated levels of
    manganese in soil or water. For example, Kawamura et al. (1941)
    reported on six Japanese families exposed to high levels (at least
    14 mg/litre) of manganese in their drinking-water; the contamination
    was believed to result from manganese that leached from batteries
    buried near the well. Children are especially likely to receive
    elevated doses from manganese-containing soils because they have a
    higher intake of soil (mainly through hand-to-mouth contact) than
    adults (Calabrese et al., 1989). Organomanganese compounds such as MMT
    can be absorbed through the skin (Tanaka, 1994).

         In the workplace, exposure to manganese is most likely to occur
    by inhalation of manganese fumes or manganese-containing dusts. These
    dusts can contain various manganese oxides as well as manganese in the
    oxides of other elements, such as potassium permanganate, manganese
    ferric oxide (MnFe2O4), and manganese silicate (MnSiO3) (Pflaumbaum
    et al., 1990). Exposure is a concern mainly in the ferromanganese,
    iron and steel, dry-cell battery, and welding industries (WHO, 1986).
    Exposure can also occur during manganese mining and ore processing,
    and dermal exposure and inhalation can occur during the application of
    manganese-containing fungicides.

         Manganese air concentrations of 1.5-450 mg/m3 have been reported
    in US manganese mines (US EPA, 1984), 0.30-20 mg/m3 in ferroalloy
    production facilities (Saric et al., 1977), 0.02-5 mg/m3 in German
    foundries (Coenen et al., 1989), 1-4 mg/m3 during welding with
    electrodes (Sjögren et al., 1990), up to 14 mg/m3 during welding with
    welding wire (Pflaumbaum et al., 1990), and 3-18 mg/m3 in a dry-cell
    battery facility (Emara et al., 1971). Many of the more recent studies
    on occupational exposures to manganese have recorded average exposure
    levels of 1 mg manganese/m3 or less in the workplace (Roels et al.,
    1987, 1992; Mergler et al., 1994; Lucchini et al., 1995). Thus, for
    workers in industries using manganese, the major route of exposure
    might be inhalation from workplace air rather than ingestion of food.


         Manganese absorption occurs primarily from the gastrointestinal
    tract after ingestion and from the alveolar lining after inhalation of
    manganese-containing dust or fumes. Several studies in animals
    indicate that key determinants of absorption are the absorption
    pathway and the specific compound in which manganese is present (Smith
    et al., 1995; Roels et al., 1997). Roels et al. (1997) studied
    manganese levels in the blood and brain tissue of rats exposed to
    repeated doses of manganese chloride or manganese dioxide administered
    by oral gavage, intraperitoneal injection, or intratracheal
    instillation. Manganese chloride was readily absorbed after
    administration by each of these routes and distributed in brain tissue
    to varying degrees. Manganese dioxide, on the other hand, was
    significantly absorbed and distributed in the brain to varying degrees
    when administered by intraperitoneal injection and intratracheal
    instillation, but not when administered orally. Higher levels of
    manganese in tissue were found after administering manganese chloride
    by intratracheal instillation compared with manganese dioxide. The
    authors concluded that the route of exposure might be a critical
    determinant of how absorbed manganese is distributed in the brain. In
    addition, when manganese dioxide was administered by either
    intratracheal instillation or oral gavage, manganese levels in the
    blood rose and fell more slowly than when manganese chloride was
    given, indicating a marked difference in the absorption kinetics of
    these two manganese compounds. The finding that the body handles
    manganese dioxide more slowly than manganese chloride suggests that
    manganese dioxide might remain in the body longer, contributing longer
    to body burden, albeit at much lower levels. Whether this is true and
    whether this indicates greater toxicological risk in cases of
    prolonged low-level exposure to manganese dioxide are unclear.

         A second study also found that route of exposure affects
    absorption of manganese. Tjälve et al. (1996) found that intranasal
    instillation of manganese (Mn2+) in rats resulted in initial uptake
    of manganese in the olfactory bulbs of the brain, whereas
    intraperitoneal administration resulted in low uptake in the olfactory
    bulbs. The authors suggested that olfactory neurons might serve as a
    pathway for manganese uptake and distribution to the brain (bypassing
    the blood-brain barrier) during intranasal exposure.

         Another key determinant of absorption appears to be dietary iron
    intake, with low iron levels leading to increased manganese absorption
    (Mena et al., 1969). In addition, several studies in animals indicate
    that gastrointestinal absorption of manganese might vary with age
    (Rehnberg et al., 1980, 1981).

         The amount of manganese absorbed across the gastrointestinal
    tract in humans varies, but typically averages about 3-5% (Mena
    et al., 1969; Davidsson et al., 1988). Particles that are deposited in
    the lower airways are probably absorbed, whereas particles deposited

    in the upper airways are generally swallowed via mucociliary
    clearance; thus, they can be absorbed from the gastrointestinal tract
    as well.

         Regardless of manganese intake, adult humans generally maintain
    stable tissue levels of manganese through a homeostatic mechanism
    regulating the excretion of excess manganese (US EPA, 1984). The major
    route of manganese excretion is via the bile, although some excretion
    occurs in urine, milk, and sweat (US EPA, 1993).

         Limited data suggest that manganese can undergo changes in
    oxidation state within the body. Support for this hypothesis comes
    from the observation that the oxidation state of the manganese ion in
    several enzymes appears to be Mn(III) (Utter, 1976; Leach & Lilburn,
    1978), whereas most manganese intake from the environment is as Mn(II)
    or Mn(IV). The rate and extent of manganese reduction/oxidation
    reactions might be important determinants of manganese retention in
    the body.


    8.1  Single exposure

         Lung inflammation has been reported following single inhalation
    exposures to 2.8-43 mg/m3 for manganese dioxide or manganese
    tetroxide particulates in rodent species (Bergstrom, 1977; Adkins et
    al., 1980; Shiotsuka, 1984). It is important to note that an
    inflammatory response of this type is not unique to
    manganese-containing particles, but is characteristic of nearly all
    inhalable particulate matter (US EPA, 1985b). Thus, it might not be
    manganese alone that causes the inflammatory response from single
    exposures, but possibly the particulate matter itself.

         Following single oral exposures, LD50s ranged from 275 to 804
    mg/kg body weight per day for manganese chloride in different rat
    strains (Holbrook et al., 1975; Kostial et al., 1989; Singh &
    Junnarkar, 1991). Reported LD50s from single exposures to manganese
    sulfate and manganese acetate in rats were 782 and 1082 mg/kg body
    weight per day, respectively (Smyth et al., 1969; Singh & Junnarkar,

    8.2  Irritation and sensitization

         Little information is available on the irritant and contact
    sensitivity properties of manganese compounds. Manganese salts failed
    to induce lymph node cell proliferation in the murine local lymph node
    assay, a predictive test for the detection of contact allergens
    (Ikarashi et al., 1992). The manganese-containing fungicide maneb has
    been reported to be a sensitizer in animal tests, but little
    information exists on whether this effect occurs in humans (Thomas et
    al., 1990). Contact sensitization in humans has been reported in one
    study (see section 9.2).

    8.3  Short-term exposure

         Results from studies of short-term exposures in experimental
    animals indicate that the lungs and nervous system are the major
    target organs following the inhalation of manganese compounds. For
    example, Maigetter et al. (1976) found increased susceptibility to
    pneumonia in mice exposed via inhalation to 69 mg manganese/m3 as
    manganese dioxide for 3 h/day for 1-4 days. Effects on the nervous
    system associated with short-term exposure to manganese compounds are
    presented in section 8.7.

    8.4  Long-term exposure

    8.4.1  Subchronic exposure

         Results from studies of subchronic exposures in experimental
    animals also indicate that the lungs and nervous system are the major
    target organs following the inhalation of manganese compounds. Signs
    of lung inflammation have been reported in rhesus monkeys exposed via

    inhalation to 0.7 mg manganese/m3 as manganese dioxide for 22 h/day
    over 10 months (Suzuki et al., 1978). Effects on the nervous system
    associated with subchronic exposure to manganese compounds are
    presented in section 8.7.

         Systemic effects reported following subchronic oral exposures to
    manganese compounds include changes in blood cell counts (leukocytes,
    erythrocytes, neutrophils), reduced liver weight, and decreased body
    weight (Gray & Laskey, 1980; Komura & Sakamoto, 1991; NTP, 1993). In
    mice fed 284 mg manganese/kg body weight per day for 100 days, for
    example, red blood cell count was decreased by manganese acetate and
    manganese chloride; white blood cell count was decreased by manganese
    acetate, manganese chloride, and manganese dioxide; and haematocrit
    was decreased by manganese carbonate (MnCO3) (Komura & Sakamoto,

    8.4.2  Chronic exposure and carcinogenicity

         Available data from animal studies involving oral exposure to
    manganese as well as from epidemiological studies involving inhalation
    exposure to manganese suggest that similar chronic toxicities (i.e.,
    neurological effects) occur regardless of the valence state of the
    inorganic manganese compounds (e.g., manganese dioxide, manganese
    tetroxide). In experimental animals, the nervous system is the major
    organ affected following long-term oral and inhalation exposure to
    manganese. These data are described in more detail in section 8.7. Few
    chronic inhalation exposure studies in animals are available, and
    these studies reported effects in the nervous system. Significant
    effects in other organ systems following long-term exposure to
    manganese have not been reported. Available data from animal studies
    suggest that it is unlikely that other significant effects result from
    long-term oral exposure to manganese (NTP, 1993).

         Information on the carcinogenic potential of manganese is
    limited, and the results are difficult to interpret with certainty.
    For example, male rats exposed to up to 331 mg manganese/kg body
    weight per day (as manganese sulfate) for 2 years had an increased
    incidence of pancreatic cell adenomas (3/50, 4/51, and 2/51 in the
    low, mid, and high dose groups); this type of tumour was noted in only
    one female in the mid dose group. The investigators indicated that
    these lesions, although low in incidence, were "a concern" and
    attributed to manganese treatment because pancreatic cell hyperplasia
    was observed in all treatment groups, although neither hyperplasia nor
    adenomas were observed in controls of either sex (Hejtmancik et al.,
    1987a). On the other hand, a small increase in the incidence of
    pituitary adenomas was noted in female mice at 905 mg manganese/kg
    body weight per day (as manganese sulfate), but not in males at 722 mg
    manganese/kg body weight per day. The incidence was considered
    equivocal because lesions had been observed in previous studies as
    well as in historical controls (Hejtmancik et al., 1987b). In a 2-year
    study, no evidence of cancer was noted in male and female F344 rats
    given 20-200 and 23-232 mg manganese sulfate/kg body weight per day,

    respectively, via feed (NTP, 1993). A marginally increased incidence
    of thyroid gland follicular cell adenomas was observed in male and
    female B6C3F1 mice given 52-585 and 65-731 mg manganese sulfate/kg
    body weight per day, respectively, in the feed for 2 years (NTP,
    1993). Intraperitoneal injection of mice with manganese sulfate
    (20 weeks) led to an increased incidence of lung tumours (Stoner
    et al., 1976), but intramuscular injection of rats and mice with
    manganese or manganese dioxide did not result in tumours (Furst,
    1978). Firm conclusions on the carcinogenic potential of manganese
    cannot be made based on the equivocal carcinogenicity data reported
    for rodents and the paucity of evidence from other species.

    8.5  Genotoxicity and related end-points

         Manganese sulfate was not mutagenic to  Salmonella typhimurium
    strains TA97, TA98, TA100, TA1535, or TA1537 in either the presence or
    absence of S9 from Aroclor 1254-induced liver from rats or Syrian
    hamsters in studies performed at two different laboratories
    (Mortelmans et al., 1986), but it was reported elsewhere to be
    genotoxic to strain TA97 (Pagano & Zeiger, 1992). Manganese chloride
    was not mutagenic in  S. typhimurium strains TA98, TA100, and TA1535,
    but it was mutagenic in TA1537, and conflicting results were obtained
    for TA102 (Wong, 1988; De Méo et al., 1991). A fungal gene conversion/
    reverse mutation assay in  Saccharomyces cerevisiae strain D7
    indicated that manganese sulfate was mutagenic (Singh, 1984).

         Manganese chloride produced gene mutations  in vitro in a mouse
    lymphoma assay (Oberly et al., 1982). It also caused DNA damage in
    human lymphocytes when tested  in vitro using the single-cell gel
    assay technique in the absence of metabolic activation, but it caused
    no DNA damage when S9 was present (De Méo et al., 1991). The results
    of an  in vitro assay using Chinese hamster ovary (CHO) cells showed
    that manganese sulfate induced sister chromatid exchange in both the
    presence and absence of S9 from Aroclor 1254-induced rat liver
    (Galloway et al., 1987). In a separate assay, manganese sulfate also
    induced chromosomal aberrations in CHO cells in the absence of S9 but
    not in its presence (Galloway et al., 1987). In contrast, manganese
    chloride was not clastogenic when tested  in vitro in the absence of
    metabolic activation using FM3A cells (Umeda & Nishimura, 1979),
    although it did cause chromosomal aberrations in the root tips of
     Vicia faba (Glass, 1955, 1956). Potassium permanganate caused
    chromosomal aberrations in FM3A cells (Umeda & Nishimura, 1979) but
    not in a primary culture of cells from Syrian hamster embryos (Tsuda &
    Kato, 1977) when tested in the absence of metabolic activation.
    Magnesium chloride caused cell transformation in Syrian hamster embryo
    cells (Casto et al., 1979).

         Manganese chloride did not produce somatic mutations in
     Drosophila melanogaster fruit flies (Rasmuson, 1985). Manganese
    sulfate did not induce sex-linked recessive lethal mutations in the
    germ cells of male  D. melanogaster (Valencia et al., 1985).

          In vivo assays in mice showed that oral doses of manganese
    sulfate or potassium permanganate caused micronuclei and chromosomal
    aberrations in bone marrow (Joardar & Sharma, 1990). In contrast, oral
    doses of manganese chloride did not cause chromosomal aberrations in
    the bone marrow or spermatogonia of rats (Dikshith & Chandra, 1978).

         The results of  in vitro studies show that at least some
    chemical forms of manganese have mutagenic potential. However, as the
    results of  in vivo studies in mammals are inconsistent, no overall
    conclusion can be made about the possible genotoxic hazard to humans
    from exposure to manganese compounds.

    8.6  Reproductive and developmental toxicity

         Considerable information is available on the reproductive and
    developmental effects of manganese in animals. Mice exposed
    subcutaneously to 0, 2, 4, 8, or 16 mg manganese chloride
    tetrahydrate/kg body weight per day on gestation days 6-15 showed no
    treatment-related effects on the number of total implants, early
    resorptions, dead fetuses, or sex ratio. However, a significant
    increase in the number of late resorptions was found in the 4, 8, and
    16 mg/kg body weight per day groups. Significant maternal toxicity was
    associated with the 8 and 16 mg/kg body weight per day groups (Sánchez
    et al., 1993). A single intratracheal dose of 160 mg manganese/kg (as
    manganese dioxide) in rabbits caused slow degenerative changes in the
    seminiferous tubules and led to sterility (Seth et al., 1973; Chandra
    et al., 1975). Abnormal sperm morphology was observed in mice treated
    with 23-198 mg manganese/kg body weight per day as potassium
    permanganate or manganese sulfate by gavage in water for up to 3 weeks
    (Joardar & Sharma, 1990). No gross or histopathological lesions or
    organ weight changes were observed in the reproductive organs of
    rodents exposed to 1300 mg manganese/kg body weight per day for 14
    days or fed up to 1950 mg manganese/kg body weight per day for 13
    weeks (NTP, 1993). From the available evidence, no firm conclusions on
    effects in male reproductive organs can be made, and reproductive
    performance was not evaluated in many of these studies.

         A slight decrease in pregnancy rate was observed in female rats
    exposed to 130 mg manganese/kg body weight per day as manganese
    tetroxide in the diet for 90-100 days before breeding (Laskey et al.,
    1982). Female reproductive parameters such as litter size, ovulations,
    resorptions, or fetal weights were not affected in rats consuming
    excess manganese as manganese tetroxide in feed or water (Laskey et
    al., 1982; Kontur & Fechter, 1985), except at concentrations so high
    (1240 mg/kg body weight per day) that water intake by the dams was
    severely reduced. In mice, inhalation exposure of females to 85 mg
    manganese/m3 (as manganese dioxide) for 16 weeks prior to conception
    and 17 days after conception led to a decrease in average pup weight
    at birth and decreased activity levels (Lown et al., 1984). Webster &
    Valois (1987) found that intraperitoneal injection of pregnant mice
    with 12.5 mg manganese/kg body weight (as manganese sulfate) on days

    8-10 of gestation resulted in exencephaly and embryolethality.
    Finally, manganese chloride administered by gavage at doses of 0, 25,
    50, or 75 mg/kg body weight per day caused major dose-dependent
    abnormalities in the fetuses when administered to gestating rats for
    the duration of gestation, but did not cause major abnormalities in
    the fetuses when administered to pregnant rabbits during the period of
    organogenesis (Szakmáry et al., 1995).

         In a rat teratology study, intravenous injection of 20 µmol
    manganese chloride/kg body weight (1.1 mg manganese/kg body weight) on
    days 6-17 of pregnancy induced mild skeletal malformations in the
    fetuses; the no-observed-adverse-effect level (NOAEL) was 0.28 mg
    manganese/kg body weight (Treinen et al., 1995). Similar effects were
    observed in another study (Grant & Ege, 1995) when administration was
    by injection, but not when manganese was administered by gavage at
    400 µmol manganese chloride/kg body weight (22 mg manganese/kg body
    weight). These results suggest that parenteral administration has a
    much greater potential for developmental toxicity than oral exposure.

         In rabbits exposed to manganese by intratracheal instillation, a
    single dose of 160 mg manganese/kg body weight (as manganese dioxide)
    resulted in a slow degeneration of the seminiferous tubules over a
    period of 1-8 months. This was associated with loss of spermatogenesis
    and complete infertility (Seth et al., 1973; Chandra et al., 1975).
    Similar degenerative changes in testes have been observed in rats and
    mice following intraperitoneal injection of manganese sulfate (Singh
    et al., 1974; Chandra et al., 1975) and in rabbits following
    intravenous injection of manganese chloride (Imam & Chandra, 1975).

    8.7  Immunological and neurological effects

         As with exposure to other airborne particulate matter, an
    increased susceptibility to infection has been observed in mice and
    guinea-pigs exposed to manganese via inhalation for a short period
    (Maigetter et al., 1976; Adkins et al., 1980). Altered blood levels of
    leukocytes, lymphocytes, and neutrophils have been observed in rats
    and mice that ingested manganese in the feed for short-term (33 mg/kg
    body weight per day for 14 days) or subchronic (284 mg/kg body weight
    per day for 100 days) durations (Komura & Sakamoto, 1991; NTP, 1993).
    However, it is unknown if these changes are associated with any
    significant impairment of the immune system.

         No evidence of neurological effects was seen in rhesus monkeys
    (0.01-1.1 mg manganese tetroxide/m3) or macaque monkeys (20-40 mg
    manganese chloride/m3) exposed to manganese via inhalation over
    subchronic and chronic periods (Ulrich et al., 1979). However,
    intravenous administration of 5-40 mg manganese/kg (as manganese
    chloride) to cebus monkeys did result in movement tremors accompanied
    by increased manganese in the globus pallidus and substantia nigra
    regions of the brain (Newland & Weiss, 1992). Decreased levels of

    dopamine were found in several regions of the brain (caudate and
    globus pallidus) in rhesus monkeys exposed to 30 mg manganese/m3 (as
    manganese dioxide) via inhalation for 2 years (Bird et al., 1984).

         A decrease in pup retrieval behaviour was observed in maternal
    mice exposed to 61 mg manganese/m3 (as manganese dioxide) via
    inhalation for 18 weeks (Lown et al., 1984). In another study,
    Morganti et al. (1985) observed moderate changes in open-field
    behaviour in mice exposed to 72 mg manganese/m3 (as manganese
    dioxide) for 18 weeks.

         In general, effects from inhalation exposure to manganese in
    experimental animals occur at levels higher (30-70 mg manganese/m3)
    than those at which effects have been reported in humans (0.14-1 mg
    total manganese dust/m3 for preclinical neurological alterations and
    2-22 mg total manganese dust/m3 for overt neurological disease). This
    evidence suggests that laboratory animals, especially rodents, might
    not be as sensitive as humans, and possibly other primates, to the
    neurological effects of inhalation exposure to manganese.

         There are substantial data on neurological effects in animals
    following ingestion of manganese. In one study, decreases in
    spontaneous activity, alertness, touch response, muscle tone, and
    respiration were observed in mice dosed once by oral gavage with 58 mg
    manganese/kg body weight (as manganese chloride) (Singh & Junnarkar,
    1991). Rats developed a rigid and unsteady gait after 2-3 weeks of
    exposure to a higher level (150 mg/kg body weight per day) of
    manganese chloride (Kristensson et al., 1986).

         Mice ingesting food containing manganese chloride, manganese
    acetate, manganese carbonate, or manganese dioxide (284 mg/kg body
    weight per day) for 100 days or manganese tetroxide (137 mg/kg body
    weight per day) for 90 days showed significantly decreased motor
    activity (Gray & Laskey, 1980; Komura & Sakamoto, 1991). Two of the
    third-generation mice exhibited staggered gait and histochemical
    changes after drinking water containing manganese chloride (10.6 mg/kg
    body weight per day) over three generations (Ishizuka et al., 1991).
    Conversely, rats showed increased activity and aggression when exposed
    to 140 mg manganese chloride/kg body weight per day in drinking-water
    for 4 weeks (Chandra, 1983) and just increased activity when exposed
    to 40 mg manganese chloride/kg body weight per day for 65 weeks
    (Nachtman et al., 1986). 

         Numerous studies have reported alterations in brain
    neurotransmitter levels and function, brain histochemistry, or
    neuronal enzyme function. These neurochemical changes have been
    observed in rats and mice following ingestion of manganese (as
    manganese chloride) administered via the feed, drinking-water, or
    gavage (in water) at doses ranging from 1 to 2270 mg manganese/kg body
    weight over intermediate exposure periods (i.e., 14-364 days)

    (Bonilla, 1978; Chandra & Shukla, 1978; Deskin et al., 1980; Gianutsos
    & Murray, 1982; Chandra, 1983; Bonilla & Prasad, 1984; Ali et al.,
    1985; Eriksson et al., 1987; Subhash & Padmashree, 1991). Similar
    alterations were reported after chronic exposures (>365 days) to 275
    mg manganese dioxide/kg body weight in the feed of mice (Komura &
    Sakamoto, 1992) or 40 mg manganese chloride/kg body weight in
    drinking-water of rats (Lai et al., 1984).

         Neurochemical alterations have also been reported in rats
    following intraperitoneal injection of manganese at doses ranging from
    2.2 to 4.4 mg manganese chloride/kg body weight over intermediate
    exposure periods (Sitaramayya et al., 1974; Shukla et al., 1980; Seth
    et al., 1981). Decreased neurotransmitter receptor binding was
    observed in macaca monkeys following subcutaneous injection of
    manganese dioxide at 38 mg/kg body weight for 26 months (Eriksson 
    et al., 1992). Changes in region-specific neuronal populations were
    reported in rats receiving manganese chloride from their
    drinking-water for either 4 or 8 weeks (Sarhan et al., 1986). The
    actual manganese dose administered over the total experimental period
    was not reported by the authors. However, daily intakes of at least
    10.7 mg manganese/kg body weight are estimated based on initial
    average body weight and water intake reported in the study.

         Neurobiochemical changes have been detected in neonate rats at
    doses similar to or slightly above dietary levels (1-10 mg
    manganese/kg body weight per day for 24-60 days, as manganese
    chloride) (Chandra & Shukla, 1978; Deskin et al., 1980), which could
    indicate that young animals may be more susceptible to manganese than
    adults. Oner & Senturk (1995) demonstrated that manganese induces
    learning deficits in rats dosed with 357 µg manganese/kg body weight
    for 15 or 30 days; these effects were reversible.


         A requirement for manganese in humans was determined based on
    symptoms observed in a subject inadvertently fed a diet deficient in
    manganese for 3.5 months (Doisy, 1972). It has been determined that
    manganese is needed for the functioning of key enzymes that play a
    role in cellular protection from damaging free radical species,
    maintenance of healthy skin, and synthesis of cholesterol
    (Freeland-Graves et al., 1987; Friedman et al., 1987). Based upon
    case-studies in people with low blood manganese and known requirements
    in animals, it is thought that manganese may also play a role in bone
    mineralization, metabolism of proteins, lipids, and carbohydrates,
    energy production, metabolic regulation, and nervous system
    functioning (Schroeder et al., 1966; Freeland-Graves et al., 1987;
    Hurley & Keen, 1987; Freeland-Graves & Llanes, 1994; Wedler, 1994).
    However, the link between inadequate manganese nutrition and its role
    in these body functions in humans requires further investigation.

         Manganism is a progressive, disabling neurological syndrome that
    typically begins with relatively mild symptoms and evolves to include
    dull affect, altered gait, fine tremor, and sometimes psychiatric
    disturbances. Because some of these symptoms resemble those of
    Parkinson's disease, many investigators have used terms such as
    "Parkinsonism-like disease" and "manganese-induced Parkinsonism" to
    describe symptoms observed with manganese poisoning. Although symptoms
    of manganism resemble those of Parkinson's disease, significant
    differences have been noted. In terms of clinical presentation,
    Barbeau (1984) noted that the hypokinesia and tremor present in
    patients suffering from manganism differed from those seen in
    Parkinson's disease. Drawing from the literature, Calne et al. (1994)
    noted other features that can also distinguish manganism from
    Parkinson's disease; psychiatric disturbances early in the disease (in
    some cases), the "cock walk" (see below), a propensity to fall
    backward when displaced, less frequent resting tremor, more frequent
    dystonia, and failure to respond to dopaminomimetics (at least in the
    late stages of the disease) were characteristic of manganism. Beuter
    et al. (1994) showed that 10 manganese-exposed workers (average
    exposure of 13.9 years; average blood manganese level of 1.06 µg/dl)
    and 11 patients with Parkinsonism were significantly different from
    the controls ( n = 11) in functional asymmetries between right and
    left hand. Therefore, use of terms such as "Parkinsonism-like disease"
    and "manganese-induced Parkinsonism" are somewhat misleading.
    Nonetheless, the use of these terms may help health providers and
    health surveillance workers recognize the effects of manganese
    poisoning when encountering it for the first time in occupational or
    environmental settings. These terms appear in the discussion below
    when they were used by study authors in their reports (shown in
    italics). The term "manganism" is used as well.

         Long-term exposures to manganese in occupational settings can
    result in a progressive neurological dysfunction, which can produce a
    disabling syndrome referred to as manganism. Mergler & Baldwin (1997)
    have described this disease progression as a "slow deterioration of
    well-being which can be initially detected as early neurofunctional
    alterations... [among exposed groups], later on, as sub-clinical signs
    in individuals... and finally as a full blown neurological disease
    -- manganism." Progression along this continuum is thought to be a
    function of the dose and duration of exposure, as well as individual
    susceptibilities. In general, the clinical effects of high-level
    inhalation exposure to manganese do not become apparent until exposure
    has occurred for several years, but some individuals begin to show
    signs of neurological alterations after as little as 1-3 months of
    exposure (Rodier, 1955).

         Pathological findings in manganism and Parkinson's disease also
    differ. In humans with chronic manganese poisoning, lesions are more
    diffuse, found mainly in the pallidum, the caudate nucleus, the
    putamen, and even the cortex. In people with Parkinson's disease,
    lesions are found in the substantia nigra and other pigmented areas of
    the brain (Barbeau, 1984). Moreover, Lewy bodies are usually not found
    in substantia nigra in cases of manganism, but are almost always found
    in cases of Parkinson's disease (Calne et al., 1994). Magnetic
    resonance imaging of the brain reveals accumulation of manganese in
    cases of manganism, but little or no changes in people with
    Parkinson's disease; fluorodopa positron emission tomography scans are
    normal in cases of manganism, but abnormal in people with Parkinson's
    disease (Calne et al., 1994).

         The first signs of manganism are usually subjective and
    non-specific, often involving generalized feelings of weakness,
    heaviness or stiffness of the legs, anorexia, muscle pain,
    nervousness, irritability, and headache (Rodier, 1955; Whitlock
    et al., 1966; Mena et al., 1967; Tanaka & Lieben, 1969; Sjögren et
    al., 1996). These signs are frequently accompanied by apathy and
    dullness, along with impotence and loss of libido; especially in the
    case of miners, more extreme manifestations of psychomotor excitement,
    such as aggressive or destructive behaviour, emotional lability, and
    bizarre compulsive activities, are also associated with the first
    stages of manganism (Rodier, 1955; Schuler et al., 1957; Mena et al.,
    1967; Emara et al., 1971; Abdel-Hamid et al., 1990; Wennberg et al.,
    1991; Chu et al., 1995).

         More specific clinical signs of basal ganglia dysfunction
    characterize the next stage and can include a slow or halting speech
    without tone or inflection, a dull and emotionless facial expression,
    slow and clumsy movement of the limbs or altered gait, late motor
    deficits, and fine tremor (Rodier, 1955; Schuler et al., 1957; Mena
    et al., 1967; Tanaka & Lieben, 1969; Smyth et al., 1973; Yamada et
    al., 1986; Ky et al., 1992; Wennberg et al., 1992; Hochberg et al.,
    1996; Mergler & Baldwin, 1997).

         As the disease progresses, walking becomes difficult and a
    characteristic staggering gait develops, the "cock walk," in which
    patients strut on their toes, with elbows flexed and the spine erect
    (Calne et al., 1994). Muscles become hypertonic, and voluntary
    movements can be accompanied by fine tremor (Chu et al., 1995; Mergler
    & Baldwin, 1997). In some cases, psychological disturbances (manganese
    mania, manganese psychosis) precede or accompany the final stages of
    disease (Rodier, 1955; Mena et al., 1967; Cook et al., 1974; Mergler &
    Baldwin, 1997). Few data are available regarding the reversibility of
    these effects; they are thought to be largely irreversible. Some
    evidence indicates that recovery can occur when exposure ceases (Smyth
    et al., 1973). Manganism has been documented in welders and in workers
    exposed to high levels of manganese dust or fumes in mines or

         The studies cited above describe overt manganism resulting from
    long-term inhalation exposures to 2-22 mg total manganese dust/m3
    (Schuler et al., 1957; Whitlock et al., 1966; Tanaka & Lieben, 1969;
    Cook et al., 1974; Saric et al., 1977; Huang et al., 1989). Evidence
    from recent occupational exposure studies (described below) suggests
    that early or preclinical signs of neurological effects can occur in
    generally asymptomatic workers exposed to much lower levels of
    manganese (about 0.14-1 mg total manganese dust/m3) for several years
    (Roels et al., 1987, 1992; Iregren, 1990; Chia et al., 1993; Mergler
    et al., 1994; Lucchini et al., 1995). However, the reported values are
    only estimates of actual exposure levels. Often, time-weighted
    averages of workplace exposures are reported, and dose-response
    relationships cannot be determined. In addition, exposures are
    generally reported as total manganese dust or the respirable fraction
    of total dust, which can be defined differently across studies (e.g.,
    PM5 [particulate matter with an aerodynamic diameter less than or
    equal to 5 µm] or PM10).

    9.1  Case reports

         Whitlock et al. (1966) reported a case-study of two workers
    exposed to manganese-containing fumes (3.5 mg manganese/m3 average;
    no data on exact compounds) from an electric arc used to cut and
    cleave manganese castings. Symptoms of ataxia, weakness, and decreased
    mental ability developed about 9-12 months following exposure. These
    symptoms improved after the patients were treated with
    ethylenediamine-tetraacetic acid (EDTA). Rosenstock et al. (1971)
    reported a case of a male who developed classic symptoms of manganism
    after 14 months of exposure to manganese (dose unknown) from the fumes
    and dust of a steel foundry. After being unable to work for 3 years,
    the patient was treated with 6-12 g levodopa/day, with the largest
    dose providing improvement in facial expression, speech, and muscle
    tone. Six men exposed to manganese (22 mg manganese/m3) for an
    unspecified period at an ore crushing plant developed signs including
    somnolence, abnormal gait, slurred speech, ataxia, masklike faces, and
    bradykinesia. Treatment with 8 g levodopa/day did not alleviate the
    neurological effects observed in these workers (Cook et al., 1974).

         An outbreak of a disease with manganism-like symptoms was
    reported in a group of six Japanese families (about 25 people) exposed
    to high levels of manganese in their drinking-water (Kawamura et al.,
    1941). Symptoms included a masklike face, muscle rigidity and tremors,
    and mental disturbance. Five people, all elderly, were severely
    affected (2 died), 2 were moderately affected, 8 were mildly affected,
    and 10 (all children or young adults) were not affected. These effects
    were postulated to be due to the contamination of well-water with
    manganese (14 mg/litre) that leached from batteries buried near the
    well. Manganese concentrations decreased over time, so the original
    level of manganese was probably higher than 14 mg/litre. This case has
    been interpreted as an indication that the elderly may be more
    sensitive than younger people to the toxic effects of manganese (Davis
    & Elias, 1996).

         A man noticed weakness and impaired mental capacity after
    mistakenly ingesting low doses of potassium permanganate (1.8 mg/kg)
    instead of potassium iodide for several weeks to treat lung congestion
    (Holzgraefe et al., 1986). Although exposure was stopped after
    4 weeks,  a syndrome similar to Parkinson's disease developed after
    about 9 months. In another case, five patients given manganese
    parenterally for an average of 6 years showed early neurological
    symptoms of poisoning, while four others, exposed for an average of 4
    years, did not (Mirowitz et al., 1991). In a child, accidental
    ingestion of potassium permanganate (174 mg/kg) resulted in severe
    local corrosion of the mouth, oesophagus, and stomach, but there was
    no evidence of systemic toxicity (Southwood et al., 1987).

         There are few reports regarding dermal exposure to manganese in
    humans. In most cases, manganese uptake across intact skin is expected
    to be very limited. However, effects and elevated urinary manganese
    levels were observed in a man burned with a hot acid solution
    containing 6% manganese (Laitung & Mercer, 1983). There are also
    reports of workers experiencing effects from dermal exposure to
    organic manganese compounds. Headache and paraesthesia were among the
    symptoms reported in workers exposed dermally to MMT after a spill
    (doses unknown; Tanaka, 1994). Two young Brazilian agricultural
    workers developed  Parkinsonian syndrome (Ferraz et al., 1988) and a
    37-year-old Italian man developed  Parkinsonism (Meco et al., 1994)
    after chronic dermal and inhalation exposure to the fungicide maneb.

    9.2  Epidemiological studies

         The lungs, nervous system, and reproductive system are the main
    organs affected following inhalation exposures to manganese, although
    other effects have also been observed. For example, in a study of 126
    enamellers and 64 decorators from five factories in the ceramics
    industry, Motolese et al. (1993) found that 48 workers were sensitized
    to at least one substance; positive sensitization test results with
    manganese dioxide were found in only 2 of the workers, however. The
    remainder of this section focuses on the effects more commonly
    reported in epidemiological studies -- lung, nervous system, and
    reproductive system effects.

         Inhalation of particulate manganese compounds such as manganese
    dioxide and manganese tetroxide leads to an inflammatory response in
    human lungs. Symptoms and signs of lung irritation and injury can
    include cough, bronchitis, pneumonitis, and reductions in lung
    function (Lloyd Davies, 1946; Roels et al., 1987; Abdel-Hamid et al.,
    1990; Akbar-Khanzadeh, 1993).

         Pneumonia has been reported to result from both acute and
    long-term inhalation exposure to manganese dioxide dusts (Lloyd
    Davies, 1946; Tanaka, 1994). These effects have been noted mainly in
    people exposed to manganese dust under occupational conditions,
    although respiratory effects have also occurred in residential
    populations (WHO, 1987). A higher incidence of pneumonia and a higher
    rate of deaths from pneumonia compared with the general population
    were observed among residents exposed to manganese dust from a
    ferromanganese factory as well as among the factory workers 
    (WHO, 1987; Tanaka, 1994). However, a threshold level for respiratory
    effects has not been established. The increased susceptibility to
    respiratory infection might be secondary to the lung irritation and
    inflammation caused by inhaled particulate matter rather than caused
    by the manganese alone. It is likely that the inflammatory response
    begins shortly after exposure and continues for the duration of the

         Although available studies are not adequate to define the
    dose-response curve or determine whether there is a threshold for
    neurotoxicity, the lowest level of exposure to manganese dust at which
    neurological effects occur was reported by Iregren (1990) and Wennberg
    et al. (1991). These investigators compared 30 male workers exposed to
    manganese for 1-35 years during employment at two Swedish foundries
    with an unexposed control group of 60 workers (matched by age, type of
    work, and geographical area) using eight tests from the Swedish
    Performance Evaluation System and two additional manual tests. The
    mean and median levels of manganese in the foundry air were measured
    at 0.25 and 0.14 mg/m3, respectively, and available data indicated
    that these levels had been consistent over the past 17-18 years. The
    exposed workers exhibited significantly inferior performance in simple
    reaction time, digit span, and finger tapping. When a secondary match
    was performed, with scores on verbal tests used as an additional
    matching criterion (which reduced the size of the reference group to
    30), the same test differences remained, although the difference was
    not significant for the digit span test. Although the subjects did not
    exhibit the signs of clinical manganism described above, these changes
    were indicators of manganese-induced neurological effects (Iregren,
    1990; Wennberg et al., 1991).

         The study results reported by Iregren (1990) and Wennberg et al.
    (1991) are supported by evidence presented by Roels et al. (1987,
    1992) and Chia et al. (1993, 1995). Roels et al. (1992) detected early
    neurological effects in male workers at an alkaline battery plant
    exposed to manganese dusts (manganese dioxide). Compared with 101 male

    workers without industrial exposure, the 92 exposed workers showed
    significantly poorer eye-hand coordination, hand steadiness, and
    visual reaction time. A Lifetime Integrated Exposure, for both
    respirable and total manganese dust, was estimated for each of the
    exposed workers (expressed as exposure in mg manganese/m3 multiplied
    by the number of years of exposure, or mg/m3 × year). Based on an
    analysis of the data by a logistic regression model, it was suggested
    that there was an increased risk of peripheral tremor at a Lifetime
    Integrated Exposure level of 3.575 mg/m3 × year total manganese dust
    or 0.73 mg/m3 × year respirable (PM5) dust; dividing by an exposure
    duration of 5.3 years, these values are equivalent to 0.67 mg/m3 and
    0.14 mg/m3 for total manganese dust and respirable manganese dust,
    respectively. This total manganese dust exposure level (0.67 mg/m3)
    is slightly higher than the median found to be associated with effects
    in the 1990 Iregren and the 1991 Wennberg et al. studies (0.14
    mg/m3). The Lifetime Integrated Exposure at which an increased risk
    of abnormal neurofunction occurs is based on exposures in an
    occupational setting and might be biased because of the "healthy
    worker effect" (i.e., the most susceptible individuals were not
    incorporated into the study).

         The Chia et al. (1993) study also reported neurological deficits
    in an occupational cohort of 17 manganese "baggers" in Singapore who
    were administered the WHO Neurobehavioural Core Test Battery, as well
    as several supplementary tests and a subjective questionnaire (with
    questions on 37 symptoms related to the nervous system) taken from the
    Operational Guide to the Neurobehavioural Core Test Battery. The
    exposed workers had significantly poorer motor speed, visual-motor
    coordination, visual scanning, visual-motor and response speed, and
    visual-motor coordination and steadiness than a control group. Twenty
    of the 37 symptoms in the questionnaire were also reported more
    frequently by the exposed workers than by the control group, although
    the differences were significant only for insomnia and profuse
    sweating. The mean manganese level in air (from 1981 to 1991) in the
    factories was reported to be 1.59 µg/litre (1.59 mg/m3; 8-hour
    time-weighted average). Chia et al. (1995) conducted another study
    with a larger group of exposed workers (32 subjects exposed to the
    same mean level of manganese in air reported above), focusing in more
    detail on postural stability; the exposed workers exhibited
    significantly poorer postural stability compared with a control group.

         A study by Mergler et al. (1994) also supports the findings of
    Iregren (1990), Wennberg et al. (1991), Roels et al. (1987, 1992), and
    Chia et al. (1993, 1995). This epidemiological study included 74 male
    workers from a ferromanganese and silicomanganese alloy factory,
    matched with 74 referents from a pool of 145 non-occupationally
    exposed men residing in the vicinity. Environmental levels of total
    manganese dust at the factory were measured at 0.014-11.48 mg/m3
    (median 0.151 mg/m3; mean 1.186 mg/m3), whereas manganese levels in
    respirable dust (PM10 samples) ranged from 0.001 to 1.27 mg/m3
    (median 0.032 mg/m3; mean 0.122 mg/m3). The authors noted that

    exposures at the factory were known to have been much higher in the
    recent past. The mean duration of exposure was 16.7 years. The
    manganese-exposed workers showed decreased performance on tests of
    motor function, and they exhibited lower levels of cognitive
    flexibility, difficulty in set shifting, and lower olfactory
    perception thresholds. This is the first study to report the latter
    effect (lower olfactory perception threshold). The workers also
    displayed significantly greater anger, tension, fatigue, and confusion
    as determined by the Profile of Mood States test.

         A study by Lucchini et al. (1995) also found evidence of
    neurobehavioural effects at exposure levels comparable to those
    reported above. During a period of forced cessation from work, 58
    clinically asymptomatic workers exposed to manganese dust for periods
    of 1-28 years (mean 13 years) were tested for simple reaction time,
    finger tapping, digit span, additions, symbol digit, and shapes
    comparison. Geometric mean concentrations of manganese in total dust
    were measured in different work areas and ranged from 70-1590 µg/m3
    (10 years before the study was undertaken) to 27-270 µg/m3 (at the
    time of the study). A Cumulative Exposure Index was calculated for
    each subject. It took into account the type of job(s) the subject
    performed at the plant, the average annual airborne manganese
    concentration in respirable dust characteristic of the job(s), and the
    duration of employment in the job(s). The authors found correlations
    between the Cumulative Exposure Index and performance on the finger
    tapping, symbol digit, digit span, and additions tests; higher indices
    were associated with poorer performance. In addition, the authors
    found correlations between manganese levels in blood and urine of the
    workers and performance (the higher the blood and urine levels, the
    poorer the performance) when the levels were measured after exposure
    ended. This study is significant in that it is the first to
    demonstrate an association between biomarkers of exposure/body burden
    and the occurrence of neurological effects.

         Impotence and loss of libido are common symptoms in male workers
    afflicted with clinically identifiable signs of manganism attributed
    to occupational exposure to manganese for 1-21 years (Rodier, 1955;
    Schuler et al., 1957; Mena et al., 1967; Emara et al., 1971). These
    effects could lead to reduced reproductive success in men. Impaired
    fertility (measured as a decreased number of children per married
    couple) has been observed in male workers exposed for 1-19 years to
    manganese dust at levels (0.97 mg/m3) that did not produce frank
    manganism (Lauwerys et al., 1985). In another study, Gennart et al.
    (1992) did not find an effect of manganese exposure (0.71 mg/m3 for
    6.2 years on average) on fertility. Impaired sexual function in men
    might be one of the earliest clinical manifestations of manganism;
    however, because dose-response information is unavailable, it is not
    possible to define a threshold for this effect. No information was
    found regarding reproductive effects in women.

         Although most effects have been seen following chronic inhalation
    exposure to manganese in occupational settings, some epidemiological
    studies have reported adverse effects from ingestion of excess
    manganese in the environment. A manganism-like neurological syndrome
    was observed in an aboriginal population living on an island near
    Australia where environmental levels of manganese are high (Kilburn,
    1987). Exposure levels were not provided, but the authors noted that
    manganese intake could occur not only through the oral route (food,
    water, soil), but also by inhaling manganese-containing dusts in the
    air (Cawte et al., 1987). Although manganese exposure was probably an
    etiologic factor, genetic factors, dietary deficiencies in
    antioxidants and calcium, and excess alcohol consumption could also
    have contributed to the neurological effects (Cawte et al., 1989).

         More recently, Kondakis et al. (1989) reported that chronic
    intake of drinking-water containing elevated levels of manganese 
    (1.8-2.3 mg/litre) led to an increased prevalence of neurological 
    signs in elderly residents (average age 67 years) of two small towns 
    in Greece. The effects were compared with those in similarly aged 
    residents in two other communities where manganese levels were within 
    ambient range (0.004 and 0.0015 mg/litre). The findings suggested that
    above-average oral exposure to manganese might be of health concern. 
    However, although the comparison populations were reportedly very 
    similar to each other, differences in age, occupational exposures, or 
    general health status could have accounted for the small differences 
    observed. Similarly, Goldsmith et al. (1990) investigated a cluster of
    Parkinson's disease in southern Israel. The authors suggested that
    excess levels of aluminum, iron, and manganese in the drinking-water
    and the use of agricultural chemicals, including maneb and paraquat,
    in the area were common environmental factors that may have
    contributed to the observed cluster. However, the observed symptoms
    could not be conclusively attributed to manganese poisoning alone. By
    contrast, a recent study by Vieregge et al. (1995) on the neurological
    impacts of chronic oral intake of manganese in well-water found no
    significant differences between exposed and control populations in
    northern Germany. A group of 41 subjects exposed to 0.300-160 mg
    manganese/litre in well-water was compared with a control group of 71
    subjects (matched for age, sex, nutritional habits, and drug intake)
    exposed to a maximum manganese concentration in well-water of 0.050
    mg/litre. Neurological assessments revealed no significant difference
    between the two groups. Although the effects reported by Kondakis et
    al. (1989) and Goldsmith et al. (1990) are consistent with the known
    toxicological effects of manganese, the findings are inconclusive and
    are contradicted by the results of Vieregge et al. (1995). As a
    result, no firm conclusions on manganese-induced neurological effects
    in humans from chronic oral intake of manganese in drinking-water can
    be made at this time.

         One report partially attributed neurological effects to chronic
    oral intake of manganese in food. Iwami et al. (1994), studying metal
    content in food and drinking-water in an area with a high rate of

    motor neuron disease (as determined from death certificates) compared
    with control areas, concluded that a high manganese content in food
    and a low  magnesium content in drinking-water together explained the
    high incidence of motor neuron disease. The manganese content per
    1800-kcal diet averaged 6.20 mg for local rice eaters and 3.83-4.67 mg
    in the control areas.

         Several studies have reported an association between chronic
    exposure to maneb and neurological symptoms, but the effects could not
    be conclusively attributed to maneb alone. Ruijten et al. (1994)
    investigated the effects of chronic exposure to mixed pesticides
    (including zineb and maneb) on peripheral and autonomic nerve function
    using a previously exposed group of 131 Dutch bulb farmers and a
    control group of 67. The findings suggested exposure-related decreases
    in both autonomic and peripheral nerve function. Ferraz et al. (1988)
    reported the results of a questionnaire and neurological examination
    administered to 50 rural workers in Brazil who had had close contact
    with maneb (preparation and/or fumigation) for at least 6 months.
    Compared with a control group, the exposed group had a significantly
    higher prevalence of plastic rigidity with cogwheel phenomenon
    (neurological examination), as well as headache, fatigue, nervousness,
    memory complaints, and sleepiness (questionnaire). In both studies,
    however, the subjects were exposed to other substances, so the effects
    could not be definitively attributed to maneb. Meco et al. (1994)
    reported that  Parkinsonism developed in a patient 2 years after
    chronic exposure to maneb had been discontinued. Initial symptoms
    observed were generalized bradykinesia, rigidity, and mild tremor
    associated with paraesthesias in the right leg, which subsequently
    spread to the right arm. Over a 3-year period, the tremor worsened and
    spread to the left limbs as well. Exposure levels were not defined in
    these studies.


    10.1  Evaluation of health effects

    10.1.1  Hazard identification and dose-response assessment

         Manganism, manganic pneumonia, and male reproductive effects
    (decreased libido, impotence, and decreased fertility) have been
    documented following chronic inhalation of manganese-containing
    respirable dusts in occupational settings (Rodier, 1955; Schuler et
    al., 1957; Mena et al., 1967; Emara et al., 1971; Lauwerys et al.,
    1985). More recent reports have shown subclinical changes in
    neurological performance at low occupational exposure levels (Roels et
    al., 1987, 1992; Iregren, 1990; Wennberg et al., 1991; Mergler et al.,
    1994; Lucchini et al., 1995); it should be noted that even these low
    occupational exposure levels were at least three orders of magnitude
    higher than manganese levels in areas without industrial sources of
    manganese. A dose-response curve has not been well defined, but early
    signs of nervous system toxicity and overt manganism have been
    observed after inhalation exposure to total manganese dust levels that
    range from 0.14 to 1 mg/m3 for the former and from 2 to 22 mg/m3
    for the latter. These neurological effects have been observed
    following exposure durations that span from 1 to 35 years (Schuler et
    al., 1957; Whitlock et al., 1966; Tanaka & Lieben, 1969; Cook et al.,
    1974; Saric et al., 1977; Roels et al., 1987, 1992; Iregren, 1990;
    Wennberg et al., 1991; Chia et al., 1993, 1995; Mergler et al., 1994;
    Lucchini et al., 1995). Estimated levels of inhalation exposure to
    manganese compounds have been reported as manganese in either total
    dust particles or the respirable fraction, based on particle size.

         Although inconclusive, limited case reports and epidemiological
    studies report neurological effects associated with ingesting water
    (or other media) containing elevated manganese (Kawamura et al., 1941;
    Kilburn, 1987; Kondakis et al., 1989; Goldsmith et al., 1990; Iwami et
    al., 1994). Reports on neurological effects following exposure to
    pesticides containing manganese are similarly inconclusive (Ferraz et
    al., 1988; Ruijten et al., 1994).

         Some evidence suggests that the elderly might be more sensitive
    than younger people to manganese (Davis & Elias, 1996). In addition,
    owing to various predisposing factors, certain other individuals might
    be more susceptible to adverse effects from exposure to excess
    manganese. These might include people with lung disease, people who
    are exposed to other lung irritants, neonates, individuals with iron
    deficiency, and people with liver disease.

         Available data suggest that neurological effects can occur
    following chronic inhalation exposures in humans and intermediate and
    chronic oral exposures in animals to different manganese compounds.
    Manganese-induced neurological effects have been reported at lower
    airborne manganese concentrations in humans than in animals (Bird et
    al., 1984; Newland & Weiss, 1992). These data suggest that animal
    models, particularly rodent species, might be less useful for defining

    quantitative dose-response relationships, but helpful in elucidating
    the mechanism(s) for these effects. The basis for the difference in
    susceptibility across species is not yet understood and may be related
    to possible differences in the sensitivity of test methods used to
    detect neurobehavioural effects in animals compared with methods used
    to detect neurobehavioural effects in humans.

         Little is known about the relative toxicity of different
    manganese compounds. Inhaled manganese compounds tend to produce more
    severe toxicity than ingested manganese compounds. This is probably
    attributable to the difference in route-specific uptake of manganese
    from the lung (often assumed at 100%) compared with the
    gastrointestinal tract (3-5%). Studies have shown that a greater
    proportion of a manganese dose appears in the blood and brain of rats
    exposed via inhalation or intranasal instillation than when the same
    dose is given orally (Tjälve et al., 1996; Roels et al., 1997).

    10.1.2  Criteria for setting guidance values for manganese

         There are several approaches to the development of a guidance
    value for manganese in air. A recently developed guidance value of
    0.15 µg manganese/m3 (WHO, 1999) is highlighted here as one example;
    other approaches are outlined in Appendix 4. The WHO (1999) guidance
    value was derived from the results of the study by Roels et al.
    (1992), which examined neurobehavioural end-points in 92 male workers
    exposed to manganese dioxide dust at an alkaline battery plant and 101
    male workers without industrial manganese exposure. The
    manganese-exposed workers exhibited significantly poorer eye-hand
    coordination, hand steadiness, and visual reaction time. Sufficient
    data on participants' exposure levels and test performance were
    provided to enable development of a dose-response relationship and
    calculation of a benchmark dose. The lower 95% confidence limit of the
    benchmark dose (30 µg/m3 for the 5% effect level) was used as an
    estimate of a NOAEL for neurological effects. The guidance value for
    manganese in air (WHO, 1999) was then derived as follows:

    Guidance value =    (30 µg/m3 ‰ 50) × (5/7) × (8/24)

                   =    0.15 µg/m3 (rounded value)


    *    30 µg/m3 is the estimated NOAEL for neurological effects,
         calculated based on a benchmark dose analysis of results from a
         quality epidemiological study of workers exposed to manganese;

    *    5/7 and 8/24 are factors used to convert intermittent exposure
         (5 days/week, 8 h/day) to continuous exposure; and 

    *    50 is the uncertainty factor (×10 for interindividual variation;
         ×5 for the potential for developmental effects in younger
         children). The uncertainty factor for developmental effects in
         younger children was obtained by analogy with lead, where
         neurobehavioural effects were found in younger children at blood
         lead levels five times lower than in adults; this finding was
         considered to be supported by evidence from studies in animals
         (WHO, 1999).

         In considering development of a guidance value for oral intake of
    manganese, it must be noted that there is wide variability in human
    intake of manganese (from all sources) and that manganese is an
    essential nutrient for humans and animals. Daily manganese intake from
    food is estimated to be about 2-9 mg for adults, with an absorbed
    amount of about 100-450 µg/day based upon 5% gastrointestinal
    absorption (WHO, 1981). Some studies have reported that neurological
    effects may be related to ingestion of manganese in non-worker
    populations. However, these reports provide little information on the
    levels of ingested manganese that were associated with these effects.
    Although neurological effects might be a potential concern for people
    working or living at or near sites where ingestion or inhalation of
    high levels of manganese can occur (see section 9.2), no firm
    conclusion on a guidance value level for oral intake of manganese
    other than estimated daily intake levels is considered possible.

    10.1.3  Sample risk characterization

         A theoretical estimate of inhalation exposures for the general
    population is presented based on available monitoring data on levels
    of manganese in air.

         Table 2 shows estimates of the average levels of manganese in
    ambient air in remote, rural, and urban areas around the world (US
    EPA, 1984; Stokes et al., 1988). Using these data and a daily
    inhalation volume of 20 m3 for a 70-kg adult, the average estimated
    daily intake of manganese from air in rural areas would be 0.8 µg/day,
    and this might increase to 1.3, 1.9, and 3.3 µg/day in urban areas in
    Canada, the USA, and Europe, respectively. In source-dominated areas
    with manganese-emitting industries or major foundry facilities, intake
    from air might rise to 4-6 µg/day (WHO, 1999). These estimates are
    based on the assumptions that there is 100% absorption of inhaled
    manganese and that an individual lives or works in these environments
    for a complete 24-h period. Thus, these exposure estimates could be
    further adjusted to reflect that fraction of a 24-h period during
    which a person is actually in any of these areas. For example, a
    person working for 8 h/day in an urban area of Canada, the USA, or
    Europe would be exposed to an adjusted estimate of 0.43-1.1 µg
    manganese during the workday (1.3-3.3 µg/day - 8/24). Consequently,
    for persons living or working in rural or urban environments,
    estimates of inhalation exposure would fall below or in the range of
    the reported guidance values for inhaled manganese. Appendix 4

    includes examples of other guideline values reported for inhaled
    manganese. These values range from 0.8 µg/day (0.04 µg/m3 × 20
    m3/day = 0.8 µg/day) up to an estimate of 3.0 µg inhaled
    manganese/day based on the guidance value described in section 10.1.2
    (0.15 µg/m3 × 20 m3/day = 3.0 µg/day). It should be noted that the
    studies used in the risk assessment of inhaled manganese are
    occupational studies of adult male workers, and there is uncertainty
    about extrapolating the risk to women and children.


         WHO (1981, 1986, 1987, 1999) has previously evaluated manganese,
    concluding that chronic manganese poisoning is a hazard in
    occupational settings. However, little information was available to
    assess the potential health risks in community exposure scenarios.

         WHO has established a provisional guideline value of 0.5 mg/litre
    for manganese in drinking-water based on health (WHO, 1993), an annual
    air quality guideline of 0.15 µg/m3 (WHO, 1999), and a workplace
    exposure limit in air of 0.3 mg/m3 for respirable particles
    containing manganese (WHO, 1984, 1986, 1987, 1999).

         Information on international hazard classification and labelling
    is included in the International Chemical Safety Card reproduced in
    this document.


         Human health hazards, together with preventative and protective
    measures and first aid recommendations, are presented in the
    International Chemical Safety Card (ICSC 0174) reproduced in this

    12.1  Human health hazards

         Following long-term or repeated exposure to manganese, humans may
    present neurological and neuropsychiatric disorders known under the
    term manganism.

    12.2  Advice to physicians

         The psychiatric symptoms of manganese poisoning are transient.
    However, the neurological damage might be irreversible, although some
    patients have experienced partial regression of their symptoms after
    early removal from exposure (Mena et al., 1974).

         Consequently, it is very important to remove from further
    exposure patients who present preclinical neurological disturbances or
    symptoms of manganism. Chelation therapy with, for example, EDTA might
    be effective in removing manganese from blood and tissues, but it has
    no permanent effect on symptomatic patients in the late stages of
    manganism (Bismuth et al., 1987; Dreisbach & Robertson, 1987;
    Ellenhorn & Barceloux, 1988; Tomes, 1997). Normal manganese levels are
    2-8 µg/dl in blood and 0.1-0.8 µg/dl in urine. Plasma and urine
    manganese levels do not seem to correlate well with the severity of

    12.3  Health surveillance programme

         The health surveillance programme of people exposed to manganese
    needs to include elements such as central nervous system disturbances
    (asthenia, anorexia, sleep problems, irritability, diminished libido).


         Information on national regulations, guidelines, and standards
    can be found in the International Register of Potentially Toxic
    Chemicals (IRPTC), available from UNEP Chemicals (IRPTC), Geneva.

         The reader should be aware that regulatory decisions about
    chemicals taken in a certain country can be fully understood only in
    the framework of the legislation of that country. The regulations and
    guidelines of all countries are subject to change and should always be
    verified with appropriate regulatory authorities before application.


    MANGANESE                                                     ICSC:0174
                                                                  March 1995
    CAS#      7439-96-5
    RTECS#    00927500


                                Atomic mass: 54.9

    EXPOSURE             SYMPTOMS                                      FIRE FIGHTING

    FIRE                 Combustible            No open                Dry sand,
                                                flames                 special powder

    EXPLOSION            Finely dispersed       Prevent deposition
                         particles form         of dust, closed
                         explosive mixtures     system, dust
                         in air                 explosion-proof
                                                electrical equipment
                                                and lighting.
    EXPOSURE                                    PREVENT DISPERSION
                                                OF DUST! AVOID
                                                EXPOSURE OF (PREGNANT)
    Inhalation           Cough, shortness       Local exhaust or       Fresh air, rest.
                         of breath.             breathing protection.  Refer for medical

    Eyes                                        Safety goggles or      First rinse with
                                                eye protection in      plenty of water 
                                                combination with       for several
                                                breathing protection   minutes (remove 
                                                if powder.             contact lenses if 
                                                                       easily possible), 
                                                                       then take to a 
    Ingestion            Abdominal pain.        Do not eat, drink,     Rinse mouth.
                         Nausea.                or smoke during        Refer for medical
                                                work. Wash hands       attention.
                                                before eating.

    SPILLAGE DISPOSAL                           PACKAGING & LABELLING
    Sweep spilled substance into containers.    EU Classification
    Carefully collect remainder, then           Symbol:
    remove to safe place (extra personal        UN Classification
    protection: P2 filter respirator
    for harmful particles).
    EMERGENCY RESPONSE                          STORAGE
                                                Separated from acids. Dry


                                      IMPORTANT DATA
    GRAY-WHITE POWDER                           The substance can be absorbed into the
                                                the body by inhalation of its aerosol or
                                                fumes, and by ingestion.

    PHYSICAL DANGERS:                           INHALATION RISK:
    Dust explosion possible if in powder        Evaporation at 20°C is negligible;
    or granular form, mixed with air.           a harmful concentration of airborne
                                                particles can, however, be reached
                                                quickly when dispersed.

    Upon heating, toxic fumes are formed.       Inhalation of dust may cause bronchitis
    Reacts violently with concentrated          and pneumonia. The effects may be
    hydrogen peroxide. Reacts slowly with       delayed.
    water more rapidly with steam and
    acids to produce flammable gas
    (hydrogen see - ICSC # 0001) causing
    fire and explosion hazard. Burns in
    nitrogen oxide above 200°C.

    TLV: ppm; 0.2 mg/m3 (ACGIH 1996).         The substance may have effects on the
    MAK: ppm; 0.5 mg/m3 (1994).               lungs and nervous system, resulting in
                                                bronchitis, pneumonia, neurologic and
                                                neuropsychiatric disorders (manganism).
                                                Animal tests show that this substance
                                                possibly causes toxic effects upon
                                                human reproduction.


                                      PHYSICAL PROPERTIES
    Boiling point:                1962 °C
    Melting point:                1244 °C
    Relative density (water = 1): 7.2-7.4
    Solubility in water:          none
                                        ENVIRONMENTAL DATA

    Depending on the degree of exposure, periodic medical examination is indicated.
    The recommendations on this Card also apply to ferro manganese.

                                      ADDITIONAL INFORMATION


    LEGAL NOTICE       Neither the CEC nor the IPCS nor any person acting on behalf of
                       the CEC or the IPCS is responsible for the use which might be
                       made of this information.


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    Agency for Toxic Substances and Disease Registry (1996)

         The  Toxicological profile for manganese (update) (ATSDR, 1996)
    was prepared by the Agency for Toxic Substances and Disease Registry
    (ATSDR) through a contract with the Research Triangle Institute. The
    updated profile was published as a draft for public comment in
    February 1998. Copies of the profile can be obtained from:

         Division of Toxicology
         Agency for Toxic Substances and Disease Registry
         Public Health Service
         US Department of Health and Human Services
         1600 Clifton Road NE, Mailstop E-29
         Atlanta, Georgia 30333

         Dr M. Williams-Johnson, Division of Toxicology, ATSDR, and Dr
    S.G. Donkin, Dr S.W. Rhodes, and L. Kolb, Sciences International,
    Inc., Alexandria, Virginia, contributed to the development of the
    toxicological profile as chemical manager and authors. The profile has
    undergone three ATSDR internal reviews, including Green Border Review
    to assure consistency with ATSDR policy, a Health Effects Review, and
    a Minimal Risk Level Review. An external peer review panel was
    assembled for the update profile for manganese. The panel consisted of
    the following members: Dr J Greger, University of Wisconsin, Madison,
    Wisconsin; Dr D.J. Hodgson, University of Wyoming, Laramie, Wyoming;
    and Dr C. Newland, Auburn University, Auburn, Alabama. These experts
    collectively have knowledge of manganese's physical and chemical
    properties, toxicokinetics, key health end-points, mechanisms of
    action, human and animal exposure, and quantification of risk to
    humans. All reviewers were selected in conformity with the conditions
    for peer review specified in Section 104(i)(13) of the US
     Comprehensive Environmental Response, Compensation, and Liability
    Act, as amended.

         Scientists from ATSDR reviewed the peer reviewers' comments and
    determined which comments were to be included in the profile. A
    listing of the peer reviewers' comments not incorporated in the
    profile, with a brief explanation of the rationale for their
    exclusion, exists as part of the administrative record for this
    compound. A list of databases reviewed and a list of unpublished
    documents cited are also included in the administrative record. The
    citation of the peer review panel should not be understood to imply
    its approval of the profile's final content.

    Hazardous Substances Data Bank (1998)

         Copies of the information on manganese stored in the Hazardous
    Substances Data Bank (HSDB) can be obtained from:

         Specialized Information Services
         National Library of Medicine
         National Institutes of Health
         Public Health Service
         US Department of Health and Human Services
         8600 Rockville Pike
         Bethesda, Maryland 20894

         HSDB is peer reviewed by a scientific review panel composed of
    expert toxicologists and other scientists.


         The draft CICAD on manganese and its compounds was sent for
    review to institutions and organizations identified by IPCS after
    contact with IPCS national Contact Points and Participating
    Institutions, as well as to identified experts. Comments were received

         BHP Minerals, San Francisco, USA

         Department of Health, London, United Kingdom

         Department of Toxicology and Chemistry, National Institute for
         Working Life, Solna, Sweden 

         Environment Canada, Ottawa, Canada

         Health Canada, Ottawa, Canada

         Institute of Occupational Health, Helsinki, Finland

         National Chemicals Inspectorate, Solna, Sweden

         National Institute for Environmental Health and Safety,
         Washington, DC, USA

         National Institute for Occupational Safety and Health, Atlanta,

         National Institute for Public Health, Prague, Czech Republic

         National Institute of Occupational Health, Budapest, Hungary

         Public Health Centre of the Capital City, Prague, Czech Republic

         United States Environmental Protection Agency, Washington, DC,

         Université de Montréal, Montreal, Canada


    Berlin, Germany, 26-28 November 1997


    Dr H. Ahlers, Education and Information Division, National Institute
    for Occupational Safety and Health, Cincinnati, OH, USA

    Mr R. Cary, Health Directorate, Health and Safety Executive, Bootle,
    United Kingdom

    Dr S. Dobson, Institute of Terrestrial Ecology, Huntingdon, United

    Dr R.F. Hertel, Federal Institute for Health Protection of Consumers &
    Veterinary Medicine, Berlin, Germany  (Chairperson)

    Mr J.R. Hickman, Health Protection Branch, Health Canada, Ottawa,
    Ontario, Canada

    Dr I. Mangelsdorf, Documentation and Assessment of Chemicals,
    Fraunhofer Institute for Toxicology and Aerosol Research, Hanover,

    Ms M.E. Meek, Environmental Health Directorate, Health Canada, Ottawa,
    Ontario, Canada  (Rapporteur)

    Dr K. Paksy, Department of Reproductive Toxicology, National Institute
    of Occupational Health, Budapest, Hungary

    Mr V. Quarg, Ministry for the Environment, Nature Conservation &
    Nuclear Safety, Bonn, Germany

    Mr D. Renshaw, Department of Health, London, United Kingdom

    Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute
    of Health Sciences, Tokyo, Japan

    Prof. S. Soliman, Department of Pesticide Chemistry, Alexandria
    University, Alexandria, Egypt  (Vice-Chairperson)

    Dr M. Wallen, National Chemicals Inspectorate (KEMI), Solna, Sweden

    Ms D. Willcocks, Chemical Assessment Division, Worksafe Australia,
    Camperdown, Australia

    Dr M. Williams-Johnson, Division of Toxicology, Agency for Toxic
    Substances and Disease Registry, Atlanta, GA, USA

    Dr K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt und
    Gesundheit GmbH, Institut für Toxikologie, Oberschleissheim, Germany


    Mrs B. Dinham1, The Pesticide Trust, London, United Kingdom

    Dr R. Ebert, KSU Ps-Toxicology, Huels AG, Marl, Germany (representing
    ECETOC, the European Centre for Ecotoxicology and Toxicology of

    Mr R. Green,1 International Federation of Chemical, Energy, Mine and
    General Workers' Unions, Brussels, Belgium

    Dr B. Hansen,1 European Chemicals Bureau, European Commission, Ispra,

    Dr J. Heuer, Federal Institute for Health Protection of Consumers &
    Veterinary Medicine, Berlin, Germany

    Mr T. Jacob,1 DuPont, Washington, DC, USA

    Ms L. Onyon, Environment Directorate, Organisation for Economic
    Co-operation and Development, Paris, France

    Dr H.J. Weideli, Ciba Speciality Chemicals Inc., Basel, Switzerland
    (representing CEFIC, the European Chemical Industry Council)


    Dr M. Baril, International Programme on Chemical Safety, World Health
    Organization, Geneva, Switzerland

    Dr R.G. Liteplo, Health Canada, Ottawa, Ontario, Canada

    Ms L. Regis, International Programme on Chemical Safety, World Health
    Organization, Geneva, Switzerland

    Mr A. Strawson, Health and Safety Executive, London, United Kingdom

    Dr P. Toft, Associate Director, International Programme on Chemical
    Safety, World Health Organization, Geneva, Switzerland

    1 Invited but unable to attend.


         An additional approach in deriving an inhalation guidance value
    for manganese could involve dividing the exposed workers from the
    Roels et al. (1992) study into four quartiles to estimate a
    dose-response relationship and using the average cumulative exposure
    and average exposure duration for the lowest quartile of workers to
    calculate a NOAEL of 32 µg/m3 (adjusted for continuous exposure),
    which could be divided by an uncertainty factor of 300 (10 to account
    for human variability, 10 to account for less than lifetime exposure,
    and 3 to account for other weaknesses in the study and overall
    database -- i.e., statistical weakness from only 23 people in each
    quartile, exposure to a manganese oxide other than manganese
    tetroxide, and a lack of reproductive data), yielding a guidance value
    of 0.1 µg/m3 (Egyed & Wood, 1996).

         A guidance value might also be derived by using the geometric
    mean integrated respirable dust concentration reported in the Roels et
    al. (1992) study and adjusting for exposure duration to calculate an
    exposure-adjusted lowest-observed-adverse-effect level (LOAEL) of 50
    µg/m3, which could be divided by an uncertainty factor of 1000 (10 to
    protect sensitive individuals, 10 to account for using a LOAEL instead
    of a NOAEL, and 10 to account for database limitations 
    -- extrapolation from subchronic to chronic exposure, inadequate
    reproductive and developmental data, and unknown differences in the
    toxicity of different forms of manganese), yielding a guidance value
    of 0.05 µg/m3 (US EPA, 1994b, 1994c; Davis, 1998). Other possible
    guideline values, calculated using other methods (e.g., benchmark,
    Bayesian, etc.), would range from 0.09 to 0.2 µg/m3 (US EPA, 1994a,
    1994b, 1994c; Davis, 1998).

         Alternatively, an inhalation guidance value could be derived
    based upon a LOAEL of 140 µg total manganese dust/m3 reported in the
    study by Iregren (1990), divided by an uncertainty/modifying factor of
    900 (10 to account for use of a LOAEL instead of a NOAEL; 10 to
    account for human variability; and two modifying factors -- 3 to
    account for effects from cumulative exposure to manganese, and 3 to
    account for potential differences in toxicity from different forms of
    manganese) and adjusted for continuous rather than intermittent
    exposure, yielding a provisional guidance value of 0.04 µg/m3 (ATSDR,


         Ce CICAD relatif au manganèse et à ses dérivés repose
    essentiellement sur un rapport intitulé  Toxicological profile for
     manganese (update), draft for public comment et rédigé par l'Agency
    for Toxic Substances and Disease Registry, US Department of Health and
    Human Services (ATSDR, 1996). On a également utilisé les informations
    contenues dans la Banque de données pour les substances dangereuses,
    une banque de données constituée et gérée par la National Library of
    Medicine, US Department of Health and Human Services (HSDB, 1998). Les
    dernières données sur lesquels s'appuient ces documents de base
    remontent à novembre 1998. Enfin, des données complémentaires ont été
    tirées des évaluations publiées par l'US Environmental Protection
    Agency (EPA) et l'Organisation mondiale de la Santé (OMS) ainsi que de
    divers autres documents. Les documents de base utilisés pour la
    rédaction de ce CICAD ne prennent pas en compte les effets du
    manganèse sur les écosystèmes. Aucune autre source documentaire
    (c'est-à-dire des documents rédigés par des organismes internationaux
    et soumis à une contrôle scientifique rigoureux) n'a pu être trouvée.
    Ce CICAD ne concerne donc que les effets que la présence de manganèse
    dans l'environnement peut avoir sur la santé humaine. On n'a pas
    cherché à déterminer les effets exercés sur les autres êtres vivants
    dans leur milieu naturel. On trouvera à l'appendice 1 des indications
    sur les sources documentaires utilisées. Les renseignements concernant
    l'examen du CICAD par des pairs font l'objet de l'appendice 2. Ce
    CICAD a été approuvé en tant qu'évaluation internationale lors d'une
    réunion du Comité d'évaluation finale qui s'est tenue à Berlin
    (Allemagne) du 26 au 28 novembre 1997. La liste des participants à
    cette réunion figure à l'appendice 3. La fiche d'information
    internationale sur la sécurité chimique (ICSC No 0174) établie par le
    Programme international sur la Sécurité chimique (IPCS, 1993) est
    également reproduite dans ce document.

         Le manganèse (Mn) est un élément présent à l'état naturel dans
    les roches, le sol, l'eau et les aliments. Tous les êtres humains sont
    donc exposés au manganèse et ce dernier est un constituant naturel de
    l'organisme. La voie d'exposition la plus importante pour l'Homme est
    habituellement la voie alimentaire. Les doses journalières considérées
    comme suffisantes et sans danger vont de 1 à 5 mg de manganèse pour
    les enfants de 1 an et plus et les adultes. Elles correspondent
    généralement à l'apport d'origine alimentaire.

         Le manganèse est libéré dans l'atmosphère principalement sous la
    forme de particules dont la destinée et le transport dépendent de leur
    taille et de leur densité ainsi que de la vitesse et de la direction
    du vent. Certains dérivés du manganèse sont très solubles dans l'eau,
    de sorte qu'on s'expose facilement à en ingérer une quantité
    importante en buvant de l'eau contaminée. Le manganèse présent dans
    l'eau peut subir une oxydation, s'adsorber sur les particules en
    suspension et sédimenter ensuite. Dans le sol, le manganèse peut
    migrer sous forme de particules dans l'air ou dans l'eau ou encore,
    s'il est présent sous la forme de composés solubles, en être éliminé
    par lessivage.

         C'est chez les personnes employées dans des ateliers libérant des
    poussières à forte teneur en manganèse, ou qui vivent dans leur
    voisinage, que l'exposition au manganèse a le plus de chances d'être
    supérieure à la moyenne. Dans certaines régions, la population peut
    être exposée au manganèse libéré dans l'atmosphère par la combustion
    d'essence sans plomb additionnée d'un antidétonnant organomanganique,
    le méthylcyclopentadiénylmanganèse-tricarbonyle (MMT). Certaines
    personnes peuvent absorber une quantité excessive de manganèse en
    consommant l'eau de puits contaminés par du manganése provenant de
    piles ou de pesticides. De même les enfants peuvent se contaminer en
    portant à leur bouche de la terre contenant du manganèse en excès.

         Le manganèse est un nutriment essentiel pour l'Homme. Il
    intervient dans la minéralisation des os, dans le métabolisme
    énergétique et dans celui des protéines, dans la régulation du
    métabolisme, dans la protection des cellules contre les radicaux
    libres et dans la formation de glycosaminoglycanes. L'inhalation ou
    l'ingestion de quantités excessives de manganèse peut toutefois avoir
    des effets indésirables. A dose administrée équivalente, on retrouve
    davantage de manganèse dans l'encéphale après inhalation qu'après
    ingestion et la plupart des effets qu'il provoque sont liés à une
    exposition chronique par la voie respiratoire. On sait peu de chose de
    la toxicité relative des divers composés du manganèse. Toutefois, les
    données disponibles indiquent que plusieurs d'entre eux sont capables
    de provoquer des effets neurologiques; on a observé ces effets chez
    l'Homme après exposition chronique (365 jours ou davantage) par la
    voie respiratoire ainsi que chez l'animal, après exposition de durée
    intermédiaire (15-364 jours) ou exposition chronique par voie buccale.

         D'une manière générale, on constate, à la lumière des données
    disponibles, qu'une exposition à des concentrations excessives de
    manganèse pendant deux semaines ou moins (exposition brève) ou une
    période pouvant aller jusqu'à un an (exposition de durée
    intermédiaire) exerce un effet sur les voies respiratoires et sur le
    système nerveux, mais peu ou pas d'effets sur les autres organes. Une
    intoxication aiguë par inhalation de poussières à forte teneur en
    manganèse (en particulier sous forme de dioxyde MnO2 ou de tétroxyde
    Mn3O4) peut provoquer une réaction inflammatoire au niveau
    pulmonaire qui, avec le temps, peut aboutir à une détérioration de la
    capacité fonctionnelle du poumon. Cette toxicité pulmonaire se
    manifeste sous la forme d'une sensibilité accrue aux maladies
    infectieuses - bronchites par exemple - et peut évoluer vers une
    pneumopathie fibreuse. On a également observé une pneumopathie après
    une brève inhalation de particules contenant d'autres métaux. Cet
    effet pourrait donc être caractéristique d'une exposition à des
    particules par la voie respiratoire et ne pas être uniquement lié à la
    teneur de ces particules en manganèse.

         Il existe quelques documents selon lesquels une exposition de
    durée intermédiaire à des dérivés du manganèse est susceptible
    d'exercer des effets sur le système nerveux central, mais on ne
    dispose pas d'estimation fiable du niveau d'exposition nécessaire pour
    produire de tels effets. Les études d'inhalation effectuées sur des

    animaux ont révélé l'existence d'effets biochimiques, respiratoires et
    neurocomportementaux. On n'a cependant pas déterminé quel était le
    seuil d'apparition de ces effets car le niveau d'exposition nécessaire
    à leur manifestation varie dans la proportion de 1 à 10.

         En cas d'exposition chronique par la voie respiratoire, les
    principaux organes-cibles sont les poumons, le système nerveux et les
    gonades, encore que l'on ait également observé des effets au niveau
    d'autres organes. On a constaté des cas de pneumopathie fibreuse
    récidivante et des effets respiratoires aigus à la suite d'une
    exposition chronique au manganèse. Les effets sur le système nerveux
    se traduisent notamment par des troubles neurologiques et
    neuropsychiatriques pouvant aboutir à une pathologie de type
    parkinsonien connue sous le nom de manganisme. L'expérience incite à
    penser que les animaux de laboratoire, et notamment les rongeurs, ne
    sont pas aussi sensibles que l'Homme aux effets neurologiques provoqué
    par l'inhalation de manganèse. Au nombre des effets sur la fonction de
    reproduction figurent une réduction de la libido, l'impuissance et une
    diminution de la fécondité chez les sujets de sexe masculin. On ne
    dispose d'aucune information concernant les effets qui s'exerceraient
    sur la fonction génitale de la femme. L'expérimentation animale
    indique que le manganèse peut provoquer des lésions testiculaires et
    des résorptions tardives. Les données tirées de l'expérimentation
    animale et relatives aux effets de l'inhalation de manganèse sur le
    système immunitaire ou sur le développement foetal sont trop limitées
    pour que l'on puisse se prononcer véritablement au sujet de la
    signification de ces effets pour l'Homme.

         On ne dispose que de données limitées sur le pouvoir cancérogène
    du manganèse et les résultats expérimentaux sont difficiles à
    interpréter de façon catégorique. L'administration chronique de
    sulfate de manganèse (MnSO4) à des rats par la voie buccale a
    provoqué une légère augmentation des tumeurs du pancréas chez les
    mâles et un nombre un peu plus élevé d'adénomes hypophysaires chez les
    femelles. D'autres études portant sur le même composé n'ont pas mis de
    cancers en évidence chez le rat et une augmentation marginale de
    l'incidence des tumeurs affectant les cellules folliculaires de la
    thyroïde a été relevée chez des souris. D'après des études  in vitro,
    il existe, chez certains composés tout au moins, un pouvoir mutagène.
    Quoi qu'il en soit, les études  in vivo chez les mammifères donnent
    des résultats irréguliers et aucune conclusion générale ne peut en
    être tirée en ce qui concerne le risque génotoxique que pourrait
    comporter une exposition aux dérivés du manganèse.

         Ingérés à forte dose par gavage, des sels concentrés de manganèse
    peuvent entraîner la mort des animaux, mais une exposition de brève
    durée par suite de la consommation d'aliments ou d'eau contaminés par
    du manganèse ne semble pas entraîner d'intoxication importante. De
    même, l'administration de sels de manganèse par la voie parentérale
    peut avoir un effet toxique sur le développement, mais ces effets ne
    s'observent pas après ingestion. On a décrit deux cas de neurotoxicité
    après ingestion, pendant une période de durée intermédiaire, de

    dérivés du manganèse par des sujets humains, mais les données sont
    trop limitées pour que l'on puisse définir le seuil de toxicité ou
    savoir si ces effets étaient imputables en totalité au manganèse. On
    possède quelques données sur les effets neurologiques ou autres,
    consécutifs, chez l'Homme, à l'ingestion prolongée de manganèse, mais
    les études dont elles sont tirées pêchent par l'incertitude qui
    entoure les voies d'exposition, les doses totales et l'existence
    d'autres facteurs de confusion. Les données fournies par les études
    sur l'Homme et l'animal sont insuffisantes pour permettre de
    déterminer les doses ou les effets à prendre en considération dans le
    cas d'une exposition de longue durée par la voie digestive. Les
    éléments dont on dispose au sujet des effets indésirables d'une
    ingestion prolongée de quantités excessives de manganèse sont
    évocateurs mais non concluants.

         La voie percutanée ne semble pas devoir être prise sérieusement
    en considération et n'a d'ailleurs guère été étudiée. Les données dont
    on dispose se limitent à l'effet corrosif du permanganate de potassium
    (KMnO4) ou à des cas d'absorption percutanée de dérivés organiques du
    manganèse comme le MMT.

         A la lumière de ces données, il apparaît clairement qu'une
    exposition au manganèse sur les lieux de travail peut entraîner des
    effets neurologiques ou respiratoires. D'autres données, plus
    limitées, incitent également à penser que l'ingestion de manganèse en
    quantités excessives du fait de sa présence dans l'environnement peut
    aussi avoir des effets neurologiques indésirables. Certains individus
    peuvent être porteurs de facteurs qui les prédisposent à être plus
    vunérables aux effets indésirables d'une exposition à des quantités
    excessives de manganèse. Il peut s'agir notamment de malades atteints
    de pneumopathies, de personnes exposées à d'autres irritants
    pulmonaires, de nouveau-nés, de personnes âgées, de sujets souffrant
    de carence martiale ou encore d'hépatiques.

         Il y a plusieurs manières de parvenir à une valeur-guide pour le
    manganèse présent dans l'air. On peut citer ici à titre d'exemple le
    chiffre de 0,15 µg de manganèse par m3 qui a été récemment proposé;
    on trouvera également d'autres méthodes envisageables pour obtenir ces


         Este CICAD sobre el manganeso y sus compuestos se basa
    fundamentalmente en el informe titulado  Perfil toxicológico del
     manganeso (actualización), proyecto de información pública,
    preparado por la Agencia para el Registro de Sustancias Tóxicas y
    Enfermedades, Departamento de Salud y Servicios Sociales de los
    Estados Unidos (ATSDR, 1996). Se utilizó asimismo la información
    contenida en el Banco de Datos de Sustancias Peligrosas, servicio que
    ha creado y mantiene la Biblioteca Nacional de Medicina del
    Departamento de Salud y Servicios Sociales de los Estados Unidos
    (HSDB, 1998). Se examinaron los datos identificados en estos
    documentos originales hasta noviembre 1998. Hay información adicional
    procedente de otras referencias, como las evaluaciones preparadas por
    la Agencia para la Protección del Medio Ambiente de los Estados Unidos
    (EPA) y la Organización Mundial de la Salud (OMS), así como de
    diversos informes publicados. Los documentos originales utilizados en
    la preparación del presente CICAD no comprenden los efectos del
    manganeso en el medio ambiente. No se identificaron otras fuentes
    (documentos preparados por una organización nacional y sujetos a un
    examen científico riguroso) sobre este tema. Por consiguiente, en este
    CICAD se abordan sólo los niveles en el medio ambiente como fuente de
    exposición humana. Tampoco se ha intentado evaluar en el presente
    documento los efectos sobre los organismos en el medio ambiente. La
    información sobre la disponibilidad de los documentos originales
    figura en el apéndice 1. La información acerca del examen colegiado de
    este CICAD se presenta en el apéndice 2. Su aprobación como evaluación
    internacional se realizó en una reunión de la Junta de Evaluación
    Final, celebrada en Berlín, Alemania, los días 26-28 de noviembre de
    1997. La lista de participantes en esta reunión figura en el apéndice
    3. La Ficha internacional de seguridad química (ICSC 0174) para el
    manganeso, preparada por el Programa Internacional de Seguridad de las
    Sustancias Químicas (IPCS, 1993), también se reproduce en el presente

         El manganeso (Mn) es un elemento natural del medio ambiente, que
    se encuentra en las rocas, el suelo, el agua y los alimentos. Así
    pues, todas las personas están expuestas al manganeso y es un
    componente normal del organismo. La vía de exposición más importante
    para el ser humano suelen ser los alimentos. Se ha establecido una
    ingesta diaria inocua y suficiente de 1-5 mg de manganeso para niños
    de un año y mayores hasta la edad adulta; estos niveles generalmente
    se corresponden con las cantidades del compuesto que se reciben a
    través de los alimentos.

         El manganeso se libera en el aire fundamentalmente como materia
    particulada, y el destino final y el transporte de las partículas
    dependen de su tamaño y densidad y de la velocidad y la dirección del
    viento. Algunos compuestos de manganeso son muy solubles en agua, de
    manera que se puede producir una exposición importante por el consumo
    de agua de bebida contaminada. El manganeso del agua superficial se
    puede oxidar o adsorber en las partículas del sedimento y depositarse

    en el fondo. El del suelo puede pasar como materia particulada al aire
    o al agua, y los compuestos solubles de manganeso pueden sufrir un
    proceso de lixiviación a partir del suelo.

         Las exposiciones al manganeso mencionadas más arriba son más
    probables en el caso de las personas que trabajan o viven cerca de
    fábricas o de otros lugares donde se liberan cantidades significativas
    de polvo de manganeso en el aire. En algunas regiones, la población
    general puede estar expuesta al manganeso liberado en el aire por la
    combustión de la gasolina sin plomo que contiene el compuesto orgánico
    de manganeso, metilciclopentadienilo-manganeso tricarbonilo (MMT) como
    ingrediente antidetonante. Algunas personas pueden estar expuestas a
    un exceso de manganeso en el agua potable, por ejemplo cuando se
    filtra al agua de los pozos manganeso de las baterías o de
    plaguicidas. Los niños pueden estar expuestos a un exceso de manganeso
    en el suelo por la costumbre de llevarse las manos a la boca.

         El manganeso es un nutriente esencial del ser humano que
    desempeña una función en la mineralización de los huesos, en el
    metabolismo proteico y energético, en la regulación metabólica, en la
    protección de las células del efecto perjudicial de sustancias con
    radicales libres nocivos y en la formación de glucosaminoglucanos. Sin
    embargo, la exposición a niveles elevados mediante inhalación o
    ingestión puede producir efectos adversos en la salud. Para dosis
    comparables, llega al cerebro más manganeso después de la inhalación
    que de la ingestión, y la mayor parte de los efectos en la salud están
    asociados con la exposición crónica por inhalación. Es poco lo que se
    sabe acerca de la toxicidad relativa de los distintos compuestos de
    manganeso. Sin embargo, hay pruebas que ponen de manifiesto que
    diversos compuestos de manganeso pueden inducir efectos neurológicos;
    estos efectos se han observado tras una exposición crónica por
    inhalación (365 días o más) en el ser humano y una exposición oral
    intermedia (15-364 días) y crónica en animales. 

         En general, los datos disponibles indican que la exposición a un
    exceso de manganeso durante 14 días o menos (aguda) o hasta un año
    (intermedia) tiene efectos en el sistema respiratorio y en el sistema
    nervioso, con un efecto escaso o nulo en otros órganos. La exposición
    aguda por inhalación a concentraciones elevadas de polvo de manganeso
    (en concreto de dióxido de manganeso [MnO2] y de tetróxido de
    manganeso [Mn3O4]) puede provocar una respuesta inflamatoria en el
    pulmón, que con el tiempo puede dar lugar a un trastorno de la función
    pulmonar. La toxicidad pulmonar se manifiesta en forma de una mayor
    susceptibilidad a infecciones como la bronquitis y puede producir
    neumonía mangánica. Se ha observado también neumonía tras exposiciones
    agudas por inhalación a partículas que contenían otros metales. Así
    pues, este efecto podría ser característico de la materia particulada
    inhalable y no depender solamente del contenido en manganeso de las

         Hay un pequeño número de informes que parecen indicar que en la
    exposición intermedia a compuestos de manganeso por inhalación se
    producen efectos en el sistema nervioso central, pero no se dispone de
    estimaciones fidedignas sobre los niveles de exposición. Los estudios
    de inhalación en animales pusieron de manifiesto efectos bioquímicos,
    respiratorios y en el neurocomportamiento. Sin embargo, no se ha
    determinado un umbral para estos efectos, porque los niveles de
    exposición asociados con ellos varían en más de un orden de magnitud.

         En la exposición crónica al manganeso por inhalación, los
    principales órganos afectados son los pulmones, el sistema nervioso y
    el sistema reproductor, aunque también se han observado efectos en
    otros sistemas de órganos. Este tipo de exposición se ha asociado con
    una neumonía mangánica recurrente y con efectos respiratorios agudos.
    Los efectos en el sistema nervioso incluyen síntomas neurológicos y
    neuropsiquiátricos que pueden culminar en una enfermedad semejante a
    la de Parkinson, conocida como manganismo; hay pruebas que indican que
    los animales de laboratorio, especialmente los roedores, no son tan
    sensibles como el ser humano, y posiblemente otros primates, a los
    efectos neurológicos provocados por la exposición al manganeso por
    inhalación. Los efectos reproductivos de la exposición crónica por
    inhalación son una reducción de la libido, impotencia y menor
    fecundidad en los hombres; no se dispone de información acerca de los
    efectos reproductivos en las mujeres. Los estudios realizados en
    animales indican que el manganeso puede producir daños directos en los
    testículos y resorciones tardías. Los datos obtenidos de estudios
    realizados con animales sobre los efectos del manganeso inhalado en el
    sistema inmunitario y en el desarrollo del feto son demasiado
    limitados para sacar conclusiones sobre la importancia de estos
    efectos en el ser humano.

         La información sobre el potencial carcinogénico del manganeso es
    limitada y los resultados son difíciles de interpretar con certeza.
    Los estudios de exposición crónica por vía oral realizados con sulfato
    de manganeso (MnSO4) en ratas pusieron de manifiesto un pequeño
    aumento en la incidencia de tumores pancreáticos en los machos y un
    ligero incremento de los adenomas de hipófisis en las hembras. En
    otros estudios realizados con sulfato de manganeso, no se observaron
    signos de cáncer en ratas y en ratones se detectó un aumento marginal
    de la incidencia de adenomas de las células foliculares de la glándula
    tiroides. Los resultados de los estudios  in vitro ponen de
    manifiesto que por lo menos algunas formas químicas del manganeso
    tienen potencial mutagénico. Sin embargo, debido a las discrepancias
    entre los resultados de los estudios  in vivo realizados en
    mamíferos, no se puede llegar a una conclusión general acerca del
    posible peligro genotóxico para el ser humano como consecuencia de la
    exposición a compuestos de manganeso.

         La administración de dosis elevadas de sales concentradas de
    manganeso por vía oral mediante sonda puede provocar la muerte de los
    animales, pero no se ha observado que la exposición oral a través de
    los alimentos o del agua produzca una toxicidad significativa durante

    una exposición aguda o breve. Igualmente, la administración parenteral
    de sales de manganeso puede producir toxicidad en el desarrollo, pero
    no se encontraron efectos tras las exposición por vía oral. Se ha
    notificado que la exposición oral de duración intermedia del ser
    humano al manganeso produjo neurotoxicidad en dos casos, pero los
    datos son demasiado limitados para definir el umbral o juzgar si estos
    efectos se debieron completamente a la exposición al manganeso.
    Existen algunos datos acerca de los efectos neurológicos o de otro
    tipo para la salud de las personas debidos a la exposición oral
    crónica al manganeso, pero estos estudios están limitados por la
    incertidumbre en relación con las vías de exposición y los niveles de
    exposición total, así como por la existencia de otros factores de
    confusión. Los estudios en el ser humano y en animales no proporcionan
    información suficiente para determinar las dosis o los efectos que
    despiertan preocupación tras la exposición crónica por vía oral. Así
    pues, las pruebas disponibles para los efectos adversos asociados con
    la ingesta crónica de un exceso de manganeso son indicativas, pero no

         La vía cutánea no parece revestir especial importancia y no se ha
    investigado en absoluto. Los datos disponibles se limitan a informes
    sobre los efectos corrosivos del permanganato potásico (KMnO4) y a
    informes de casos de efectos debidos a la absorción cutánea de
    compuestos orgánicos del manganeso, como el MMT.

         Según estos datos, es evidente que la exposición al manganeso
    puede producir efectos neurológicos y respiratorios adversos en el
    ámbito ocupacional. También hay pruebas limitadas que indican que los
    efectos neurológicos adversos pueden estar asociados con la ingesta de
    un exceso de manganeso en las condiciones del medio ambiente. Como
    consecuencia de los factores de predisposición, determinadas personas
    podrían ser más susceptibles a los efectos adversos de la exposición a
    un exceso de manganeso. Entre ellas podrían estar las afectadas por
    enfermedades pulmonares, las expuestas a otras sustancias irritantes
    de los pulmones, los recién nacidos, los ancianos, y las personas con
    déficit de hierro o con enfermedades hepáticas.

         Existen varios métodos para la obtención de un valor guía para el
    manganeso en el aire. Recientemente se ha obtenido un valor guía de
    0,15 µg de manganeso/m3, que se destaca aquí como un posible ejemplo;
    también se han presentado algunos métodos adicionales.

    See Also:
       Toxicological Abbreviations