IPCS INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 17
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ENVIRONMENTAL HEALTH CRITERIA FOR MANGANESE
1. SUMMARY AND RECOMMENDATIONS FOR FURTHER STUDIES
1.1.1. Analytical methods
1.1.2. Sources and pathways of exposure
1.1.3. Essentiality of manganese
1.1.4. Magnitude of environmental exposure
1.1.6. Effects on experimental animals
1.1.7. Effects on man
126.96.36.199 Occupational exposure
188.8.131.52 Community exposure
1.1.8. Organomanganese compounds
1.2. Recommendations for further studies
1.2.1. Analytical methods
1.2.2. Environmental exposure
1.2.4. Experimental animal studies
1.2.5. Epidemiological and clinical studies
2. PROPERTIES AND ANALYTICAL METHODS
2.1. Chemical and physical properties of manganese
and its compounds
2.2. Sampling and analysis
2.2.1. Collection and preparation of samples
2.2.2. Separation and concentration
2.2.3. Methods for quantitative determination
184.108.40.206 Optical spectroscopy
220.127.116.11 Atomic absorption spectroscopy
18.104.22.168 Neutron-activation analysis
22.214.171.124 X-ray fluorescence
126.96.36.199 Other methods
188.8.131.52 Comparability of methods
3. SOURCES OF MANGANESE IN THE ENVIRONMENT
3.1. Natural occurrence
3.2. Industrial production and consumption
3.2.2. Contamination by waste disposal
3.2.3. Other sources of pollution
4. ENVIRONMENTAL LEVELS AND EXPOSURE
4.1.1. Ambient air
4.1.2. Air in workplaces
4.5. Total exposure from environmental media
5. TRANSPORT AND DISTRIBUTION IN ENVIRONMENTAL MEDIA
5.1. Photochemical and thermal reactions in the lower atmosphere
5.2. Decomposition in fresh water and seawater
5.3. Atmospheric washout and rainfall
5.4. Run-off into fresh water and sea water
5.5. Microbiological utilization in soils
5.6. Uptake by soil and plants
5.8. Organic manganese fuel additives
6. METABOLISM OF MANGANESE
6.1.1. Absorption by inhalation
6.1.2. Absorption from the gastrointestinal tract
6.2.1. Distribution in the human body
6.2.2. Distribution in the animal body
6.2.3. Transport mechanisms
6.3. Biological indicators of manganese exposure
6.5. Biological half-times
7. MANGANESE DEFICIENCY
7.1. Metabolic role of manganese
7.2. Manganese deficiency and requirements in man
7.3. Manganese deficiency in animals
8. EXPERIMENTAL STUDIES ON THE EFFECTS OF MANGANESE
8.1. Median lethal dose
8.2. Effects on specific organs and systems
8.2.1. Central nervous system
8.2.2. Respiratory system
8.2.4. Cardiovascular effects
8.2.5. Haematological effects
8.3. Effects on reproduction
8.5. Mutagenicity and chromosomal abnormalities
8.6. Miscellaneous effects
8.7. Toxicity of organic manganese fuel additives
8.8. Mechanisms and toxic effects
9. HUMAN EPIDEMIOLOGICAL AND CLINICAL STUDIES
9.1. Occupational exposure and health effects
9.2. General population exposure and health effects
9.3. Clinical studies
9.3.1. Pathomorphological studies
9.3.2. Therapeutic studies
9.4. Susceptibility to manganese poisoning
10. EVALUATION OF THE HEALTH RISKS TO MAN FROM EXPOSURE TO
MANGANESE AND ITS COMPOUNDS
10.1. Relative contributions of air, food and water to total
10.1.1. General population
10.1.2. Occupationally-exposed groups
10.2. Manganese requirements and deficiency
10.3. Effects in relation to exposure
10.3.1. General population
10.3.2. Occupationally-exposed groups
10.3.2.1 Effects on the central nervous system
10.3.2.2 Manganese pneumonia
10.3.2.3 Nonspecific effects on the respiratory
10.3.2.4 Diagnosis of manganese poisoning and
indices of exposure
10.3.2.5 Susceptibility and interaction
10.4. Organomanganese compounds
10.5. Conclusions and recommendations
10.5.1. Occupational exposure
10.5.2. General population exposure
NOTE TO READERS OF THE CRITERIA DOCUMENTS
While every effort has been made to present information in the
criteria documents as accurately as possible without unduly delaying
their publication, mistakes might have occurred and are likely to
occur in the future. In the interest of all users of the environmental
health criteria documents, readers are kindly requested to communicate
any errors found to the Division of Environmental Health, World Health
Organization, Geneva, Switzerland, in order that they may be included
in corrigenda which will appear in subsequent volumes.
In addition, experts in any particular field dealt with in the
criteria documents are kindly requested to make available to the WHO
Secretariat any important published information that may have
inadvertently been omitted and which may change the evaluation of
health risks from exposure to the environmental agent under
examination, so that the information may be considered in the event of
updating and re-evaluation of the conclusions contained in the
WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR MANGANESE
Dr M. Cikrt, Institute of Hygiene and Epidemiology, Prague,
Dr G J. van Esch, Toxicology and Food Chemistry, National Institute of
Public Health, Bilthoven, Netherlands (Chairman)
Dr G. F. Hueter, Environmental Research Center, US Environmental
Protection Agency, Research Triangle Park, NC, USA
Dr I. C. Munro, Toxicology Research Division, Bureau of Chemical
Safety, Department of National Health and Welfare, Ottawa,
Ontario, Canada (Rapporteur)
Dr H. Oyanguren, Institute of Occupational Health and Air Pollution,
National Health Service, Santiago, Chile
Dr M. Saric, Institute of Medical Research and Occupational Health,
Dr S. Sigan, Sysin Institute of General and Community Hygiene, Moscow,
Dr N. Skvortsova, Laboratory for Air Pollution Control, Sysin
Institute of General and Community Hygiene, Moscow, USSR
Professor M. Tati, Department of Public Health, Gifu University
Medical School, Gifu, Japan
Dr I. Ulanova, Institute of Industrial Hygiene and Occupational
Diseases, Moscow, USSR (Vice-Chairman)
Representatives of other agencies
Dr H. M. Mollenhauer, Division of Geophysics, Global Pollution and
Health, United Nations Environment Programme, Nairobi, Kenya
Dr D. Djordjevic, Occupational Health and Safety Branch, International
Mrs M. Th. van der Venne, Health Protection Directorate, Commission of
the European Communities, Luxembourg
Dr Y. Hasegawa, Medical Officer, Control of Environmental Pollution
and Hazards, World Health Organization, Geneva, Switzerland
Dr H. de Koning, Scientist, Control of Environmental Pollution and
Hazards, World Health Organization, Geneva, Switzerland
Dr J. E. Korneev, Scientist, Control of Environmental Pollution and
Hazards, World Health Organization, Geneva, Switzerland
Dr G. E. Lambert, Scientist, Occupational Health, World Health
Organization, Geneva, Switzerland
Dr B. Marschall, Medical Officer, Occupational Health, World Health
Organization, Geneva, Switzerland
Dr V. B. Vouk, Chief, Control of Environmental Pollution and Hazards,
World Health Organization, Geneva, Switzerland (Secretary)
ENVIRONMENTAL HEALTH CRITERIA FOR MANGANESE
A WHO Task Group on Environmental Health Criteria for Manganese
met in Geneva from 22 to 26 September 1975. Dr B. H. Dieterich,
Director, Division of Environmental Health, opened the meeting on
behalf of the Director-General. The Task Group reviewed and revised
the second draft Of the criteria document and made an evaluation of
the health risks from exposure to manganese and its compounds.
The first and second drafts of the criteria document were
prepared by Dr P. S. Elias of the Department of Health and Social
Security, London, England. The first draft was based on national
reviews received from the national focal points for the WHO
Environmental Health Criteria Programme in Bulgaria, Japan, New
Zealand, the United Kingdom, the USA, and the USSR. The second draft
was prepared according to comments received from national focal points
in Canada, Chile, Czechoslovakia, Greece, Japan, Netherlands, New
Zealand, Poland, Sweden, the USA, and the USSR; and from the
Commission of the European Communities, the Food and Agriculture
Organization of the United Nations, the Ethyl Corporation, the
International Union of Biological Sciences, the International Union of
Pure and Applied Chemistry, the United Nations Economic Commission for
Europe, and the World Meteorological Organization. Dr P. S. Elias and
Dr I. C. Munro, Bureau of Chemical Safety, Department of National
Health and Welfare, Ontario, Canada, assisted the Secretariat in the
preparation of a third draft, which was distributed for comments to
the Task Group members. Additional comments on this draft were
received from Dr R. J. M. Horton, US Environmental Protection Agency,
Research Triangle Park, USA, and Professor M. Piscator, the Karolinska
Institute, Stockholm, Sweden. Following the recommendations made by a
WHO Consultative Group on the application of environmental health
criteria, Bilthoven, Netherlands, 2-5 May 1977, a final draft was
prepared by Dr H. Nordman, Institute of Occupational Health, Helsinki,
Finland, taking into consideration the comments of members of the Task
Group and of Professor P. S. Papavasiliou, the New York Hospital
Centre-Cornell Medical Center, New York, USA, and Professor M.
The collaboration of these institutions, organizations, and
individual experts is gratefully acknowledged. The Secretariat wishes
to thank, in particular, Dr P. S. Elias, Dr. I. C. Munro, and Dr H.
Nordman for their help in the various phases of preparation of the
This document is based on original publications listed in the
reference section but much valuable information was also obtained from
publications reviewing and evaluating the essentiality and toxicity of
manganese, including those by Cotzias (1958, 1962), Stokinger (1962),
Schroeder et al. (1966), Suzuki et al. (1973a, 1973b, 1973c), WHO
(1973), WHO Working Group (1973), US Environmental Protection Agency
(1975), International Agency for Cancer Research (1976), and Saric
(1978). Owing to unforseen circumstances, it has not been possible to
update the document beyond 1978.
Details of the WHO Environmental Health Criteria Programme,
including some terms frequently used in the documents, can be found in
the general introduction to the Environmental Health Criteria
Programme published together with the environmental health criteria
document on mercury (Environmental Health Criteria 1, Mercury, Geneva,
World Health Organization, 1976) and now available as a reprint.
Financial support for the publication of this criteria document
was kindly provided by the Department of Health and Human Services
through a contract from the National Institute of Environmental Health
Sciences, Research Triangle Park, North Carolina, USA -- a WHO
Collaborating Centre for Environmental Health Sciences.
1. SUMMARY AND RECOMMENDATIONS FOR FURTHER STUDIES
1.1.1 Analytical methods
Numerous analytical methods are available for the quantitative
determination of manganese in environmental media and biological
samples. The method the most frequently used is atomic absorption
spectroscopy, which appears to be sufficiently sensitive for most
analytical purposes. The way in which biological and environmental
samples are procured and stored, prior to analysis, has an important
bearing on the accuracy and validity of the results. For example, in
air sampling, it is important to ensure that respirable particulate
matter is collected. In the collection of biological samples with a
low manganese content, contamination may constitute a major
1.1.2 Sources and pathways of exposure
Manganese is one of the more abundant elements in the earth's
crust and is widely distributed in soils, sediments, rocks, water, and
biological materials. The major sources of man-made environmental
pollution by manganese arise in the manufacture of alloys, steel, and
iron products. Other sources include mining operations, the production
and use of fertilizers and fungicides, and the production of synthetic
manganese oxide and dry-cell batteries. Organomanganese fuel
additives, though only a minor source at present, could significantly
increase exposure, if they come into widespread use. Average manganese
concentrationsa in soils range from about 500 to 900 mg/kg and
concentrations in sea water range from 0.1 to 5 µg/litre. Surface
waters may have a manganese content of 1-500 µg/litre, but in areas
where high concentrations of manganese occur naturally, levels may be
considerably higher. Average manganese levels in drinking water range
from 5 to 25 µg/litre.
Manganese is present in all foodstuffs, usually at concentrations
below 5 mg/kg. However, concentrations in certain cereals, nuts, and
shellfish can be much higher, exceeding 30 mg/kg in some cases. Levels
in finished tea leaves may amount to several hundred mg/kg.
Manganese has been found in measurable quantities in practically
all air samples of suspended particulate matter. Annual average levels
in ambient air in unpolluted urban and rural areas vary from 0.01 to
0.07 µg/m3. However, in areas associated with the manganese industry,
a Throughout the document, the term concentration refers to mass
concentration, unless otherwise stated.
annual averages may be higher than 0.5 µg/m3, and have occasionally
exceeded 8 µg/m3. About 80% of the manganese in suspended particulate
matter is associated with particles having a mass median equivalent
diameter (MMED)b of less than 5 µm, i.e., particles within the
respirable range. This association with small particles favours the
widespread airborne distribution of manganese.
1.1.3 Essentiality of manganese
Manganese is an essential trace element for both animals and man.
It is necessary for the formation of connective tissue and bone, and
for growth, carbohydrate and lipid metabolism, the embryonic
development of the inner ear, and reproductive functions. Some
specific biochemical functions of manganese have been discovered such
as the catalysing of the glucosamine-serine linkages in the synthesis
of the mucopolysaccharides of cartilage.
Estimates from intake and balance studies in man show that the
daily requirement for adults is 2-3 mg/day and that of pre-adolescent
children, at least 1.25 mg/day. Manganese deficiency states, which
have been detected in a wide variety of animals, have been described
only once in man, in association with vitamin K deficiency and the
accidental omission of manganese from the diet. A distinctly negative
manganese balance is found in newborn infants, the metal being
excreted from stores that have accumulated in the tissues during fetal
life. However, deficiency symptoms have not been detected.
1.1.4 Magnitude of environmental exposure
Food is the major source of manganese for man. Daily intake
ranges from 2 to 9 mg, depending on the relative consumption of foods
with a high manganese content, especially cereals and tea. In young
children and up to the age of adolescence, the daily intake is about
0.06-0.08 mg/kg body weight; for breastfed and bottlefed infants, it
is only about 0.002-0.004 mg/kg body weight. Daily intake with
drinking water may range from a few micrograms to 200 µg, the average
intake being about 10-50 µg/day.
b Mass median equivalent diameter: equivalent diameter above and
below which the weights of all larger and smaller particles are
The daily intake of manganese in the air by the general
population in areas without manganese emitting industries is below
2 µg/day. In areas with major foundry facilities, intake may rise to
4-6 µg/day and in areas associated with ferro- or silicomanganese
industries it may be as high as 10 µg, with 24-h peak values exceeding
The respiratory and gastrointestinal tracts constitute the major
routes of absorption of manganese. Quantitative data are not
available, but it seems unlikely that the skin is an important route
of absorption for inorganic manganese compounds, although
organomanganese compounds can be absorbed by this route.
The extent of absorption of manganese following inhalation is
unknown. A certain proportion of inhaled manganese particles is
cleared by mucociliary action and swallowed, and is available for
gastrointestinal absorption. The small amount of information available
concerning the gastrointestinal absorption of manganese in man
indicates that the absorption rate in healthy adults is below 5% but
that it is higher in anaemic subjects. This is supported by data from
studies on mice and rats. There is little information on
gastrointestinal absorption in infants and children and not much is
known about the mechanism of absorption from the gastrointestinal
In studies on experimental animals, preloading with high dietary
levels of manganese caused a decrease in the rate of absorption and
young rats appeared to have a considerably higher absorption rate than
The total manganese body burden for a man of 70 kg is about
10-20 mg. It is transported in the plasma bound to a beta1-globulin,
most likely transferrin, and is widely distributed throughout the
body. Manganese concentrates in tissues rich in mitochondria, the
highest concentrations being found in the liver, pancreas, kidney, and
the intestines. It can also penetrate both the blood-brain barrier and
the placenta. The disappearance half-time for manganese from the whole
body is about 37 days and the half-time in the brain appears to be
longer than that for the whole body. Tissue concentrations in man are
remarkably stable throughout life. Variable excretion is known to play
an important role in the homeostasis of manganese, but recent studies
have shown that the variability of absorption is also important.
Inorganic manganese is mainly eliminated in the faeces. The
principal route of excretion is with the bile, part of which is
reabsorbed in the enterohepatic circulation. To some extent, manganese
is also excreted with the pancreatic juice and through the intestinal
wall; the importance of these routes may increase under abnormal
conditions such as biliary obstruction or increased manganese
exposure. It has been shown that only about 0.1-1.3% of the daily
intake of inorganic manganese is normally excreted in the urine.
However, larger amounts are excreted through the kidney following
exposure to organomanganese tricarbonyl compounds, indicating that
these compounds, which are used as additives in gasoline, are
metabolized in the body.
1.1.6 Effects on experimental animals
The toxic effects of manganese on the central nervous system have
been induced in various animal species, including the rat and monkey,
mainly by the administration of manganese dioxide or dichloride.
Exposure of a monkey to manganese dioxide aerosol, by inhalation, at
concentrations of 0.6-3.0 mg/m3, for 95 1-h periods over 4 months,
induced typical signs of central nervous system effects. Parenteral
administration of manganese dioxide or dichloride also induced signs
of central nervous system disturbance but oral administration produced
fewer effects, presumably because of poor gastrointestinal absorption.
Histopathological lesions found in intoxicated animals included
degenerative changes, primarily in the striatum and pallidum, but
lesions in the subthalamic nucleus, cortex, cerebrum, cerebellum, and
the brain stem have also been observed. It has been shown that
manganese causes depletion of dopamine, and probably serotonin, in the
basal ganglia of monkeys, rabbits, and rats. These biochemical
findings may explain, at least in part, the neurotoxic effects of
Inflammatory changes were produced in rats by intratracheal
administration of manganese dioxide at concentration of 0.3 mg/m3 for
5-6 h daily, over 4 months; mottling was seen on the pulmonary
radiographs of monkeys exposed to the same compound by inhalation
(0.7 mg/m3). Sulfur dioxide was found to act synergistically with
manganese dioxide on the respiratory tract of guineapigs.
Biochemical and histopathological changes have been reported in
other organ systems, notably the liver. Testicular changes have been
demonstrated in the rat after intravenous administration of
permanganate at 50 mg/kg body weight and in the rabbit after
administration of manganese dichloride at 3.5 mg/kg. Intraperitoneal
injections of manganese(II) sulfate (10 mg/kg body weight, 15
injections) in mice increased the incidence of lung rumours; however,
the carcinogenic, mutagenic, and teratogenic potential of manganese
needs further investigation.
1.1.7 Effects on man
184.108.40.206 Occupational exposure
Chronic manganese poisoning is a hazard in the mining and
processing of manganese ores, in the manganese alloy and dry-cell
battery industries, and in welding. The disorder is characterized by
psychological and neurological manifestations, the neurological signs
closely resembling those that occur in other extrapyramidal disorders,
notably parkinsonism. Autopsy reports on cases of chronic manganese
poisoning have shown that lesions of the central nervous system are
most severe in the striatum and pallidum, and may also be found in the
substantia nigra. In one case, post-mortem analysis revealed a reduced
concentration of dopamine. This finding combined with animal data and
the fact that a precursor of dopamine, 3-hydroxy L-tyrosine (L-dopa),
has been effective in the treatment of chronic manganese poisoning
implicates the dopaminergic pathway in the etiology of extrapyramidal
manifestations of the disease.
Individual susceptibility to the adverse effects of manganese
varies considerably. The minimum dose that produces effects in the
central nervous system is not known, but signs of adverse effects may
occur at manganese concentrations in air ranging from 2 to 5 mg/m3.
Although an increased incidence of pneumonia has repeatedly been
reported in manganese workers, it is not possible to establish any
exposure-effect relationships from available data. It may be that
particle size distribution and the type of manganese compound are more
important than the mass concentration of manganese in air. This may
also be true for the nonspecific effects on the respiratory tract
reported in manganese workers. Smoking appears to act synergistically
with manganese in causing such effects.
The early diagnosis of manganese poisoning is difficult in the
absence of reliable biological indicators of exposure. Repeated
screening for subjective symptoms and thorough clinical examinations
should be undertaken at regular intervals together with measurements
of manganese in blood and urine. Measurement of manganese levels in
faeces may serve as a useful guide to exposure.
With better understanding of the pathophysiology of manganese
poisoning, new drugs have been introduced for its treatment. In many
cases, the use of the dopamine precursor L-dopa, has been successful.
The use of chelating agents has also been reported to have a
beneficial effect, although sometimes only temporarily and mainly in
the early stages of poisoning. This treatment cannot be expected to
bring about any improvement in cases where structural neurological
injury has already occurred.
220.127.116.11 Community exposure
Adverse effects have been reported in populations, in areas
associated with manganese-processing plants. In 1939, increased
morbidity and mortality due to lobar pneumonia were reported from
Sauda in Norway, where a ferro- and silicomanganese plant was
operating. The mortality rate was positively correlated with the
amount of manganese alloy produced. Manganese was reported to occur in
the ambient air as Mn (II, III) oxide (Mn3O4) at manganese
concentrations of up to 45 µg/m3. In another study, a higher
prevalence of nose and throat symptoms and lowered respiratory
function were registered in schoolchildren exposed to manganese
concentrations in air ranging from 4 to 7 µg/m3 (5-day mean values)
compared with an unexposed control group. However, short-time sampling
(1-h) of the factory smoke, down-wind, yielded a maximum level of
A 4-year study performed in a population living in the vicinity
of a ferromanganese plant indicated that even a manganese exposure of
only 1 µg/m3 might be connected with an increase in the rate of acute
respiratory disease. However, it is possible that some other factors,
which were not sufficiently controlled, might have influenced the
In one study, the incidence of abortions and stillbirths was
reported to be higher in wives of workers exposed to manganese for
10-20 years than in a control group. The study is difficult to
evaluate as factors such as the occupations of the wives were not
1.1.8 Organomanganese compounds
There are two groups of organomanganese compounds of
toxicological importance. Manganese ethylene-bis-dithiocarbamate
(Maneb) is used as a fungicide on edible crops. Toxicologically, the
manganese fraction is of little importance, whereas the organic
portion is part of a larger problem concerning this type of fungicide.
The manganese tricarbonyl compounds constitute the other group of
organomanganese compounds of toxicological significance. These are
used as additives in unleaded petrol (gasoline) and future widespread
use seems likely. After combustion, only a small fraction of the
compound is emitted and this undergoes rapid photodecomposition to
form compounds that, so far, have not been satisfactorily identified.
Exposure to manganese tricarbonyl compounds is therefore likely to
constitute an occupational hazard but community exposure to the parent
compound will remain very small, even if the use of these compounds
increases. Nevertheless, widespread use would result in increased
community exposure to inorganic manganese and to other possible
combustion products. Rats, hamsters, and monkeys have been exposed
experimentally to combusted methylcyclopentadienyl manganese
tricarbonyl (MMT) at concentrations of manganese in air ranging from
12 to 5000 µg/m3 for various periods ranging up to 66 weeks without
any adverse effects. However, tissue levels of manganese increased in
monkeys exposed to a manganese concentration in air of 100 µg/m3.
1.2 Recommendations for Further Studies
1.2.1 Analytical methods
There is a need for interlaboratory comparison to determine the
accuracy of methods available for the estimation of manganese.
Additional studies are required to determine particle size in airborne
manganese particulate matter, so that total intake through the
respiratory pathway can be estimated more precisely.
1.2.2 Environmental exposure
More precise data are needed on manganese intake, especially by
inhalation. A better understanding of the translocation of manganese
in the environment and factors that affect this process is required
and its potential for bioaccumulation in environmental compartments
should be explored in more depth.
Chemobiokinetic studies are necessary to identify, more
precisely, the mechanisms involved in the uptake and clearance of
manganese from the gastrointestinal tract and the respiratory system
in both experimental animals and exposed populations and to obtain a
better understanding of factors that affect these processes. Tissue
levels at which adverse effects are observed should be established and
special attention should be paid to the role of nutritional status and
age in the metabolism of manganese.
1.2.4 Experimental animal studies
More information is needed on the long-term, low-level effects of
manganese in order to develop dose-response data. Further studies are
also necessary on the neurotoxicity and potential carcinogenicity,
teratogenicity, and mutagenicity of manganese and on factors that
might affect toxicity such as nutrition, age, disease state, and the
presence of other pollutants.
Not enough is known about the essentiality of manganese as a
nutrient and more studies are needed on the biochemical role of this
metal to obtain a better understanding of toxic mechanisms and to
develop a rational basis for the treatment of manganese intoxication.
1.2.5 Epidemiological and clinical studies in man
Studies are required to elucidate the dose-effect and
dose-response characteristics of manganese with particular emphasis on
the effects of long-term, low-level, inhalation exposure on the
respiratory and central nervous systems. Interactions with other
pollutants, diet, age, and general health status should be studied in
more detail. The effects of manganese on the cardiovascular system,
particularly its effects on blood pressure and the myocardium, need to
be more fully understood. Reliable diagnostic procedures for manganese
intoxication should be established, paying particular attention to the
development of methods for its early detection. Additional studies are
necessary to assess the embryotoxic potential of manganese and its
compounds in communities exposed to elevated levels of manganese in
air. Organomanganese compounds may come into widespread use as fuel
additives. This would result in increased exposure of the general
population to manganese and probably to other combustion products of
the additive. Thus, the potential hazards to public health of the use
of organomanganese fuel additives should be examined by means of
carefully conducted controlled and epidemiological studies.
2. PROPERTIES AND ANALYTICAL METHODS
2.1 Chemical and Physical Properties of Manganese and its Compounds
Manganese, Mn (atomic number Z = 25; relative atomic mass Ar =
54.938) is an element of the VIIb group of the periodic table of
elements, together with technetium and rhenium. It belongs to the
first series of d-block transition elements which also contains
titanium, vanadium, chromium, nickel, and copper. Because of their
electron configuration, transition elements have some characteristic
properties: they are all metals; they exist in a variety of oxidation
states; and they form many coloured and paramagnetic compounds.
Several transition elements have an important role in biological
In the elemental state, manganese is a white-grey, brittle, and
reactive metal with a melting point of 1244°C and a boiling point of
1962°C. It is the most common transition metal after iron and
titanium. It can form compounds in a number of oxidation states, the
most important being +2, +3, and +7.
Manganous (Manganese(II), Mn2+) salts are mostly water-soluble,
with the exception of the phosphate and carbonate, the solubilities of
which are rather low. Dihalides of manganese include MnF2, MnCl2,
MnBr2, and MnI2. Addition of OH- ion to the Mn2+ solutions gives
the gelatinous white hydroxide Mn(OH)2. MnO and MnS are also known.
The MnII complexes are generally weakly coloured (pale pink). Mn2+
is in many ways similar to Mg2+, and can replace it in some
Mn3O4 (hausmannite) contains both MnII and MnIII, i.e., MnII
MnIII2O4. The manganic Mn(III) ion (Mn3+) easily hydrolyses in weak
acid solutions into Mn2+ and MnO2. Manganese(III) and manganese(IV)
complexes seem to be important in photosynthesis.
Manganese dioxide (MnO2), found naturally as pyrolusite, is the
most important manganese (II) compound. It is insoluble in water and
in cold acids. The little-known manganese(IV) ion occurs in blue
Manganese(VI) exists in the deep green manganate ion, MnO42-,
which is stable only in very basic solutions. Otherwise, it breaks
down to give the permanganate ion MnO4- and MnO2. The permanganate
ion is the best known form of MnVII. Permanganate, which is a good
oxidant in basic solutions, is reduced to Mn2+ in acid solutions.
The properties of some inorganic manganese compounds are
summarized in Table 1.
Table 1. Chemical and physical properties of manganese and some manganese compoundsa
Chemical Relative atomic Melting Boiling
Compound formula or molecular point point Solubility
mass (°C) (°C)
Manganese Mn 54.94 1244 1962 Decomposes in cold and hot
water; soluble in dilute acid.
(II) acetate Mn(C2H3O2)2 173.02 Soluble in cold water
(decomposes); soluble in
(II) carbonate MnCO3 114.95 decomposes Soluble in cold water;
soluble in dilute acids.
dichloride MnCl2 125.84 650 1190 Soluble In cold and hot water,
and in alcohol.
(II) nitrate Mn(NO3)2 . 4H2O 251.01 25.8 1294 Soluble in cold and hot water,
and in alcohol.
(II, III) oxide Mn3O4 228.81 1705 Soluble In hydrochloric acid.
dioxide MnO2 86.94 -0.535 Soluble In hydrochloric acid.
(III) oxide Mn2O3 157.87 -0.1080 Soluble In acid.
(II) metasilicate MnSiO3 131.02 1323 Insoluble In water and
(II) sulfate MnSO4 151.00 700 850 Soluble in cold and hot water, and
(decomposes) in alcohol.
Table 1. (contd).
Chemical Relative atomic Melting Boiling
Compound formula or molecular point point Solubility
mass (°C) (°C)
(III) sulfate Mn2(SO4)3 398.06 160 Decomposes in water, soluble in
hydrochloric acid, and
dilute sulfuric acid.
(II) sulfide MnS 87.00 decomposes Soluble In cold water, dilute
acid, and alcohol.
(IV) sulfide MnS2 119.07 decomposes Decomposes in hydrochloric acid.
Potassium KMnO4 158.00 decomposes < 240 Soluble in cold and hot water,
permanganateb in sulfuric acid, alcohol, and
acetone. Decomposes in alcohol.
a From: Weest (1974).
b From: Stokinger (1962).
Manganese may form a variety of complexes particularly in the +2
state. The +1 state is present in hexacyano complexes such as
K5Mn(CN)6, which exist also with manganese in the +3 state,
Manganese forms various organometallic compounds such as
Mn2(CO)10, sodium pentacarbonylmanganate (NaMn (CO)5), and
manganocene (C5H5)2Mn. However, of major practical interest is
methylcyclopentadienyl manganese tricarbonyl (CH3C5H4Mn(Co)3),
often referred to as MMT, Cl-2 or Ak-33X (antiknock 33X), which has
been used as an additive in fuel oil, as a smoke inhibitor, and as an
antiknock additive in petrol, usually as a supplement to
2.2 Sampling and Analysis
2.2.1 Collection and preparation of samples
Nonmetallic sampling systems should be used for the collection of
environmental materials, and suitable precautions should be taken to
avoid contamination during the analytical process.
Filters for ambient air particulates must be chosen with care so
that trace amounts of manganese in the filter material do not distort
the results. Generally the air sampling techniques chosen will depend
on the purpose of the investigation. High-volume air samplers and
centripeters are expensive, require power points, and are unsuitable
for large-scale monitoring at multiple sites. The use of standard
deposit gauges is limited to the collection of particles larger than
5 µm; particles with a smaller diameter are deposited only by
impaction. In Japanese studies, a high-volume air sampler is used for
suspended particulate matter, and a cyclone type low-volume air
sampler for suspended particulate matter with a particle size of 10 µm
or less (Environment Agency, Japan, 1972).
Sphagnum moss techniques are useful for comparing fallout in
different areas or for studying seasonal variations in one area.
Continuous sampling drawing measured air volumes through filter paper,
or dry deposition on filter papers protected from the rain combined
with rain water collecting, may also be used. According to normal
practice in emission studies, sampling for manganese at stationary air
pollution sources is carried out isokinetically, using a sampling
train that will remove manganese efficiently. In the source sampling
method used by the US Environmental Protection Agency (1971), it is
possible to analyse the particulates collected in the probe, on the
filter, and in the water impingers.
Manganese is emitted in automobile exhaust in the form of
particulate matter. Concentrations vary according to the natural
manganese levels in the fuel and to the concentration of
manganese-containing additives, if present. Exhaust particulates may
be collected by total or proportional sampling of the hot exhaust or
by proportional sampling of the exhaust mixed with air, which allows
cooling and condensation of the compounds of greater relative atomic
mass associated with short-time ambient exhaust particulates. The
second method provides a more realistic assessment of the mass and
composition of the primary exhaust particulates. Collection using this
technique can be carried out using a single filter, multiple filter,
beta gauge (Dresia & Spohr, 1971), or particulate-size-fractionating
devices. Gaseous samples may be collected either by the cold-trap
technique or on chromatographic columns.
The following considerations are important in the sampling of
water for manganese analysis: (a) selection of sampling sites; (b)
frequency of sampling; (c) sampling equipment; and (d) sample
preparation (Brown et al., 1970). Usually, little or no sample
preparation is required but freeze-drying operations can be used.
Aqueous samples should be filtered immediately on collection,
using a membrane or other suitable filtering material if
differentiation between soluble and particulate phases is to be
attempted. Once the particulates are collected on a filter, the
analytical problems are similar to those of air analysis. Special
precautions are required in the handling and storage of solid and
aqueous samples with regard to the choice of equipment and containers.
Because of the extremely low concentration of manganese in some
biological tissues and body fluids, contamination of the samples
constitutes a major difficulty, a fact which is often overlooked or
underestimated. It seems likely that the wide variation in manganese
concentrations reported, for instance, in serum (section 6.2.1) can
portly be explained by contamination.
Steel equipment is considered unsuitable for tissue biopsy, and
quartz or glass knives have been suggested as alternatives; the use of
a laser beam has also been discussed (Becker & Maienthal, 1975).
Versieck et al. (1973a) reported that the radioactivated Menghini
needles used in liver biopsy could cause up to 30% manganese
contamination. It has also been suggested that skin-pricking is
inferior to venepuncture in the drawing of blood samples because of
the possible introduction of tissue manganese into the sample
(Papavasiliou & Cotzias, 1961). Single transfer of blood through
conventional steel needles has caused serious contamination of samples
(Cotzias et al., 1966), and the use of platinum-rhodium alloy needles
with Kel-F hubs has been proposed to overcome this problem (Becker &
A considerable contamination problem may arise in the presence of
some anticoagulants. Bethard et al. (1964) reported a manganese
concentration in heparin of 3.56 µg/ml whereas acid-citrate-dextrose
contained only 0.002 µg/ml. Consequently, when heparin was used as an
anticoagulant, the manganese concentration was 0.17 ± 0.03 µg/ml
compared with 0.00014 µg/ml when acid-citrate-dextrose was used.
Sampling of hair may be complicated by the fact that manganese is
associated with melanin-containing structures, black and brown hair
containing much higher concentrations of manganese than white hair
(Cotzias et al., 1964).
2.2.2 Separation and concentration
Special procedures are not normally necessary for the separation
of manganese from other metals prior to the analysis or concentration
of samples. Chromatographic methods for the determination of manganese
have been reviewed by Fishbein (1973).
2.2.3 Methods for quantitative determination
18.104.22.168 Optical spectroscopy
Trace metals, including manganese, have been determined
spectroscopically by a number of research workers. With suitable
variations in sample preparation, the available standard spectroscopic
methods can be used equally well for mineral ores, air particulates,
or biological samples (Cholak & Hubbard, 1960; Tipton, 1963;
Angelieva, 1969, 1970, 1971; Bugaeva, 1969; Carlberg et al., 1971; El
Alfy et al., 1973; Pépin et al., 1973). The advantages of spectroscopy
are that it can be applied to most elements with a satisfactory
specificity and sensitivity and that it can be used for the
simultaneous determination of several elements (US Environmental
Protection Agency, 1972, 1973). Drawbacks of the emission
spectroscopic assay include the exacting nature of the method, which
necessitates the use of highly qualified personnel, the cost of the
instrument, the complexity of the method, and the detection limits,
which are too high to detect metals occurring in low concentrations
(Thompson et al., 1970).
22.214.171.124 Atomic absorption spectroscopy
This is the most commonly used method of determining manganese at
present, because the procedure is relatively simple and fast and the
sensitivity is high. The application to ambient air samples has been
described by Thompson et al. (1970), Begak et al. (1972), and Muradov
& Muradova (1972). The method is fairly free from interference except
for possible matrix effects, which can generally be avoided. Any
silica extracted from glass-fibre filters can cause interference
unless removed by the addition of calcium to the solution, prior to
analysis (Slavin, 1968). Atomic absorption methods have also been used
to determine manganese in water and other materials. Little or no
preparation of the sample solution is required (Thompson et al., 1970;
Tichy et al., 1971; US Environmental Protection Agency, 1974).
The advantage of flameless atomizers is that the determination
can be carried out with high sensitivity using only a small sample.
The method was initiated by L'vov (1961) to avoid interference caused
by reactions in the flame. However, the precision of the results is
not necessarily good since atomizing can easily be altered by various
conditions such as the type of the sample which, for instance, may
stick to the wall of the boat. These difficulties are especially
significant when directly atomizing biological samples. Graphite
furnace or carbon rod techniques can be used for the direct analysis
of water samples, although matrix interference must be checked for and
eliminated. Concentration of fresh water can be achieved simply by
evaporation. Other variants have been developed for biological
substrates, foodstuffs, soils, and plant materials (Ajemian & Whitman,
1960; Suzuki, 1968; Suzuki et al., 1968; Obelanskaja et al., 1971; Bak
et al., 1972; Van Ormer & Purdy, 1973).
An atomic absorption assay using direct aspiration of the sample
into the burner has been described for the determination of
methylcyclopentadienyl manganese tricarbonyl (MMT) in gasoline. The
drawback of this method is that it does not discriminate between MMT
and other manganese compounds (Bartels & Wilson, 1969).
Atomic absorption methods can be classified, according to the
type of sample or sample solution to be applied to the atomizer, into
(a) the direct method, in which the sample or sample solution is
used directly; and (b) the solvent-extraction method in which a
clean-up and concentration process by solvent extraction is carried
out before atomizing. The gross matrix effects of saline waters
necessitate a preliminary extraction, which usually entails a
concentration procedure. Chelating ion-exchange (Riley & Taylor, 1968)
and solvent extraction are also often used (Hasegawa & Ijichi, 1973).
126.96.36.199 Neutron-activation analysis
This method has a high specificity and sensitivity for very low
concentrations of manganese as well as several other elements (Dams et
al., 1970). However, the user must be aware that neutron-activation of
biological samples may result in the production of isotopes that
interfere with the determination of manganese. Irradiated samples are
treated by a chemical separation process with a certain amount of
manganese carrier and then determined by gamma-spectroscopy. The
1810.7 Kev gamma line of 56Mn is measured. This method can be used to
check the accuracy of results obtained by other analytical methods and
for the determination of manganese at very low concentrations in a
small number of samples. It is essential to collect particulate matter
on filters that have a very low trace element content (ashless filter
paper). Variations of this method have been used for determining
manganese concentrations in blood and serum (Cotzias et al., 1966) and
in plants (Hatamov et al., 1972).
188.8.131.52 X-ray fluorescence
The use of X-ray fluorescence spectroscopy provides a means for
the non-destructive analysis of elements in sediments and
X-ray fluorescence can also be used to determine manganese in
solutions, if the sample is prepared by freeze-drying. Birks et al.
(1972) have made a complete elemental analysis with high sensitivity
in 100 seconds using multichannel analysers with 14-24 crystals. The
necessity of distinguishing unreactive, structurally incorporated
manganese in particulates and sediments from the more reactive
absorbed, biogenic, and hydrogenic phases was discussed in a paper by
Chester & Hughes (1967), who proposed a selective acid-leaching
technique for this purpose. Manganese in water was determined by
Watanabe et al. (1972), using a nickel carrier, with a limit of
detection of 0.03 µg. Another method that has been developed for the
analysis of various elements including manganese, is proton-induced
X-ray emission analysis (Johansson et al., 1975). Manganese in dust
samples collected by an impactor was detected at nanogram levels using
184.108.40.206 Other methods
The periodate method is the classical wet chemical method of
analysing air samples for manganese (American Conference of
Governmental Industrial Hygienists, 1958). The advantage of this
method is that it can be used in almost any chemical laboratory with
relatively simple equipment, but the sensitivity (0.1 mg/m3) is
rather poor in comparison with that of other methods (Peregud &
Gernet, 1970). This technique has also been widely used for
determining total manganese in the soil but it is considered to give a
poor estimate of the manganese available to plants.
The permanganate method is the most commonly used method for the
analysis of manganese in water samples. Interference caused by
manganese in the glassware has to be eliminated when the manganese
level in the sample is low, and prior removal of organic material may
be necessary. However, not all forms of manganese likely to occur in
water can be measured by the permanganate method (e.g., the complexes
of trivalent manganese and manganese dioxide), and an improved, simply
performed formaldoxime method has been developed for the analysis of
both water and soils (Samohvalov et al., 1971; Cheeseman & Wilson,
A rapid drop quantitative method, developed for determining
manganese in the air of the working environment, is based on the
colour reaction of manganese ions with potassium ferricyanide. The
method is specific and results compare well with those obtained by
emission spectroscopy (Muhtarova et al., 1969).
A kinetic method based on the ability of manganese to catalyse
the atmospheric oxidation of the morin-beryllium complex has been
developed for the determination of manganese in atmospheric
precipitates (Morgen et al., 1972). Polarography can be used for
determining manganese in industrial waste waters with a sensitivity of
0.05 mg/litre. Chromium interference can be removed by phosphate
precipitation (Bertoglio-Riolo et al., 1972). A similar method for
analysing animal foodstuffs, organs, and tissues has been developed
for samples weighing only 2 g. Interference caused by iron can be
avoided by precipitating it with a mixture of ammonium chloride and
ammonium hydroxide (Usovic, 1967). An alternative method for the
determination of manganese in biological material is electron
paramagnetic resonance spectroscopy (Cohn & Townsend, 1954; Miller et
Spark source mass spectroscopy is probably a suitable method for
the determination of manganese in petrol (US Environmental Protection
Agency, 1975). Cyclopentadienyl manganese tricarbonyl can be
determined by treating the sample with nitric and sulfuric acid and
subsequently converting the manganese to permanganate (Byhovskaja et
220.127.116.11 Comparability of methods
As already stated, atomic absorption spectroscopy combined, when
necessary, with a separation solvent procedure, can be applied to most
environmental samples. Each of the other methods described has its
particular advantages and characteristics and can be used according to
the need for sensitivity and to the type of sample. Studies such as
that of Harms (1974) on the comparison of data from several different
analytical methods are useful. The inter-comparison of analytical
techniques carried out under the responsibility of EURATOMa also
provides interesting information. In this study, good agreement was
obtained when neutron-activation analysis, X-ray fluorescence,
emission spectroscopy, and atomic absorption spectroscopy were
compared for the determination of manganese.
a EURATOM (unpublished data, 1974) Chemical analysis of airborne
particulates: intercomparison and evaluation of analytical
techniques. In: Guzzi, G., ed. Minutes of the Meeting held at
Ispra, Italy, 8-9 July 1974, Ispra Establishment, Chemistry
Division, Joint Research Centre of the European Communities,
3. SOURCES OF MANGANESE IN THE ENVIRONMENT
3.1 Natural Occurrence
Manganese is widely distributed in nature but does not occur as
the free metal. The most abundant compounds are the oxide (in
pyrolusite, brannite, manganite, and hausmannite), sulfide (in
manganese blonde and hauserite), carbonate (in manganesespar), and the
silicate (in tephroite, knebelite, and rhodamite). It also occurs in
most iron ores in concentrations ranging from 50-350 g/kg, and in many
other minerals throughout the world.
A rough estimate of the average concentration of manganese in the
earth's crust is about 1000 mg/kg (NAS-NRC, 1973). Manganese
concentrations in igneous rock may range from about 400 mg/kg in
low-calcium granitic rock to 1600 mg/kg in ultrabasic rock and
sedimentary rocks. Deep sea sediments contain concentrations of about
1000 mg/kg (Turekian & Wedepohl, 1961). It has been reported that the
manganese content of coal ranges from 6 to 100 mg/kg (Ruch et al.,
1973) and that of crude oil from 0.001 to 0.15 mg/kg (Bryan, 1970).
In soil, manganese concentrations depend primarily on the
geothermal characteristics of the soil, but also on the environmental
transformation of natural manganese compounds, the activity of soil
microorganisms, and the uptake by plants.
Although the principal ores are only slightly soluble in water,
gradual weathering and conversion to soluble salts contribute to the
manganese contents of river and sea water. Considerable amounts of
manganese are present in deposits in large areas of the oceans in the
form of nodules. These are formed continuously at a rate of several
million tonnes per year (Schroeder et al., 1966). The average
concentration of manganese in these nodules is about 200 mg/kg (Zajic,
1969) with a range of about 150-500 mg/kg (Schroeder et al., 1966).
3.2 Industrial Production and Consumption
Elemental manganese was isolated in 1774, though the oxide has
been used in the manufacture of glass since antiquity. The total world
production of manganese, which was 18 million tonnes in 1969, rose to
about 27 million tonnes in 1975. However, consumption, which had risen
by 20% between 1970 and 1975, dropped by 3% in 1975 (Mineral Yearbook,
Fumes, dust, and aerosols from metallurgical processing, mining
operations, steel casting (Mihajlov, 1969) and metal welding and
cutting, (Erman, 1972), mainly in the form of manganese oxide are the
principal sources of environmental pollution. Emissions into the
atmosphere from blast and electric furnaces vary considerably
depending on the process involved and the degree of control exercised.
Dust from the handling of raw materials in metallurgical processing
and other manufacturing activities probably makes only a small
contribution to the atmospheric concentration of manganese. Calculated
emission factors for manganese are given in Table 2.
Table 2. Emission factors for manganese
Mining 0.09 kg/tonne of manganese mined
manganese metal 11.36 kg/tonne of manganese processed
blast furnace 1.86 kg/tonne of ferromanganese produced
electric furnace 10.86 kg/tonne of ferromanganese produced
electric furnace 31.55 kg/tonne of silicomanganese produced
blast furnace 10.22 kg/1000 tonnes of pig iron produced
open-hearthfurnace 23.18 kg/1000 tonnes of steel produced
basic oxygen furnace 20.00 kg/1000 tonnes of steel produced
electric furnace 35.45 kg/1000 tonnes of steel produced
cast iron 150.00 kg/1000 tonnes of cast iron
welding rods 7.27 kg/tonne of manganese processed
nonferrous alloys 5.45 kg/tonne of manganese processed
batteries 4.54 kg/tonne of manganese processed
chemicals 4.54 kg/tonne of manganese processed
coal 3.50 kg/tonne of coal burned
From: Davis & Associates (1971).
Over 90% of the manganese produced in the world is used in the
making of steel, either as ferromanganese, silicomanganese, or
spiegeleisen. Manganese is also used in the production of nonferrous
alloys, such as manganese bronze, for machinery requiring high
strength and resistance to sea water, and in alloys with copper,
nickel, or both in the electrical industry. In dry-cell batteries,
manganese is used in the form of manganese dioxide, which is also used
as an oxidizing agent in the chemical industry. Many manganese
chemicals, eg., potassium permanganate, manganese(II) sulfate,
manganese dichloride, and manganese dioxide are used in fertilizers,
animal feeds, pharmaceutical products, dyes, paint dryers, catalysts,
wood preservatives and, in small quantities, in glass and ceramics.
Some of these uses contribute to environmental pollution.
3.2.2 Contamination by waste disposal
The disposal of liquid and solid waste products containing
manganese may contribute to the contamination of land, water courses,
and soil. For example, sludges and various waste waters containing
manganese are used in the production of micronutrient fertilizers
(Eliseeva, 1973) and manganese slurries have been used in the
production of clay blocks for road construction. Information
concerning the degree of pollution arising from the incineration of
refuse containing manganese is not available.
3.2.3 Other sources of pollution
The emission of manganese from motor vehicles powered by petrol
that does not contain manganese additives has been estimated to
average 0.03-0.1 mg/km (Moran et al., 1972; Gentel et al., 1974a;
Gentel et al., 1974b).
Methylcyclopentadienyl manganese tricarbonyl (MMT) was initially
marketed in the USA as a supplement to tetraethyl lead in an antiknock
preparation. During the 1960s, it was introduced as a fuel-oil
combustion improver and as a smoke suppressant for gas turbines using
liquid fuels. In 1974, it came into commercial use as a fuel additive
in unleaded petrol in the USA; in 1976 about 20% of the fuel was
unleaded, and 40% of this amount contained MMT at an average
concentration of 10.56 mg/litre (0.04 g/US gallon) (Ethyl Corporation,
private communication). The use of MMT is likely to increase during
the coming years. At the manufacturer's recommended maximum level of
MMT (a manganese concentration of 33 mg/litre),a the emission of MMT
is approximately 0.62-3.1 µg/km (1-5 µg/mile); levels of about
0.62-1.55 µg/km (1-2.5 µg/mile) have been reported in lubrication oil
(Hurn et al., 1974). This low emission rate together with the fact
that MMT rapidly undergoes photochemical decomposition (section 5.8)
suggests that exposure to the parent compound through the exhaust gas
would be low.
Taking data on lead emissions in exhaust gas as a model, it has
been calculated that the use of MMT in petrol might result in the
emission of 0-0.25 µg of manganese per m3 of air, with a median of
0.05 µg/m3, and that the organic component of this would be about
1.2 × 10-5 µg/m3 (Ter Haar et al., 1975). This is not far from the
estimate of 0.05-0.2 µg/m3 made by Keane & Fisher, (1968). It has
been reported that 50% of emitted manganese particles have a mass
median diameter (MMD) of 0.5 µm or less (Moran, 1975).
At the 1975 SAE Automobile Engineering Meeting, it was claimed
that the use of manganese in petrol resulted in increased total
particulate emissions that could not be totally accounted for on the
basis of increased manganese content (Moran, 1975). This was disputed
at the same meeting by Desmond (1975), who argued that the figures
presented by Moran (1975) for increased total particulate emissions
were compatible with the theoretical maximum emissions of Mn3O4
resulting from combustion of the manganese in the fuel.
It appears that the use of MMT in petrol causes increased
emission of hydrocarbons (Gentel et al., 1974b; Hurn et al., 1974;
Kocmond et al., 1975). However, there is no conclusive evidence to
indicate that MMT decreases the efficiency of catalysts (Faggan et
al., 1975; Moran, 1975).
It is possible that MMT in petrol increases aldehyde emissions,
though the data so far available are conflicting (Ethyl Corporation,
1974; Gentel et al., 1974b; Hurn et al., 1974). Too little information
is available to draw any conclusions with regard to the effects of MMT
in petrol on the emission of polynuclear aromatic hydrocarbons. Tests
performed by the Ethyl Corporation (1974) showed a decrease in
benzo(a)pyrene concentrations in exhaust gas. A similar decrease in
benzo(a)pyrene concentrations was reported by Lerner (1974) using an
analogous compound, cyclopentadienyl manganese tricarbonyl. In one
study, it was shown that MMT in petrol could decrease atmospheric
visibility (Kocmond et al., 1975). Results of other studies conducted
by the Ethyl Corporation (1971) indicated that comparatively high
concentrations of manganese in air were needed to influence the
reaction converting sulfur dioxide to sulfuric acid and sulfates.
Thus, the reaction rate was unchanged at a manganese concentration of
4 µg/m3 and no effect was detectable at a concentration of 36 µg/m3,
when the humidity was below 70%.
a In June 1977, the manufacturer reduced the recommended maximum
level of manganese in petrol to 16 mg/litre, bringing about a
corresponding cut in the estimated emission levels (Ethyl
Corporation, private communition).
The effects of MMT in petrol on the emission of carbon monoxide
and oxides of nitrogen are not clear (Moran, 1975).
Another organic manganese compound, manganese
ethylene-bis-dithiocarbamate (Maneb), is used as a fungicide.
A large-scale investigation was made in Japan using a pilot
plant, equipped with a desulfurization device containing activated
manganese dioxide, to explore its influence on manganese levels in the
surrounding environment. The operation of the device increased the
manganese level in air by an average value of 0.002 µg/m3 (Ministry
of International Trade and Industry & Ministry of Health and Welfare,
Minor uses of manganese compounds in the manufacture of linoleum
and calico printing and in the manufacture of matches and fireworks
may be an additional source of environmental contamination.
4. ENVIRONMENTAL LEVELS AND EXPOSURE
4.1.1 Ambient air
The natural level of manganese in air is low. A concentration in
air of 0.006 µg/m3 at a height of 2500 m and an annual average
concentration of 0.027 µg/m3 at 823 m were reported by Georgii et al.
(1974). In rural areas, manganese levels in air may range from 0.01 to
0.03 µg/m3 (US Environmental Protection Agency, 1973).
Because nearly all the manganese emitted into the atmosphere is
in association with small particles, it may be distributed over
considerable distances. According to Lee et al. (1972), about 80% of
manganese emitted into the atmosphere is associated with particles
with a mass median equivalent diameter of less than 5 µm and about 50%
with particles of less than 2 µm. Thus, most of the particles are
within the respirable range.
A survey of manganese concentrations in suspended particulate
matter, conducted during the period 1957-1969 at some 300 urban and
300 nonurban sites in the USA, has been summarized by the US
Environmental Protection Agency (1975). Annual average manganese
concentrations ranged from less than 0.099 µg/m3 for about 80% of the
sites to more than 0.3 µg/m3 for about 5% of the sites (Table 3). In
areas associated with local ferromanganese or silicomanganese
industries such as Johnstown, Charleston, and Niagara Falls, the
annual average concentrations ranged upwards from 0.50 µg/m3
(Table 4). The average 24-h concentrations in such places can exceed
10 µg/m3 and may present an important health risk. Urban centres
without major foundry facilities, such as New York, Los Angeles, and
Chicago, exhibited annual average manganese concentrations in air
ranging from 0.03 to 0.07 µg/m3, whereas in cities with these
facilities, such as Pittsburg, Birmingham, and East Chicago, values
ranged from 0.22 to 0.30 µg/m3 (US Environmental Protection Agency,
1973). These concentrations are in agreement with those found in other
studies from the USA (Brar et al., 1970; Lee et al., 1972). The
highest reported annual average concentration of 8.3 µg/m3, was
measured in Kanawha Valley, West Virginia, during 1964-65. The major
source of pollution was a ferromanganese plant situated in a nearby
area (US Environmental Protection Agency, 1975).
Manganese values from air sampling sites in the United Kingdom
during 1971-1972 ranged from 0.004 to 0.049 µg/m3; Keane & Fisher
(1968) reported mean manganese concentrations of 0.013-0.033 µg/m3 in
relatively unpolluted areas of the United Kingdom.
Table 3. Number of National Air Surveillance Network (NASN) stations within selected
annual average manganese concentration intervals, 1957--1969a
Concentration interval (µg/m3)
Year <0.099 0.100-0.199 0.200-0.299 >0.300 Total
1957- No. stations 76 29 10 13 128
1963 % 59.4 22.7 7.8 10.2 100
1964 No. stations 68 12 6 7 93
% 73.1 12.9 6.5 7.5 100
1965 No. stations 132 14 5 6 157
% 84.1 8.9 3.2 3.8 100
1966 No. stations 113 8 4 3 128
% 88.3 6.3 3.1 2.3 100
1967 No. stations 121 13 4 4 142
% 85.2 9.2 2.8 2.8 100
1968 No. stations 126 11 2 6 145
% 86.9 7.6 1.4 4.1 100
1969 No. stations 169 23 9 8 209
% 80.9 11.0 4.3 3.8 100
1957- No. stations 805 110 40 47 1002
1969 % 80.4 11.0 4.0 4.7 100
a From: US Environmental Protection Agency (1975).
Table 4. National Air Surveillance Network (NASN) stations with annual
average manganese concentrations greater than 0.5 µg/m3a
Manganese concentration (µg/m3)
Year Station Average Max. quarterly Max. 24-h
1958 Charleston, W.VA 0.61 1.10 7.10
1959 Johnstown, PA 2.50 5.40 7.80
Canton, OH 0.72 1.10 2.20
1960 Gary, Ind. 0.97 3.10
1961 Canton, OH 0.57 2.90
Philadelphia, PA 0.70 >10.00
1963 Johnstown, PA 1.44 6.90
Philadelphia, PA 0.62 3.70
1964 Charleston, W.VA 1.33 >10.00
1965 Johnstown, PA 2.45 3.90
Philadelphia, PA 0.72 1.70
Lynchburg, VA 1.71 2.50
Charleston, W.VA 0.60 1.70
1966 Niagara Falls, NY 0.66 1.30
1967 Knoxville, TN 0.81 1.50
1968 Johnstown, PA 3.27 14.00
1969 Niagara Falls, NY 0.66 1.30
Johnstown, PA 1.77 2.10
Philadelphia, PA 0.50 1.30
a From: US Environmental Protection Agency (1975).
In the Federal Republic of Germany, manganese concentrations were
found to range from 0.08 to 0.16 µg/m3 in different areas of
Frankfurt, with a maximum 24-h concentration of 0.49 µg/m3 (Georgii &
Müller, 1974), whereas in a residential area of Munich levels of
0.030-0.034 µg/m3 were reported, with 0.06-0.27 µg/m3 in a street
with heavy traffic (Bouquiaux, 1974).
The Environment Agency, Japan (1975) reported an annual mean
manganese concentration in the air of Japanese cities of about
0.02-0.80 µg/m3 with maximum 24-h concentrations of 2-3 µg/m3
(Environment Agency, Japan, 1975). Studies are also available from a
district in Kanazawa, Japan, close to a plant using electric furnaces
for the production of manganese alloys. Average levels during 1970
varied from 1.1 to 9.8 µg/m3, when measured over 2-day periods at a
point 300 m from the emitting source. Unpolluted areas of the same
city showed average levels of 0.035 µg/m3 during the period
1968-1970 (Itakura & Tajima, 1972). When manganese concentrations were
measured at underground shopping districts adjoining subway stations
in Tokyo, Osaka, and Nagoya, open-air concentrations of
0.042-0.074 µg/m3 and subway concentrations of 0.040-0.353 µg/m3
were found, indicating that heavy subway traffic on railway lines
containing manganese as a ferroalloy may increase manganese exposure
(Japan Environmental Sanitation Centre, 1974).
Thus, it can be concluded that annual average levels for
manganese in ambient air in nonpolluted areas range from approximately
0.01 to 0.03 µg/m3, while in urban and rural areas without
significant manganese pollution, annual averages are mainly in the
range of 0.01-0.07 µg/m3. With local pollution near foundries, this
level can rise to an annual average of 0.2-0.3 µg/m3 and in the
presence of ferro- and silicomanganese industries, to over 0.5 µg/m3.
The data available are not adequate for drawing valid conclusions with
respect to trends in ambient manganese concentrations.
4.1.2 Air in workplaces
In recent years, most of the industrialized countries have
established occupational exposure limits for manganese. Thus, working
conditions have improved and earlier reports of excessive exposure to
manganese do not always represent more recent conditions. This should
be borne in mind when considering the information presented in this
According to one report (Ansola et al., 1944a), Chilean manganese
miners were exposed to manganese concentrations in air of
62.5-250 mg/m3. However in a later study in a Chilean mine, Schuler
et al. (1957) reported a concentration range of 0.5-46 mg/m3, the
highest levels being found in connection with the drilling of pure,
dry ore and the drilling of manganese-bearing rock. Manganese
concentrations of up to 926 mg/m3 of air were found in Moroccan mines
(Rodier, 1955). Flinn et al. (1940) recorded a manganese concentration
of 173 mg/m3 in an ore-crushing mill in the USA but a much later
survey of dust levels in the air of a ferromanganese crushing plant in
the United Kingdom (as measured by personal sampling devices) showed
manganese concentrations of 0.8-8.6 mg/m3. The device of one man
cleaning down the crusher showed an exceptionally high concentration
of 44.1 mg/m3. When levels in air were measured at fixed sampling
points, they ranged from 8.6 to 83.4 mg/m3 (Department of Health &
Social Security, unpublished data).a
In an electric steel foundry in Japan, manganese concentrations
ranged from 4.0 to 38.2 mg/m3 around an electric furnace and from 4.9
to 10.6 mg/m3 around the mouth of the kiln (Ueno & Ohara, 1958).
In studies in the USSR reported by Mihajlov (1969), manganese
concentrations in air of 0.3 mg/m3 or more were found in 98% of 1905
samples collected in the furnace area of a steel shop, during the
period 1948-1983. The levels reached 1.8-2.4 mg/m3 during melting
operations and increased to as much as 10 mg/m3, when the molten
steel was being poured. Additional data on manganese concentrations in
air can be found in section 9.1.
Few studies have included details of the size distribution of
manganese dust, which is of importance in the evaluation of dust
absorption following inhalation. Akselsson et al. (1975) reported
manganese concentrations of up to 3 mg/m3 in the breathing zone of
welders. The highest concentrations were associated with particles
ranging in size from 0.1 to 1.0 µm. This is in agreement with the
finding that 80% of particles from a ferromanganese furnace ranged in
size from 0.1 to 1.0 µm (Sullivan, 1969). In studies by Smyth et al.
(1973), more than 99% of the particles in airborne fume around a blast
furnace were smaller than 2 µm and 95% of airborne dust particles at a
crushing and screening plant were smaller than 5 µm.
Manganese may be present in fresh water in both soluble and
suspended forms. However, in most reported studies, only total
manganese has been determined.
Surface waters of various American lakes were found to contain
from 0.02 to 87.5 µg of manganese per litre with a mean of
3.8 µg/litre (Kleinkopf, 1960). In two other studies the contents of
large rivers in the USA ranged from below the detection limit to
185 µg/litre (Durum & Haffty, 1961; Kroner & Kopp, 1965). A range of
0.8-28.0 µg/litre was found in Welsh rivers (Abdullah & Royle, 1972).
Manganese concentrations at 37 river sampling sites in the United
Kingdom (Department of Health and Social Security, 1975 --
unpublished) and in the Rhine and the Maas and their tributaries
(Bouquiaux, 1974) ranged from 1 to 530 µg/litre. There are some
reports indicating a seasonal variation in the manganese contents of
rivers (Bescetnova et al., 1968; Kolesnikova et al., 1973) and inshore
waters, manganese levels being lowest during the winter months
(Morris, 1974). High manganese concentrations reaching several
mg/litre have been found in waters draining mineralized areas
(Kolomijeeva, 1970; Department of Health and Social Security, 1975 --
unpublished) and in water contaminated by industrial discharges
(Kozuka et al., 1971).
a Department of Health and Social Security (1975) Environmental
health criteria for manganese and its compounds: Review of work
in the United Kingdom, 1967-1973.
In the USSR, groundwater not associated with manganese-bearing
rock, contained manganese concentrations ranging from 1 to
250 µg/litre (Kolomijeeva, 1970). A comparatively high average
concentration of 0.55 mg/litre was reported in a study of 6329
untreated samples of groundwater in Japan (Kimura et al., 1069) and
concentrations ranging from 0.22 to 2.76 mg/litre were found in deep
well water in the Takamatsu City area (Itoyama, 1971).
An average concentration of manganese in seawater of 0.4 µg/litre
was reported by Turekian (1969). In other studies on the manganese
contents of sea water in the North Sea, the Northeast Atlantic, the
English Channel, and the Indian Ocean, concentrations ranged from 0.03
to 4.0 µg/litre with mean values of 0.06-1.2 µg/litre. In estuarine
and coastal waters of the Irish Sea and in waters along the North Sea
shores of the United Kingdom, values ranging from 0.2 to 25.5 µg/litre
have been reported with mean values of 1.5-6.1 µg/litre (Topping,
1969; Preston et al., 1972; Jones et al., 1973; Bouquiaux, 1974).
Manganese concentrations in treated drinking-water supplies in
100 large cities in the USA ranged from undetectable to 1.1 mg/litre,
with a median level of 5 µg/litre; 97% of the supplies contained
concentrations below 100 µg/litre (Durfor & Becker, 1964). According
to a US Public Health Service survey quoted by Schroeder (1966),
manganese levels in tap water from 148 municipal supplies ranged from
0.002 to 1.0 mg/litre, with a median level of 10 µg/litre. Mean
concentrations of manganese in drinking-water in the Federal Republic
of Germany were reported to range from 1 to 63 µg/litre (Bouquiaux,
The average concentration of manganese in soils is probably about
500-900 mg/kg (NAS/NRC, 1973). Earlier analyses are of doubtful value,
as errors arising from contamination and interference with other
substances were not fully appreciated (Mitchell, 1964). The
significance of manganese levels in soils depends largely on the type
of compounds present and on the characteristics of the soil such as
the pH and the redox potential. Accumulation usually occurs in the
subsoil and not in the surface, 60-90% of manganese being found in the
sand fraction of the soil. In well-drained areas, the manganese
contents of stream sediments and of parent rocks and soils have been
found to be comparable. In areas of poorly-drained, peaty gleys and
podzols, stream sediments may be greatly enriched. For example, stream
sediments from poorly drained Welsh moorlands with rock and soil
concentrations of 540 mg/kg and 300 mg/kg, respectively, contained an
excess of 1% manganese (Nichol et al., 1967).
Soddy-podzolic soils in the USSR contained manganese
concentrations of 21-200 mg/kg, chernozem soils, up to 6400 mg/kg, and
boggy soils, 10-500 mg/kg. Mobile manganese in the USSR soils varied
from 23 to 149 mg/kg (Vasilevskaja & Bogatyrev, 1970). In Belgium,
loess formation in a forest region contained manganese concentrations
of 113-450 mg/kg. In a semi-industrialized region, concentrations
ranging from 135 to 320 mg/kg were found, while in sandy uncultivated
soil, concentrations ranged from 30 to 43 mg/kg (Bouquiaux, 1974).
The manganese contents of various foodstuffs vary markedly
In cereal crops from the USSR, manganese concentrations varied
from 2 to 100 mg/kg wet weight, concentrations in pulse crops ranged
from 0.36 to 32 mg/kg, and those in root crops from 0.2 to 15 mg/kg;
beet crops contained up to 37 mg/kg (Aljab'ev & Dmitrienko, 1971;
Musaeva & Kozlova, 1973).
The edible muscle tissue of 8 common commercial species of fish
in New Zealand was reported by Brooks & Rumsey (1974) to have mean
concentrations of manganese ranging from 0.08 to 1.15 mg/kg wet
weight. Similar values (0.03-0.2 mg/kg wet weight) were found in North
Sea fish. In cod and plaice, most values were lower than 0.1 mg/kg.
Shellfish may concentrate manganese. Scallops, oysters, and mussels
dredged from Tasman Bay contained average manganese levels of 111 mg,
8 mg, and 27 mg/kg dry weight, respectively (Brooks & Rumsey, 1965).
High concentrations of manganese have been found in tea including
levels of 780-930 mg/kg in the finished leaves (Nakamura & Osada,
1957) and 1.4-3.6 mg/litre in liquid tea (Nakagawa, 1968).
In most human studies, the average daily intake of manganese, via
food, by an adult has been reported to be between 2 and 9 mg/day.
Values of about 2.3-2.4 mg/day have been reported from the Netherlands
(Belz, 1960) and the USA (Schroeder et al., 1966). North et al. (1960)
obtained an average daily intake of 3.7 mg for 9 American college
women, and Tipton et al. (1969), using the duplicate portion method,
reported 50-week, mean daily intakes of 3.3 and 5.5 mg, respectively,
for two American adult males. Similarly, an average intake of
4.1 mg/day was reported from a Canadian composite diet (Méranger &
Smith, 1972). In a study by Soman et al. (1969), also using the
duplicate portion method, the average manganese intake for Indian
adults was 8.3 mg/day, while the intake from drinking-water ranged
from 0.004 to 0.24 mg/day. These results agree well with previously
reported values for Indian adults on a rice diet (9.81 mg of
manganese/day) and on a wheat diet (9.61 mg of manganese/day) (De,
Table 5. Manganese levels in some foodstuffs
Category Manganese (mg/kg wet weight)
Shroeder et al. (1966) Guthrie (1975)
barley, meal 17.8 9.9
corn 2.1 3.8
rice, polished 1.5 9.6
unpolished 2.1 32.5
rye 13.3 34.6
wheat 5.2-11.3 13.7-40.3
Meat and poultry < 0.1-0.8 < 0.1-2.7
Fish < 0.1 0.1-0.5
milk 0.2 0.5
butter 1.0 0.1
Eggs 0.5 0.3
beans 0.2 1.8
peas 0.6 2.6
cabbage 1.1 0.8
spinach 7.8 1.8
tomatoes 0.3 0.2-0.6
apples 0.3 0.2-0.3
oranges 0.4 0.3
pears 0.3 0.1-0.4
walnuts 7.5 19.7
The daily intake of manganese by bottlefed and breastfed infants
is very low because of the low concentrations of manganese in cow's
milk and, especially, in breast milk (McLeod & Robinson, 1972a).
Widdowson (1969) reported a daily intake of 0.002 mg/kg body weight
for 1-week-old babies. Values of a similar order of magnitude
(0.002-0.004 mg/kg) have been reported for the first 3 months of life
by Belz (1960) and McLeod & Robinson (1972a). When a child is
established on a mixed food regimen after 3-4 months of age, the
intake increases considerably (McLeod & Robinson, 1972a).
Belz (1960) reported a daily intake of 1.7 mg for children aged
7-9 years, and Schlage & Wortberg (1972) reported intakes of
1.4 mg/day for 6 children aged 3-5 years, and 2.2 mg/day for 5
children aged 9-13 years, corresponding to 0.08 mg and 0.06 mg/kg body
weight, respectively. Day-to-day intake varied considerably, the
maximum intake being 10 times the minimum. Similar values for daily
intake were obtained by Alexander et al. (1974) for 8 children aged
between 3 months and 8 years; the mean intake was 0.06 mg/kg body
4.5 Total Exposure from Environmental Media
Based on annual average air concentrations and a respiratory rate
of 20 m3/day, an estimate of the daily exposure to manganese of
populations living in areas without manganese-emitting industries
would be less than 2 µg/day. For populations living in areas with
major foundry facilities, the value is likely to be about 4-6 µg,
while in areas associated with ferromanganese or silicomanganese
industries, the exposure may rise to 10 µg, and 24-peak values may
exceed 200 µg.
Considering the manganese concentrations in the vast majority of
drinking-water supplies, and assuming a water intake of 2 litres per
day, the average daily intake of manganese with drinking-water would
be about 10-50 µg with a range of about 2-200 µg. Although the
variation is considerable, an intake exceeding 1.0 mg/day would be
The daily intake of manganese from food appears to be 2-9 mg.
Some European and American studies suggest a likely range of 2-5 mg,
while in countries where grain and rice make up a major portion of the
diet, the intake is more likely to be in the range of 5-9 mg. The
consumption of tea may substantially add to the daily intake.
The average intake for children from a very early age up to
adolescence is about 0.06-0.08 mg/kg body weight whereas for breastfed
or bottlefed infants intake is only about 0.002-0.004 mg/kg body
5. TRANSPORT AND DISTRIBUTION IN ENVIRONMENTAL MEDIA
5.1 Photochemical and Thermal Reactions in the Lower Atmosphere
Atmospheric manganese compounds seem to promote the conversion of
sulfur dioxide to sulfuric acid (Coughanowr & Krause, 1965; Matteson
et al., 1969; Ethyl Corporation, 1971; McKay, 1971). However, the
concentration of manganese required to achieve this conversion and the
significance of its effect remain unknown. The available evidence
seems to indicate that a higher concentration of atmospheric manganese
than is normally observed would be necessary.
Manganese dioxide reacts with nitrogen dioxide, in the
laboratory, to form manganous nitrate (Schroeder, 1970). There is the
possibility that such a reaction might occur in the atmosphere but
further studies are needed before any conclusion can be reached.
5.2 Decomposition in Fresh Water and Seawater
All water contains manganese derived from soil and rocks.
Manganese in seawater is found mostly as manganese dioxide (MnO2),
some of which is produced from manganese salts by several species of
bacteria common to soils and ocean muds. The aqueous chemistry of
manganese is complex. Mobilization of manganese is favoured by low Eh
and/or pH conditions. Thus acid mine-drainage waters can give rise to
high environmental concentrations of dissolved manganese. Mitchell
(1971) showed that mobilization was greatly enhanced in acid, poorly
drained podzolic soils and groundwaters. It was suggested by Nichol et
al., (1967) that, in acid waterlogged soils, manganese passes freely
into solution and circulates in the groundwaters but that it is
precipitated on entering stream waters with average pH and Eh, thus
giving rise to stream sediments enriched with manganese.
Particulate material suspended in natural waters may contain an
appreciable proportion of manganese. Preston et al., (1972) found that
67-84% of the total manganese in shoreline and offshore areas of the
British Isles was associated with particulate matter that contained
manganese levels of several hundred mg/kg. Levels of particulate
manganese present in ocean waters are low in comparison with levels of
dissolved manganese. However, much larger amounts of particulate
manganese occur in estuarine and river waters, where resuspension of
bottom material may occur. Spencer & Sachs (1970) found that organic
particulate matter in the Gulf of Maine was predominantly regenerated
in the water column and that the amount of manganese transported to
the sediments in this way was negligible.
In deep-sea sediments, manganese is concentrated in the form of
both crustal material and coastal and shelf sediments. The composition
of manganese nodules on the ocean floors is related to factors such as
water composition, sedimentation rates, volcanic influences, and
organic productivity. Regional variations have also been observed,
especially in the Atlantic Ocean (Elderfield, 1972).
5.3 Atmospheric Washout and Rainfall
On the basis of samples taken at 32 stations in the USA, Lazrus
et al., (1970) concluded that the manganese in atmospheric
precipitation was derived mainly from human activity. The average
manganese concentration in the samples was 0.012 mg/kg. These data do
not show the immediate influence of major sources of industrial
5.4 Run-off into Fresh Water and Seawater
Aerosols, pesticides, limestone and phosphate fertilizers,
manures, sewage sludge, and mine wastes have all been identified as
possible sources of soil contamination that can add to the manganese
burden of fresh water and seawater (Lagerwerff, 1967). The
concentrations of trace elements in soil additives are generally low
and do not significantly affect the total manganese content of soil
(Swaine, 1962; Mitchell, 1971).
5.5 Microbiological Utilization in Soils
Manganese cycles in the soil have been proposed involving di-,
tri-, and tetravalent manganese. Divalent manganese is transformed
through biological oxidation to the less available trivalent form and
later, through dismutation, the Mn+++ form is biologically reduced
to Mn++. A dynamic equilibrium may exist between all forms. The
oxidizing power of higher oxides increases with acidity and thus
reduction by organic matter is more likely at low pH values. If the
oxygen tension is low, biological reduction can take place at any pH
value. Bacterial oxidation is very slow or absent in very acid soils
and Mn++ predominates; organic matter can reduce the higher oxides.
In alkaline soils, the divalent form nearly disappears bacterial
oxidation is rapid and reduction by organic matter is slow. In
well-aerated soils with a pH of more than 5.5, soil microorganisms can
oxidize the divalent form rapidly. The rates of exchange between the
various forms are not known at the present time but there is a very
pronounced seasonal variation. This is probably due to oxidation and
reduction induced by microbial action. The manganous form predominates
in summer and the manganic form in winter, though the opposite is said
to be true for alkaline soils (Zajic, 1969).
5.6 Uptake by Soil and Plants
It appears that plants mainly absorb manganese in the divalent
state and that the availability of soil manganese is closely
influenced by the activity of microorganisms that can alter pH and
oxidation reduction potentials. Reducing the soil pH or the soil
aeration by flooding or compaction favours the reduction of manganese
to the Mn++ form and thereby increases its solubility and
availability to plants. Heavy fertilization of acid soils without
liming (particularly with materials containing chlorides, nitrates, or
sulfates) may also increase manganese solubility and availability.
Under some conditions of pH and aeration, the addition of organic
compounds to soil can increase the chemical reduction of manganese and
its uptake by plants. In a study by NAS/NRC (1973), it was shown that
the capacity of plants to absorb manganese varied according to
species. For example, in 20 different species of flowering plants, the
absorption capacity of some species was 20-60 times greater than that
of the species with the lowest capacity for absorbing the element
Areas with low manganese concentrations in the soil (below
500 mg/kg) are associated with low manganese levels in the herbage
(30-70 mg/kg dry weight) (Department of Health & Social Security, 1975
-- unpublished). Liming has been shown to reduce the availability of
manganese in soils; on plots with pH values ranging from 5.0 to 7.0,
the average manganese content of clover fell from 55 to 12 mg/kg and
that of rye grass from 104 to 13 mg/kg, alter liming (Reith, 1970).
Nitrogen applications consistently reduce the availability of
manganese. Organic material associated with a high pH can produce
organic complexes of divalent manganese leading to insufficient
available manganese for susceptible plants such as peas or cereals.
Aging of manganese oxides reduces their availability. Manganese
toxicity in plants may occur in soils containing manganese levels
exceeding 1000 mg/kg dry weight; this generally occurs in very acid
soils and can usually be remedied by liming (Mitchell, 1971). It
should be noted that the total manganese content of soil is of little
biological significance, since only a small amount is present in an
The uptake of manganese by barley p.!ants is stimulated by the
presence of microorganisms, which also appear to break down
EDTA-manganese chelates (Barber & Lee, 1974). On a dry-weight basis,
perennial rye and timothy grass have been shown to have about three
times the manganese content of lucerne, and rather more than
tetraploid red clover. Under deficiency conditions, plants destined
for herbage contained manganese concentrations of less than 10 mg/kg
dry weight (Fleming, 1974).
Terrestrial mammals may concentrate available manganese up to a
factor of 10, whereas fish and marine plants concentrate it by factors
of 100 and 100 000, respectively. Porphyra spp. in the Irish Sea
contained 13-93 mg/kg dry weight and Fucus spp. from British coasts
contained 33-190 mg/kg dry weight (Preston et al., 1972).
All vegetation appears to concentrate manganese to some extent,
the greatest degree of concentration taking place. in new growth and
seeds. Surface enrichment occurs through plant uptake and leaf
Aquatic and terrestrial food chains have not been fully
determined for manganese. Variations reported in manganese
concentrations in foods may be caused by a number of factors, such as
the level and availability of manganese in the soil and water, the use
of agricultural chemicals, species differences in uptake, and
variations in sampling techniques and analyses.
The form in which manganese exists in animal and plant tissues is
5.8 Organic manganese fuel additives
In the petrol engine, over 99% of the methylcyclopentadienyl
manganese tricarbonyl (MMT) is combusted, the principal combustion
product being Mn3O4 (Ethyl Corporation, 1974; Moran, 1975).
According to available studies, less than 0.5% of MMT itself is likely
to be emitted with the exhaust gas (Ethyl Corporation, 1974; Hurn et
al., 1974). The emitted MMT is rapidly decomposed photochemically and
has an atmospheric half-time of only a few minutes, at the most (Ter
Haar et al., 1975). The photolytic decomposition products of MMT are
not well known. Nearly all the manganese in this compound is converted
by photochemical decomposition to a mixture of solid manganese oxides
and carbonates; manganese carbonyl compounds do not appear to be
formed (Ter Haar et al., 1975).
6. METABOLISM OF MANGANESE
The main routes of absorption of manganese are the respiratory
and gastrointestinal tracts. Absorption through the skin is not
considered to occur to any great extent (Rodier, 1955).
6.1.1 Absorption by inhalation
Little is known about the absorption of manganese through the
respiratory system. The absorption of some metals and metallic
compounds was considered by the Task Group on Metal Accumulation
(1973) and certain of the basic principles outlined in that group's
report can be applied to inhaled metals in general. Particles small
enough to reach the alveolar lining of the lung (less than a few
tenths of a micrometre in diameter) are eventually absorbed into the
blood. Mucociliary clearance, which differs with each individual,
affects the degree of particle deposition in the lung. Furthermore, in
studies by Hubutija (1972), it was shown that deposition of inhaled
manganese oxide dust depended on the electrical charge carried, up to
33% more positively charged dust being deposited than negatively
charged dust. As a certain percentage of inhaled manganese particles
cleared by mucociliary action may be swallowed (Mena et al., 1969),
absorption from the gastrointestinal tract should also be considered
6.1.2 Absorption from the gastrointestinal tract
Not much is known about the mechanisms of absorption of manganese
from the gastrointestinal tract. From in vitro studies using the
everted sac method, it would seem that manganese may be actively
transported across the duodenal and ileal segments of the small
intestine (Cikrt & Vostal, 1969). Results of studies in man and the
rat on the interrelationship between manganese and iron absorption
have indicated that intestinal absorption of manganese takes place by
diffusion in iron-overload states and by active transport in the
duodenum and jejunum in iron-deficiency states (Thomson et al., 1971).
Few quantitative data are available concerning absorption from
the gastrointestinal tract in man. Mena et al. (1969) studied
gastrointestinal absorption in 11 healthy, human subjects, each of
whom received 100 µc (3.7 MBq) of radioactive manganese dichloride
(54MnCl2) using 200 µg of manganese dichloride (55MnCl2) as a
carrier. About 3 ± 0.5% of the amount administered was found to be
absorbed. There were individual variations showing a five-fold
difference between the lowest and highest values of absorption. The
reported rate of absorption did not take into account reabsorption
into the enterohepatic circulation, but the authors considered this
underestimation to be small.
The rate of absorption may be influenced by such factors as
dietary levels of manganese and iron, the type of the manganese
compound, iron deficiency, and age. Thus, in the study just described,
Mena et al., found an absorption of 7.5 ± 2.0% in 13 patients with
iron-deficiency anaemia. They also found that, in 6 miners with high
tissue levels of manganese, an increase in the rate of excretion of
manganese was accompanied by an increase in iron excretion. This
interrelationship may further aggravate a pre-existing anaemia, thus
increasing the rate of manganese absorption and may be a relevant
factor in occupational exposure to manganese. Similarly, Thomson et
al. (1971), using duodenal perfusion with a manganese dichloride
solution containing a manganese concentration of 0.5 µg/ml, noted an
increased rate of absorption in iron-deficient patients that could be
inhibited by adding iron to the solution.
Figures for gastrointestinal absorption in infants and young
children are not available.
Most studies on animals have indicated a gastrointestinal
absorption of less than 4%. Suzuki (1974) reported an intestinal
absorption of only 0.5-2.0% in mice fed dietary levelsa of manganese
dichloride of 20-2000 mg/kg.
However, when rats were given 0.1 mg of radioactive manganese
orally, 3-4% of the dose was absorbed (Greenberg et al., 1943).
Similar results were obtained by Pollack et al. (1965), who reported
an absorption of 2.5-3.5% in rats given an oral dose of radioactive
manganese dichloride (54MnCl2). Thus, absorption data for the adult
rat agree with the figure obtained for the absorption of manganese
dichloride in man. However, Mena (1974) reported that intestinal
absorption in the young rat was of the order of 70% compared with 1-2%
in the adult rat.
In a study by Abrams et al. (1976), rats were given dietary
levels of manganese ranging from 4 to 2000 mg/kg for about 2 weeks,
followed by a single oral dose of radioactive manganese (54Mn).
Absorption of 54Mn was significantly lower in rats receiving high
dietary levels (1000-2000 mg/kg) than in animals receiving the lowest
level (4 mg/kg).
Ethanol given to fasting rats in doses of 4 g/kg body weight
increased absorption of manganese from the gastrointestinal tract and
resulted in a two-fold increase in uptake of manganese in the liver.
Furthermore, in vitro experiments indicated a four-fold increase in
the transmural migration of manganese (Schafer et al., 1974). It has
long been known that calcium in the diet can reduce the amount of
manganese absorbed by poultry, probably by reducing the amount of
manganese available for absorption (Wilgus & Patton, 1939).
However, recent studies suggest that calcium may, under certain
circumstances, enhance gastrointestinal absorption of manganese.
Lassiter et al. (1970) noted a higher rate of absorption in rats fed a
dietary level of calcium of 6 g/kg for 21 days before oral dosing with
54Mn, compared with rats receiving a level of only 1 g/kg. In studies
on sheep, the same authors found that phosphoric acid, mixed into the
ground hay at a concentration of 15 g/kg, decreased gastrointestinal
absorption of the stable manganese in the hay.
In rats, the enterohepatic circulation appears to be of
importance. Intraduodenal administration of manganese that had been
excreted into the bile resulted in about 35% absorption, whereas only
15% of an equivalent dose of manganese dichloride administered
intraduodenally was absorbed (Cikrt, 1973). This indicates that
manganese present in bile is in a form that is more easily absorbed
than manganese dichloride.
6.2.1 Distribution in the human body
Manganese is an essential element for man and animals and thus
occurs in the cells of all living organisms. Concentrations of
manganese present in individual tissues, particularly in the blood,
remain constant, in spite of some rapid phases in transport,
indicating that such amounts may be considered characteristic for
these particular organs irrespective of the animal species (Cotzias,
The total manganese body burden of a standard man of 70 kg has
been estimated to be about 10-20 mg (Underwood, 1971; WHO Working
Group, 1973; Kitamura et al., 1974). Thus, tissue concentrations will
frequently be below the µg/kg level. In general, higher manganese
concentrations can be expected in tissues with a high mitochondria
content (Maynard & Cotzias, 1955; Thiers & Vallee, 1957), with the
exception of the brain which contains only low concentrations (Maynard
& Cotzias, 1955). There also appears to be a tendency towards higher
concentrations in pigmented tissues such as dark hair or pigmented
skin (van Koetsveld, 1958; Cotzias et al., 1964).
a The approximate relation between concentration in diet in mg/kg
(ppm) and mg per kg body weight per day is given for a number of
animal species in Nelson (1954).
Table 6. Manganese in human tissues (mg/kg wet weight)
Tissue Kehoe et al. (1940) Tipton & Cook (1963)a Kitamura (1974)
(emission spectroscopy) (emission spectroscopy) (atomic absorption)
aorta -- 0.11 --
brain 0.30 0.27 0.25
fat -- -- 0.07
heart 0.32 0.22 0.19
intestine 0.35 -- --
kidney 0.60 0.90 0.58
liver 2.05 1.30 1.20
lung 0.22 0.19 0.21
muscle -- 0.06 0.08
ovary -- 0.16 0.19
pancreas -- 1.18 0.74
spleen -- 0.13 0.08
testis -- 0.13 0.20
trachea -- 0.19 0.22
rib -- -- 0.06
a Values calculated using the given ash percentage wet weight
and the median value of manganese in tissue ash.
Table 6 gives the results of 3 studies on the manganese contents
of various tissues in people without any known occupational or other
additional exposure to manganese. Two are studies on adults from the
USA (Kehoe et al., 1940; Tipton & Cook, 1963). In a study by Kitamura
(1974) performed on 15 Japanese males and 15 females who had died in
accidents, the highest concentrations of manganese were found in the
liver, pancreas, kidney, and intestines. Comparatively high
concentrations were also found in the suprarenal glands.
From birth to 6 weeks, infants have relatively higher tissue
concentrations of manganese than older children, especially in tissues
normally associated with low manganese levels. However, after about 6
weeks of age, no accumulation of manganese appears to take place with
increasing age (Schroeder et al., 1966). This is in agreement with the
study of Dobrynina & Davidjan (1969), who reported that manganese did
not accumulate with age, and that the manganese content of the lung
actually decreased with increasing age. Anke & Schneider (1974) also
found a statistically significant decrease in the kidney content of
manganese beginning at about 60 years of age; they reported a slightly
higher mean concentration in females (4.4 mg/kg) than in males
(3.8 mg/kg). With respect to manganese concentrations in the liver,
Widdowson et al. (1972) reported that there was no consistent change
with age in 30 fetuses from 20 weeks' gestation to full-term, but
that, generally, manganese concentrations in full-term livers were
7-9% higher than concentrations in adult livers. Studies by Schroeder
et al. (1966) and Widdowson et al. (1972) confirmed that human
placental transfer of manganese takes place.
Table 7. Concentrations of manganese in the whole blood of people without occupational
exposure to manganese
Number of Mean Range
subjects (µg/100 ml) (µg/100 ml) Method Reference
14 0.844 n.r.a neutron Cotzias et al.
19 n.r. 0.86-1.45 neutron Cotzias & Papavasiliou
7 1.16 0.90-1.45 neutron Papavasiliou & Cotzias
18 2.4 n.r. neutron Bowen (1956)
232 3.47b n.r. spectrographic Horiuchi et al.
47 4.0 n.r. spectrographic Butt et al. (1964)
12 4.6 2.2-7.9 spectrographic Cholak & Hubbard (1960)
13 7.6 4.0-15.0 colorimetric Barborik & Sehnalova
30 12.0 n.r. spectrographic Kehoe et al. (1940)
a n.r. = not reported.
Table 8. Concentrations of manganese in the plasma and serum of people without occupational
Number of Mean Range Method Reference
subjects (µg/100 ml) (µg/100 ml)
12 (S)a n.r.c 0.036-0.090 colorimetric Fernandez et al. (1963)
14 (P)b 0.059 n.r. neutron activation Cotzias et al. (1966)
25 (S) (F)d 0.055 0.038-0.104 neutron activation Versieck et al. (1974a)
25 (S) (M)e 0.059 0.045-0.101 neutron activation Versieck et al. (1974a)
19 (P) n.r. 0.183-0.310 neutron activation Cotzias & Papavasiliou
7 (P) 0.269 0.210-0.302 neutron activation Papavasiliou & Cotzias
16 (S) 0.250 0.205-0.297 neutron activation Papavasiliou & Cotzias
7 (P) 0.18f n.r. neutron activation Hagenfeldt et al. (1973)
-- 0.32g n.r. neutron activation Hagenfeldt et al. (1973)
15 (P) 0.43 n.r. neutron activation Olehy et al. (1966)
90 (S) (F) 1.05 n.r. spectrographic Zernakova (1967)
60 (S) (M) 0.96 n.r. spectrographic Zernakova (1967)
48 (S) 1.3 n.r. spectrographic Butt et al. (1964)
30 (S)h 1.3 0.9-1.9 neutron activation Kanabrocki et al. (1964)
40 (S) 2.4 1.2-3.8 atomic absorption Mahoney et al. (1969)
a (S) = serum, e (M) = male.
b (P) = plasma, f sampled at days 16-18 of a menstrual cycle.
c n.r. = not reported. g sampled at days 6-8 of a menstrual cycle.
d (F) = female, h non-dialysable serum.
Some reports on the manganese contents of whole blood, plasma,
and serum have been summarized in Tables 7 and 8. All studies were on
subjects without any occupational exposure to manganese. The
concentrations of manganese are low in blood and still lower in plasma
and serum, thus increasing the vulnerability of sampling and
analytical procedures to the possibilities of contamination (section
2.2.1). This may partly explain the wide range of manganese
concentrations found in the literature. Support for this theory comes
from Cotzias et al. (1966), who considered that systematic
contamination was responsible for the fact that previous plasma levels
obtained by this group (Papavasiliou & Cotzias, 1961; Cotzias &
Papavasiliou, 1962) were 4 times higher than those obtained in the
1966 study (Table 8). A low order of magnitude of manganese levels in
plasma and serum was reported by Fernandez et al. (1963) and more
recently by Versieck et al. (1973b, 1974a).
The concentrations of manganese in blood and serum appear to be
fairly stable over long periods of time (Cotzias et al., 1966; Mahoney
et al., 1969). A slight seasonal variation in blood manganese
concentration, has been reported, the levels being somewhat lower
during the summer and autumn months (Horiuchi et al., 1967). In this
study, manganese concentrations in blood did not differ between age
groups. Diurnal variations were reported by Sabadas (1969), the
concentrations in blood being higher during the day than during the
night. There do not appear to be any differences in the concentrations
of manganese in the blood of men and women (Horiuchi et al., 1967;
Zernakova, 1967; Mahoney et al., 1969; Versieck et al., 1974a).
Hegde et al. (1961) claimed that manganese concentrations in
serum increased following myocardial infarction, but, in more recent
studies, Versieck et al. (1975) were unable to detect such a
relationship. However, during the active phase of hepatitis, serum
concentrations of manganese were invariably elevated (Versieck et al.,
The mean concentration of manganese in the urine of unexposed
people has been reported to be in the range of 3-21 µg/litre (Kehoe et
al., 1940; Cholak & Hubbard, 1960; Horiuchi et al., 1967; Tichy et
al., 1971; McLeod & Robinson, 1972b).
6.2.2 Distribution in the animal body
Average levels of manganese in unexposed rabbit tissues were
reported to be: 2.1 mg/kg wet weight in the liver; 2.4 mg/kg in the
pituitary; 1.6 mg/kg in the pancreas; and 1.2 mg/kg in the kidney. The
brain has a relatively low average content of 0.4 mg/kg wet weight
(Fore & Morton, 1952). The lowest levels occur in bone marrow
(0.04 mg/kg wet weight), blood (0.03 mg/kg wet weight) and lung
(0.01 mg/kg wet weight) (Cotzias, 1958). According to Suzuki (1974),
when aqueous solutions of manganese dichloride at concentrations
ranging from 20 to 2000 mg/litre were given to mice, concentrations
below 500 mg/litre did not result in accumulation in the organs.
However, there was distinct accumulation at doses exceeding
1000 mg/litre. When mice were exposed through inhalation to manganese
dioxide concentrations of 5.6 and 8.9 mg/m3 (particle size 3 µm)
every 2 h, for 8 and 15 days, respectively, the highest concentrations
of manganese were found in the kidney (10.8 and 8.4 mg/kg dry weight),
liver (9.0 and 7.1 mg/kg), pancreas (8.4 and 8.2 mg/kg), and brain
(5.9 mg/kg). Because of the route of administration, even higher
concentrations were observed in the lungs, trachea, and
gastrointestinal tract (Mouri, 1973).
In a study in which monkeys were given a subcutaneous injection
or a suspension of manganese dioxide once a week, for 9 weeks, the
manganese concentration increased markedly in the tissues of the endo-
and exocrine glands and of the cerebral basal ganglion, the
accumulation rate being proportional to the dose administered (Suzuki
et al., 1975).
After intraperitoneal administration of radioactive manganese to
rats, the highest concentrations were found in the suprarenal,
pituitary, liver, and kidney tissues (Dastur et al., 1969). The uptake
by glandular structures was also high in monkeys after intraperitoneal
injection of radioactive manganese (Dastur et al., 1971).
Several experimental studies have shown that manganese penetrates
the placental barrier of various species (Koshida et al., 1963;
Järvinen & Ahlström, 1975; Miller et al., 1975). It has been reported
that manganese is more uniformly distributed in the fetal tissues of
the mouse than in adult tissues. The main differences were seen in the
concentrations in kidney and liver tissues, which were lower in the
fetuses than in the adults. At a later embryonic stage, manganese
accumulation in the bone took place parallel with the process of
ossification (Koshida et al., 1963; 1965). Miller et at. (1975) showed
that, in contrast to adult animals and man, neonatal mice did not
excrete manganese during the first 17-18 days of life, despite
vigorous absorption of the radioactive metal (54Mn) with accumulation
in both mitochondria and tissues, notably in the brain. This suggested
an initial accumulation of the essential micronutrient, supplied in
trace amounts in mouse milk (54 µg/litre) by mothers consuming much
higher dietary concentrations (50 mg/kg). In subsequent experiments,
the same authors noted an absence of manganese excretion during the
first 18 days of life in neonatal rats and kittens. Moreover, when
lactating mothers were fed diets containing concentrations of
manganese ranging from 40 to 40 000 mg/litre, the lactation barrier
appeared to give adequate protection to the young. However, when the
dietary level exceeded 280 mg/litre, the newborn initiated excretion
before the 16th day of life. The neonates showed a greater
accumulation than their mothers, whereas the increase in liver
concentrations was proportional to concentrations found in the
mother's liver. The findings suggest that the neonatal brain may be at
higher risk of reaching abnormal concentrations than other tissues. In
the Syrian hamster, manganese was found in embryonic tissues 24 h
after intravenously injecting the mother with radioactive manganese at
1.36 mg/kg body weight (Hanlon et al., 1975).
After a single intragastric dose of 0.5 or 2.5 mg of
methylcyclopentadienyl manganese tricarbonyl MMT) labelled with 54Mn,
rat tissue and organs showed a distribution characteristic of
inorganic manganese, i.e., the highest concentrations were found in
the liver, kidney, and pancreas. However, high concentrations were
also found in the lungs and to lesser degree in abdominal fat (Moore
et al., 1974).
6.2.3 Transport mechanisms
Absorbed manganese is concentrated in the liver and it has been
suggested that it forms complexes with bile components (Tichy & Cikrt,
1972). It has also been suggested that manganese is transported
directly into the bile (Klaassen, 1974). At one time, it was thought
to be transported in the plasma in its trivalent form by a
beta1-globulin other than transferrin, called transmanganin (Cotzias,
1962), but the results of later in vitro studies on the serum of
cows and human serum and in vivo studies on rabbit and rat blood
have refuted this theory (Panic, 1967, Hancock et al., 1973). At
present, it is largely accepted that manganese and iron are both
transported by the transferrin in the plasma (Panic, 1967; Mena et
al., 1974). It has already been pointed out that mitochondria have
been shown to contain a non-dialysable fraction of manganese (Fore &
Morton, 1952). Studies using radioactive manganese (56Mn) indicated
that newly deposited 56Mn was easily removed from mitochondria
whereas older, stable manganese was not, suggesting different types of
bonding with mitochondria (Cotzias, 1958).
6.3 Biological Indicators of Manganese Exposure
Estimation of manganese exposure in man by examination of
biological fluids or tissues has not proved to be a reliable index.
Analyses of blood or urine samples from persons with signs and
symptoms of manganese poisoning do not usually reveal high levels of
manganese. However, a rough correlation between urine levels and
average air concentrations seems to exist (Tanaka & Lieben, 1969).
There is also some evidence that manganese may concentrate in hair
following exposure to high concentrations (Rosenstock et al., 1971).
Because of the short biological half-time, manganese levels in tissues
and organs can only be related to recent exposure. At present, no
specific diagnostic biological materials are known that could be used
to monitor manganese exposure in epidemiological studies or for
It has already been pointed out that tissue concentrations of
manganese are remarkably constant without any tendency to accumulate
with age, after the first few weeks of life. From earlier studies, it
was considered that variable excretion rather than variable absorption
played an important role in manganese homeostasis (Britton & Cotzias,
1966). However some later results, from studies using oral dosing in
rats, have indicated that variable absorption is also an important
factor (Abrams et al., 1976).
The manganese absorbed in the body, whatever the route of
absorption, is eliminated almost exclusively in the faeces. At
ordinary exposure levels, manganese is mainly excreted into the bile
(Papavasiliou et al., 1966). Quantitative data concerning excretion in
man are not available. After intravenous injection of 0.6 µg of
manganese dichloride (MnCl24H2O) in rats, 12% of the injected dose
was excreted into the bile within 3 h (Tichy et al., 1973), and 27%
within 24 h (Cikrt, 1972). Intraperitoneal administration of 0.01 mg
of manganese to rats resulted in the biliary excretion of 26% of the
dose within 48 h; at a dose of 0.1 mg, the fraction appearing in the
bile was 37% (Greenberg et al., 1943). Manganese excreted with the
bile flow into the intestine is partly reabsorbed (section 6.1.2). In
the rat, there is some evidence of the excretion of manganese through
the intestinal wall into the duodenum, jejunum and, to a lesser
extent, the terminal ileum (Bertinchamps et al., 1966; Cikrt, 1972).
In dogs, some manganese is also excreted with the pancreatic
juice (Burnett et al., 1952). It has been shown that, while excretion
by the biliary route predominates under normal conditions, excretion
by the auxiliary gastrointestinal routes may increase in significance
in the presence of biliary obstruction or with overloading with
manganese (Bertinchamps et al., 1966; Papavasiliou et al., 1966).
Results of human studies have shown that only a small amount of
manganese (about 0.1-1.3% of the daily intake) is excreted through the
kidneys into the urine (Maynard & Fink, 1956; Tipton et al., 1969;
McLeod & Robinson, 1972b). Urinary excretion is not increased by
biliary obstruction or by overloading (Papavasiliou et al., 1966), but
in rats it was increased many times by the administration of
ethylenediamine tetraacetic acid (EDTA), urine becoming the
predominant excretory route for 24 h, after which time faecal
elimination was resumed (Kosai & Boyle, 1956; Maynard & Fink, 1956).
Following intravenous administration of radiolabelled
methylcyclopentadienyl manganese tricarbonyl (MMT) and manganese
dichloride to rats, retention of 54Mn was similar, but the route of
excretion was different. After intravenous administration of
radioactive manganese chloride, only a trace was detected in urine,
54Mn being excreted in the faeces. However, both oral and intravenous
administration of MMT resulted in excretion in both faeces and urine.
With oral administration of MMT, the urine/faeces ratio of manganese
varied from 0.68 to 0.25. No MMT was detectable in the faeces,
indicating a biotransformation of MMT. In vitro experiments showed
that MMT was metabolized in the liver, lung and kidney and to a small
extent in the brain. Biotransformation of MMT by kidney homogenate may
explain the high concentrations of manganese found in the urine of the
rats (Moore et al., 1974).
Insufficient data are available on dermal losses of manganese. An
average excretion in human sweat was given as 60 µg/litre by Mitchell
& Hamilton (1949). Although sweat volumes are known to vary over a
wide range (International Commission on Radiological Protection,
1975), the average daily excretion of manganese with sweat is probably
in the range of 30-120 µg, assuming a sweat volume of 0.5-2 litre/day.
This is in good agreement with a study by Conzolazio et al. (1964),
who found a daily mean excretion of about 100 µg (corresponding to
2.3% of the total daily intake of manganese) in 3 men exposed to
37.8°C for 7.5-h periods. The loss of manganese with human hair and
nails has been estimated to about 2 µg/day (International Commission
on Radiological Protection, 1975), although allowance must be made for
the considerable variation of manganese concentrations in hair
(Cotzias et al., 1964). Small quantities of manganese are also
transferred through the placenta (section 6) and the excretion with
breast milk is about 10-20 µg/day (McLeod & Robinson, 1972a).
6.5 Biological Half-times
A few studies have been performed on animals and man in order to
assess the biological half-times of inorganic manganese. However,
half-times for organic forms of manganese have only been studied in
animals. When considering biological half-times of trace elements in
living organisms, the following factors should be taken into account:
(a) type of exposure (oral or parenteral, single or multiple);
(b) type of metabolic model (single compartment or
(c) inter- and intraspecies variations; and
(d) the rates of phases of excretion (rapid and slow
Mahoney & Small (1968) used single injections of radiolabelled
manganese dichloride on 6 human volunteers to study the biological
half-time of manganese in man. They found 2 phases in the elimination
of manganese from the body, one of which was slow and the other fast.
The mean biological half-time for the 3 "normal" adults was about 4
days for the fast phase and 39 days for the slow phase. About 60-65%
of elimination occurred during the slow phase, although in one subject
90% was eliminated during this phase. In subjects with a high oral
intake of manganese, elimination from the body took place at an
increased rate. Iron reserves may also influence the retention of
Cotzias et al. (1968) studied the tissue clearance of manganese
in 19 healthy "normal" volunteers after a single injection of 54Mn.
Clearance half-time of 54Mn was 37.5 days for the whole body, 25 days
for the liver, 57 days for the thigh, and 54 days for the head. The
clearance half-time from blood and plasma was less than 1.5 minutes.
A clearance half-time for the whole body of 37 days was reported
by Mena et al. (1969) in healthy subjects, compared with a half-time
of 23 days in iron-deficient, anaemic patients. They also reported a
half-time of 34 days in miners suffering from chronic manganese
intoxication, while healthy miners exhibited a fast turnover of only
15 days. This finding may have a bearing on the question of individual
susceptibility to manganese intoxication.
Britton & Cotzias (1966) reported a two-component whole-body
clearance of manganese in mice comparable with that reported by
Mahoney & Small (1968) in man. The half-time of the slow component was
given as 50 days and that of the fast component as 10 days. The
fraction eliminated with the slow component was lower in mice than in
man, i.e., approximately 35%. However, on a low-manganese diet, it
increased to about 95% and the half-time for this component decreased
from 50 to about 35 days. With a high-manganese diet, the half-time
for the fast component decreased from 10 to 2 days.
The effect of dietary manganese levels on the biological
half-time of manganese was studied in mice by Suzuki (1974). The
animals received an aqueous solution of manganese dichloride in
concentrations ranging from 20 to 2000 mg/litre for 26-30 days, after
which radioactive manganese was administered. The whole body clearance
half-time was about 6 days in the 20 mg/litre group, about 3 days in
the 100 mg/litre group, and 1-1.5 days in the group that had received
2000 mg/litre, i.e., the heavier the preloading, the more rapid was
elimination from the whole body. The half-time in the brain was longer
than that in the whole body.
Chemobiokinetic studies on 54Mn in monkeys disclosed a half-time
of 95 days for whole-body elimination. Brain levels did not decrease
significantly over the experimental period of 278 days, suggesting
that the clearance half-time in the brain was longer than that for the
whole body (Dastur et al., 1871).
Adrenal glucocorticoids accelerated the total body clearance of
manganese in mice (Hughes & Cotzias, 1960), and later studies using
ACTH stimulation suggested the existence of an adrenal regulatory
mechanism for the metabolism of manganese (Hughes et al., 1966).
The whole-body retention curve for methylcyclopentadienyl
manganese tricarbonyl (MMT) in rats was similar to that for manganese
dichloride (section 6.4). The authors considered that this was due to
the rapid metabolism of MMT and that the retention curve only
reflected the metabolism of the labelled manganese (54Mn) (Moore et
7. MANGANESE DEFICIENCY
7.1 Metabolic Role of Manganese
The essential role of manganese as a trace metal nutrient for
mammals was discovered mainly through experimental and epidemiological
studies of deficiency states in animals. Thus, manganese has been
shown to be associated with the formation of connective tissue and
bone, with growth, carbohydrate and lipid metabolism, the embryonic
development of the inner ear, reproductive function, and, probably,
brain function (Underwood, 1971; NAS/NRC, 1973).
The biochemical background of the metabolic defects that have
been observed is poorly understood, though a few specific biochemical
properties of manganese have been discovered. One is that manganese
catalyses the formation of glucosamine-serine linkages in the
synthesis of the mucopolysaccharides of cartilage; another, that the
mitochondrial enzyme pyruvate carboxylase (EC 18.104.22.168) is a manganese
metalloenzyme, thus, manganese is linked with carbohydrate metabolism.
It has also been discovered that the digestive enzymes prolidase (EC
22.214.171.124) and succinic dehydrogenase (EC 126.96.36.199) are
manganese-dependent and that, in vitro, manganese can substitute for
other metals, especially magnesium, in various biological reactions
(Underwood, 1971; NAS/NRC, 1973). Lindberg & Ernster (1954) performed
in vitro experiments on rat liver mitochondria that demonstrated
that manganese was required as a co-factor in oxidative
phosphorylation. Manganese deficiency in mice was reported by Hurley
(1968) to be associated with a decreased oxygen uptake by the liver
mitochondria. However, the relationship between these findings and
defects due to manganese deficiency remains obscure.
7.2 Manganese Deficiency and Requirements in Man
No definite syndrome of manganese deficiency has been described
in man. However, in a human subject with experimentally induced
vitamin K deficiency, a sequence of signs was attributed to the
accidental omission of manganese from the diet during 1 week; the
daily intake during 16 subsequent weeks was retrospectively calculated
to have been about 0.35 mg. The subject was unable to elevate the
depressed clotting proteins in response to vitamin K and this finding
was experimentally reproduced in the chick. Moreover, marked
hypocholesterolaemia, retarded growth of hair and nails, mild
dermatitis, pigment changes in hair and beard, and moderate weight
loss were present (Doisy, 1973).
It has been difficult to estimate the minimum physiological
requirements of manganese for man. On the basis of existing data on
the daily manganese intake and manganese balance in man, a WHO Expert
Committee concluded that an intake of 2-3 mg/day was adequate for
adults (WHO, 1973). This is compatible with the figures quoted in
section 4.5 and also agrees with the estimate of 2.7 mg made by De
(1949) on the basis of balance studies on male subjects. A negative
manganese balance was recorded by De in subjects with a mean manganese
intake of 0.71 mg per day.
Engel et al. (1967) measured the daily intake of manganese in 6
to 10-year-old girls and estimated that 1 mg per day was needed to
maintain the balance. Taking into account growth needs, integumental
losses, and a reasonable safety margin, they suggested a required
daily intake of 1.25 mg (0.045 mg/kg body weight). This also agrees
well with the data presented in section 4.5, which show that healthy
children within the age ranges of 9-13 and 3-5 years had daily intakes
of 0.06 and 0.08 mg/kg body weight, respectively (Schlage & Wortberg,
1972). A positive manganese balance was observed in girls, aged 7-9
years, with a daily intake of 2.1-2.4 mg of manganese (Price et al.,
1970). Breastfed infants may have a daily intake as low as
0.002-0.003 mg/kg (Widdowson, 1969; McLeod & Robinson, 1972b) and may
exhibit a distinctly negative manganese balance during the first week
of life. Widdowson (1969) reported that the amount excreted in the
faeces during the first week amounted to 3-5 times the amount ingested
daily with breast milk, indicating the excretion of manganese from
tissue reserves that had accumulated during fetal life (section
6.2.1). This is in agreement with the observation of Schroeder et al.
(1966) that tissue levels decreased during the first 45 days of life.
An association has been suggested between manganese deficiency
and lupus erythematosus found in patients following treatment with
hydralazine. This is based on the fact that administration of
manganese(II) salts improved the condition of such patients and of
patients suffering from the spontaneous variety of disseminated lupus
erythematosus (Comens, 1956).
7.3 Manganese Deficiency in Animals
Defects due to manganese deficiency have been shown
experimentally in a variety of laboratory animals. The best-documented
manifestations are those associated with skeletal abnormalities and
impaired growth. Abnormally fragile bones that are shorter than
normal, and bowed forelegs resulting from these changes have
frequently been reported in mice, rats, and rabbits (Amdur et al.,
1945; Ellis et al, 1947; Plumlee et al., 1956). Perosis with deformity
of bones and dislocation of the achilles tendon ("slipped tendon") has
long been known in young chickens (Wilgus & Patton, 1939). Early
changes observed in chick embryos include nutritional
chondrodystrophy, retarded growth, and shortening of the lower
mandible (Lyons & Insko, 1937). In his review of manganese deficiency,
Underwood (1971) quotes crooked and shortened legs and enlarged hock
joints in pigs, leg deformities with "overknuckling" in cattle, joint
pains in sheep, and tarsal joint excrescences in goats.
Ataxia with loss of equilibrium and altered postural reactions to
stimuli, without histological changes in the brain tissue have been
reported in rats (Hill et al., 1950). It is likely that ataxia is due
to the impaired development of the inner ear, where the otoliths
appear to be absent or defective in several species of laboratory
animals (NAS/NRC, 1973).
Manganese deficiency can induce congenital malformations,
stillbirths, and neonatal deaths in rats and guineapigs and seminal
tubular degeneration and aspermia have been observed in rats and
rabbits (NAS/NRC, 1973). In manganese-deficient female rats, estrous
cycles may be absent or irregular, and the rats may be sterile; in
severe deficiency states, the animals will not mate (Underwood, 1971).
A decreased tolerance to orally administered glucose and an
impaired peripheral use of parenterally administered glucose have been
reported in guineapigs (Everson & Shrader, 1968). Newborn offspring of
manganese-deficient guineapigs displayed aplasia or distinct
hypoplasia of all cellular components of the pancreas; islets
contained a reduced number of beta cells, which were also less
intensely granulated (Shrader & Everson, 1968).
There have been some reports relating manganese to lipid
metabolism. Interaction between choline and manganese has long been
recognized (Underwood, 1971). Pigs, fed manganese-deficient food,
showed a statistically significant increase in fat deposits, measured
as back-fat thickness (Plumlee et al., 1956). Curran (1954) reported
that manganese stimulated the synthesis of fatty acids and cholesterol
in the rat liver. Although the biological implications of these
findings are not clear, it has been suggested that a decrease in the
synthesis of cholesterol and its precursors due to manganese
deficiency might limit the synthesis of sex hormones. This could
explain the sterility of manganese-deficient animals (Doisy, 1972).
A reduction in liver arginase (EC 188.8.131.52) activity in
manganese-deficient rats and rabbits has been reported, but the
importance of this remains to be assessed (Underwood, 1971).
Table 9. The acute toxicity of various forms of manganese
Compound Animal route (mg/kg) Reference
manganese mouse subcutaneous 550b Date (1960)
manganese mouse oral 275-450 Sigan & Vitvickaja (1971)
chloride rat oral 250-275 Hazaradze (1961)
guineapig oral 400-810 Hazaradze (1961)
manganese mouse intraperitoneal 64 Yamamoto & Suzuki,
mouse subcutaneous 146b Date (1960)
mouse oral 305b Date (1960)
manganese mouse intraperitoneal 56 Yamamoto & Suzuki
potassium mouse subcutaneous 500b Date (1960)
permanganate mouse oral 750 Sigan & Vitvickaja (1971)
rat oral 750 Sigan & Vitvickaja (1971)
guineapig oral 810 Sigan & Vitvickaia (1971)
DAP-Mn mouse oral >8000 Suzuki et al. (1972)
cakea mouse intraperitoneal >1200 Suzuki et al. (1972)
DAP-Mn mouse, male oral 2790 Suzuki et al. (1972)
dusta mouse, female oral 2570 Suzuki et al. (1972)
mouse, male intraperitoneal 378 Suzuki et al. (1972)
mouse, female intraperitoneal 352 Suzuki et al. (1972)
a DAP refers to a process for the removal of sulfur dioxide from flue gas. DAP-Mn cake:
manganese oxides used in the desulfurization process. DAP-Mn dust: exhaust gas and dust
from the desulfurization process in a plant.
b Lethal dose (LD100).
8. EXPERIMENTAL ANIMAL STUDIES ON THE EFFECTS OF MANGANESE
8.1 Median Lethal Dose
The toxicity of manganese varies according to the chemical form
administered. Divalent manganese has been shown to be 2.5-3 times more
toxic than the trivalent form. The median lethal doses (LD50) of
various forms of manganese are listed in Table 9.
8.2 Effects on Specific Organs and Systems
8.2.1 Central nervous system
Attempts to induce brain damage characteristic of manganese
intoxication by feeding manganese compounds to experimental animals
have not been completely successful (van Bogaert & Dallemagne, 1946).
This may partly be due to the low absorption of orally administered
manganese. Sigan & Vitvickaja (1971) showed that potassium
permanganate altered conditioned reflex activity in rats, when
administered orally at 10 mg/kg body weight per day for 9 months, and
to a lesser extent when administered at a dose of 1 mg/kg.
Exposure of a monkey to manganese dioxide aerosol at
concentrations of 0.6-3.0 mg/m3 for 95 1-h periods during 4 months,
initially produced alternating periods of sudden movement and torpor,
nervousness, severe tremor, flexion-extension movements of upper
limbs, yawning, and cyanosis. Sequelae after 5 months included gross
tremors, uncertain gait, and paresis. Histological examination of the
brain revealed atrophy of the cerebellar cortex, whereas the putamen,
caudate, and pallidum did not exhibit any clear changes (van Bogaert &
Dallemagne, 1946). Intraperitoneal administration of manganese
dichloride to 4 monkeys on alternate days for up to 18 months,
starting with a dose of 5 mg and increasing the dose to between 15 and
25 mg, resulted in the characteristic lesions of the basal ganglia
associated with choreiform movements and muscular rigidity, tremors,
and limb contractions. Histologically, lesions with shrunken and
pyknotic cells were detected in the putamen, caudate, and the
pallidum. Demyelinized fibres were found in these areas. A slight
chromatolysis was found in the cortex of Macacus rhesus (Mella,
1924). In studies on monkeys by Osipova et al. (1968), a clinical
picture suggesting extrapyramidal dysfunction was obtained in animals
given manganese dichloride subarachnoideally at 1-2 mg/kg body weight,
in 3-8 doses. Similar effects were produced in 5 monkeys given
repeated intramuscular administrations of manganese dioxide at several
injection sites (Pentschew et al., 1963). In this study, the doses
administrated (2000 and 3500 mg injected with an interval of 3 months)
were reported for only one monkey, which was sacrificed 14´ months
after the first injection. The histopathological findings in the
monkey mainly involved the subthalamic nucleus and the medial and
lateral pallidum and were characterized by proliferation of bizarre
cells and by extensive loss of neurons. Diffuse alterations were
reported in the cerebrum, brainstem, and cerebellum. A study on early
brain lesions in rats was reported by Chandra & Srivastava (1970).
Animals which had received intraperitoneal administrations of
manganese dichloride (8 mg/kg body weight) were sacrificed at 30-day
intervals. The first histological changes, seen at 120 days, consisted
of neuronal degeneration in the cerebellar and cerebral cortex. The
extent of brain lesions increased in intensity up to 180 days and was
directly related to the amount of manganese present in the brain
When monkeys were given subcutaneous injections of a suspension
of manganese dioxide, once a week for 9 weeks, at doses of 0.25-1.0 g,
the typical extrapyramidal symptoms that appeared after 3-4 weeks were
not proportional to the dose administered. However, the time of
appearance of the symptoms was dose-related (Suzuki et al., 1975).
Symptoms such as muscular rigidity and tremor were induced in squirrel
monkeys by subcutaneous injection of a total of 400 mg of manganese
dioxide divided into 2 doses, administered with a 5-week interval.
These animals did not show any histologica] abnormalities of the
brain, when sacrificed 3´ months after the first injection, indicating
that symptoms and signs as well as biochemical changes may appear
before histological alterations can be found (Neff et al., 1969).
8.2.2 Respiratory system
"Manganese pneumonitis" is associated with inhalation of fine
dust containing a relatively low concentration of manganese dioxide
and probably other oxides of manganese, and does not lead to permanent
pulmonary changes or fibrosis. Acute pneumonitis can be induced in
rats by intratracheal administration of manganese dioxide dust or a
solution of manganese dichloride. Characteristically, shedding of
bronchial and alveolar epithelium is seen with intense mononuclear
cell infiltration of the alveolar walls and alveoli. In a study on
rats by Lloyd Davies & Harding (1949), intratracheal administration of
manganese dioxide solutions produced intense mononuclear infiltration
of the alveolar walls and alveoli, followed by granulomatous and giant
cell formation. The changes disappeared within a year. Pulmonary
congestion and oedema were observed after intratracheal injection of
manganese dichloride. Similar intense mononuclear infiltration of the
alveolar walls was produced in young rats by intratracheal
administration of suspensions of various manganese compounds (particle
size less than 3 µm). The higher oxides of manganese and freshly
prepared solutions were more toxic (Levina & Robacevskaja, 1955).
Peribronchial and perivascular sclerosis and the appearance of
collagenic threads were observed in rats after intratracheal
administration of either 25 mg of ferromanganese dust containing 10 mg
of manganese dioxide once a month for 4 months, or 10-30 mg of
manganese dioxide in 6-10 doses over a period of 7´ months (Levina &
Robacevskaja, 1955). Similarly, peribronchial and perivascular
sclerosis and inflammatory changes were seen in 15 out of 15 female
rats exposed by inhalation to manganese dioxide at a mean
concentration in air of 0.3 mg/m3, for 5-6 h daily, for 6 months but
not in rats exposed to 0.033 mg/m3 for 5-6 daily for 7 months
(Dokucaeva & Skvortsova, 1966).
Nishiyama et al. (1975) exposed groups of 3 and 2 monkeys, 20
rats, and 70 mice to air concentrations of manganese dioxide of
3 mg/m3 and/or 0.7 mg/m3 (particle size less than 1 µm), for 22 h
daily, over a period of 5 months. Thorax X-rays appeared mottled in
both groups of monkeys after 2-4 months of exposure. In 2 monkeys
exposed to 3 mg/m3, the mottled picture appeared after 2 months, the
patches growing larger and increasingly confluent at 3-5 months. The
X-rays of these monkeys showed accentuation of blood vessels,
indicating pulmonary congestion. The third monkey in this group and 2
control animals did not show any signs of adverse effects. The 2
monkeys exposed to a level of 0.7 mg/m3 showed abnormal findings that
were less severe and appeared at a later stage, i.e., at 3-4 months.
Mice showed inflammatory changes after 2 weeks at both levels of
exposure. The inflammation disappeared after 2 months, at which time
desquamation of bronchial epithelium was observed.
Maigretter et al. (1976) exposed mice to aerosols containing a
manganese dioxide concentration of 109 mg/m3 for one or more 3-h
periods, after which the animals where challenged with Klebsiella
pneumoniae or influenza A virus. A decrease in resistance to
infection was observed, even after a single exposure to the manganese
aerosol. The authors discussed the possible causal association between
the reduced resistance to infection and in vitro observations
showing that manganese dioxide reduced the number and viability of
alveolar macrophages (Walters et al., 1975), and also impaired the
phagocytic activity of these cells (Graham et al., 1975).
Studies have been reported indicating the possibility of a
synergistic effect of manganese dioxide and sulfur dioxide on the
lungs of guineapigs (Rylander et al., 1971; Rylander & Bergström,
1973). The ability to clear inert particles was lower in guineapigs
exposed for 4 weeks (6 h per day, 5 days per week) to manganese
dioxide (5.9 mg/m3) + sulfur dioxide (14.2 mg/m3) than in control
animals or animals exposed to either of the two compounds singly
(Rylander et al., 1971). Exposure of guineapigs to a combination of
manganese dioxide at 20 mg/m3 and sulfur dioxide at 56.8 mg/m3
resulted in a marked increase in leukocytes in the lungs, and a
histological evaluation of the tracheal epithelium gave an "irritation
score" of 3.0 for exposed animals compared with 1.8 for controls.
Animals exposed to sulfur dioxide alone had a score of 1.9, while the
score was 2.3 for those exposed to manganese dioxide only (Rylander &
Rats given an intravenous dose of manganese at a concentration of
55-60 mg/kg body weight showed a marked decrease in the ability of the
liver to clear bilirubin from the bile. This was associated
histologically with cholestatic changes. Reduction in bile flow
occurred within 4 h (Witzleben, 1969). However, no decrease in bile
flow was noted in rats 24 h after an intravenous dose of manganese
dichloride of 30 µg (Cikrt, 1972).
A subcutaneous dose of 170 mg/kg body weight produced hepatic
necrosis in rats within 18 h (Baxter et al., 1965). The metabolism of
thiamine appears to be linked with that of manganese, the storage of
manganese in the liver being related to the level of thiamine in the
diet (Hill & Holtkamp, 1954). Subcutaneous injection of 1.5 and
25 mg/kg body weight of manganese sulfate produced a decrease in
monoamine oxidase (EC 184.108.40.206.) activity in rat liver. The reduction
in activity was more pronounced after repeated injections of 5 and
25 mg/kg for 10 and 5 days, respectively (Levina & Tcekunova, 1969).
Rats exposed to manganese dioxide by inhalation for 5-6 h daily,
6 times a week for 7 months, displayed a decreased serum
albumen/globulin ration, which might have been a result of liver
effects (Dokucaeva & Skvorcova, 1966).
Ultrastructural alterations were found in the liver cells of rats
after administration of manganese dichloride in the drinking-water at
200 mg/litre for 10 weeks. The treated animals exhibited an increased
amount of rough endoplasmic reticulum, a proliferated smooth
endoplasmic reticulum in the centrolobular area, prominent Golgi
apparatus in the biliary area, numerous mitochondria which were
sometimes polymorphous and frequently had an electron-dense matrix.
The changes suggested a process of adaptation to increased exposure to
manganese dichloride (Wassermann & Wassermann, 1977).
Rabbits given 3.5 mg per day of manganese dichloride
intravenously, for 32 days, developed hepatic congestion, central vein
thrombosis, and focal necrosis with leukocyte infiltration (Jonderko &
Other effects of manganese possibly associated with the liver
metabolism that have been observed include an increase in cholesterol
synthesis in the rat (Curran, 1954), a disturbance in lipid and
carbohydrate metabolism with lipid deposition in the liver and
adrenals (Roscin, 1971), and an enhancement of the coagulating
activity of the blood (Cereteli & Kipiani, 1971).
8.2.4 Cardiovascular effects
As early as 1883, Kobert noted that manganese could produce a
reduction in blood pressure. Antihypertensive effects in the rat and
the cat were also reported by Schroeder et al. (1955) and Kostial et
al. (1974). Mjacina (1972) found an increase in the activity of
monoamine oxidase (EC 220.127.116.11) in the cardiac tissue of rats following
subcutaneous injection of manganese dichloride at 10 mg/kg body
8.2.5 Haematological effects
Rats given manganese dichloride in doses of 50-1500 mg/kg body
weight showed an increase in haemoglobin and haematocrit, mean
corpuscular volume, and serum chloride, phosphate, and magnesium after
4 h (Baxter et al., 1965). In anaemic lambs, manganese levels in diet
of 1000-2000 mg/kg caused a retardation in haemoglobin regeneration
and a decrease in serum iron concentrations (Hartman et al., 1955). At
a dietary level of 2000 mg/kg, haemoglobin formation was also
depressed in anaemic rabbits and baby pigs. The effect in pigs was
reversed by a dietary supplement of iron of 400 mg/kg (Matrone et al.,
1959). Dietary levels of manganese ranging from 50 to 125 mg/kg were
found to be the minimum levels that would interfere with the
formulation of haemoglobin in the baby pigs. The minimum level for
lambs was 45 mg/kg (Hartman et al., 1955).
8.3 Effects on Reproduction
Disturbances in sex function and testicular changes have been
noted in rats following exposure to potassium permanganate. Animals
exposed orally or by inhalation to doses of 50 mg/kg body weight for
various periods of time exhibited changes in spermatogenesis.
Embryogenesis was also adversely affected (Mandzgaladze, 1966b, 1967).
In studies on rabbits, intravenous administration of manganese
dichloride at 3.5 mg/kg body weight was reported to produce
histochemically detectable alterations in the testes, confirmed by
decreases in NADH diaphorase, succinic dehydrogenase (18.104.22.168), and
glucose-6-phosphate-dehydrogenase (22.214.171.124) activities. These changes
affected germinal activity (Iman & Chandra, 1975).
Few experimental studies have been conducted on the
carcinogenicity of manganese and its compounds. In one recent study,
manganese(II) sulfate was administered intraperitoneally to mice over
a period of 30 weeks. The highest dose of 10 mg/kg body weight (15
injections) produced a statistically significant (p < 0.05) increase
in the incidence of lung tumours in treated animals compared with
controls (Stoner et al., 1976). There are no other available studies
indicating that inorganic manganese compounds are carcinogenic.
A commercial fungicide containing manganese
ethylene-bis-dithiocarbamate was evaluated for carcinogenicity by the
International Agency for Research on Cancer (IARC Working Group,
1976). Mice of 4 different strains were given 6 weekly doses of the
compound at the rate of 500 mg/kg body weight. An increase in lung
adenomas after 9 months was seen in only one of the 4 strains. It was
concluded that the data available were too meagre to allow an
evaluation of the carcinogenicity of this organomanganese compound.
8.5 Mutagenicity and Chromosomal Abnormalities
There is little information concerning the mutagenicity of
manganese. Processes such as genetic recombination might be affected
by manganese through its influence on enzymes that control DNA
structure and metabolism. Manganese can be substituted for magnesium
in the binding of the two ribosomal subunits as well as in the binding
of M-RNA to the whole ribosome (Buttin & Kornberg, 1966). The
bone-marrow cells of rats given manganese dichloride at 50 mg/kg body
weight, orally, showed an unusual incidence of chromosome aberrations
(30.9%) compared with those of control animals (8.5%) (Mandzgaladze,
1966 a,b,c; Mandzgaladze & Vasakidze, 1966). Permanganate given to
rats in daily doses of 10 mg/kg body weight, for 9 months, produced an
increase in the mitotic activity of bone-marrow cells (Shigan &
Vitvitskaja, 1971). Manganous chloride has been reported to be
mutagenic for Escherichia coli (Demerec et al., 1951; Durham & Wyss,
1957) and Serretia marcescens (Kaplan, 1962). Studies on
manganese(II,III) oxide (Mn3O4) and methylcyclopentadienyl manganese
tricarbonyl revealed that neither compound was mutagenic for
Salmonella typhimurium or Saccharomyces cerevisiae (Simmon &
8.6 Miscellaneous Effects
Rats given doses of manganese sulfate of the order of 0.7-2.0 mg
showed depressed thyroid activity accompanied by reduced thyroid
weight, thinning of follicular epithelium, and smaller follicles
(Hakimova et al., 1969). Observations over 6-12 months on rabbits
injected with manganese dichloride at 3.5 mg of manganese per kg body
weight showed an increase in serum calcium and decreases in serum
magnesium and inorganic phosphorus (Jonderko, 1965). Other effects of
manganese that have been observed include alterations in immunological
activity (Antonova, 1968), disturbance of nitrogen metabolism,
(Slavnov & Mandadziev, 1968), and a depression by manganous chloride
of the acetylcholine output in the myenteric plexus of guineapigs
(Kosterlitz & Waterfield, 1972).
Table 10. Acute toxicity of methylcyclopentadienyl manganese tricarbonyl (MMT) and
cyclopentadienyl manganese tricarbonyl (CMT) following a single administration
Administration LD50 LC50
Compound route Animal (mg/kg) (mg/m3) Reference
MMT oral mouse 352 Pfitzer at el. (1972)
rat (male) 175
rat (male) 58 Hysell et el. (1974)
rat (female) 89 Pfitzer at al. (1972)
guineapig 905 Pfitzer at al. (1972)
rabbit 95 Pfitzer et al. (1972)
intravenous rabbit 6.6 Pfitzer et al. (1972)
percutaneous rat 665 Pfitzer at el. (1972)
(6 h, 10%
(24 h, 10% rabbit 1350 Pfitzer et el. (1972)
CMT oral mouse 150 Arhipova (1963)
rat 80 Arhipova (1963)
inhalation rat 120 Arhipova et al. (1965)
(2 h) (LD80)
8.7 Toxicity of Organomanganese Fuel Additives
There are two organomanganese carbonyl compounds that have been
considered as gasoline (petrol) additives. In the USSR,
cyclopentadienyl manganese tricarbonyl (CMT) has been studied for use
as an additive, while, in the USA, the methylated homologue
methylcyclopentadienyl manganese tricarbonyl (MMT) has been
introduced. In assessing the potential toxicity of the two compounds,
both occupational exposure to the parent compounds and exposure of the
general population to the combustion products should be considered.
Studies on acute toxicity in a number of animal species, following
single administrations of MMT and CMT have been summarized in Table
Following oral administration of MMT, rats developed huddling,
roughened hair coats, tremors, progressive weakness, laboured
respiration, serosanguineous nasal discharge, and terminal coma. All
deaths occurred within 6 days. Survivors appeared normal 14 days after
exposure. Necropsy findings consisted of saccular atonic stomachs,
severe congestion of the liver and lungs, and tubular degeneration in
the kidney. The picture differed from acute manganese toxicity, the
dose administered being smaller than is needed for acute manganese
poisoning in rats, and the liver lesions progressing from acute
centrolobular congestion to parenchymal necrosis and, later, extensive
cytoplasmic vacuolar changes. Whether the MMT itself or one of its
metabolic products was responsible for the toxic effects, could not be
assessed (Hysell et al., 1974).
Rats appeared to be more sensitive to MMT and CMT than mice,
guineapigs and rabbits, and males seemed more sensitive than females
(Arhipova et al., 1963; Pfizer et al., 1972).
Eight out of 20 mice died after 20 days of oral administration of
CMT in oil at 25 mg/kg body weight, 6 times weekly. Daily oral
administration of 5 mg/kg body weight to rats, for 2 months, only
resulted in decreased osmotic resistance of the erythrocytes (Arhipova
et al., 1963).
Prolonged inhalation of MMT at a concentration of 15 mg/m3 for
7 h daily, for 150 days, was lethal to mice and rats, whereas a
concentration of 6 mg/m3 did not cause any deaths (Pfitzer et al.,
1972). Repeated inhalation of CMT at a concentration of 20-40 mg/m3
caused 50% mortality in rats. Prolonged inhalation (10 months) of
concentrations of 0.7-1 mg/m3 by rabbits, guineapigs and rats
resulted in muscarine effects on the central nervous system, a
decrease in diuresis together with an increase in the urinary albumen
content, and decreased resistance to infection (Arhipova, 1963).
Three studies have been conducted on the effects of prolonged
exposure to the combustion products of MMT. Moore et al. (1975)
exposed rats and hamsters for 8 h daily for 56 days to mean
concentrations of manganese in air of 131 and 117 µg/m3 in
non-irradiated and irradiated exposure chambers, respectively. The
general condition and appearance of the experimental animals was not
affected during the experiment and no histopathological lesions
attributable to manganese exposure were found. However, an increase
was noted in manganese tissue concentrations in the exposed rats
compared with control rats. In another experiment, rats and monkeys
were exposed for 24 h per day over 9 months to combustion products
produced by burning MMT vapours in a propane flame. The exposure
levels measured as inorganic manganese were 11.6, 112.5, and
1152 µg/m3. Clinical and histopathological investigations performed
during, at the end of, and 6 months after the exposure period failed
to reveal any adverse effects (Huntingdon Research Center, 1975). In a
study by Coulston & Griffin (1976), monkeys were exposed to
concentrations of manganese in air of 100 µg/m3 for periods up to 66
weeks without any signs of toxicity. However, manganese levels in
tissues increased, particularly in the lungs and pons. Rats exposed in
a similar way for periods up to 3 weeks also showed increased
manganese concentrations in lung and brain tissue. Two monkeys exposed
to about 5000 µg/m3 for 23 weeks failed to exhibit any neurological
or behavioural disorders during the exposure period and the following
10-month observation period.
8.8 Mechanisms and Toxic Effects
At present, the relationship between a large number of in vivo
and in vitro effects of manganese cannot be explained in terms of
biochemical mechanisms. However, effects on the central nervous system
may, to some extent, be explained by recent pathophysiological
findings in the brain. Because of its clinical and histochemical
resemblance to parkinsonism, it has been possible to associate
alterations of the catecholamine metabolism in the brain with
extrapyramidal manifestations of manganese poisoning. In parkinsonism,
the most constantly affected area of the brain is the substantia
nigra, whereas the striatum and pallidum show little damage (Faurbye,
1970; Barbeau et al, 1976). It has been repeatedly shown that the
dopamine concentration in the striatum and pallidum is reduced in
patients with parkinsonism (Faurbye, 1970), and a causal relationship
between cellular loss of the pars compacta of the substantia nigra and
depletion of dopamine in the ipsilateral striatum and pallidum has
been experimentally demonstrated in monkeys (Poirier & Sourkes, 1965;
Sharman et al., 1967; Goldstein et al, 1969), cats (Poirier et al,
1967a), and rats (Faull & Laverty, 1969). In monkeys, this type of
brain damage resulted in abnormal motor function on the contralateral
side. There was also an ipsilateral decrease in the synthesis of
dopamine from the precursor 3,4-dihydroxyphenylalanine (L-dopa)
(Poirier et al., 1967b; 1969), the rate-limiting factor of which may
be the decreased activity of tyrosine 3-hydroxylase (EC 126.96.36.199)
(Levitt et al., 1965; Goldstein et al., 1966). Similarly, it has been
shown that lesions at the midbrain level in monkeys were associated
with contralateral choreiform movements and depletion of striatal
serotonin (Sourkes & Poirier, 1966; Goldstein et al., 1969). In
manganese poisoning, the characteristic brain lesions, unlike the
lesions in parkinsonism, are in the striatum and pallidum, with little
alteration in the substantia nigra (section 9.3.1); nevertheless, in
experimental studies on monkeys (Neff et al., 1969) rabbits (Mustafa &
Chandra, 1971) and rats (Bonilla & Diez-Ewald, 1974), it was shown
that manganese caused depletion of dopamine in the basal ganglia,
especially in the striatum. In the study on monkeys, depletion of
serotonin was also noted. Moreover, post-mortem biochemical analysis
of the brain of a patient suffering from chronic manganese poisoning
showed a reduced concentration of dopamine in the striatum and also in
the substantia nigra (Bernheimer et al., 1973). These findings
implicate the dopaminergic system in the extrapyramidal manifestations
of chronic manganese poisoning and this is further supported by the
fact that a remarkable improvement in the central nervous system
symptoms can be achieved by the administration of L-dopa, a precursor
of dopamine (section 9.3.2).
Oxidative enzymes, which are abundant in the pallidum and
striatum (Shimizu & Morikawa, 1957), are probably located within the
mitochondria (Maynard & Cotzias, 1955) and, thus, are liable to be
affected by the accumulation of manganese at these sites. Intact
oxidative enzyme systems are needed to supply the energy for the
degradation and synthesis of catecholamines involved in synaptic
transmission. Any changes in these systems may affect behaviour and
could be related to the initial psychiatric phase of chronic manganese
poisoning (Mandell & Spooner, 1968). Similarly, tyrosine 3-hydroxylase
and other enzymes in the biosynthetic pathway of catecholamines
require oxygen (von Euler, 1965), and energy from ATP is needed to
transport and compartmentalize essential compounds and to maintain the
appropriate membrane and action potentials necessary for neuronal
transmission. Any degeneration of neuronal cells would profoundly
alter the neural mechanism with consequent clinical effects.
Manganese may also be involved in the interrelationship between
biogenic amines and adenosine 3',5'-monophosphate (cyclic AMP).
Inhibition by manganese of adenyl cyclase (EC 188.8.131.52) in the membrane
of the receptor cell may lead to decreased formation of cyclic AMP and
thus uncouple processes that link the interaction of neurohypophyseal
hormones with the formation of cyclic AMP. As a result, hormonal
action may be inhibited (Bentley, 1967; Cotzias, 1969; Sutherland et
Because of the involvement of metal ions in the neural
transmission processes related to neurohormones, manganese
concentrations have been determined in various regions of the rat
brain. The hypothalamus contained the highest concentration and this
may be related to the neuroendocrine function and oestrus disorders
observed as a result of manganese deficiency in some species. It may
also be required for the proper functioning of glycosyltransferases in
the central nervous system (Donaldson et al., 1973).
9. HUMAN EPIDEMIOLOGICAL AND CLINICAL STUDIES
9.1 Occupational Exposure and Health Effects
Manganese exposure is a health hazard in the mining and
processing of manganese ores and in the use of manganese alloys in the
steel and chemical industries. The majority of cases of manganese
poisoning that have been reported have been associated with a
combination of high-speed drilling, which produces large amounts of
manganese dust, and poor ventilation. However, manganese poisoning can
also occur in other types of industry, such as in the production of
dry-cell batteries (Emara et al., 1971). Chronic manganese poisoning
can result from exposure to high concentrations of manganese dusts.
Onset of the disease may occur after only a few months or several
years according to the severity of exposure (Ansola et al., 1944b;
Rodier, 1955). Damage is reversible, if the patient is removed from
exposure at an early stage. However, apparently a sensitivity can
develop, since a person who has recovered seems to be prone to
contract the illness again.
The signs and symptoms of chronic manganese poisoning have been
described in detail by several authors (Flinn et al., 1940; Ansola et
al., 1944b; Rodier, 1955; Peñalver, 1955; Schuler et al., 1957; Mena
et al., 1967; Letavet, 1973).
According to the severity of the signs and symptoms, poisoning
may be divided into 3 stages: (a) A prodromal stage including the
generally insidious beginning of the disease, with rather vague
symptoms such as anorexia, asthenia, somnolence, insomnia,
hyposexuality, and headache; (b) An early clinical stage, when the
onset of extrapyramidal manifestations occurs. Speech disturbances are
early symptoms in this phase, sometimes leading to muteness. An
increased tone of facial muscles results in a mask-like facies and
there is also decreased ability to perform skilled movements.
Hyperemotionalism is frequent and tendon reflexes in the lower limbs
may be exaggerated; (c) Established chronic manganese poisoning,
which is characterized by psychomotor disturbances and neurological
signs and symptoms. Marked rigidity due to muscular hypertonia, the
most conspicuous sign, is most pronounced in the lower limbs and the
face. Asthenia, adynamia, muscle pain, paraesthesia, speech
disturbances, and disturbances of the libido are typical. The
extrapyramidal dysfunction appearing clearly at this stage results in
a close resemblance to parkinsonism. However, the tremor is frequently
an intention tremor and not resting tremor that is typical of
parkinsonism (Klawans et al., 1970). It has been pointed out that,
contrary to parkinsonism, manganese intoxication is frequently
associated with some degree of dystonia, defined as a postural
instability of complementary muscle groups (Barbeau et al., 1976).
Psychological signs and symptoms include apathy, unmotivated laughter,
a tendency to weep, irritability, restlessness, and hallucinations.
Increased salivation and sweating indicate that an autonomic
disturbance is also present.
Although manganese levels are elevated in most tissues in chronic
manganese poisoning, studies of individuals with well-developed
neurological signs and symptoms have revealed serum and blood
manganese levels within the normal range. In contrast, healthy miners
may have elevated blood manganese levels, suggesting that these
indices are of limited value in the diagnosis of chronic intoxication
(Mena & Cotzias, 1970).
Another significant aspect of chronic manganese poisoning is
marked individual susceptibility (section 9.4), since many miners are
exposed to manganese dust but only a small percentage develop
manifestations of poisoning (Rodier, 1955; Smyth et al., 1973).
The possible toxic effects of manganese on the lungs were
overshadowed during the earlier years by the effects on the central
nervous system. It was only after a high death rate from pneumonia in
a pyrolusite mill was reported that this association was suspected
(Baader, 1932). The cases of pneumonia described by Lloyd Davies
(1946) occurred in workers employed in the manufacture of potassium
permanganate and exposed to manganese dioxide and, to a lesser extent,
to the higher oxides of manganese. The incidence of cases diagnosed as
pneumonia over the period 1938-1945 among the men employed (from 40 to
124 men over the 8-year period) averaged 26 per 1000 workers (range
15-63 per 1000) compared with an average of 0.73 per 1000 in a control
group. Analysis of dust was performed on 2 days in 1944. Manganese
concentrations in air, calculated from the manganese dioxide content
of dust, displayed a range, for 6 measurements of 0.1-13.7 mg/m3. In
general, particles were small, 80% being below 0.2 µm. No case of
chronic manganese poisoning was detected over the 8-year period. The
clinical features of the pneumonia did not differ from conventional
pneumonia with the exception that the response to sulfonamide was slow
and that the entire respiratory tract from the nose, through the
nasopharynx to the alveoli was involved. Permanent pulmonary changes
including fibrosis were not observed. As in other workers exposed to
chemical irritants in air, pharyngitis was a frequent finding. Mice
exposed to dust from the milling room did not show any increased
susceptibility to pneumococci types II and IV or to streptococci. The
high incidence of pneumonia continued during the period 1946-1948
(Lloyd Davies & Harding, 1949). The primary change was suggested to be
an oedematous reaction of the respiratory epithelium resembling
chemical pneumonitis, whereas manganese pneumonia was referred to by
Rodier (1955) as a condition of acute alveolar inflammation with
marked dyspnoea, shallow respiration, and cyanosis.
Suzuki (1970) reported that the incidence of pneumonia in workers
in a ferromanganase plant was twice as high as that in another plant
situated in the same area.
The laboratory diagnosis of chronic manganese poisoning is
nonspecific and, at present, there is no adequate diagnostic test,
although urinary manganese concentrations may have some value. This
measurement, however, does not correlate well with the severity of the
clinical signs. Blood levels of manganese provide little clinical
information and blood urea nitrogen, fasting blood sugar, enzymes, and
electrolytes are usually normal. Rodier (1955) mentions a reduction in
excretion of 17-ketosteroids in 81% of his patients, a relative
increase in lymphocytes and a decrease in polymorphonuclear leukocytes
in 52%, and an increased basal metabolic rate in 57% of patients.
Increased haemoglobin values and erythrocyte counts and decreased
monocyte counts were reported by Kesic & Häusler (1954) and an
increased serum calcium level was observed by Chandra et al., (1974)
in 12 cases of manganese poisoning. In mild cases of intoxication,
serum adenosine deaminase levels were also elevated. Cotzias (1966)
reported that cerebrospinal fluid findings were nonspecific but tended
to show slightly increased cell and protein contents.
Most of the cases of manganese poisoning described have occurred
in manganese mines. Rodier (1955) reported on 150 cases from Moroccan
mines with a total of about 4000 employees. Underground workers
engaged in drilling blast holes ran a high risk of developing
manganese poisoning; 132 out of 150 cases occurred among such workers.
The concentration of manganese in air in the immediate vicinity of
rock drilling was reported in one mine to be about 450 mg/m3 and in
another, 250 mg/m3.
In a study on 72 Chilean miners exposed to manganese
concentrations in air of 62.5-250 mg/m3, 12(16.5%) were found to have
neurological disorders. The average exposure time was 178 days, with a
range of 49-480 days (Ansola et al., 1944a). A further study on 370
miners exposed to manganese concentrations in air of 0.5-46 mg/m3
showed that 15 workers (4%) had contracted typical manganese
intoxication. In these workers, the average time of exposure was 8
years, 2 months, with a range of 9 months-16 years (Schuler et al.,
Flinn et al. (1940) detected 11 cases of manganese poisoning
among 34 workers in 2 manganese ore-crushing mills. The highest
recorded concentration of manganese in air was 173 mg/m3. The
prevalence of manganese poisoning was correlated with both manganese
concentrations in air and the duration of employment. No cases were
found among 9 workers exposed to concentrations of less than
30 mg/m3. Five out of 6 men exposed for more than 3 years to
concentrations exceeding 90 mg/m3 had chronic manganese poisoning.
An occupational health investigation was carried out in Japan in
3 types of industry: a crushing and refining factory, a dry-cell
manufacturing plant, and a welding-rod manufacturing plant (Horiguchi
et al., 1966; Horiuchi et al., 1970). The results of medical
examinations of 134 workers from the 3 establishments were summarized
as follows: On neurological examination, signs of disturbances of the
central nervous system were clearly observed in 4 refinery workers,
and 11 out of 47 refinery workers were suspected of having some
neurological disturbances. Four out of 32 persons in the electric
welding-rod plant, and 7 out of 55 persons from the dry-cell factory
were also suspected of having some form of neurological disturbance
(Horiguchi et al., 1966). Horiuchi et al. (1970) reported that a
statistically significant correlation existed between the neurological
findings and the levels of manganese in the urine of these workers.
The concentrations of manganese in the blood and urine of these
workers are shown in Table 11 together with the concentrations in the
air of the work area.
No significant relationship between the length of employment and
the concentrations of manganese in blood and urine was found. The
manganese concentrations in the blood and urine were higher in the
manganese-refining workers than in workers in the other 2 industries,
and neurological observations differed significantly. The coefficient
of correlation between the manganese quantities in the blood and urine
was +0.283 (Horiuchi et al., 1970).
Table 11. Manganese concentrations in the blood and urine of mangenese workers in relation to air
concentrations in the work areaa
Mn in whole Statistical significance
Type of work Mn in air blood Mn in urine
(mg/m3) (mcg/100 g) (mcg/1) Mn in whole Mn in urine
crushing 2.3-17.1 4-54 8-165
manganese ore median = 8.4 median = 9.5 median = 68.5
manufacturing 1.9-21.1 4-20 1-42 P = 0.0113b P = 0.00049b
dry-cell batteries median = 4.3 median = 8 median = 6
manufacturing 3.8-8.1 4-17 3-19
electrodes median = 4.9 median = 6 median = 5
a From: Horiuchi et al. (1970).
b Statistically significant.
Suzuki et al. (1973a, 1973b) carried out an investigation in 2
ferromanganese factories (factories A and B). The manganese
concentrations in air were 4.86 mg/m3 in the mixing and sintering
plant and less than 1-2 mg/m3 in other places in factory A. Medical
examination of 160 persons revealed that 27 were not healthy, as
assessed by a screening questionnaire. More than a third of the 160
workers examined complained of such symptoms as failing memory,
fatigue, increased perspiration, and hyposexuality. Thirty-four out of
144 male workers, (24%) exhibited tremor in the fingers, 5 (3,5%),
displayed muscle rigidity, 7 (5%), adiadochokinesis and 19 (13%),
disturbed balance. The geometric mean manganese concentrations in the
blood and urine of 144 out of a total of 160 subjects were
18.4 µg/100 ml and 46 µg/litre, respectively (Suzuki et al., 1973a;
In the group of workers that had a blood level of manganese of
more than 32.7/µg/100 ml (=geometric mean + 1 standard deviation),
reduced specific gravity of the whole blood, reduced haemoglobin and
haematocrit values, and increased blood pressure, serum GOT, and
urinary urobilinogen levels were observed. In the group in which the
levels of manganese in the urine exceeded 75 µg/litre (= geometric
mean + 1 standard deviation), the specific gravity of the whole blood
and haemoglobin values were comparatively high (Suzuki et al., 1973c).
The ratio of the concentrations of manganese in urine and blood
was positively correlated with both the specific gravity of the whole
blood and the haemoglobin value. A negative correlation was found
between the urine/blood ratio and the length of a worker's service,
the diastolic blood pressure, and serum GOT. In the groups with a low
urine/blood ratio, there were many cases of symptoms such as dynamia,
failing memory, and hyposexuality (Suzuki et al., 1973c).
In factory B, the concentration of manganese in the air near the
electric furnace was 0.6 mg/m3 before tap, rising to 3.2-8.6 mg/m3,
at tap. An occasional value of 24.3 mg/m3 was recorded under the
conveyor belt, when the crusher was operating. During the medical
examinations of 100 electric furnace workers, more than 40% complained
of increased perspiration, failing memory, lumbago, footsores,
headache, and sleepiness. Furthermore, 8% of the subjects exhibited
adiadochokinesis, 10%, finger tremor, and 8%, acceleration of the
patellar reflex. However, muscular force, whole blood gravity, and
haematocrit values were within the normal range. The geometric means
of the concentrations of manganese were 11 µg/100 ml in blood and
45 µg/litre in urine (Suzuki et al., 1973b).
Two investigations of 34 and 199 workers in a manganese steel
mill exposed to concentrations of manganese in air in the range of
0.4-15 mg/m3 showed that manganese levels in blood exceeding
20 µg/100 ml were accompanied by rises in blood cholesterol, total
serum lipids, lipoproteins, serum bilirubin, calcium, aminolevulinic
acid, and asparagine aminotransferase and decreases in magnesium,
haemoglobin, serum proteins, and the glutathione contents of red
cells. A review of morbidity and sickness records for a period of 6
years showed a higher incidence of absenteeism and atherosclerosis in
exposed workers (Jonderko et al., 1971, 1973a, 1973b, 1974).
A recent epidemiological study of 369 male workers employed in
the production of manganese alloys was reported by Saric et al.
(1974). The mean concentration of manganese in air ranged from 0.39 to
16.35 mg/m3 for the exposed population, while 2 control groups were
exposed to concentrations of 4-40 µg/m3 and 0.05-0.07 µg/m3
respectively. The data from this study suggest that manganese may
contribute to the development of a chronic lung disease. Individuals
with a history of smoking appeared to be more affected than nonsmokers
and there was a relationship between the degree of smoking and the
prevalence of respiratory tract symptoms in the manganese-exposed
workers suggesting that smoking may act synergistically with manganese
(Saric & Lucic-Palaic, 1977). A retrospective analysis of absenteeism
due to pneumonia and bronchitis, in the same group of workers,
revealed that those who were occupationally exposed to manganese were
affected by these diseases more frequently than the controls. Data for
this study were obtained from medical files covering a 13-year period.
Bronchitis was classified into 2 categories: (a) acute and not
specifically defined, and (b) chronic (Saric, 1972; 1978). During
the epidemiological study, it was noted that manganese-exposed
workers, particularly those involved in the production of alloys, had
a lower mean systolic blood pressure than the controls. Diastolic
pressure was not affected and the lowest mean diastolic pressure was
observed in the controls. Factors such as age, body weight, and
smoking habits, which may have influenced the results, were taken into
account in their interpretation (Saric & Hrustic, 1975). A
neurological examination performed in the same group of ferromanganese
workers showed that 62 out of 369 workers (16.8%) had some
neurological signs (Saric et al., 1977). In most cases, the sign was
only a tremor of the fingers (47 workers); 11 workers had pathological
reflexes with or without tremor and in 4 workers, cogwheel phenomenon
was present as an isolated finding or combined with tremor or
Whitlock et al. (1966) reported 2 cases of chronic manganese
poisoning, which occurred in a ferromanganese plant where the
concentrations of manganese in air were in the range of
0.1-4.7 mg/m3. Examination 4 years later (Tanaka & Lieben, 1969),
showed little improvement in one of the cases, the neurological
manifestations being unchanged. The other case had improved but
walking backward was still a little difficult. His face lacked
expression to some extent but was no longer mask-like and the Babinski
reflex was unilaterally positive.
In studies by Sabnis et al. (1966), the daily weighted average
exposure to manganese was estimated in a ferromanganese plant with
1000 workers. No worker had a weighted average exposure exceeding
2.3 mg/m3. During one year of weekly measurement, the highest
recorded manganese concentration in air was 10 mg/m3 and the mean
concentrations for various operations ranged from 0.5 to 5 mg/m3. No
cases of manganese poisoning were detected in this plant, and when
screening for symptoms and signs associated with early manifestation
of manganese intoxication, all findings were "almost negative with
respect to most of the symptoms".
Weighted average concentrations were also estimated by Smyth et
al., (1973), who discovered 5 cases of manganese poisoning among 71
workers studied in a ferromanganese plant. No members of a control
group of 71 unexposed workers displayed similar signs and symptoms.
Three out of the 5 cases were exposed to manganese fumes and 2 to
manganese dust; exposure times varied from 8 to 23 years. One case
with 10´ years of exposure to fumes, mainly of Mn(II,III) oxide, was
exposed at the time of the investigations to a weighted average
concentration of only 0.33 mg/m3, as calculated from 13 air
measurements, each sampling period extending over 30 minutes; the
highest recorded level was 5.9 mg/m3 and the other 12 measurements
were below 5 mg/m3. The patient exhibited facial masking, reduced
blinking reflex, micrographia, loss of associated arm movements on the
right, tremor of the right hand and some cogwheel rigidity of the
right extremities. A high degree of individual susceptibility or
additional exposure to manganese seemed to be the likely explanation
for this case of poisoning. However, the time of onset of the symptoms
in this patient was not discussed, and the beginning of the disease
may have been associated with the higher concentrations that prevailed
earlier at this plant.
9.2 General Population Exposure and Health Effects
Only one epidemiological report is available on adverse effects
from drinking-water contaminated with manganese. Kawamura et al.
(1941) studied 16 cases of manganese poisoning, 3 of which were fatal
(including one suicide), in a small Japanese community. About 400
dry-cell batteries were found buried within 2 m of a well used as a
water supply. The manganese content of the water was about 14 mg/litre
and concentrations of 8 and 11 mg/litre were found in 2 other wells.
All 16 intoxicated subjects drank water from these wells. The subjects
exhibited psychological and neurological disorders associated with
manganese poisoning, and high manganese and zinc levels were found in
organs at autopsy.
With the introduction of a ferro- and silicomanganese plant in
Sauda (Norway), an increase was reported in the incidence of lobar
pneumonia in the population living in the vicinity of the plant
(Elstad, 1939a; 1939b). During the period 1924-1937; mortality due to
lobar pneumonia was 8 times that in the whole country and morbidity
was four times higher. Mortality due to lobar pneumonia in the age
group 15-39 years was about 20 times that in the whole country and the
course of the disease was more severe in Sauda (lethality 35.6%) than
in the rest of Norway (lethality 20.3%). The following factors
implicated manganese in the etiology of the disease: (a) men working
at the factory had a 50% higher mortality due to lobar pneumonia than
men employed elsewhere (Elstad, 1939b); (b) there was a positive
correlation between morbidity and mortality and the amount of metal
produced; and (c) the occurrence and types of pneumococci in Sauda
did not differ from the rest of the country (Elstad, 1939a; Riddervold
& Halvorsen, 1943). Air analyses were performed in 1930 at a sampling
site 3 km downwind from the factory, using a colorimetric assay which
involved oxidation of manganese to permanganate. Air was found to
contain Mn(II,III) oxide at 30-64 µg/m3 and silica (SiO2) at
6.4-8.9 mg/m3. However, the author stated that the oxidation of
manganese to permanganate may have been incomplete, thus yielding
rather low results (Bockman, 1939). Elstad (1939a) reported that air
samples taken at various places contained levels of manganese oxides
ranging from 45 to 64 µg/m3. Thus, both reports indicate that
manganese levels expressed as the metal may have been about 45 µg/m3,
at least. Exposure to manganese was further confirmed by the finding
of a manganese concentration of more than 150 mg/kg dry weight in the
lungs of a woman, who was not working in the factory (Bockman, 1939).
Povoleri (1947) also noted that the prevalence of respiratory diseases
among the inhabitants of Aosta (Italy) increased with the production
of ferromanganese by a plant in that town, but no detailed study of
the situation was conducted.
Investigations in Japan include those of Nogawa et al. (1973) and
Kagamimori et al. (1973), who studied the health of people living in
the vicinity of a ferromanganese plant. The amount of manganese in
dustfall that was collected in 4 places in Kanazawa city, far from the
factory, averaged 8 kg/km2 per month. However, in 3 places, 200-300 m
from the factory, the average manganese level was 200 kg/km2 per
month. There was no difference in the quantities of dustfall and
sulfur dioxide in the 2 areas. The 5-day mean concentration of
manganese in suspended particulates was 4.04 µg/m3 at a point 100 m
away from the factory, and 6.70 µg/m3 at a distance of 300 m.
However, following the smoke downwind, a range of 1-h manganese
concentrations of 4.5-260 µg/m3 was measured at a distance of
50-700 m from the chimney (Itakura & Tajima, 1972). A comparative
study of junior high school students (1258) housed in a school 100 m
away from the plant and a similar group (648) housed 7 km away
produced the following findings: students in the school 100 m from the
factory had a higher prevalence of nose and throat symptoms, a higher
prevalence of past-history pneumonia, and a lower pulmonary function
(as assessed by measuring the forced expiratory volume, one second
capacity, one second ratio, and maximum expiratory flow) than students
in the control school. Among the exposed schoolchildren, pulmonary
function was lowest in those who had lived in the area longest and in
those who lived closest to the factory. A follow-up study, conducted 1
year after a dust collector had been established, showed that the
manganese concentrations in suspended particulate matter had decreased
by about half at 200-300 m distance from the factory. Furthermore, no
differences were found in the symptoms or pulmonary function between
exposed and control groups except in third-grade students, who had,
presumably, been subjected to long-term exposure and whose lung
function showed some deficit. Suzuki (1970) also made observations on
pneumonia morbidity in the same area. He found a history of higher
rates of pneumonia in schoolchildren and their families near the
factory than in a control group.
A 4-year study of the incidence of acute bronchitis,
peribronchitis, and pneumonia was carried out on 31 000 inhabitants of
a town on the coast of Dalmatia, Yugoslavia, where the atmosphere was
polluted by the emissions from a manganese alloy plant. The
concentrations of both manganese and sulfur dioxide in the atmosphere
were monitored. According to the annual mean concentions of manganese
in air, the town was divided into the following 3 zones: Zone I,
0.27-0.44 µg/m3; Zone II, 0.17-0.25 µg/m3; Zone III,
0.05-0.07 µg/m3. Since a low-volume sampling technique was used, the
particles collected were mainly of respirable size. The concentrations
of sulfur dioxide were permanently low, with annual mean levels below
30 µg/m3. The incidence of respiratory diseases was analysed
according to zones of manganese exposure and age, sex, and seasonal
factors (manganese concentrations usually being higher in the summer
than in winter) were taken into consideration. In residential zones,
the incidence of acute bronchitis for both sexes was lowest in the
zone with the lowest manganese concentration, but the highest
incidence did not occur in the zone nearest the factory; however, the
concentrations of manganese did not significantly differ in zones I
and II. The incidence of pneumonia did not seem to exceed expected
values and did not differ significantly in relation to sex, zone, or
season. Thus, the expected higher rate of pneumonia in the winter
failed to occur, and the authors raised the question as to whether
this might be associated with higher summer concentrations of
manganese (Saric, 1978; Saric et al., 1975). In the evaluation of the
study, allowance should be made for the fact that 2-6 times higher
concentrations were obtained using a high-volume technique than with a
low-volume sampling technique (Saric, 1978) and that, apart from
measuring sulfur dioxide levels, environmental and socioeconomic
factors associated with the occurrence of respiratory illness were not
taken into consideration.
A study in the USSR carried out on 928 wives of workers employed
in various manganese-processing plants showed that 13.8% had
spontaneous abortions and 3.2% had stillbirths, while in a matched
control group the incidence of these disorders was 8.1% and 1.7%,
respectively. The rate of spontaneous abortion appeared to increase
with the duration of exposure of the workers. Thus, the wives of
workers employed for 10-20 years had a spontaneous abortion rate of
15.4%, while the wives of workers exposed for 5-10 years had a
spontaneous abortion rate of 11.7% (Mandzgaladze, 1967). No
information regarding the type of work of the wives was given.
9.3 Clinical Studies
9.3.1 Pathomorphological studies
There have been relatively few documented autopsy reports
concerning pathological changes in man related to manganese poisoning
(Casamajor, 1913; Ashizawa, 1927; Canavan & Drinker, 1934; Stadler,
1936; Voss, 1939, 1941; Flinn et al., 1940; Kawamura et al., 1941;
Parnitzke & Peiffer, 1954). In the central nervous system, the most
extensive changes have been found in the striatum (caudate nucleus and
putamen) and pallidum. Ashizawa (1927) noted a loss of ganglion cells
in the pallidum and marked degeneration of the putamen and caudate
nucleus; he also reported slight changes in the substantia nigra.
Brain atrophy over the vertex and lateral aspects was reported by
Canavan & Drinker (1934) in a patient who died 14 years after the
onset of symptoms. On the frontal section, the atrophy was conspicuous
and dilatation of the lateral ventricles with shrinking of the basal
ganglia was found. Degeneration of nerve cells was seen in the basal
ganglia together with gliosis and satellitosis. The caudate nucleus,
putamen, globus pallidus, and thalamus were equally affected. Only
diffuse cellular changes were seen in the cerebral cortex and
cerebellum. Kawamura et al. (1941) reported that a 46-year-old patient
died one month after the onset of an illness contracted from
drinking-water heavily contaminated with manganese. Moderate
congestion was noted in the brain, spinal cord, and meninges, with
meningeal oedema most prominent in the occipital part. Severe
degeneration was found in the globus pallidus, whereas the thalamus,
caudate nucleus, and Louis' body were histologically normal and no
increase in glial cells was found. The most pronounced changes found
by Stadler (1936) were in the striatum and pallidum which were equally
affected. Perivascular degeneration with loss of ganglion cells and
proliferation of glial cells were typical findings in the putamen and
the caudate nucleus. Less severe changes were found in the cortex and
only slight changes in thalamus, hypothalamus, and cerebellum.
Generalized atrophy of the liver cell cords, most marked at the
centre of the lobules, was found by Flinn et al. (1940). However,
because of post-mortem changes, the findings on examination of the
brain remained obscure. The 2 cases described by Voss (1939, 1941)
both displayed degenerative changes of the pyramidal tract, whereas
histopathological autopsy findings in the striatum, pallidum, caudate
nucleus, putamen, and the cortex were minimal. Degeneration of
peripheral nerves was present in both cases: however, one of the
patients suffered also from amyotrophic lateral sclerosis (Voss,
1939). According to Parnitzke & Peiffer (1954), a 19-year-old
manganese miller, who developed symptoms and signs after 1 year of
exposure, died 24 years later after progressive impairment of
neurological function. The total exposure time was approximately 2´
years. A loss of ganglia cells in the pallidum with glial cell
proliferation and high concentrations of manganese, lead, and iron in
the plexus chorioideus were the major findings at autopsy.
Bernheimer et al. (1973) described morphological findings in a
woman with chronic manganese encephalopathy, who died with the
clinical picture of a rigid-akinetic parkinsonian syndrome. She had
been working for many years in a battery factory, and, 10 years after
giving up this work, she had blood manganese levels 10 times higher
than reference values. Generalized astroglial proliferation was found
with a preference for certain cortical areas, the putamen, pallidum,
and red nucleus. There was also mild pallidal atrophy and marked
degeneration in the zona compacta of the substantia nigra. An
interesting finding was the low concentrations of dopamine in the
striatum and of noradrenaline in the hypothalamus; however, serotonin
levels were considered to be normal.
9.3.2 Therapeutic studies
Treatment of chronic manganese poisoning has recently undergone a
basic change reflecting a better understanding of the pathophysiology
of the condition. Early attempts using various chelating agents,
particularly EDTA, were of conflicting benefit but did seem to produce
some improvement in the condition, if applied in its early phase, when
presumably neuronal destruction had not yet occurred. No improvement
could be expected after structural neurological injury had occurred.
The results of Penalver (1955) and Tepper (1961) confirmed this and
they regarded the treatment as ineffective. Whitlock et al. (1966)
reported that treatment with intravenous calcium EDTA mobilized body
deposits of manganese (as evidenced by increased levels of manganese
in the urine) and led to improvement in muscle strength and
coordination within 2-3 months of treatment; however, a follow-up of
the 2 cases, 4 years later, revealed that the improvement was
persistent in only one case and that the other had deteriorated
(Tanaka & Lieben, 1969). That the improvement following EDTA treatment
might be temporary was also reported by Cook et al. (1974). Successful
treatment has been reported, particularly for early manifestations of
manganese poisoning, using calcium EDTA and other chelating agents
derived from polyamino-polyphosphoric acid (Mihajlov et al., 1967;
Arhipova et al., 1968). Wynter (1962) reported poor results with EDTA
in 7 cases in the advanced phase but encouraging results in one
patient with early signs and symptoms. Similarly, Smyth et al. (1973)
found EDTA treatment successful in 2 cases, both of which displayed
loss of associated arm movement as the only neurological sign, but no
improvement in 3 cases with more advanced neurological signs.
The essentially negative results with chelating agents may be
explained by the fact that increased levels of tissue manganese, that
would be amenable to such treatment, were found only in healthy,
actively working miners. Apparently, crippled ex-miners had cleared
the manganese loads they once had, but did not show any improvement in
their neurological picture, indicating that neurological signs can
persist in the absence of elevated tissue concentrations (Cotzias et
al., 1968). Thus, chelating agents can hardly be expected to have
beneficial effects except in early cases, as no tissue concentrations
remain to be cleared in the later stages of the disease.
Recognizing that a similar biochemical defect was present in
parkinsonism (section 8.6), Mena et al. (1970) used oral doses
increasing up to 8.0 gm per day of the dopamine precursor
3-hydroxy-L-tyrosine (L-dopa) in 6 patients. Five subjects showed
reduction or disappearance of rigidity and hypokinesia, and regained
their sense of balance. The sixth patient displayed aggravation of
neurological signs during L-dopa treatment but responded favourably to
a daily dose of 3 gm of 5-hydroxytryptophane, a precursor of
serotonin. The rational basis for the use of 5-hydroxytryptophane was
that muscle hypotonia, sometimes present in chronic manganese
poisoning, but hardly ever present in parkinsonism (Cotzias, 1969),
was probably related to low striatal serotonin levels. This is the
case of the hypotonia of Down's syndrome, which can be reversed by the
administration of the serotonin precursor (Bazelon et al., 1967).
Experimental support for the use of dopamine or serotonin precursors
in manganese poisoning includes the fact that the administration of
manganese to rats, rabbits, and monkeys was followed by depletion of
striatal dopamine and serotonin (Neff et al., 1966; Mustafa & Chandra,
1971; Bonilla & Diez-Ewald, 1974) and that administration of dopamine
and serotonin precursors resulted in an increase in the striatal
concentrations of both dopamine and serotonin (Poirier et al., 1967b;
Goldstein et al., 1969; Neff et al., 1969; Bonilla & Diez-Ewald,
1974). However, data on the depletion of serotonin are still
conflicting (Goldstein et al., 1969). A favourable result using L-dopa
in one case of chronic manganese poisoning was also obtained by
Rosenstock et al. (1971), but the beneficial response to L-dopa could
not be confirmed by Cook et al. (1974), who treated 3 patients with
the drug. It has been proposed that the beneficial therapeutic effect
of L-dopa depends on the dopaminergic fibres not being completely
degenerated (Goldstein et al., 1969; Mena et al., 1970). The
therapeutic doses used in chronic manganese poisoning have generally
been well tolerated, although doses of up to 12 g of L-dopa have been
administered daily (Rosenstock et al., 1971). Considering the high
doses needed, Cotzias (1969) drew attention to the possibility of
choline or methionine deficiency resulting from the donation of their
methyl groups, which are needed for the metabolism of L-dopa.
9.4 Susceptibility to Manganese Poisoning
Several authors have tried to explain the individual
susceptibility of miners to chronic manganese poisoning on the basis
of nutritional deficiencies and variations in intestinal absorption.
Altstatt et al. (1968) showed that manganese and iron metabolism are
closely related, and Mena et al. (1969) reported that individuals with
increased intestinal iron absorption had an increased absorption of
manganese as well. Thus, an intestinal absorption of manganese of 7.5%
was found in anaemic subjects compared with 3% in healthy subjects.
The accelerated turn-over of manganese with a concomitant increase in
iron excretion found in heavily exposed workers with elevated tissue
levels of manganese (Section 184.108.40.206) may further aggravate a
pre-existing anaemia (Mena et al., 1969). Moreover, Mena et al. (1974)
reported that the binding capacity of the plasma of anaemic rats was
more than twice that of healthy rats. The authors considered that the
increase in the transport capacity of the plasma to the blood-brain
barrier was related to the finding of about 100% higher concentrations
in the brain of anaemic rats.
It was also found that the penetration of the blood-brain barrier
in newborn and infant rats less than 18 days old was 4 times that of
adult rats (Mena et al., 1974). According to Mena (1974), young rats
had an intestinal absorption of 70% of manganese compared with 1-2% in
the adult rat. Human data on these aspects are not available.
Apart from individual susceptibility, some individuals may be at
higher risk because of exposure to certain chemical or physical
factors that may influence the toxicity of manganese. A recent study
on occupationally exposed workers (section 9.1) indicated that smoking
may act synergistically with manganese in the development of
nonspecific respiratory disorders (Saric & Lucic-Palaic, 1977).
Combined exposure to manganese and vibrations or X-rays increased the
toxic effects of manganese, particularly in the central nervous system
and the adreno-cortical system (Mihajlov et al., 1969; Levanovskaja &
Neizvestnova, 1972; Neizvestnova, 1972a, b; Pocasev & Neizvestnova,
1972). An increase in the toxicity of manganese compounds has been
noted with exposure to chemicals such as carbon monoxide, silicon
dioxide, sulfur dioxide, fluorine, copper, and lead (Belobragina &
El'nicnyh, 1969; Belobragina et al., 1969; Davydova, 1969; El'nicnyh,
1969; Mihajlov et al, 1969; Davydova et al, 1971; Rylander et al.,
1971; Belobragina, 1972; Mavrinskaja et al., 1972; Rylander &
An inhibiting effect of manganese on muscle tumorigenesis caused
by nickel subsulfide in rats was reported by Sunderman et al. (1974).
Manganese ions were also found to antagonize the excitation of
myocardial fibres in frogs caused by nickel ions (Babskiji & Donskih,
1972; Donskih & Mukumov 1974).
10. EVALUATION OF HEALTH RISKS TO MAN FROM EXPOSURE TO MANGANESE
AND ITS COMPOUNDS
10.1 Relative Contributions of Air, Food, and Water to Total Intake
10.1.1 General population
In areas without manganese-emitting industries, the annual
average concentrations of manganese in air are usually in the range of
0.01-0.07 µg/m3. In areas with major foundry facilities,
concentrations of about 0.2-0.3 µg/m3 can be expected. When
ferromanganese or silicomanganese industries are present, the annual
average concentration in the surrounding areas may increase to over
0.5 µg/m3; occasionally, annual values up to 8.3 µg/m3 have been
recorded. Assuming a standard respiration rate of 20 m3 per day, the
daily intake of manganese through inhalation in unpolluted areas would
be below 2 µg/day, whereas in the presence of ferromanganese and
silicomanganese industries, in extreme situations, the daily mean
intake may increase to over 150 µg/day. Thus, in most instances, the
daily intake through inhalation constitutes less than 0.1% of the
total daily intake, and rarely exceeds 1%, even in heavily polluted
There is no information on the rate of absorption of inhaled
manganese particles. The particle size with which airborne manganese
is associated is usually within the respirable range. Inhaled
manganese particles are partly cleared through pulmonary defence
mechanisms and swallowed. The small size of the particles favours a
widespread airborne distribution of manganese, that reaches man
indirectly, as a result of fallout on soil and water and through
uptake by plants and animals.
The mean levels of manganese in drinking-water are usually about
5-25 µg/litre, but individual samples from municipal supplies have
shown concentrations ranging from trace levels to 100 µg/litre. Values
one order of magnitude higher have been determined in certain rivers.
Assuming a standard daily water consumption of 500-2200 ml (ICRP,
1975), the average daily intake of manganese with water is in the
range of 2-55 µg and is unlikely to constitute more than 1-2% of the
total intake of manganese. Data on the form of manganese present in
drinking-water and on the rate of absorption from the gastrointestinal
tract of manganese in water are not available.
Most foodstuffs contain manganese in concentrations below 5 mg/kg
(wet weight). Grain, rice, and nuts may have manganese levels
exceeding 10 mg/kg, whereas finished tealeaves contain several hundred
mg/kg. The daily intake of manganese with food, by adults, is about
2-9 mg. In young children and up to adolescence, the intake is about
0.06-0.08 mg/kg body weight and in breastfed and bottlefed infants is
as low as 0.002-0.004 mg/kg body weight. The small amount of
information available indicates an absorption from the human
gastrointestinal tract of less than 5% in healthy adults. The low
absorption is supported by studies on mice and rats, in which
absorption may range from 0.2 to 3%. There is no information available
concerning absorption in infants and young children, but animal data
indicate that it could be significantly higher than in adults. A
gastrointestinal absorption of 5% would result in an absorbed dose of
100-450 µg/day for adults. The chemical forms and the possible
differences in biological availability of manganese present in various
foods are not known.
10.1.2 Occupationally-exposed groups
Recent data on the levels of manganese in air in manganese mines
were not available to the Task Group, but most studies indicate that
levels of several hundred milligrams per cubic metre may occur. Values
ranging from 0.8 to 17 mg/m3 have been reported in ore-crushing
plants. In steel plants, air concentrations are generally in the range
of 0.1-5 mg/m3, only rarely exceeding 10 mg/m3. However, welders may
be exposed to air concentrations exceeding 10 mg/m3. A major part of
manganese present in the air in work areas is in the form of oxides,
and data concerning other compounds are not available. Manganese in
dust and fumes appears to be predominantly associated with particles
below 5 µm.
10.2 Manganese Requirements and Deficiency
The daily required intake of manganese for adult man appears to
be 2-3 mg, and taking into account available data, an estimated
minimum daily intake of 1.25 mg would seem adequate for pre-adolescent
children. Although newborn infants display a negative manganese
balance during the first weeks of life, as manganese is excreted from
tissue stores accumulated during fetal life, signs of manganese
deficiency have not been seen. Manganese deficiency has been described
only once in man in connexion with experimentally induced vitamin-K
deficiency and the accidental omission of manganese from the diet. All
dietary studies on daily manganese intake have indicated that the
daily requirements mentioned earlier are met. Furthermore, it seems
that regulatory absorption and excretion mechanisms exist which make
manganese deficiency unlikely in man.
10.3 Effects in Relation to Exposure
The primary target organs of inhaled manganese are the lungs and
the central nervous system, although effects have occasionally been
noted in other organs. The effects of manganese are not specific and a
suitable biological indicator of the absorbed dose of manganese has
not been identified, so far. In the measurement of inhalation
exposures, personal samplers have rarely been used. Most data have
been derived from occasional measurements at fixed sampling sites and
do not necessarily represent actual exposure. Thus, exposure-effect
and exposure-response relationships cannot be established for
manganese on the basis of existing data. The scantiness of
retrospective exposure data makes it difficult to associate effects
with any long-term exposure levels.
10.3.1 General population
With a few exceptions, effects on the central nervous system have
only been observed in occupationally exposed individuals. However, one
incident involving 16 cases of severe manganese poisoning from
drinking-water (manganese concentrations ranging from 8 to
14 mg/litre) contaminated by discarded dry-cell batteries indicates
the importance of ensuring the proper disposal of manganese-containing
An increased incidence of pneumonia and nonspecific effects on
the respiratory tract have been reported in populations living in
areas associated with manganese alloy production. In Sauda, Norway, a
4-fold increase in morbidity and an 8-fold increase in mortality due
to lobar pneumonia were noted over a 14-year period, in a community
living in the vicinity of a ferromanganese and silicomanganese plant.
Moreover, the morbidity and mortality due to lobar pneumonia varied
with the amount of manganese alloy produced by the plant. Results of
bacteriological investigations in Sauda were similar to those in the
rest of the country, which further indicates that manganese played at
least some part in the etiology of the pneumonia. The actual exposure
of the population to manganese oxide in air is uncertain in this case
as only one value (64 µg/m3) was given and it was later proved that
the analytical method used gave rather low results. Another study,
from Aosta, Italy, reporting an increase in mortality due to pneumonia
as production of manganese alloys increased at the local
ferromanganese plant is even more difficult to evaluate as no detailed
investigations were carried out.
A higher prevalence of nose and throat symptoms, anamnestic
pneumonia, and decreases in pulmonary function were registered in a
group of schoolchildren living about 100 m from a ferromanganese
plant, compared with children attending a school 7 km away from the
factory. The manganese concentrations in air in the polluted area
ranged from 4.0 to 6.7 µg/m3, (5-day mean values). However, on 3
occasions, short-time samples (1-h) following the smoke downwind
exceeded 100 µg/m2 at distances of 50-700 m from the chimney, with a
maximum value of 200 µg/m3. The fact that a follow-up study, carried
out after a dust collector 'had been in operation for 1 year, failed
to show similar differences between more exposed and less exposed
groups further incriminates manganese in the etiology of the
In a study in Yugoslavia, health effects in 2 populations (8700
and 17 100 individuals), exposed to mean annual concentrations of
manganese in air of about 0.27-0.44 and 0.10-0.24 µg/m3,
respectively, arising from a manganese alloy plant, were compared with
those in a population exposed to concentrations below 0.1 µg/m3. An
increased incidence of bronchitis was noted in the exposed
populations, but the incidence of pneumonia did not exceed expected
values. The exposures may have been considerably higher owing to the
low-volume sampling technique used. Although sulfur dioxide
concentrations were measured, other environmental and socioeconomic
factors, not considered, might have influenced the results.
10.3.2 Occupationally-exposed groups
Confounding factors have been reported in all the available
studies relating effects to occupational manganese exposure. Some
studies have related certain effects of manganese (including
pneumonia, effects on the central nervous system, and subjective
symptoms) to levels of exposure. As there are very few data concerning
retrospective exposure, and subtle neurological and psychological
symptoms and signs may have existed unrecognized for several years,
the development of effects may, in fact, have been related to earlier,
higher exposures. Moreover, the relationship between the development
of signs and symptoms and short-term exposure to high concentrations
is not known. Although these considerations should be borne in mind in
the assessment of exposure-effect relationships, sufficient
information exists to relate at least some effects to a range of
manganese concentrations in air.
10.3.2.1 Effects on the central nervous system
Signs and symptoms of extrapyramidal disorders, characteristic of
manganese poisoning, were reported in 2 manganese steel workers
engaged in arc-burning. Measurements of manganese concentrations in
air ranged up to 4.7 mg/m3. At re-examination 4 years later, one
worker showed further neurological deterioration, and the other still
displayed slight neurological signs.
In a ferromanganese plant, manganese concentrations in air ranged
from 1.9 to 4.9 mg/m3 in the sintering area and were below 2 mg/m3
in other areas of the plant. Examination of 160 workers revealed
symptoms such as failing memory, fatigue, increased perspiration, and
hyposexuality in 30% of the subjects. Of 144 workers, 24% exhibited
tremor of the fingers, 13% disturbed balance, 5%, adiadochokinesis,
and 3.5%, muscular rigidity. In another ferromanganese plant, exposure
levels were mainly below 1 mg/m3, and manganese concentrations up to
3.2-8.6 mg/m3 were measured around the electric furnace at tap only
(one value of 24.4 mg/m3 was measured under a conveyor belt that was
in operation). Among the 100 workers, 40% complained of symptoms but
not all the symptoms were necessarily due to manganese exposure.
Adiadochokinesis was found in 8% of the workers, tremor of the fingers
in 10%, and accelerated patellar reflex in 8%. Similarly, slight
neurological signs were found in 7 out of 55 dry-cell battery plant
workers exposed to a median manganese concentration in air of
4.3 mg/m3 (range 1.9-21.1 mg/m3).
One report from a ferromanganese plant with 1000 employees
indicated annual mean concentrations for various operations ranging
from 0.5 to 5 mg/m3; the highest concentration recorded was
10 mg/m3, and the highest daily weighted average exposure for any
worker was 2.3 mg/m3. The plant physician's register did not show any
complaints that suggested manganese poisoning and a screening for
subjective symptoms was negative. Unfortunately, clinical examinations
were not carried out on the workers and reporting on symptoms was
In this context, it is pertinent to consider the fact that
characteristic central nervous system signs were produced in monkeys
exposed to 0.6-3.0 mg of manganese dioxide per m3 of air, for 1 h per
day, over a 4-month period.
10.3.2.2 Manganese pneumonia
Considering that a causal connexion between exposure to manganese
and pneumonia has been repeatedly suggested in the literature since
1921, there have been surprisingly few studies concerned with the
relationship between the incidence of pneumonia and the type and level
of exposure. However, a 35-fold increase in the incidence of pneumonia
was reported in workers engaged in the manufacture of potassium
permanganate. The incidence was 26 per 1000 workers compared with 0.73
in a control group. The manganese concentrations in air ranged up to
14 mg/m3, as calculated from measurements of manganese dioxide in
dust. Although measurements were scarce and higher concentrations may
have existed in the beginning of the 8-year period of the study, the
fact that no signs of chronic manganese poisoning were observed
suggests that the exposure was comparatively low. It is not possible
to conclude whether manganese exerts a direct chemical action on the
lungs or causes an increased susceptibility to bacterial or viral
10.3.2.3 Nonspecific effects on the respiratory tract
A recent epidemiological study of 367 male workers, exposed to a
mean concentration of manganese in air of up to 16.4 mg/m3, indicated
that manganese may contribute to the development of chronic
bronchitis. The higher rate of symptoms related to the respiratory
tract in smokers from the exposed group compared with smokers in the
control group suggested that smoking may act synergistically with
manganese. Retrospective studies of absenteeism because of respiratory
disorders have also indicated that populations occupationally exposed
to manganese are more frequently affected by these conditions than
In the assessment of exposure-effect levels in occupational
health, it may be useful to consider that exposure of rats to
manganese dioxide at 0.3 mg/m3, by inhalation, caused inflammatory
changes in the respiratory tract of the animals, and that inhalation
of the same compound at 0.7 mg/m3 and 3.0 mg/m3 caused mottling of
the pulmonary X-rays of monkeys as well inflammatory alterations in
the respiratory tract of mice.
10.3.2.4 Diagnosis of manganese poisoning and indices of exposure
The clinical diagnosis of manganese poisoning may be difficult,
particularly in the early stages of the disease, since reliable
diagnostic procedures are not available. Urine and blood manganese
levels are only weakly correlated with the degree of exposure and with
the severity of the toxic response. Pulmonary manifestations may be
absent and when present in smokers, for instance, they may easily be
ignored. The onset of psychological and neurological signs and
symptoms is often insidious, and the manifestations nonspecific,
whereas later stages resemble parkinsonism. Apart from the
ascertainment of exposure, repeated screening for subjective symptoms
and thorough neurological examinations, together with the
determination of the manganese concentrations in urine and blood
appear, at present, to be the only methods available for the detection
of the disease. Since manganese is eliminated primarily in the faeces,
the estimation of faeces manganese may serve as a useful guide to
exposure, although this approach has rarely been applied.
10.3.2.5 Susceptibility and interaction
The incidence of chronic manganese poisoning among workers
exposed to high manganese concentrations has shown highly variable
individual susceptibility to the effects of manganese. The reasons for
higher susceptibility in some individuals are not clear though the
close relationship between manganese and iron metabolism may afford
one explanation. The intestinal absorption of manganese in anaemic
subjects is twice that of healthy individuals. Moreover, exposed
workers with elevated tissue levels of manganese have an increased
excretion of manganese combined with a concomitant increase in iron
excretion, which may aggravate a pre-existing anaemia. Animal
experiments have shown that the binding capacity of the plasma of
anaemic rats is more than double that of healthy rats and that the
entrance of manganese into brain is higher in anaemic rats.
Penetration into the brain of newborn and infant rats is 4 times that
of adult rats and the intestinal absorbtion of manganese in young rats
may be up to 70%, compared with 1-2% in adult rats.
There is little information on the interaction between manganese
and other chemical and physical factors. However, some studies have
indicated that manganese, smoking, and sulfur dioxide may produce
synergistic effects on the respiratory tract. Vibration and X-rays
have been reported to increase the toxic effects of manganese on the
central nervous system and this may also be true of other chemicals
such as carbon monoxide, silicon dioxide, fluorine, copper, and lead.
10.4 Organomanganese Compounds
Two classes of organomanganese compounds should be considered
from the toxicological point of view. One includes manganese
ethylene-bis-dithiocarbamate (Maneb), a fungicide used on edible
crops. Here, the manganese entity is of little toxicological
significance, while the organic fraction is part of a larger problem
concerning the use of this class of fungicides. These fungicides have
been considered by a joint FAO/WHO Meeting on Pesticide Residues in
food (WHO, 1969). The International Agency for Research on Cancer
recently considered data relevant to the carcinogenicity of manganese
ethylene-bis-dithiocarbamate and concluded that the data available
were too meagre for an evaluation of the carcinogenic risks of this
compound man (IARC Working Group, 1976).
The second class of organomanganese compounds of potential
toxicological significance is constituted by the manganese tricarbonyl
compounds used as additives in petrol. As only a small portion of the
parent compound is emitted and this is rapidly photo-decomposed to
mainly unknown compounds, exposure to manganese tricarbonyl compounds
is more likely to constitute an occupational hazard than a public one.
Widespread use of these compounds as petrol additives will, however,
result in increased exposure of the general population to the
combustion products, mainly inorganic manganese, and will especially
affect urban environments. Animal experiments have not revealed any
adverse effects from the long-term exposure (up to 66 meeks) of rats,
hamsters, and monkeys to combustion products of
methylcyclopentadienylmanganese tricarbonyl with manganese
concentrations in air in the range of 12-5000 µg/m3. However, at
100 µg/m3 for up to 66 weeks, the tissue levels of manganese
increased significantly in monkeys. At present, data on the effects of
prolonged exposure of man to low concentrations of manganese in air
and on the effects of combined exposure to manganese and other
pollutants are inadequate for an evaluation of the health risks, if
any, that may arise from an substantial increase in the use of
manganese tricarbonyl compounds in petrol. Studies on the effects on
exhaust gas emissions of manganese tricarbonyl compounds as additives
in petrol are also, in some respects, conflicting and further studies
10.5 Conclusions and Recommendations
Manganese is an essential trace metal for both man and animals.
Manganese deficiency is extremely unlikely to occur in man because
there is a sufficient supply of manganese in the diet and because of
homeostatic mechanisms present in man.
Systemic effects from over-exposure to manganese, which
constitute an inhalation hazard for occupationally-exposed
populations, may occur in other populations, but only in cases of
accidental or intentional ingestion of exceptional amounts of the
metal. Pneumonia and nonspecific effects on the respiratory tract may
occur both in occupationally-exposed populations and in the general
population, in areas associated with industrial emissions of
The assessment of health risks related to both occupational and
community exposure to manganese is made more difficult by the
generally poor quality of available information particularly in the
case of exposure data.
10.5.1 Occupational exposure
Signs and symptoms of effects on the central nervous system may
already occur at air concentrations of manganese in the range of
2-5 mg/m3. A minimum exposure-effect level cannot be assessed, but
considering human and animal data as well as the highly variable
individual susceptibility to manganese, it is probably less than
Exposure-effect relationships for pneumonia and nonspecific
respiratory effects cannot be established from available occupational
data. Animal data indicate a local effect of manganese dioxide on the
respiratory tract at concentrations ranging from 0.3 to 3.0 mg/m3. It
seems possible that characteristics such as particle-size distribution
and type of manganese compound are etiologically more important than
mass concentrations of manganese. Special attention should be paid to
the possibility of concomitant exposure to other pollutants which may
act synergistically with manganese on the respiratory tract. There is
a conspicuous discrepancy between, on the one hand, extremely low
concentrations of manganese in the ambient air reported to cause
effects on the respiratory tract, and, on the other hand, the
scantiness of reports of similar effects in populations
occupationally-exposed to about 100-1000 times these levels.
Persons with psychological or neurological disorders are not
suitable for work associated with exposure to manganese.
Nutritional deficiency states may predispose to anaemia,
increasing susceptibility to manganese; and subjects suffering from
such deficiencies should be under surveillance.
In the absence of specific diagnostic means, the worker should be
screened for subjective symptoms and subjected to clinical
examinations at regular and not too long intervals. A pre-employment
examination is clearly needed.
10.5.2 General population exposure
At present, there is no evidence that the manganese
concentrations of less than 0.1 µg/m3 generally found in ambient
rural and urban air are associated with any health risk to man.
Annual mean concentrations of manganese in air exceeding
0.1 µg/m3 are invariably man-made and are found in areas associated
with manganese-processing industries. Manganese compounds may be
widely used as petrol additives in the future and may cause urban air
concentrations of manganese to exceed this level.
Increased morbidity and mortality due to pneumonia, and
nonspecific effects on the respiratory tract in the general population
have been related to increased exposure caused by nearby manganese
alloy plant. The documentation available is inadequate for the
establishment of guidelines with respect to manganese concentrations
in ambient air.
In view of existing data and considering the possibility of
increasing use in the future of organomanganese compounds as petrol
additives, it is recommended that epidemiological surveys be conducted
in communities exposed to annual mean concentrations of manganese in
air exceeding 1 µg/m3.
ABDULLAH, M. I. & ROYLE, L. G. (1972) Heavy metal content of some
rivers and lakes in Wales. Nature (Lond.), 23: 329-330.
ABRAMS, E., LASSITER, J. W., MILLER, W. J., NEATHERY, M. W., GENTRY,
R. P., & SEARTH, R. D. (1976) Absorption as a factor in manganese
homeostasis. J. anim. Sci. 42: 630-636.
AJEMIAN, R. S. & WHITMAN, N. E. (1969) Determination of manganese in
urine by atomic absorption spectrometry. Am. Ind. Hyg. Assoc.
J., 30: 52-56.
AKSELSSON, R., JOHANSSON, K., MALMQVIST, K., FRISMARK, J., &
JOHANSSON, T. B. (1975) Elemental abundance of variation with
particle size in aerosols from welding operations. In:
Proceedings of the Conference on Nuclear Methods in
Environmental Research, Columbia, Missouri July 29-31, 1974,
ALEXANDER, F. W., CLAYTON, B. E., & DELVES, H. T. (1974) Mineral and
trace-metal balances in children receiving normal and synthetic
diets. Q. J. Med., 169: 89-111.
ALJAB'EV, G. A. & DMITRIENKO, M. M. (1971) [Trace elements in edible
and poisonous fungi in the Irkutsk Oblast.] Nauk. Tr. Irkutsk.
med. Inst., 107: 90-94 (in Russian).
ALTSTATT, L. B., POLLACK, S., FELDMAN, M. H., REBA, R. C., & CROSBY,
W. H. (1968) Liver manganese in hemachromatosis. Proc. Soc. Exp.
Biol. Med., 124: 353-357.
AMDUR, M. O., NORRIS, L. C., & HEUSER, G. F. (1945) The need for
manganese in bone development in the rat. Proc. Soc. Exp. Biol.,
AMERICAN CONFERENCE OF GOVERNMENTAL INDUSTRIAL HYGIENISTS (1958)
Determination of manganese in air.: Periodate oxidation method.
In: Manual of analytical methods recommended for sampling and
analysis of atmospheric contaminants, Cincinnati, OH, American
Conference of Governmental Hygienists, pp. MN-1 to Mn-4.
ANGELIEVA, R. (1969) [Spectrographic method for determination of
manganese in foodstuffs of vegetable origin by emissive spectral
analysis.] Hig. Zdraveop., 3: 312-320 (in Bulgarian).
ANGELIEVA, R. (1970) [Method for determination of the quantity of
manganese in foodstuffs of vegetable origin by emissive spectral
analysis.] Hig Zdraveop., 3: 312-320 (in Bulgarian).
ANGELIEVA, R. (1971) [Spectrographic method for determination of the
manganese content of urine.] Hig. Zdraveop., 5: 517-520 (in
ANKE, M. & SCHNEIDER, H.-J. (1974) [Trace element concentrations in
human kidney in relation to age and sex.] Zschr. Urol.,
67: 357-362 (in German).
ANSOLA, J., UIBERALL, E., & ESCUDERO, E. (1944a) [Intoxication by
manganese in Chile (Study on 64 cases). I. Environmental and
etiological factors.] Rev. Med. Chile, 72: 222-228 (in
ANSOLA, J., UIBERALL, E., & ESCUDERO, E. (1944b) [Intoxication by
manganese in Chile (Study on 64 cases). II. Clinical aspects,
incapacity and medico-legal reparation.] Rev. Med. Chile,
72: 311-322 (in Spanish).
ANTONOVA, M. V. (1968) [The action of the trace element manganese
contained in the food ration on the immunobiological reactivity
of the organism.] Vopr. Pitan., 3: 36-41 (in Russian).
ANTOV, G. ZLATEVA, M. (1974) [On the effect of lead and manganese upon
the connective tissue of the aorta in albino rats.] Farmakol.
Toksikol., 37: 96-98 (in Russian).
ARHIPOVA, O. G. (1963) [On the mechanism underlying the action of
cyclopentadienyltricarbonyl manganese - a new antiknock
compound.] Gig. Tr. prof. Zabol., 7: 43-49 (in Russian).
ARHIPOVA, O. G., TOLGSKAJA, M.S., & KOCETOVA, T. A. (1963) [Toxic
properties of manganese cyclopentadienyltricarbonyl antiknock
substance.] Gig. i Sanit., 28 (4): 29-32 (in Russian).
ARHIPOVA, O. G., TOLGSKAJA, M. S. & KOCETKOVA, T. A. (1965) [The
toxicity of vapours of a new antidetonator - manganese
cyclopentadienyltricarbonyl in the air of industrial premises.]
Gig. i Sanit., 30: 36-39 (in Russian).
ARHIPOVA, O. G., DJATLOVA, N.M., KABACNIK, M. I., MEDVED', T. J., &
MEDYNCEV, V. V. (1968) [On some regularities governing the
formation of metal complexes by using polyamino-polyphosphonic
acids and elimination of metals from the organism.] Bjull. eksp.
Biol. Med., 12; 66-69 (in Russian).
ASHIZAWA, R. (1927) [Report on an autopsy case of chronic manganese
poisoning.] Jpn. J. med. Sci. Trans., 7 (1): 173-191
BAADER, E. W. (1932) [Manganese poisoning in dry cell battery
factories.] Arch. Gewerbepathol. Gewerbehyg., 4: 101-116
BABSKIJ, E. B. & DONSKIH, E. H. (1972) [Nature of antagonistic effects
of manganese and nickel ions on action potentials of myocardial
muscle fibres.] Dokl. Akad. Nauk., 27 (5): 1250-1258
BARBEAU, A., INOUE, N., & CLOUTIER, T. (1976) Role of manganese in
dystonia. In: Eldridge, R. & Fahn, S., ed. Advances in
Neurology, New York, Raven Press, pp. 339-352.
BARBER, D. A. & LEE, R. B. (1974) The effect of micro-organisms on the
absorption of manganese by plants. New Phytol., 73: 97-106.
BARBORIK, M. & SEHNALOVA, H. (1967) [Blood levels and urinary
excretion in electric arc welders. The effect of NaCa2 EDTA on
manganese elimination in urine.] Prac. Lék., 19 (4): 155-158
BARTELS, T. T. & WILSON, C. E. (1969) Determination of
methylcyclopentadienyl manganese tricarbonyl in JP-4 fuel by
atomic absorption spectrophotometry. At. Absorpt. Newsl.,
BAXTER, D. J., SMITH, W. O., & KLEIN, G. C. (1965) Some effects of
acute manganese excess in rats. Proc. Soc. Exp. Biol. Med.,
BAZELON, M., PAINE, R. S., COWIE, V. A., HUNT, P., HOUCK, J. C., &
MAHANAND, D. (1967) Reversal of hypotonia in infants with Down's
syndrome by administration of 5-hydroxytryptophan. Lancet,
BECKER, D. A. & MAIENTHAL, E. J. (1975) Evaluation and research of
methodology for the national environmental specimen bank. Final
Report to US Environmental Protection Agency by US Department of
Commerce, Washington, DC, National Bureau of Standards (Report
BEGAK, O. Ju., KUKUSKIN, Ju.N., NIKOLAEV, G.I., & POKROVSKAJA, K. A.
(1972) [The effect of acids and some elements on the
determination of manganese by atomic absorption using an
air-acetylene flame.] Z. prikl. Himii, 45 (10): 2188-2191
BEK, F., JANOVSKOVA, J., & MOLDAN, B. (1972) [Direct determination of
manganese and strontium in the blood serum using a Perkin-Almer
HGA-70 graphite cuvette.] Chem. Listy, 66 (8): 867-75
BELOBRAGINA, G. V. (1972) [The development of nodular structures in
the lungs in pneumoconiosis caused by condensed aerosols
containing silicon dioxide and manganese oxides.] In:
Kombinirovannoe dejstvie himiceskih in fiziceskih faktorov
proizvodstvennoj sredy, Sverdlovsk, pp. 128-138 (in Russian).
BELOBRAGINA, G. V. & EL'NICNYH, L. N. (1969) [Characteristics of the
changes occurring in parenchymatous organs in pneumoconiosis
caused by condensed aerosols containing silicon dioxide and
manganese oxides.] In: Klinika, patogenez i profilaktika
profzabolevanii himiceskoj etiologii na predprijatijah cvetnoj i
cernoj metallurgii, Sverdlovsk, Part II, pp. 107-114
BELOBRAGINA, G. V., EL'NICNYH, L. N., & BABUSKINA, L. C. (1969) [On
pneumosclerosis caused by condensed aerosols containing silicon
dioxide and manganese oxides.] In: Klinika, patogenez i
profilaktika profzabolevanii himiceskoj etiologii na
predprijatijah cvetnoj i cernoj metallurgii, Sverdlovsk, Part
II, pp. 95-106 (in Russian).
BELZ, R. (1960) [The amounts of iron, copper, manganese and cobalt in
average diets of various age groups in the Netherlands.]
Voeding, 21: 236-251 (in Dutch).
BENTLEY, P. J. (1967) Mechanism of action of neurohypophyseal
hormones; actions of manganese and zinc on the permeability of
the toad bladder. J. Endocrinol., 39: 493-506.
BERNHEIMER, H., BIRKMAYER, W., HORNYKIEWICZ, O., JELLINGER, K., &
SEITELBERGER, F. (1973) Brain dopamine and the syndromes of
Parkinson and Huntington. Clinical, morphological and
neurochemical correlations. J. neurol. Sci., 20: 415-455.
BERTINCHAMPS, A. J., MILLER, S. T., & COTZIAS, G. C. (1966)
Interdependence of routes excreting manganese. Am. J. Physiol.,
BERTOGLIO-RIOLO, C., FULLE-SOLDI, T., & SPINI, G. (1972)
[Determination of Cu (II), Cd (II), Pb (II), Zn (II), Cr (VI) in
industrial waste waters by oscillopolarography.] Ann. Chim.
62: 730-739 (in Italian).
BESCETNOVA, E. I., SAMOJLOV, V. V., KUPCIK, G. L., & SAMILKINA, N. C.
(1968) [Concentrations of nickel, manganese, molybdenum,
vanadium, titanium, copper and lead in the water of the lower
reaches and delta of the Volga.] Gig. i Sanit., 33 (8): 105
BETHARD, W. F., OLEHY, D. A., & SCHMITT, R. A. (1964) The use of
neutron activation analysis for the quantitation of selected
cations in human blood. In: L'analyse par radioactivation et ses
applications aux sciences biologiques. III Colloque
International de Biologie de Saclay, Septembre 1963, Paris,
Presses Universitaires de France, pp. 379-393.
BIRKS, L. S., GILFRICH, J. V., & BURKHALTER, P. G. (1972) Development
of X-ray fluorescence spectroscopy for elemental analysis of
particulate matter in the atmosphere and in source emission,
Washington, US Environmental Protection agency, Office of
Research and Monitoring, 43 pp. (EPA-R2-72-063).
BOCKMAN, P. W. K. (1939) [The Sauda pneumonia from the point of view
of occupational hygiene.] Nord. Med., 3: 2548-2552
van BOGAERT, L. & DALLEMAGNE, M. J. (1946) Approche expérimentale des
troubles du manganisme. Mschr. Psychiatr. Neurol., 111: 60-89.
BONILLA, E. & DIEZ-EWALD, M. (1974) Effect of L-Dopa on brain
concentration of dopamine and homovanillic acid in rats after
chronic manganese chloride administration. J. Neurochem.,
BOUQUIAUX, J. (1974) Non-organic micropollutants of the environment.
Vol. 2. Detailed list of levels present in the environment.
Luxembourg, Commission of the European Communities, pp. 194-221
(Document V/ F/1966/74e).
BOWEN, H. J. M. (1956) The determination of manganese in biological
material by activation analysis with a note on the gamma spectrum
of blood. J. nucl. Energy. 3: 18-24.
BRAR, S.S., NELSON, D. M., KANABROCKI, E. L., MOORE, C. E., BURNHAM,
C. D., & HATTORI, D. M. (1970) Thermal neutron activation
analysis of particulate matter in surface air of the Chicago
metropolitan area. One-minute irradiations. Environ. Sci.
Technol., 4: 50-54.
BRITTON, A. A. & COTZIAS, G. C. (1966) Dependence of manganese
turnover on intake. Am. J. Physiol., 211: 203-206.
BROOKS, R. R. & RUMSBY, M. G. (1965) The biogeochemistry of trace
element uptake by some New Zealand bivalves. Limnol. Oceanogr.,
BROOKS, R. R. & RUMSEY, D. (1974) Heavy metals in some New Zealand
commercial sea fishes. N. Z. J. Mar. Freshwater Res.,
BROWN, E., SKOUGSTAD, M. W., & FISHMAN, M. J. (1970) Methods for
collection and analysis of water samples for dissolved minerals
and gases. Part. I. Sampling. In.: Techniques of Water Resources
Investigations of the United States Geological Survey, Book 5,
Washington, DC, US Government Printing Office, pp. 4-18.
BRYAN, D. E. (1970) Development of nuclear analytical techniques for
oil slick identification (Phase 1). Work done under AEC
contract No. AT (904-3)-167 by Gulf General Atomic (Report
BUGAEVA, M. A. (1969) [On the determination of lead and manganese in
blood by spectrum analysis.] In: Novoe v oblasti prom-sanhimii,
Moscow, Medicina, pp. 239-242 (in Russian).
BURNETT, W. T., Jr, BIGELOW, R. R., KIMBALL, A. W., & SHEPPARD, C. W.
(1952) Radiomanganese studies on the mouse, rat and pancreatic
fistula dog. Am. J. Physiol., 168: 620-625.
BUTT, E. M., NUSBAUM, R. E., GILMOUR, T. C., DIDIO, S. L., & SISTER
MARIANO (1964) Trace metal levels in human serum and blood.
Arch. environ. Health, 8: 52-57.
BUTTIN, G. & KORNBERG, A. (1966) Enzymatic synthesis of
deoxyribonucleic acid. XXI. Utilization of deoxyribonucleoside
triphosphates by Escherichia coli cells. J. biol. Chem.,
241 (22): 5419-5427.
BYHOVSKAJA, M. S., GINZBURG, S. L., & HALIZOVA, O. D. (1966)
[Cyclopentadienyltricarbonylmanganese.] In: Metody opredelenija
rednyh vescest v vozduhe, Moscow, Goshimizdat, pp. 176-178
CANAVAN, M. M. & DRINKER, C. K. (1934) Chronic manganese poisoning.
Report of a case, with autopsy. Arch. Neurol. Psychiatr.,
CARLBERG, J. R., CRABLE, J. V., LIMTIACA, L. P., NORRIS, H. B., HOLTZ,
J. L., MAUER, P., & WOLOWICZ, F. R. (1971) Total dust, coal, free
silica and trace metal concentrations in bituminous coal miners'
lungs. Am. Ind. Hyg. Assoc. J., 32: 432-440.
CASAMAJOR, L. (1913) An unusual form of mineral poisoning affecting
the nervous system; manganese. J. Am. Med. Assoc. 69: 646-649.
CERETELI, M. N. & KIPIANI, S. L. (1971) Activity of the coagulative
and anticoagulative system of the blood in Mn poisoning. In:
Documentation for the I All-Union Conference on Early Diagnosis
and Prophylaxis of Occupational Diseases of Chemical Etiology,
Moscow, Ministry of Public Health, pp. 36-37.
CHANDRA, S. V. & SRIVASTAVA, S. P. (1970) Experimental production of
early brain lesions by parenteral administration of manganese
chloride. Acta Pharmacol. Toxicol., 28: 177-183.
CHANDRA, S. V., SETH, P. K., & MANKESHWAR, J. K. (1974) Manganese
poisoning; clinical and biochemical observations. Environ. Res.,
CHEESEMAN, R. V. & WILSON, A. L. (1972) A method lot the
determination of manganese in water. Marlow, England, Water
Research Association (TP 85).
CHESTER, R. & HUGHES, M. J. (1967) A chemical technique for the
separation of ferro-manganese minerals, carbonate minerals and
absorbed trace elements from pelagic sediments. Chem. Geol.,
CHOLAK, J. & HUBBARD, D. M. (1960) Determination of manganese in air
and biological material. Am. Ind. Hyg. Assoc. J., 21: 356-360.
CIKRT, M. (1972) Biliary excretion of 203Hg, 64Cu 52Mn and 210Pb in
the rat. Br. J. ind. Med., 29: 74-80.
CIKRT, M. (1973) Enterohepatic circulation of 64Cu, 52Mn and 203Hg in
rats. Arch. Toxicol., 31: 51-59.
CIKRT, M. & VOSTAL, J. (1969) Study of manganese resorption in vitro
through intestinal wall. Int. Z klin. Pharmakol. Ther. Toxikol.,
COHN, M. & TOWNSEND, J. (1954) A study of manganous complexes by
paramagnetic resonance absorption. Nature (Lond),
COMENS, P. (1956) Manganese depletion as an etiological factor in
hydralazine disease. Am. J. Med., 20: 944-945.
CONSOLAZIO, C. F., NELSON, R. A., MATOUSH, L. O., HUGHES, R. C., &
URONE, P. (1964) The trace mineral losses in sweat, Denver, CO,
US Army Medical Research and Nutrition Laboratory, 14 pp. (Report
COOK, D. G., FAHN, S., & BRAIT, K. A. (1974) Chronic manganese
intoxication. Arch. Neurol., 30: 59-64.
COOPER, J. A. (1973) Comparison of particle and photon -- excited
X-ray fluorescence applied to trace element measurements of
environmental samples. Nucl. Instr. Met., 106: 525-539.
COTZIAS, G. C. (1958) Manganese in health and disease. Phys. Rev.,
COTZIAS, G. C. (1962) Manganese. In: Comar & Bronner, ed. Mineral
metabolism: An advanced treatise, New York, Academic Press,
Vol. 2, Part B, pp. 403-442.
COTZIAS, G. C. (1966) Manganese, melanins and the extrapyramidal
system. J. Neurosurg., 24: 170-180.
COTZIAS, G. C. (1969) Metabolic modification of some neurological
disorders. J. Am. Med. Assoc., 210: 1255 1262.
COTZIAS, G. C. & PAPAVASILIOU, P.S. (1962) State of binding of natural
manganese in human cerebrospinal fluid, blood and plasma. Nature
(Lond.) 195: 823-834.
COTZIAS, G. C., PAPAVASILIOU, P.S., & MILLER, S. T. (1964) Manganese
in melanins. Nature (Lond.), 201: 1228-1229.
COTZIAS, G. C., MILLER, S. T., & EDWARDS, J. (1966) Neutron activation
analysis: the stability of manganese concentrations in human
blood and serum. J. lab. clin. Med., 67: 836-849.
COTZIAS, G. C., HORIUCHI, K., FUENZALIDO, S., & MENA, I. (1968)
Chronic manganese poisoning. Clearance of tissue manganese
concentrations with persistence of the neurological picture.
Neurology, 18: 376-382.
COUGHANOWR, D. R. & KRAUSE, F. E. (1965) The reaction of SO2 and O2
in aqueous solutions of MnSO4. Ind. eng. Chem. Fundam.,
COULSTON, F. & GRIFFIN, T. (1976) Inhalation toxicology of airborne
particulate manganese in rhesus monkeys, Institute of
Comparative and Human toxicology, Albany Medical College, and New
Mexico, International Center of Environmental Safety, Holloman
Air Force Base, 97 pp. (Final report of US EPA Contract
CURRAN, G. L. (1954) Effect of certain transition group elements on
hepatic synthesis of cholesterol in the rat. J. biol. Chem.,
DAIRMAN, W. & UDENFRIEND, S. (1971) Decrease in adrenal tyrosine
hydroxylase and increase in norepinephrine synthesis in rats
given L-dopa. Science, 171: 1022-1024.
DAMS, R., ROBBINS, J. A., RAHM, K. A., & WINCHESTER, S. W. (1970)
Non-destructive neutron activation analysis of air pollution
particulates. Anal. Chem., 42: 861-867.
DASTUR, D. K., MANGHANI, D. K., RAGHAVENDRAN, K. V., & JEEJEEBHOY, K.
N. (1969) Distribution and fate of 54Mn in rat with special
reference to the CNS. Q. J. exp. Physiol., 54 (3): 322-331.
DASTUR, D. K., MANGHANI, D. K., & RAGHAVENDRAN, K. V. (1971)
Distribution and fate of 54Mn in the monkey: studies of
different parts of the central nervous system and other organs.
J. clin. Invest., 50: 9-20.
DATE, S. (1960) The experimental studies on Mn intoxication.
J. Kumamoto Med. Soc., 34: 159-182.
DAVIS, W. E. & ASSOCIATES (1971) National inventory of sources and
emissions: manganese-1968. NC, US Environmental Protection
Agency, Office of Air Programmes (Report No. APTD-1509).
DAVYDOVA, V. I. (1969) [The combined effect of manganese compounds and
fluorine.] In: Klinika, patogenez i profilaktika profzabolevanij
himceskoj etiologii na predprijatijah cvetnoj i cernoj
metallurgii, Sverdlovsk, Part II, pp. 100-106 (in Russian).
DAVYDOVA, V. I., SABEL'NIKOVA, N. I., PANYCEVA, E. N., & MIHAJLOV, V.
A. (1971) [On the toxicity of dust containing manganese and
fluorine.] In: Voprosy gigieny fisiologii truda i profpatologii,
Sverdlovsk, pp. 45 46, (in Russian).
DE, H. N. (1949) Copper and manganese metabolism with typical Indian
diets and assessment of their requirement for Indian adult.
Ind. J. med. Res., 37: 301-309.
DEMEREC, M., BERTANI, G., & FLINT, J. (1951) A survey of chemicals for
mutagenic action on E. coli. Am. Nat., 85: 119-136.
DESMOND, E. A. (1975) The environmental implications of manganese as
an alternate antiknock. Discussion of SAE Paper No. 750926,
presented at the 1975 SAE Automobile Engineering Meeting,
Detroit, MI, October 1975.
DOBRYNINA, O. Ju. & DAVIDJAN, L. G. (1969) [Changes with age in the
levels of iron, manganese, copper and cobalt in the organs of
healthy men.] Med. Z. Usb., 12: 47-50 (in Russian).
DOISY, E. A. (1973) Micronutrient controls on biosynthesis of clotting
proteins and cholesterol. In: Hemphill, D.D., ed. Trace
substances in environmental health -- VI, Columbia, MO,
University of Missouri, pp. 193-199.
DOKUCAEVA, V. F. & SKVORTSOVA, N. N. (1966) [On the problem of the
biological effects of low concentrations of inhaled manganese.]
In: [Biological effects and hygienic significance of atmospheric
concentrations.] pp. 173-185 (in Russian).
DONALDSON, J., ST PIERRE, T., MINNICH J. L., & BARBEAU, A. (1973)
Determination of Na+, K+, Mg2+, Cu2+, Zn2+ and Mn2 in rat
brain regions. Can. J. Biochem., 51: 87-92.
DONSKIH, E. A. & MUKUMOV, M. R. (1974) [The action of manganese ions
on automatic activity of myocardial fibres induced by nickel
ions.] Bjull. Eksp. Biol. Med 78 (9): 7-9 (in Russian).
DRESIA, H. & SPOHR, F. (1971) Experience with the radiometric
dust-measuring unit "Beta Staubmeter". Staub, Reinhalt. Luft,
31 (6): 19-27.
DURFOR, C. N. & BECKER, E. (1964) Public water supplies of the 100
largest cities in the US, 1962. I. Am. Water Works Assoc.,
56 (3): 237-246.
DURHAM, N. N. & WYSS, O. (1957) Modified method of determining
mutation rates in bacteria. J. Bacteriol., 74: 548-552.
DURUM, W. H. & HAFFTY, J. (1961) Occurrence of minor elements in
water, Washington, DC, US Geological Survey, 11 pp.
EL ALFY, S., LAQUA, R., & MASSMANN, H. (1973) [Spectrochemical
analysis with a glow discharge lamp as a light source. III.
Development and description of an universal method for the
determination of the main constituents in electrically
non-conducting powder samples.] J. anal. Chem., 263: 1-14
ELDERFIELD, H. (1972) Compositional variations in the manganese oxide
component of marine sediments. Nature (Lond),
237 (70): 110-112.
ELISEEVA, T.N. (1973) [Micronutrient fertilizers in pickling liquors.
The treatment of waste waters and industrial atmospheric
emissions.] In: Tezicy dokladov Volgogradskogo Medinskogo
Instituta, pp. 45-47 (in Russian).
ELLIS, G. H., SMITH, S. E., & GATES, E. M. (1947) Further studies of
manganese deficiency in the rabbit. J. Nutr., 34: 21-31.
EL'NICNYH, L. N. (1969) [Changes occurring in the synapses of the
cerebral cortex during administration of dusts containing silicon
dioxide and manganese oxides.] In: Klinika, patogenez i
profilaktika profzabolevanii himiceskoj etiologii na
predprijatijah cvetnoj i cernoj metallurgii, Sverdlovsk,
Part II, pp. 115-118 (in Russian).
ELSTAD, D. (1939a) [Factory smoke containing manganese as predisposing
cause in epidemics of pneumonia in an industrial district.]
Nord. Med., 3: 2527-2533, 2544-2548 (in Norwegian).
ELSTAD, D. (1939b) [Observations on manganese pneumonia.] In:
Proceedings of the VIII International Congress of Accident
Medicine and Occupational Diseases, Frankfurt, AM, 26-30
September, 1938, Vol.2, Leipzig, Georg Thieme Verlag,
pp. 1014-1022 (in German).
EMARA, A.M., EL-GHAWABI, S. H., MADKOUR, O. I., & EL-SAMRA, G. H.
(1971) Chronic manganese poisoning in the dry battery industry.
Br. J. ind. Med., 28: 78-82.
ENGEL, R. W, PRICE, N. O., & MILLER, R. F. (1967) Copper, manganese,
cobalt, and molybdenum balance in pre-adolescent girls.
J. Nutr., 92: 197-204.
ENVIRONMENT AGENCY, JAPAN (1972) [Notification of Director of Air
Quality Bureau, June 1, 1972 Sampling and measurement method
of suspended particulate matter.] (in Japanese).
ENVIRONMENT AGENCY JAPAN (1975) [Results of measurements at National
Air Sampling Stations during 1973 (fiscal year).]
ERMAN, M. I. (1972) [Electric welding of low-carbon and low-alloy
steel in shielding gases; hygienic and occupational-pathological
aspects.] Gig. Tr. prof. Zabol., 16 (5): 26-30 (in Russian).
ETHYL CORPORATION (1971) The effect of manganese on the oxidation of
sulfur dioxide, Detroit, Ethyl Corp. 5 pp.
ETHYL CORPORATION (1974) Methylcyclopentadienylmanganese tricarbonyl
(MMT), an anti-knock agent for unleaded gasoline
(Status report, 2nd ed.), Ferndale, MI, Ethyl Corp. Research Lab.
von EULER, U.S. (1965) Catecholamines in nerve and organ granules. In:
von Euler, U.S., Rosell, S., & Uvnäs, B., ed. Mechanisms of
release of biogenic amines, London, Pergamon Press,
EVERSON, G. J. & SHRADER, R. E. (1968) Abnormal glucose tolerance in
manganese deficient guinea pigs. J. Nutr., 94: 89-94.
FAGGAN, J. E., BAILIE, J. D., DESMOND, E. A., & LENANE, D. L. (1975)
An evaluation of manganese as an antiknock in unleaded gasoline.
Presented at the 1975 SAE Automobile Engineering Meeting,
Detroit, MI October 13-17, 1975.
FAULL, R. L. M. & LAVERTY, R. (1969) Changes in dopamine levels in the
corpus striatum following lesions in the substantia nigra.
Exp. Neurol., 23: 332-340.
FAURBYE, A. (1970) The structural and biochemical basis of movement
disorders in treatment with neuroleptic drugs and in
extrapyramidal diseases. Comp. Psychiatr., 11 (3): 205-225.
FERNANDEZ, A. A., SOBEL, C., & JACOBS, S. L. (1963) Sensitive method
for the determination of submicrogram quantities of manganese and
its application to human serum. Anal. Chem., 35: 1721-1724.
FISHBEIN, L. (1973) Manganese, cobalt, nickel and cadmium. I.
Manganese. In: Chromatography of environmental hazards, New
York, American Elsevier Publishing Company, Vol. 2, pp. 37-42.
FLEMING, G. A. (1974) Trace elements in plants with particular
reference to pasture species. Outlook Agric., 4 (6): 270-285.
FLINN, R. H., NEAL, P. A., REINHART, W. H., DALLAVALLE, J. M., FULTON,
W. B., & DOOLEY, A. E. (1940) Chronic manganese poisoning in
an ore-crushing mill, Washington, DC, US Government Printing
Office, pp. 1-77 (Public Health Bull. No. 247).
FORE, H. & MORTON, R. A. (1952) Microdetermination of manganese in
biological materials by a modified catalytic method.
Biochem. J., 51: 594-598.
GENTEL, J. E., MANARY, O. J., & VALENTA, J. C. (1974a) Development of
a methodology for the assessment of the effects of fuels and
additives on the control devices, Washington, DC, US
Environmental Protection Agency (EPA-650/2-74-060).
GENTEL, J. E., MANARY, O. J., & VALENTA, J. C. (1974b) Determination
of effect of particulate exhaust emissions of additives and
impurities in gasoline, Washington, DC, US Environmental
Protection Agency (EPA-650/2-74-061).
GEORGII, H.-W. & MÜLLER, J. (1974) [Heavy metal aerosols in
metropolitan air.] Schriftenr. Vereins Wasser, Boden Lufthyg.,
42: 39-50 (in German).
GEORGII, H.-W., JENDRICKE, U., JOST, D., & MÜLLER, J. (1974) The
distribution of heavy metals in clean and polluted atmospheres.
Staub Reinhalt Luft, 34: 16-18.
GIAQUE, R. D., GOULDING, F. S., JAKLEVIC, J. M., & PEHL, R. H. (1973)
Trace element determination with semiconductor detector X-ray
spectrometers. Anal. Chem., 45: 671-681.
GOLDSTEIN, M., ANAGNOSTE, B., BATTISTA, A. F., OWEN, W. S., &
NAKATANI, S. (1969) Studies of the amines in the striatum in
monkeys with nigral lesions; the disposition, biosynthesis and
metabolites of (H3) dopamine and (C14) serotonin in the
striatum. J. Neurochem., 16: 645-653.
GOULDING, F. S. & JAKLEVIC, J. M. (1973) X-ray fluorescence
spectrometer for airborne particulate monitoring. Washington,
DC, US Environmental Protection Agency (EPA-R2-73-182).
GOULDING, F. S., WALTON, J. T., & PEHL, R. H. (1970) Recent results on
the cytoelectronic feedback preamplifier. IEEE Trans. Nucl.
Sci., NS-17: 218-225.
GRAHAM, J. A., GARDNER, D. E., WALTERS, M.D., & COFFIN, D. L. (1975)
Effect of trace metals on phagocytosis by alveolar macrophages.
Infect. Immunol., 11: 1278-1283.
GREENBERG, D. M., COPP, D. H., & CUTHBERTSON, E. M. (1943) Studies in
mineral metabolism with the aid of artificial radioactive
isotopes. VII. The distribution and excretion, particularly by
way of the bile of iron, cobalt and manganese. J. biol. Chem.,
GUTHRIE, B. E. (1975) Chromium, manganese, copper, zinc and cadmium
content of New Zealand foods. N. Z. med. J., 82: 418-424.
HAGENFELDT, K., PLANTIN, L. O., & DICZFALSY, E. (1973) Trace elements
in the human endometrium. II. Zinc, copper and manganese levels
in the endometrium, cervical mucus and plasma. Acta Endocrinol.,
HAKIMOVA, A.M., ZELENKOVA, N. P., & PANCENKO, E. I. (1969) [Changes in
the thyroid gland of rats with increasing amounts of manganese in
the diet.] Gig. i Sanit., 34 (1): 113-114 (in Russian).
HANCOCK, R. G. V., EVANS, D. J. R., & FRITZE, K. (1973) Manganese
proteins in blood plasma. Biochim. Biophys. Acta, 320: 486-493.
HANLON, D. P., GALE, T. F., & FERM, V. H. (1975) Permeability of the
syrian hamster placenta to manganous ions during early
embryogenesis. J. Reprod. Fertil., 44: 109-112.
HARMS, U. (1974) [Determination of the transition metals manganese,
iron, cobalt, copper and zinc in river fishes with help of X-ray
fluorescence analysis and flameless atomic absorption
spetroscopy.] Arch. Fischereiwiss., 25 (1/2): 63-74
HARTMAN, R. H., MATRONE, G. & WISE, G. H. (1955) Effect of high
dietary manganese on hemoglobin formation. J. Nutr.,
HASEGAWA, N. & IJICHI, R. (1973) [Atomic absorption spectrophotometry
-- problems in the preparation of the sample and its
determinations.] J. occup. Health Eng., 13: 38-46
HATAMOV, S., BADALOV, N. Ju., & RUSTAMOV, R. (1972) [Determination of
potassium, manganese, phosphorus, sodium and chlorine in the
cotton plant by neutron activation analysis.] Tr. Samarkandskogo
Inst., 223: 88-93 (in Russian).
HAZARADZE, R. E. (1961) [Hygienic background for determining the
maximum permissible concentration of manganese in water basins.]
Gig. i Sanit., 26 (12): 8-14 (in Russian).
HEGDE, B., GRIFFITH, G. C., & BUTT, E. M. (1961) Tissue and serum
manganese levels in evaluation of heart muscle damage. A
comparison with SGOT (26738). Proc. Soc. Exp. Biol. Med.,
HILL, R. M. & HOLTKAMP, D. E. (1954) Storage of dietary manganese and
thiamine in the rat. J. Nutr., 53: 73-82.
HILL, R. M., HOLTKAMP, D. E., BUCHANAN, A. R., & RUTLEDGE, E. K.
(1950) Manganese deficiency in rats in relation to ataxia and
loss of equilibrium. J. Nutr., 41: 359-371.
HORIGUCHI, S., UTSONOMIYA, T., KASAHARA, A., SHINAGAWA, K., IYODA, K.,
TANAKA, N., TSUYAMA, N., IKUTOMI, H., & MIURA, K. (1966) [A
survey of the actual conditions of factories handling manganese
compounds.] Jpn. J. ind. Health, 8 (6): 333-342 (in Japanese)
HORIUCHI, K., HORIGUCHI, S., TANAKA, N., & SHINAGAWA, K. (1967)
Manganese contents in the whole blood, urine and feces of a
healthy Japanese population. Osaka City med. J., 13: 151-163.
HORIUCHI, K., HORIGUCHI, S., SHINAGAWA, K., UTSUNOMIYA, T., & TSUYAMA,
Y. (1970) On the significance of manganese contents in the whole
blood and urine of manganese handlers. Osaka City med. J.,
HUBUTIJA, V. A. (1972) [Distribution and retention of unipolar
electrically charged industrial manganese dust in the respiratory
organs.] Gig. Tr. prof. Zabol., 2: 27-31 (in Russian).
HUGHES, E. R. & COTZIAS, G. C. (1960) Manganese metabolism and
adrenacortical activity; an isotropic study. Fed. Proc.,
HUGHES, E. R., MILLER, S. T., & COTZIAS, G. C. (1966) Tissue
concentrations of manganese and adrenal function.
Am. J. Physiol., 211: 207-210.
HUNTINGDON RESEARCH CENTER (1975) Evaluation of the chronic
inhalation toxicity associated with a manganese aerosol produced
from the combustion of methylcyclopentadienyl manganese
tricarbonyl (MMT), 213 pp. (Final report submitted to Ethyl
Corporation, Project no. 731-339).
HURLEY, L. S. (1968) Genetic-nutritional interactions concerning
manganese. In: Hemphill, D.D., ed. Trace substances in
environmental health -- II, Columbia, MO, University of
Missouri, pp. 41-51.
HURN, R. W., ALLSUP, J. R., & COX, F. (1974) Effect of gasoline
additives on gaseous emissions, Washington, DC, US
Environmental Protection Agency, 64 pp. (EPA-650/2-75-014).
HYSELL, D. K., MOORE, W. Jr, STARA, J. F., MILLER, R., & CAMPBELL, K.
I. (1974) Oral toxicity of methylcyclopentadienyl manganese
tricarbonyl (MMT) in rats. Environ. Res., 7: 158-168.
IARC WORKING GROUP (1976) IARC Monographs on the evaluation of
carcinogenic risk of chemicals to man. Lyons, International
Agency for Research on Cancer, Vol. 12, pp. 137-149.
IMAM, Z. & CHANDRA, S. V. (1975) Histochemical alterations in rabbit
testis produced by manganese chloride. Toxicol. appl.
Pharmacol., 32: 534-544.
INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION (1975) Report of
the Task Group on Reference Man, Oxford, Pergamon Press,
pp. 361-364, 393-394.
ITAKURA, T. & TAJIMA, T. (1972) [A survey of environmental pollution
by manganese dust from a ferro-manganese plant in Kanazawa.]
Ishikawa Prefecture, Institute for Hygiene and Environmental
Pollution, Annual Report, Vol. 9, pp. 40-50 (in Japanese).
ITOYAMA, T. (1971) [Total iron and manganese in the piestic ground
waters in the main artesian wells at Takamatsu city.] J. Water
Waste, 152: 5-11 (in Japanese).
JAPAN ENVIRONMENTAL SANITATION CENTRE (1974) [Report on the survey of
air pollution in special environments.] (in Japanese).
JÄRVINEN, R. & AHLSTRÖM, A. (1975) Effect of the dietary manganese
level on tissue manganese, iron, copper and zinc concentrations
in female rats and their fetuses. Med. Biol., 53: 93-99.
JOHANSSON, T. B., VAN GRIEKEN, R. E., NELSON, J. W., & WINCHESTER, J.
W. (1975) Elemental trace analysis of small samples by
proton-induced X-ray emission. Anal. Chem., 47: 855-860.
JONDERKO, G. (1965) [Calcium, magnesium, inorganic phosphorus, sodium,
potassium and iron levels in blood serum in the course of acute
experimental manganese poisoning.] Med. Pr., 16: 288-292
JONDERKO, G. & SZCZUREK, Z. (1967) [Pathomorphological studies of the
internal organs in experimental manganese poisoning.] Arch.
Gewerbepathol Gewerbehyg., 23: 106-116 (in German).
JONDERKO, G., KUJAWSKA, A., & LANGAUER-LEWOWICKA, H. (1971) [Studies
on the early symptoms of manganese toxicity.] Med. Pr.,
22 (1): 1-10 (in Polish).
JONDERKO, G., CZEKANSKA, D., TWARDOWSKI, Z., & TYRNA E. (1973a)
[Effects of occupational exposure to manganese on the development
of atherosclerosis.] Med. Pr., 24 (6): 589-599 (in Polish).
JONDERKO, G., TWARDOWSKI, Z., & TYRNA, E. (1973b) [Effect of manganese
exposure upon sickness absenteeism and morbidity.] Med. Pr.
24 (6): 629-638 (in Polish).
JONDERKO, G., KUJAWSKA, A., & LANGAUER-LEWOWICKA, H. (1974) [Effect of
interruption of occupational contact with manganese upon
neurological and biochemical symptoms of the toxic effect of
manganese.] Med. Pr., 25 (6): 543-548 (in Polish).
JONES, P. G. W., HENRY, J. L., & FOLKARD, A. R. (1973)
The distribution of selected trace metals in the water of the
North Sea 1971-73, Lowestoft, International Council for the
Exploration of the Sea (ICES), Fisheries Improvement Committee,
Fisheries Laboratory, 13 pp. (C.M. 1973/C: 5).
KAGAMIMORI, S., MAKINO, T., HIRAMARU, Y., KAWANO, S., KATO, T.,
NOGAWA, K., KOBAYASHI, E., SAKAMOTO, M., FUKUSHIMA, M., ISHIZAKI,
A., KANAGAWA, K., & AZAMI, S. (1973) [Epidemiological studies on
disturbance of respiratory system caused by manganese air
pollution (Report 2). Improvement of respiratory functions after
setting up dust collectors.] Jpn. J. Public Health,
20 (8): 413-421 (in Japanese).
KANABROCKI, E. L., FIELDS, T., DECKER, C. F., CASE, L. F., MILLER, E.
B., KAPLAN, F., & OESTER, Y. T. (1964) Neutron activation studies
of biological fluids; manganese and copper. Int. J. appl.
Radiat. Isot., 15: 175-190.
KAPLAN, R. W. (1962) [Problems in testing pharmaceutical products,
additives and other chemicals for their mutagenic action.]
Naturwissenschaften, 49: 457-462 (in German).
KAWAMURA, R., IKUTA, H., FUKUZUMI, S., YAMADA, R., & TSUBAKI, S.
(1941) Intoxication by manganese in well water. Kitasato Arch.
exp. Med., 18: 145-169.
KEANE, J. R. & FISHER, E. M. R. (1968) Analysis of trace elements in
airborne particulates by neutron activation and X-ray
spectrometry. Atmos. Environ., 2: 603-614.
KEHOE, R. A., CHOLAK, J., & STORY, R. V. (1940) A spectrochemical
study of the normal ranges of concentration of certain trace
metals in biological materials. J. Nutr., 19: 579-592.
KESIC, B. & HÄUSLER, V. (1954) Heamatological investigation on workers
exposed to manganese dust. Am. Med. Assoc. Arch. ind. Health
occup. Med., 10: 336-343.
KIMURA, Y., MINURA, S., & HIGUCHI, I. (1969) [Nature of underground
water in Japan.] Ann. Rep. Tokyo Metrop. Res. Lab., Public
Health, 20: 119-121 (in Japanese).
KITAMURA, S., SUMINO, K., HAYAKAWA, K., & SHIBATA, T. (1974) [Heavy
metals in normal Japanese subjects (Amounts of 15 heavy metals in
30 subjects).] Environ. Health Rep., 28: 29-60 (in Japanese).
KLAASSEN, C. D. (1974) Biliary excretion of manganese in rats, rabbits
and dogs. Toxicol. appl. Pharmacol., 29: 458-467.
KLAWANS, H., Jr, ILAHI, M. M., & SHENKER, D. (1970) Theoretical
implications of the use of L-dopa in Parkinsonism. Acta neurol.
Scand., 46: 409-441.
KLEINKOPF, M.D. (1960) Spectrographic determination of trace elements
in lake waters of Northern Maine. Geol. Soc. Am. Bull.,
KOBERT, R. (1883) [On the pharmacology of manganese and iron.]
Arch. exp. Pathol. Pharmakol., 16: 361-392 (in German).
KOCMOND, W. C., YANG, J. Y., & DAVIS, J. A. (1975) A methodology for
determining the effects of fuel and additive combustion products
on atmospheric visibility, Buffalo, New York, Calspan
Corporation (Calspan Rep. No. NA. 5300-M-1).
KOLESNIKOVA, V. G., KASATKINA, L. A., MALAHOVA, O. P., MUSYCENKO, V.
I., & BABOV, D. M. (1973) [Concentrations of the trace elements
copper and manganese in river water, soils and plants in the
southern Ukraine.] Gig. i Sanit., 38 (3): 110-111 (in Russian).
KOLOMIJEEVA, M. G. (1970) [Trace elements in medicine.] Moscow,
Medicina, 287 pp. (in Russian).
KOSAI, M. F. & BOYLE, A. J. (1956) Ethylenediaminetetraacetic acid in
manganese poisoning of rats. A preliminary study. Ind. Med.
Surg., 25: 1-3.
KOSHIDA, Y., KATO, M., & HARA, T. (1963) Autoradiographic observations
of manganese in adult and embryo mice. Q. J. exp. Physiol.,
KOSHIDA, Y., KATO, M., & HARA, T. (1965) Distribution of
radiomanganese in embryonic tissues of the mouse. Annot. zool.
Jpn, 38 (1): 1-7.
KOSTERLITZ, H. W. & WATERFIELD, A. A. (1972) Effects of calcium and
manganese on acetylcholine release from the myenteric plexus of
guinea pig and rabbit ileum. Br. J. Pharmacol., 45: 157-158.
KOSTIAL, K., LANDEKA, M., & SLAT, B. (1974) Manganese ions and
synoptic transmission in the superior cervical ganglion of the
rat. Br. J. Pharmacol., 51: 231-235.
KOZUKA, T., MIYAGI, K., SATO, T., MORI, R., & SHIKANAI, H. (1971) [Cd
and Mn in streams of the upper Iwaki river.] Bull. Fac. Educ.
Hirosaki Univ., 24B: 7-13 (in Japanese).
KRONER, R. C. & KOPP, J. F. (1965) Trace elements in six water systems
of the United States. Am. Water Works Assoc. J., 57: 150-156.
LAGERWERFF, J. V. (1967) Heavy-metal contamination of soils. In:
Brady, N.C., ed. Agriculture and the quality of our
environment, Norwood, MA, Plimpton Press, pp. 343-364.
LANDIS, D. A., GOULDING, F. S., PEHL, R. H., & WALTON, J. T. (1971)
Pulsed feedback techniques for semiconductor detector radiation
spectrometers. IEEE Trans. Nucl. Sci., N. S. 18: 115-124.
LASSITER, J. W., MORTON, J. D., & MILLER, W. J. (1970) Influence of
manganese on skeletal development in the sheep and rat. In:
Mills, C.F., ed. Trace element metabolism in animals,
Proceedings of WAAP/IBP International Symposium, Aberdeen,
July 1969, Edinburgh, E & S Livingstone, pp. 130-132.
LAZRUS, A. L., LORANGE, E., & LODGE, J.P. Jr (1970) Lead and other
metal ions in United States precipitation. Environ. Sci.
Technol., 4: 55-58.
LEE, R. E., GORANSON, S.S., ENRIONE, R. E., & MORGAN, G. B. (1972)
NASN cascade impactor network. Part II: Size distribution of
trace metal components. Environ. Sci. Technol., 6: 1025-1030.
LERNER, M. O., GONCAROV, V. V., HESINA, A. Y., & BAKALEINIK, A.M.
(1974) [Effects of the nature of fuel and the additive
cyclopentadie-nyltricarbonyl-manganese on the concentration of
benzo pyrene in exhaust gases of a carburator motor.]
Ekspl.-Tekh. Svoistva Primen. Avtomov. Topl. Smaz. Mater.
Spetszhidk., No 8, pp. 51-54 (in Russian) (Abstract in
Air Pollut. ind. Hyg., 1974, 8: 365).
LETAVET, A. A. (1973) [Manganese.] In: Professional'nye bolezni,
Moscow (in Russian).
LEVANOVSKAJA, A. I. & NEIZVESTNOVA, E. M. (1972) [Morphological and
histochemical characteristics of the adrenal glands on exposure
to manganese chloride and generalized vibration.] In:
Kombinirovannoe dejstvie himiceskih i fiziceskih faktorov
proizvodstvennonj sredy, Sverdlovsk, pp. 84-90 (in Russian).
LEVINA, E. N. & ROBACEVSKAJA, E.G. (1955) [Changes in the lung tissues
under intratracheal injections of manganese oxides.] Gig. i
Sanit. 20 (1): 25-28 (in Russian).
LEVINA, E. N. & TCEKUNOVA, M.P. (1969) [Manganese on monoaminoxidase
activity.] Vopr. Med. Him., 15: 634-637 (in Russian).
LEVITT, M., SPECTOR, S., SJOERDSMA, A., & UDENFRIEND, S. (1965)
Elucidation of the rate-limiting step in norepinephrine
biosynthesis in the perfused guinea pig heart J. Pharmacol. exp.
Ther., 148: 1-8.
LINDBERG, O. & ERNSTER, L. (1954) Manganese a co-factor of oxidative
phosphorylation. Nature (Lond.) 173: 1037-1038.
LLOYD DAVIES, T. A. (1946) Manganese pneumonitis. Br. J. ind. Med.,
LLOYD DAVIES, T. A. & HARDING, H. E. (1949) Manganese pneumonitis.
Further clinical and experimental observations. Br. J. ind.
Med., 6: 82-90.
L'VOV, B. V. (1961) The analytical use of atomic absorption spectra.
Spectrochim. Acta 17: 761-770.
LYONS, M. & INSKO, W. M. (1937) Chondrodystrophy in the chick embryo
produced by manganese deficiency in the diet of the hen.
Kentucky Agric. Exp. Stn Bull., 371: 63-75.
MAHONEY, J.P. & SMALL, W. J. (1968) Studies on manganese. III. The
biological half-life of radiomangenese in man and factors which
affect this half-life. J. clin. Invest., 47: 643-653.
MAHONEY, J. P., SARGENT, K., GRELAND, M., & SMALL, W. (1969) Studies
on manganese. I. Determination in serum by atomic absorption
spectrophotometry. Clin. Chem., 15: 312-322.
MAIGRETTER, R. Z., EHRLICH, R., FENTERS, J. D., & GARDNER, D. E.
(1976) Potentiating effects of manganese dioxide on experimental
respiratory infections. Environ. Res., 11: 386-391.
MANDELL, A. J. & SPOONER, C. E. (1968) Psycho-chemical research
studies in man. Science, 162: 1442-1453.
MANDZGALADZE, R. N. (1966a) [On the effect of manganese compounds on
sexual functions in the male rat.] Vopr. Gig. Tr. Profpatol.,
10: 191-195 (in Russian).
MANDZGALADZE, R. N. (1966b) [The effect of manganese compounds on the
estrous cycle and embryogenesis in experimental animals.] Vopr.
Gig. Tr. Profpatol., 10: 219-225 (in Russian).
MANDZGALADZE, R. N. (196c) [On the mutagenic properties of manganese
compounds.] Vopr. Gig. Tr. Profpatol. 10: 225-226 (in Russian).
MANDZGALADZE, R. N. (1967) [Some clinical and experimental data on the
effect of manganese compounds on sexual function.] Vopr. Gig.
Tr. Profpatol. 11: 126-130 (in Russian).
MANDZGALADZE, R. N. & VASAKIDZE, M. I. (1966) [The effect of small
doses of manganese compounds, nitrogenous organomercury
pesticides and some anticoagulants on chromosome rearrangements
in white rat bone marrow cells.] Vopr. Gig. Tr. Profpatol.
10: 209-212 (in Russian).
MATRONE, G., HARTMAN, R. H., & CLAWSON, A. J. (1959) Studies of a
manganese-iron antagonism in the nutrition of rabbits and baby
pigs. J. Nutr., 67: 309-317.
MATTESON M. J., STÖBER, W., & LUTHER, H. (1969) Kinetics of the
oxidation of sulfur dioxide by aerosols of manganese sulfate.
Ind. eng. Chem. Fundam., 8: 677-687.
MAVRINSKAJA, L. F., MIHAJLOV, V. A., & DAVYDOVA, V. I. (1972)
[Morphological changes in the nerve components of somatic muscle
on combined exposure to manganese and carbon monoxide.] In:
Kombinirovannoe dejstvie himiceskih i fiziceskih faktorov
proizvodstvennoj sredy. Sverdlovsk, pp. 109-114 (in Russian).
MAYNARD, L. S. & COTZIAS, G. C. (1955) The partition of manganese
among organs and intracellular organelles of the rat. J. biol.
Chem., 214: 489-495.
MAYNARD, L. S. & FINK, S. (1956) The influence of chelation on
radiomanganese excretion in man and mouse. J. clin. Invest.,
McKAY, H. A. C. (1971) The atmospheric oxidation of sulfur dioxide in
water droplets in the presence of ammonia. Atmos. Environ.,
McLEOD, B. E. & ROBINSON, M. F. (1972a) Dietary intake of manganese by
New Zealand infants during the first six months of life. Br. J.
Nutr., 27: 229-232.
McLEOD, B. E. & ROBINSON, M. F. (1972b) Metabolic balance of manganese
in young women. Br. J. Nutr., 27: 221-227.
MELLA, J. (1924) The experimental production of basal ganglion
symptomatology in Macacus rhesus. Arch. Neurol. Psychiatr.,
MENA, I. (1974) The role of manganese in human disease. Ann. clin.
lab. Sci., 4 (6): 487-491.
MENA, I. & COTZIAS, G. C. (1970) Manganese poisoning: a metabolic
disorder. Final report on US PHS research project. pp. 21-26
(Grant No. EC-213-07).
MENA, I., MARIN, O, FUENZALIDA, S., COTZIAS, G. C. (1967) Chronic
manganese poisoning. Clinical picture and manganese turnover.
Neurology, 17: 128-136.
MENA, I., HORIUCHI, K., BURKE, K., & COTZIAS, G. C. (1969) Chronic
manganese poisoning. Individual susceptibility and absorption of
iron. Neurology, 19: 1000-1006.
MENA, I., COURT, J., FUENZALIDA, S., PAPAVASILIOU, P.S., & COTZIAS, G.
C. (1970) Modification of chronic manganese poisoning: treatment
with L-dopa or 5-OH tryptophane. New Engl. J. Med.,
MENA, I., HORIUCHI, K., & LOPEZ, G. (1974) Factors enhancing entrance
of manganese into the brain: Iron deficiency and age. J. nucl.
Med., 15: 516.
MERANGER, J. C. & SMITH, D.C. (1972) The heavy metal content of a
typical Canadian diet. Can. J. public Health, 63: 53-57.
MIHAJLOV, V. A. (1969) [Manganese poisoning in steel casting shop
workers.] In: Klinika, patogenez i profilaktika profzabolevanij
himiceskoj etiologii na predprijatijah cvetnoj i cernoj
metallurgii. Sverdlovsk, pp. 190-206 (in Russian).
MIHAJLOV, V. A. (1971) [Some urgent problems of interest in the
pathogenesis and therapy of manganesotoxicosis.] Gig. Tr. prof.
Zabol., 6: 14-19 (in Russian).
MIHAJLOV, V. A., KLJACINA, K. N., BELJAEVA, L. N., SADILOVA, M. S.,
KAZANCEVA, T. I., TROP, F. C., KLEINER, A.-M., BELOBRAGINA, G.
B., OKONISNIKOVA, I. E., DORINOVSKAJA, A. P., NEIZVESTNOVA, E.
M., SIGOVA, N. V., & BLOHIN, V. (1967) [Research results and
future lines of investigation with regard to pathogenesis,
therapy and individual preventive care in the case of poisoning
by compounds of manganese, chromium and fluoride.] In: Obscie
voprosy promyslennoj toksikologii, Moscow, Institute of
Industrial Hygiene and Occupational Diseases, pp. 124-127
MIHAJLOV, V. A., DAVYDOVA, V. I., & EL'NICNYH, L. I. (1969)
[Experimental data on aspects of the combined effect of manganese
compounds and carbon monoxide.] In: Klinika, patogenez i
profilaktika profzabolevanij himiceskoj etiologii na
predprijatijah cvetnoj i cernoj metallurgii, Sverdlovsk,
Part II, pp. 104-108 (in Russian).
MILLER, R. S., MILDVAN, A. S., CHANG, H. C., EASTERDAY, R. L.,
MARUYAMA, H., & LANE, M.D. (1968) The enzymatic carboxylation of
phosphoenolpyruvate. IV. The binding of manganese and substrates
by phosphoenolpyruvate carboxy-kinase and phosphoenol pyruvate
carboxylase. J. biol. Chem., 243: 6030-6040.
MILLER, S. T., COTZIAS, G. C., & EVERT, H. A. (1975) Control of tissue
manganese; initial absence and sudden emergence of excretion in
the neonatal mouse. Am. J. Physiol., 229: 1080-1084.
MINERALS YEARBOOK, (1977) Washington, DC, US Department of Interior,
Bureau of Mines.
MINISTRY OF INTERNATIONAL TRADE AND INDUSTRY AND MINISTRY OF HEALTH
AND WELFARE, JAPAN (1969) [Report on the survey of
environmental manganese concentrations in Yokkaichi
district.] Tokyo, 139 pp. (in Japanese).
MITCHELL, H. H. & HAMILTON, T. S. (1949) The dermal excretion under
controlled environmental conditions of nitrogen and minerals in
human subjects, with particular reference to calcium and iron.
J. biol. Chem., 178: 345-361.
MITCHELL, R. L. (1964) Trace elements in soils. In: Bear, F. E., ed.
Chemistry of the soil, 2nd ed., New York, Reinhold Publ. Corp.,
MITCHELL, R. L. (1971) Trace elements in soils, Aberdeen, Macaulay
Institute for Soil Research, pp. 8-20 (Tech. Bull. No. 20).
MJACINA, L.Ja. (1972) [Monoaminoxidase activity in nerve components
and muscle tissue in manganese poisoning.] In: Kombinirovannoe
dejstvie himiceskij i fiziceskij faktorov proizvodstvennoj
sredy; Sverdlovsk, pp. 114-116 (in Russian).
MOORE, W. Jr., HALL, L., CROCKER, W., ADAMS, J., & STARA, J. F.,
Metabolic aspects of methylcyclopentadienyl manganese tricarbonyl
in rats. Environ. Res., 8: 171-177.
MOORE, W., HYSELL, D., MILLER, R., MALANCHUK, M., HINNERS, H., YANG,
Y., & STARA, J. F. (1975) Exposure of laboratory animals to
atmospheric manganese from automotive emissions. Environ. Res.,
MORAN, J. B. (1975) The environmental implications of manganese as an
alternate antiknock. Paper, presented at the 1975 SAE Automobile
Engineering Meeting, Detroit, MI, October, 1975,
(No. SAE 750926).
MORAN, J. B., BALDWIN, M. J., MANARY, O. J., & VALENTA, J. C. (1972)
Effect of fuel additives on the chemical and physical
characteristics of particulate emissions in automotive exhaust,
Washington, DC, US Environmental Protection Agency, 345
MORGEN, E. A., VLASOV, N. A., & KOZEMJAKINA, L. A. (1972) [A kinetic
method for determining trace amounts of manganese according to
the decreasing fluorescence of the morin complex of beryllium.]
Z. Anal. Him., 97 (10): 2064-2067 (in Russian).
MORRIS, A. W. (1974) Seasonal variation of dissolved metals on inshore
waters of the Menai straits. Mar. Pollut. Bull., 5 (4): 54-59.
MOSENDZ, S. A. (1968) [Effect of electric-welding dust on the
metabolism of nitrogenous substances in the tissues.] Vrach.
Delo., 5: 109-111 (in Russian).
MOURI, T. (1973) [Experimental study of inhalation of manganese dust.]
Shikoku Acta Med., 29 (2): 118-129 (in Japanese).
MUHTAROVA, M., BOBEV, G., COHEN, E., & GENOVA, S. (1969) [A rapid drop
wise quantitative method for determination of manganese aerosols
in the air of the working environment.] Works Inst. Labour Prot.
occup. Dis., 18 (11): 257-261 (in Bulgarian).
MURADOV, V. G. & MURADOVA, O. N. (1972) [Determination of the absolute
concentration of manganese atoms in the gas phase by an atomic
absorption method.] Z. Prikl. Spektrosk., 17 (6): 1102-1104
MUSAEVA, L. D. & KOZLOVA, G.I. (1973) [The accumulation of manganese
in bilberries as a result of the environmental condition of the
leaves.] Nauc. dokl. vyssh. sk. biol. n., 7: 71-76
MUSTAFA, S. J. & CHANDRA, S. V. (1971) Levels of 5-hydroxytryptamine,
dopamine, and norepinephrine in whole brain of rabbits in chronic
manganese toxicity. J. Neurochem., 18: 931-933.
NAKAGAWA, T. (1968) [A study on the manganese content in daily food
consumption in Japan.] J. Osaka City Cent., 17 (9-10): 401-424
NAKAMURA, Y. & OSADA, M. (1957) [Studies on trace elements in food and
beverages. III. Manganese content in green tea.] Ann. Rep.
Kyoritsu Coll Pharm., 3: 19-21 (in Japanese).
NAS/NRC (1973) Manganese, Washington, DC, National Academy of
National Research Council, pp. 1-191.
NEFF, N. H., BARRET, R. E., & COSTA, E. (1969) Selective depletion of
caudate nucleus dopamine and serotonin during chronic manganese
dioxide administration to squirrel monkeys. Experientia (Basel),
NEIZVESTNOVA, E. M. (1972a) [An investigation into the effect on the
body of manganese dioxide and generalized vibration.] In:
Kombinirovannoe dejstvie himiceskih i fiziceskih faktorov
proizvodstvennoj sredy, Sverdlovsk, pp. 76-80 (in Russian).
NEIZVESTNOVA, E. M. (1972b) [The toxicity of manganous chloride under
conditions of generalized vibration.] In: Kombinirovannoe
dejstvie himiceskih i fiziceskih faktorov proizvodstvennoj
sredy, Sverdlovsk, pp. 84-90 (in Russian).
NICHOL, I., HORSNAIL, R. F., & WEBB, J. S. (1967) Geochemical patterns
in stream sediment related to precipitation of manganese oxides.
Trans Inst. Min. Metall. Sect. B, 76: 113-115.
NISHIYAMA, K., SUZUKI, Y., FUJII, N., YANO, H., MIYAI, T., & ONISHI,
K. (1975) [Effect of long-term exposure to manganese particles.
Part 2. Periodical observation of respiratory organs in monkeys
and mice.] Jpn. J. Hyg., 30: 117 (in Japanese).
NOGAWA, K., KOBAYASHI, E., SAKAMOTO, M., FUKUSHIMA, M., ISHIZAKI, A.,
KAGAMIMORI, S., MAKINO, T., HIRAMARU, Y., KAWANO, S., KATO, T.,
KANAGAWA, K., & AZAMI, S. (1973) [Epidemiological studies on
disturbance of respiratory system caused by manganese air
pollution. Report 1: Effects on respiratory system of junior high
school students.] Jpn. J. public Health, 20 (6): 315-326.
NORDBERG, G. F., ed. (1976) Effects and dose-response relationships
of toxic metals, Amsterdam, Elsevier, 559 pp.
NORTH, B. B., LEICHSENRING, J. M., & NORRIS, L. M. (1960) Manganese
metabolism in college women. J. Nutr., 72: 217-223.
OBOLENSKAJA, L. I., KAMENSKAJA, L. S., & BUZJUKINA, V. V. (1971) [An
atomic absorption method for determining zinc, manganese, iron
and magnesium in plants and soil.] Agrohimija, 1: 136-142
OLEHY, D. A., SCHMITT, R. A., & BETHARD, W. F. (1966) Neutron
activation analysis of magnesium, calcium, strontium, barium,
manganese, cobalt, copper, zinc, sodium, and potassium in human
erythrocytes and plasma. J. nucl. Med., 7: 917-927.
OSIPOVA, I. A., D'JAKOVA, I. N., & URMANCEEVA, T. G. (1968) [Manganese
parkinsonism in experiments on macaque and rhesus monkeys (Part
I).] Gig. Tr. prof. Zabol., 12 (8): 48-49 (in Russian).
PANIC, B. (1967) [ In vitro binding of manganese to serum transferrin
in cattle.] Acta Vet. Sand., 8: 228-233.
PAPAVASILIOU, P. S. & COTZIAS, G. C. (1961) Neutron activation
analysis; the determination of manganese. J. biol. Chem.,
PAPAVASILIOU, P. S., MILLER, S. T., & COTZIAS, G. C. (1966) Role of
liver in regulating distribution and excretion of manganese.
Am. J. Physiol., 211: 211-216.
PARNITZKE, K. H. & PEIFFER, J. (1954) [On the clinical and
pathological anatomy in chronic manganese poisoning.] Arch.
Psychiatr. Z. Neurol., 192: 405-429 (in German).
PENALVER, R. (1955) Manganese poisoning: The 1954 Ramazzini oration.
Ind. Med. Surg., 24: 1-7.
PENTSCHEW, A., EBNER, F. F., & KOVATCH, R. M. (1963) Experimental
manganese encephalopathy in monkeys. A preliminary report.
J. Neuropathol. exp. Neurol., 22: 488-499.
PEPIN, D., GARDES, A., PETIT, J., BERGER, J.-A., & GAILLARD, G. (1973)
Étude spectrographique des éléments-traces des eaux minérales. I.
Analyse directe du résidu sec. Analysis, 25: 337-342.
PEREGUD, E. A. & GERNET, E. V. (1970) [Determination of manganese
oxides and salts.] In: Himiceskih analiz vozduha promyslennyh
predprijatij, Leningrad, Himija, pp. 342-343 (in Russian).
PFITZER, E. A., WITHERUP, S. O., LARSEN, E. E., & STEMMER, K. L.
(1972) Toxicity of methylcyclopentadienyl manganese tricarbonyl
(MMT). (Internal report to US Environmental Protection Agency.
Kettering Laboratory, University of Cincinnati).
PLUMLEE, M.P., THRASHER, D. M., BEESON, W. M., ANDREWS, F. N., &
PARKER, H. E. (1956) The effects of a manganese deficiency upon
the growth, development and reproduction of swine. J. anim.
Sci., 15: 354-367.
POCASEV, E. N. & NEIZVESTNOVA, E. M. (1972) [Morphological changes in
some internal organs of white rats on exposure to a combination
of manganese and vibration.] In: Kombinirovannoe dejstvie
himiceskih i fiziceskih faktorov proizvodstvennoj sredy,
Sverdlovsk, pp. 90-94 (in Russian).
POIRIER, L. J. & SOURKES, T. L. (1964) Influence of substantia nigra
on the catecholamine content of the striatum. Brain,
POIRIER, L. J., SINGH, P., BOUCHER, R., BOUVIER, G., OLIVIER, A., &
LAROCHELLE, P. (1967a) Effect of brain lesion on striatal
monamines in the cat. Arch. Neurol. (Chic.), 17: 601-608.
POIRIER, L. J., SlNGH, P., SOURKES T. L., & BOUCHER, R. (1967b) Effect
of amine precursors on the concentration of striatal dopamine and
serotonin in cats with and without unilateral brainstem lesions.
Brain Res., 6: 654-666.
POIRIER, L. J., McGEER, E.G., LAROCHELLE, L., McGEER, P. L. BEDARD,
P., & BOUCHER, R. (1969) The effect of brain stem lesions on
tyrosine and tryptophan hydroxylases in various structures of the
telencephalon of the cat. Brain. Res., 14: 147-155.
POLLACK, S., GEORGE, J. N., REBA, R. C., KAUFMAN, R. M., & CROSBY, W.
H. (1965) The absorption of nonferrous metals in iron deficiency.
J. clin. Invest., 44: 1470-1473.
POVOLERI, F. (1974) [Bronchopneumonia and the production of
ferro-manganese.] Med. Lav., 38: 30-34 (in Italian).
PRESTON, A., JEFFERIES, D. F., DUTTON, J. W. R., HARVEY, B. R., &
STEELE, A. K. (1972) British isles coastal waters. The
concentrations of selected heavy metals in sea water, suspended
matter and biological indicators -- a pilot survey. Environ.
Pollut., 3: 69-82.
PRICE, N. O., BUNCE, G. E., & ENGEL, R. W. (1970) Copper, manganese,
and zinc balance in pre-adolescent girls. Am. J. clin. Nutr.,
REITH, J. W. S. (1970) Soil factors influencing the trace element
content of herbage. In: Mills, C. F., ed. Trace element
metabolism in animals, London, Livingstone, E. & S.,
RHODES, J. R., PRADZYNSKI, A. H., HUNTER, C. B., PAYNE J. S., &
LINDGREN, J. L. (1972) Energy dispersive X-ray fluorescence
analysis of air particulates in Texas. Environ. Sci. Technol.,
RIDDERVOLD, J. & HALVORSEN, K. (1943) Bacteriological investigations
on pneumonia and pneumococcus carriers in Sauda, an isolated
industrial community. Acta Pathol. Microbiol. Scand.,
RILEY, J. P. & TAYLOR, D. (1968) Chelating resins for the
concentration of trace elements from sea water and their
analytical use in conjunction with atomic absorption
spectrophotometry. Anal. Chim. Acta, 40: 479-485.
RODIER, J. (1955) Manganese poisoning in Moroccan mines. Br. J.
ind. Med., 12: 21-35.
ROSCIN, A. V. (1971) [On some mechanisms of the toxic effects of
metals.] In: Material Vsesojuznoj konferencii po rannej
diagnostike i profilaktike professional'nyh zabolevanij
himiceskoj etiologii, Moscow, Institute of Hygiene and
Occupational Diseases, pp. 42-45 (in Russian).
ROSENSTOCK, H. A., SIMONS, D. G., & MEYER, J. S. (1971) Chronic
manganism. Neurological and laboratory studies during treatment
with levodopa. J. Am. Med. Assoc., 217: 135-1359.
RUCH, R. R., GLUSKOTER, H. J., & SHIMP, N. F. (1973) Occurrence and
distribution of potentially volatile trace elements in coal:
An interim report, Illinois State Geological Survey,
Environmental Geology Notes, No. 61, pp. 1-43.
RYLANDER, R. & BERGSTRÖM R. (1973) Particles and SO2 -- Synergistic
effects for pulmonary damage. In: Proceedings of the 3rd
International Clean Air Congress, Düsseldorf, 1973, Düsseldorf,
VDI Verlag, pp. A23-A25.
RYLANDER, R., ÖHRSTROM, M., HELLSTRÖM, P. A., & BERGSTRÖM, R. (1971)
SO2 and particles -- synergistic effects on guinea-pig lungs.
In: Walton, W. H., ed. Inhaled Particles III Working, Surrey,
Unwin Brothers Ltd., pp. 535-571.
SABADAS, E. (1969) [On the neurohumoral regulation of the daily cycle
of the manganese level of the blood.] In: II Vsesojuznyh
biohimiceskij S'ezd g. Taskent 1969. Tez. seke. soobc.
Tashkent, Izdatel'stvo FAN Uzbekskoj, SSR, Vol. 13, pp. 159-160
SABNIS, C. V., YEANNAWAR, P. K., PAMPATTIWAR, V. L., & DESHPANDE,
J. M. (1966) An environmental study of a ferro-manganese alloy
concern. Indian J. ind. Med., (11-12): 207-222.
SAMOHVALOV, S. G., CEBOTAREVA, N. A., & ZUKOVA, L. F. (1971)
[Determination of available manganese in soils using
formaldoxine.] Him. Sel. Hoz., 9 (4) 63-65 (in Russian).
SARIC, M. (1972) Manganese exposure and respiratory impairment In:
XVII International Congress on Occupational Health, Buenos
Aires, 17-23 September, 1972, pp. 101 (Abstract D2-16).
SARIC, M. (1978) Biological effects of manganese. Research Triangle
Pask, NC, USA, US Environmental Protection Agency 152 pp.
(Environmental Health Effects Research Series, EPA-600/1-78-001).
SARIC, M. & HRUSTIC, O. (1975) Exposure to air-borne manganese and
arterial blood pressure. Environ. Res., 10: 314-318.
SARIC, M. & LUCIC-PALAIC, S. (1977) Possible synergism of exposure to
airborne manganese and smoking habit in occurrence of respiratory
symptoms. In: Inhaled Particles IV, Oxford & New York, Pergamon
Press pp. 773-779.
SARIC, M., LUCIC-PALAIC, S., PAUKOVIC, R., & HOLETIC, A. (1974)
[Respiratory effects of manganese.] Arh. hig. Rada, 25: 15-26
SARIC, M., OFNER, E., & HOLETIC, A. (1975) Acute respiratory diseases
in a manganese contaminated area. In: International Conference
on Heavy Metals in the Environment Proceedings, Toronto,
Canada, Institute for Environmental Studies, University of
Toronto, pp. 389-398.
SARIC, M., MARKICEVIC, A., & HRUSTIC, O. (1977) Occupational exposure
to manganese. Br. J. ind. Med., 34: 114-118.
SCHAFER, D. F., STEPHENSON, D. V., BARAK, A. J., & SORRELL, M. F.
(1974) Effects of ethanol on the transport of manganese by small
intestine of the rat. J. Nutr, 104: 101-104.
SCHLAGE, C. & WORTBERG, B. (1972) Manganese in the diet of healthy
preschool and school children. Acta Paediatr. Scand.,
SCHROEDER, H. A. (1970) Manganese -- Air Quality Monograph,
Washington, DC, American Petroleum Institute, 34
pp. (No. 70-17).
SCHROEDER, H. A., PERRY, H. M., DENNIS, E.G., & MAHONEY, L. E. (1955)
Pressor substances in arterial hypertension. V. Chemical and
pharmacological characteristics of pherentasin. J. exp. Med.,
SCHROEDER, H. A., BALASSA, D. D., & TIPTON, I. H. (1966) Essential
trace elements in man; manganese, a study on homeostasis.
J. chron. Dis., 19: 545-571.
SCHULER, p., OYANGUREN, H., MATURANA, V., VALENZUELA, A., CRUZ, E.,
PLAZA, V., SCHMIDT, E., & HADDAD, R. (1957) Manganese poisoning.
Environmental and medical study at a Chilean mine. Ind. Med.
Surg., 26: 167-173.
SHARMAN, D. F., POIRIER, L. J., MURPHY, G. F., & SOURKES, T. L. (1967)
Homovanillic acid and dihydroxyphenylacetic acid in the striatum
of monkeys with brain lesions. Can. J. Physiol. Pharmacol.,
SHIMIZU, N. & MORIKAWA, N. (1957) Histochemical studies of succinic
dehydrogenase of brain of mice, rats, guinea pigs and rabbits.
J. Histochem. Cytochem., 5: 33-345.
SHRADER, R. E. & EVERSON, G. J. (1968) Pancreatic pathology in
manganese-deficient guinea pigs. J. Nutr., 94: 269-281.
SIGAN, S. A. & VITVICKAJA, B. R. (1971) [Experimental substantiation
of permissible residual concentrations of potassium permanganate
in drinking water.] Gig. i Sanit., 36 (9): 15-18 (in Russian).
SIMMON, V. F. & LIGON, S. (1977) In vitro microbiological
mutagenicity studies of ethyl corporation compounds.
Interim report, California, Stanford Research Institute,
SLAVIN, W. (1968) Atomic absorption spectroscopy, New York,
Inter-science. Publishers Inc., pp. 129-130.
SLAVNOV, B. I. & MANDADZIEV, I. H. (1968) [A research into the effect
of lead, manganese and zinc upon some indices of the reactivity
of the body and on non-specific morbidity.] Gig. Tr. prof.
Zabol., 12 (10): 22-26 (in Russian).
SMYTH, L. T., RUHF, R. C., WHITMAN, N. E., & DUGAN, T. (1973) Clinical
manganism and exposure to manganese in the production and
processing of ferromanganese alloy. J. occup. Med.,
SOMAN, S. D., PANDAY, V. K., JOSEPH, K. T., & RAUT, S. J. (1969) Daily
intake of some major and trace elements. Health Phys.,
SOURKES, T. L. & POIRIER, L. J. (1966) Neurochemical bases of tremor
and other disorders of movement. Can. Med. Assoc. J.,
SPENCER, D. W. & SACHS, P. L. (1970) Some aspects of the distribution,
chemistry and mineralogy of suspended matter in the Gulf of
Maine. Mar. Geol., 9: 117-136.
STADLER, H. (1936) [Histopathology of the brain resulting from
manganese poisoning.] Z. Ges. Neurol. Psychiatr., 154: 62-76
STOKINGER, H. E. (1962) The metals (excluding lead): Manganese, Mn.
In: Patty, F. A., Fassett, D. W., & Irish, D. D., ed. Industrial
Hygiene and Toxicology, 2nd revised edition, New York,
Interscience Publishers, Inc., Vol. 2, pp. 1079-1089.
STONER, G. D., SHIMKIN, M. B., TROXELL, M. C., THOMPSON, T. L. &
TERRY, L. S. (1976) Test for carcinogenicity of metallic
compounds by the pulmonary tumor response in strain A mice.
Cancer Res., 36: 1744-1747.
SULLIVAN, R. J. (1969) Preliminary air pollution survey of manganese
and its compounds. A literature review, Raleigh, NC, National
Air Pollution Control Administration, US Department of Health,
Education and Welfare, 54 pp. (Publ. No. APTD 69-39).
SUNDERMAN, F. W. Jr, LAU, T. J., & CRALLEY, L. J. (1974) Inhibitory
effect of manganese upon muscle tumorigenesis by nickel
subsulfide. Cancer Res., 34: 92-95.
SUTHERLAND, E. W., ROBISON, G. A., & BUTCHER, R. W. (1968) Some
aspects of the biological role of adenosine 3,5-monophosphate
(cyclic AMP). Circulation, 37: 279-306.
SUZUKI, Y. (1968) [Quantitative determination of manganese in plant
leaves by atomic absorption spectrophotometry.] Shikoku Acta
Med., 24 (4): 453-456 (in Japanese).
SUZUKI, Y. (1970) [Environmental contamination by manganese.]
Jpn. J.ind. Health, 12 (11): 529-533 (in Japanese).
SUZUKI, Y. (1974 [Studies on excessive oral intake of manganese.
Part 2. Minimum dose for manganese accumulation in mouse organs.]
Shikoku Acta Med., 30: 32-45 (in Japanese).
SUZUKI, Y., KAZIMOTO, M., KONDO, T., MATSUOKA, C., TANIOKA, Y.,
NISHIYAMA, S., HIROSE, A., KAWAKITA, H., & SHIMADA, K. (1968)
[Determination of manganese in biological materials by atomic
absorption spectrophotometry.] Shikoku Acta Med., 24: 449-456.
SUZUKI, Y., NISHIYAMA, K., SUZUKI, Y., & KURAMOTO, M. (1972) [Acute
toxicity of dust from a new dry process of SO2 removal in mice.]
Shikoku Acta Med., 28: 339-343 (in Japanese).
SUZUKI, Y., NISHIYAMA, K., SUZUKI Y., KAJIMOTO, M., FUJII, N.,
NISHIDONO, N., KONDO, T., SOKABE, E., MATSUHASHI, M., UENO, E., &
YAMADA, Y. (1973a) [The effects of chronic manganese exposure on
ferromanganese workers (Part I).] Shikoku Acta Med.,
29: 412-424 (in Japanese).
SUZUKI, Y., NISHIYAMA, K., SUZUKI, Y., KAJIMOTO, M., FUJII, N.,
NISHIDONO, N., KONDO, T., SOKABE, E., MATSUHASHI, M., UENO, E., &
YAMADA, Y (1973b) [The effects of chronic manganese exposure on
ferromanganese workers (Part 2).] Shikoku Acta Med.,
29: 433-438 In Japanese).
SUZUKI, Y., NISHIYAMA, K., SUZUKI, Y., KAJIMOTO, M., FUJII, N.,
NISHIDONO, N., KONDO, T., SOKABE, E., MATSUHASHI, M., UENO, E., &
YAMADA, Y. (1973c) [Blood and urinary manganese in ferromanganese
workers.] Shikoku Acta Med., 29: 425-432 (in Japanese).
SUZUKI, Y., MOURI, T., SUZUKI, Y., NISHIYAMA, K., FUJII, N., & YANO,
H. (1975) [Study of subacute toxicity of manganese dioxide in
monkeys.] Tokushima J. exp. Med., 22: 5-10 (in Japanese).
SWAINE, D. J. (1962) The trace-element content of fertilizers.
Commonwealth Bureau of Soil Science, pp. 150-177 (Technical
Communication No. 52).
TANAKA, S. & LIEBEN, J. (1969) Manganese poisoning and exposure in
Pennsylvania. Arch. environ. Health, 19: 674-684.
TASK GROUP ON METAL ACCUMULATION (1973) Accumulation of toxic metals
with special reference to their absorption, excretion and
biological half-lives. Environ. Physiol. Biochem., 3: 65-107.
TEPPER, L. B. (1961) Hazards to health: manganese. New Engl. J. Med.,
TER HAAR, G. L., GRIFFING, M. E., BRANDT, M., OBERDING, D. G., &
KAPRON, M. (1975) Methyleyclopentadienyl manganese tricarbonyl as
an antiknock: Composition and fate of manganese exhaust products.
J. Air Pollut. Control Assoc., 25 (8): 858-860.
THIERS, R. E. & VALLEE, B. L. (1957) Distribution of metals in
subcellular fractions of rat liver. J. biol. Chem.,
THOMPSON, R. J., MORGAN, G. B., & PURDUE, L. J. (1970) Analysis of
selected elements in atmospheric particulate matter by atomic
absorption. At. Absorpt. Newsl., 9: 53-57.
THOMSON, A. B. R., OLATUNBOSYN, D. & VALBERG, L. S. (1971)
Interrelation of intestinal transport system for manganese and
iron. J. lab. clin. Med., 78 (4): 642-655.
TICHY, M. & CIKRT, M. (1972) Manganese transfer into the bile in rats.
Arch. Toxicol., 29: 51-58.
TICHY, M., HAVRDOVA, J., & CIKRT, M. (1971) [Determination of
manganese in urine by atomic absorption spectrometry.] Pr. Lek.,
23: 336-341 (in Czech).
TICHY, M., CIKRT, M., & HAVRDOVA, J. (1973) Manganese binding in rat
bile. Arch. Toxicol., 30: 227-236.
TIPTON, I. H. & COOK, M. J. (1963) Trace elements in human tissue.
Part II. Adult subjects from the United States. Health Phys.,
TIPTON, I. H., COOK, M. J., STEINER, R. L., BOYE, C. A., PERRY, H. M.
Jr, & SCHROEDER, H. A. (1976) Trace elements in human tissue. I.
Methods. Health Phys., 9: 89-101.
TIPTON, I. H., STEWART, P. L., & DICKSON, J. (1969) Patterns of
elemental excretion in long term balance studies. Health Phys.,
TOPPING, G. (1969) Concentrations of Mn, Co, Cu, Fe, and Zn in the
Northern Indian Ocean and Arabian Sea. J. Mar. Res.,
TUREKIAN, N. K. (1969) The oceans, streams, and atmosphere. In:
Wedephol, K. H., ed. Handbook of geochemistry, Vol. 1, New
York, Springer-Verlag, pp. 297-323.
TUREKIAN, N. K. & WEDEPOHL, K. H. (1961) Distribution of the elements
in some major units of the earth's crust. Geol. Soc. Am. Bull.,
UENO, K. & OHARA, S. (1958) [On manganese poisoning in a steel
smelting factory and loadtest of manganese.] J. Labour Hyg.
Iron. Steel Ind., 7 (4): 3-19 (in Japanese).
UNDERWOOD, E. J. (1971) Manganese. In: Trace Elements in Human and
Animal Nutrition, 3rd ed., New York, Academic Press,
US ENVIRONMENTAL PROTECTION AGENCY (1971) Reference method for the
determination of suspended particulates in the atmosphere.
Fed. Reg., 36 (84): Part II, 8191-8194.
US ENVIRONMENTAL PROTECTION AGENCY (1972a) Atmosphere and in source
emissions, Washington, DC, Office of Research and Monitoring,
43 pp. (Report No. EPA-R-2-72-063).
US ENVIRONMENTAL PROTECTION AGENCY (1972b) Air quality data for 1968
from the National Air Surveillance networks and contributing
State and Local networks, Washington, US EPA, 231 pp.
(EPA Report No. APTD-0978).
US ENVIRONMENTAL PROTECTION AGENCY (1973) Air quality data for metals
1968 from the National Air Surveillance Networks, Washington,
US EPA, pp. 1-1-14-B (EPA Report No. APTD-1467).
US ENVIRONMENTAL PROTECTION AGENCY (1974) Methods for chemical
analyses of water and wastes, Washington, US EPA, 298 pp.
(EPA Report. No. EPA-600/6-72-002).
US ENVIRONMENTAL PROTECTION AGENCY (1975) Scientific and technical
assessment report on manganese, Washington, US EPA, Office of
Research and Development, 48 pp. (EPA Report
USOVIC, A. T. (1967) [The application of polarography to the
determination of trace elements in biological material.] In:
Mikroelementy v biosfere i ih primenenie v sel'skom hozjajstve i
medicine Sibiri i Dal'nego Vostoka, Ulan Ude, pp. 608-611
VAN KOETSVELD, E. E. (1958) The manganese and copper contents of hair
as an indication of the feeding condition of cattle regarding
manganese and copper. Tijdschr. Diergeneeskd., 83: 229-236.
VAN ORMER, D. G. & PURDY, W. C. (1973) The determination of manganese
in urine by atomic absorption spectrometry. Anal. Chim. Acta,
VASILEVSKAJA, V. D. & BOGATYREV, A. G. (1970) [Trace elements in the
soils of Western Tamir.] Vestn. Mosk. Univ., ser. 6, Biol.,
poovovedenie, 4: 53-59 (in Russian).
VERSIECK, J., BARBIER, F., & HOSTE, J. (1975) Influence of myocardial
infarction on serum manganese, copper, and zinc concentrations.
Clin. Chem., 21 (4): 578-581.
VERSIECK, J., SPEECKE, A., HOSTE, J., & BARBIER, F. (1973a) Trace
contamination in biopsies of the liver. Clin. Chem.,
VERSIECK, J., SPEECKE, A., HOSTE, H., & BARBIER, F. (1973b)
Determination of manganese, copper and zinc in serum and packed
blood sells by neutron activation analysis. Z. klin. Chem. klin.
Biochem., 11 (5): 193-196.
VERSIECK, J., BARBIER, F., SPEECKE, A., & HOSTE, J. (1974a) Normal
manganese concentrations in human serum. Acta Endocrinol.,
VERSIECK, J., BARBIER, F., SPEECKE, A., & HOSTE, J. (1974b) Manganese,
copper and zinc concentrations in serum and packed blood cells
during acute hepatitis, chronic hepatitis and posthepatic
cirrhosis. Clin. Chem., 20 (9): 1141-1145.
VOSS, H. (1939) [Progressive bulbar paralysis and amyotrophic lateral
sclerosis from chronic manganese poisoning.] Arch.
Gewerbepathol. Gewerbehyg., 9: 464-476 (in German).
VOSS, H. (1941) [Spinal cord and peripheral nervous system in chronic
manganese poisoning.] Arch. Gewerbepathol. Gewerbehyg.,
10: 550-568 (in German).
WALTERS, M. D., GARDNER, D. E., ARANYI, C., & COFFIN, D. L. (1975)
Metal toxicity for rabbit alveolar macrophages in vitro.
Environ. Res., 9: 32-47.
WASSERMANN, D. & WASSERMANN, M. (1977) The ultrastructure of the liver
cell in subacute manganese administration. Environ. Res.,
WATANABE, H., BERMAN, S., & RUSSEL, D. S. (1972) Determination of
trace metals in water using X-ray fluorescence spectrometry.
Talanta, 19: (12) 1363-1375.
WEAST, R. C., ed. (1974) Handbook of chemistry and physics, 55th
ed., Cleveland, CRC Press, pp. B107-B109.
WHITLOCK, C. M. Jr, AMUSO, S. J., & BITTENBENDER, J. B. (1966) Chronic
neurological disease in two manganese steel workers. Am. Ind.
Hyg. Assoc. J. 27: 454-459.
WORLD HEALTH ORGANIZATION (1969) WHO Technical Report Series No. 417
(Pesticide Residues in food. Report of the 1968 Joint FAO/WHO
Meeting), Geneva, WHO, 40 pp.
WORLD HEALTH ORGANIZATION (1973) WHO Technical Report Series, No. 532
(Trace elements in human nutrition - Report of a WHO Expert
Committee), pp. 34-36.
WORLD HEALTH ORGANIZATION WORKING GROUP (1973) Technical document on
manganese. In: The hazards to health of persistent substances in
water. Annexes to the Report of a WHO Working Group,
Coppenhaguen, WHO Regional Office for Europe, pp. 111-134.
WIDDOWSON, E. M. (1969) Trace elements in human development. In:
Barltrop & Burland, ed. Mineral metabolism in paediatrics,
Oxford, Blackwell, pp. 85-98.
WIDDOWSON, E. M., CHAN, H., HARRISON, G. E. & MILNER, R. G. D. (1972)
Accumulation of Cu, Zn, Mn, Cr, and Co in the human liver before
birth. Biol. Neonate, 20 (5-6): 360-367.
WILGUS, H. S. & PATTON, A. R. (1939) Factors affecting manganese
utilization in the chicken. J. Nutr., 18: 35-45.
WITZLEBEN, C. L. (1969) Manganese-induced cholestasis: concurrent
observations on bile flow rate and hepatic ultrastructure.
Am. J. Pathol., 57: 617-625.
WYNTER, J. E. (1962) The prevention of manganese poisoning. Ind. Med.
Surg., 31: 308-310.
YAMAMOTO, H. & SUZUKI, T. (1969) [Chemical structure of manganese
compounds and their biological effects.] In: [Proceedings of the
42nd Annual Meeting of the Japan Association of Industrial
Health, 28-31 March, 1959.] Fukuoka City, Japan, Japan
Association of Industrial Health (in Japanese).
ZAJIC, J. E. (1969) Microbial biochemistry, New York, Academic
Press, pp. 156-168.
ZAPADNJUK, V. I. & ZAIKA, M. U. (1970) [The effect of repeated courses
of administration of biotic doses of copper and manganese both
singly and together, on some biochemical indices in mice.]
Farmakol. Toksikol., 5: 606-607 (in Russian).
ZERNAKOVA, T. V. (1967) [Correlation between iron, manganese and
copper content in the blood serum of healthy individuals.]
Bjull. eksp. Biol. Med., 63: 47-48 (in Russian).
ZOOK, G. E., GREENE, F. E., & MORRIS, E. R. (1970) Nutrient
composition of selected wheats and wheat products. VI.
Distribution of manganese, copper nickel, zinc, magnesium, lead,
tin, cadmium, chromium and selenium as determined by atomic
absorption spectroscopy and colorimetry. Cereal Chem.,
ZUCKERMAN, J. J., ed. (1976) Organotin compounds: New chemistry and
applications, Washington, DC, American Chemical Society.
ZUI, L. B. (1970) [Effect of pear varieties on the corrosion of cans
made of electrolytically tin-plated sheet iron.] Nauch. Tr.
Vissh. Inst Khrant. Vkusova Prom. Plovdic., 17: 312-320