United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
EPA-600/8-83-013
June 1983
External Review Draft
Research and Development
?,EPA
Health Assessment
Document for
Manganese
Part 1 of 2
Review
Draft
(Do Not
Cite or Quote)
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its
technical accurecy and policy implicetions.
-------
EPA-600/8-83-013
External Review Draft
DRAFT
Do not cite or quote
HEALTH ASSESSMENT DOCUMENT
FOR
MANGANESE
Notice
This document 1s a preliminary draft. It has not been
formally released by EPA and should not at this stage be
construed to represent Agency policy. It 1s being circu-
lated for comment on Us technical accuracy and policy Im-
plications.
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
Project Managers: Dr. Linda S. Erdrelch
Dr. Jerry F. Stara
[1 C^ r-
-------
DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products does
not constitute endorsement or recommendation for use.
11
1794A 5/06/83
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PREFACE
The Office of Health and Environmental Assessment of the Office of
Research and Development has prepared this Health Assessment Document (HAD)
at the request of the Office of A1r Quality Planning and Standards (OAQPS).
Manganese 1s one of several metals and associated compounds emitted to the
ambient air which are currently being studied by the Environmental Protec-
tion Agency to determine whether they should be regulated as hazardous air
pollutants under the Clean A1r Act.
A Multimedia Health Assessment for Manganese had been drafted 1n 1979 to
evaluate the health effects of manganese. The original document has since
been modified 1n scope and emphasis and updated. This HAD 1s designed to be
used by OAQPS for decision making.
In the development of this assessment document, the scientific litera-
ture has been Inventoried, key studies have been evaluated and summaries and
conclusions have been directed at qualitatively Identifying the toxic
effects of manganese. Observed effect levels and dose-response relation-
ships are discussed where appropriate 1n order to Identify the critical
effect and to place adverse health reponses 1n perspective with observed
environmental levels.
111
1794A 5/09/83
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LIST OF AUTHORS, CONTRIBUTORS AND REVIEWERS
Dr. D1nko Kello (author)
Institute for Medical Research
Zagreb, Yugoslavia
Mr. Randall J.F. Bruins (author)
ECAO-C1n, U.S. Environmental Protection Agency
Dr. Linda S. Erdrelch (author, document manager)
ECAO-C1n, U.S. Environmental Protection Agency
Dr. Jerry F. Stara (document manager)
ECAO-C1n, U.S. Environmental Protection Agency
Dr. Steven J. Bosch
Syracuse Research Corporation
Syracuse, NY
Dr. Tom Clarkson
University of Rochester
Rochester, NY
Dr. Herb Cornish
School of Public Health
University of Michigan
Ann Arbor, MI
Dr. Michael Dourson, ECAO-C1n
U.S. Environmental Protection Agency
Dr. D. Anthony Gray
Syracuse Research Corporation
Syracuse, NY
Dr. Paul Hammond
University of Cincinnati
Cincinnati, OH
Dr. Rolf Hartung
School of Public Health
University of Michigan
Ann Arbor, MI
Dr. Bernard Haberman
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, DC
Dr. T.J. Knelp
NYU Medical Center
Tuxedo, NY
1v
1794A 5/11/83
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Dr. James Lai
Burke Rehabilitation Center
Dementia Research
White Plains, NY
Mr. C.A. Hall
Ethyl Corporation
Ferndale, MI
Dr. Fred Moore
Elklns Metal Company
Marietta, OH
Dr. Debdas Mukerjee, ECAO-CIn
U.S. Environmental Protection Agency
Dr. Nancy Pate
U.S. Environmental Protection Agency
Office of A1r Quality Planning and Standards
Research Triangle Park, NC
Dr. W. Bruce Pelrano, ECAO-C1n
U.S. Environmental Protection Agency
Dr. William Pepelko, ECAO-C1n
U.S. Environmental Protection Agency
Dr. Mangus Plscator
School of Public Health
University of Pittsburgh
Pittsburgh, PA
Dr. Ivan Rabar
Institute for Medical Research
Zagreb, Yugoslavia
Dr. Marco Sarlc
Institute for Medical Research
Zagreb, Yugoslavia
Dr. Samuel Shlbko
Contaminants and Nat. Toxic. Evaluation Branch
Division of Toxicology, Food and Drug Administration
Washington, DC
Dr. Ellen Sllbergeld
Environmental Defense Fund
Washington, DC
Dr. Melvyn Tochman
John Hopkins Hospital
Baltimore, MD
1794A 5/11/83
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Dr. Otto Weber
Institute for Medical Research
Zagreb, Yugoslavia
Dr. David Well
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, NC
Dr. James WUhey
Food Directorate, Bureau of Chemical Safety
Ottawa, Ontario
Special Acknowledgement: Technical Services and Support Staff, ECAO-C1n
U.S. Environmental Protection Agency
v1
1794A ? 5/11/83
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1-1
2. SUMMARY AND CONCLUSIONS 2-1
2.1. SUMMARY OF EXPOSURE 2-1
2.2. SUMMARY OF BIOLOGICAL ROLE AND HEALTH EFFECTS 2-6
2.2.1. Biological Role 2-6
2.2.2. Tox1c1ty 2-7
2.3. CONCLUSIONS 2-11
3. GENERAL PROPERTIES AND BACKGROUND INFORMATION 3-1
3.1. PHYSICAL AND CHEMICAL PROPERTIES 3-1
3.1.1. Manganese Compounds 3-4
3.2. SAMPLING AND ANALYTICAL METHODS 3-8
3.2.1. Sampling 3-9
3.2.2. Sample Preparation 3-14
3.2.3. Analysis 3-15
3.3. PRODUCTION AND USE 3-17
3.3.1. Production 3-17
3.3.2. Use 3-24
3.4. SOURCES OF MANGANESE IN THE ENVIRONMENT 3-27
3.4.1. Crustal Materials and Soils 3-27
3.4.2. Industrial and Combustion Processes 3-30
3.4.3. Relative Importance of Manganese Sources at
Several Locations as Determined by Mass Balance
and Enrichment Models 3-38
3.5. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES 3-48
3.5.1. Principal Cycling Pathways and Compartments . . . 3-48
3.5.2. Atmospheric Fate and Transport 3-50
3.5.3. Fate and Transport 1n Water and Soil 3-54
3.6. ENVIRONMENTAL LEVELS AND EXPOSURE 3-60
3.6.1. A1r 3-60
3.6.2. Water 3-75
3.6.3. Food 3-79
3.6.4. Human Exposure 3-81
1794A 5/09/83
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3.7. SUMMARY OF GENERAL PROPERTIES AND BACKGROUND INFORMATION.
Page
3-89
3.7.1. Chemical and Physical Properties 3-89
3.7.2. Sampling and Analysis 3-89
3.7.3. Production and Use 3-91
3.7.4. Sources of Manganese 1n the Environment 3-92
3.7.5. Environmental Fate and Transport Processes. . . . 3-94
3.7.6. Environmental Levels and Exposure 3-95
4. BIOLOGICAL ROLE AND PHARMACOKINETICS 4-1
4.1. BIOLOGICAL ROLE OF MANGANESE 4-1
4.1.1. Biochemical Role 4-1
4.1.2. Manganese Deficiency 4-1
4.1.3. Manganese Requirements 4-2
4.1.4. Summary 4-2
4.2. COMPOUND DISPOSITION AND RELEVANT PHARMACOKINETICS. ... 4-3
4.2.1. Absorption 4-3
4.2.2. Distribution and Normal Tissue Levels 4-6
4.2.3. Excretion 4-10
4.2.4. Biological Half-time 4-12
4.2.5. Homeostasls 4-13
4.2.6. Summary 4-20
4.3. SYNERGISTIC/ANTAGONISTIC FACTORS 4-21
4.3.1. Interaction with Metals 4-21
4.3.2. Effect of Age 4-23
4.3.3. Summary 4-26
5. TOXIC EFFECTS AFTER ACUTE EXPOSURE 5-1
5.1. ANIMAL STUDIES 5-1
5.2. HUMAN STUDIES 5-4
5.3. SUMMARY 5-5
6. TOXIC EFFECTS AFTER CHRONIC EXPOSURE 6-1
6.1. NEUROTOXIC EFFECTS — HUMAN STUDIES 6-1
6.1.1. Case Reports and Ep1dem1olog1c Studies 6-3
6.1.2. Pathology of Manganese Poisoning 6-14
6.1.3. Summary 6-14
1794A
5/09/83
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Page
6.2. NEUROTOXIC EFFECTS — ANIMAL STUDIES 6-15
6.2.1. Mechanism of Manganese NeurotoxIcUy 6-23
6.2.2. Altered Neurotransmltter Metabolism 6-25
6.2.3. Summary 6-35
6.3. LUNG EFFECTS 6-36
6.3.1. Human Studies 6-36
6.3.2. Animal Studies 6-46
6.4. REPRODUCTIVE EFFECTS 6-58
6.4.1. Human Studies 6-58
6.4.2. Animal Studies 6-58
6.4.3. Summary 6-61
6.5. HEMATOLOGIC EFFECTS 6-62
6.5.1. Human Studies 6-62
6.5.2. Animal Studies 6-63
6.5.3. Summary 6-64
6.6. CARDIOVASCULAR SYSTEM EFFECTS 6-65
6.6.1. Human Studies 6-65
6.6.2. Animal Studies 6-66
6.6.3. Summary 6-66
6.7. BIOCHEMICAL EFFECTS 6-66
6.7.1. Human Studies 6-66
6.7.2. Animal Studies 6-67
6.7.3. Summary 6-68
6.8. DIGESTIVE SYSTEM EFFECTS 6-68
6.8.1. Gastrointestinal Tract Effects 6-68
6.8.2. Liver Effects 6-69
6.8.3. Summary 6-71
CARCINOGENICITY 7-1
7.1. ANIMAL STUDIES 7-1
7.2. HUMAN STUDIES 7-7
7.3. SUMMARY 7-10
1x
1794A 5/09/83
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Page
8. MUTAGENICITY AND TERATOGENICITY 8-1
8.1. MUTAGENICITY 8-1
8.1.1. Tests for Gene Mutations 8-1
8.1.2. Tests for Chromosomal Damage 8-1
8.1.3. Tests for Other Genetic Damage 8-1
8.2. TERATOGENICITY 8-3
8.3. SUMMARY 8-4
9. EFFECTS OF CONCERN AND HEALTH HAZARD EVALUATION 9-1
9.1. EXISTING GUIDELINES, RECOMMENDATIONS AND STANDARDS. ... 9-1
9.1.1. A1r 9-1
9.1.2. Water 9-1
9.2. SUMMARY OF TOXICITY 9-2
9.3. SPECIAL GROUPS AT RISK 9-5
9.4. EFFECTS OF MAJOR CONCERN AND EXPOSURE/RESPONSE INFORMATION 9-7
9.4.1. Effects of Major Concern 9-7
9.4.2. Exposure/Response Information 9-7
9.5. HEALTH HAZARD EVALUATION 9-11
9.5.1. Critical Effect and Effect Levels 9-11
10. REFERENCES 10-1
APPENDIX: ESTIMATING HUMAN EQUIVALENT INTAKE LEVELS FROM ANIMAL
STUDIES A-l
1794A 5/09/83
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LIST OF TABLES
No. TUIe Page
3-1 Physical Properties of Manganese 3-2
3-2 Normal Oxidation Potentials of Manganese Couples 3-3
3-3 Physical Properties of Some Manganese Compounds 3-5
3-4 Relative Sensitivity of Some Important Analytical Techniques
for Manganese 3-18
3-5 Estimated United States Production, Capacity and Use of
Selected Manganese Compounds 3-21
3-6 Manganese Supply-Demand Relationships, 1969-1979 3-22
3-7 Net United States Production of Ferromanganse and
SHIcomanganese 3-23
3-8 Commercial Forms of Manganese 3-25
3-9 Manganese Content of Selected Minerals 3-29
3-10 Sources and Estimated Atmospheric Emissions of Manganese
1n 1968 3-31
3-11 Estimated Manganese Emissions from Controlled Submerged-Arc
Furnaces Producing Manganese Alloys 3-34
3-12 Manganese Concentrations of Coal, Fuel 011, Crude 011,
Gasoline, Fuel Additives and Motor 011 3-35
3-13 Manganese Content 1n Coal Ash 3-36
3-14 Manganese Concentration 1n Fine (<2.0 urn) and Coarse
(2.0-20 v.m) Particle Fractions of Aerosols from Several
Sources 1n the Portland Aerosol Characterization Study. . . 3-40
3-15 Manganese Concentrations 1n Aerosols from Various Sources,
and Estimated Percent Contribution of Each Source to Observed
Ambient Manganese and Total Aerosol Mass at Two Sites . . . 3-42
3-16 Manganese Concentrations 1n Aerosols from Various Sources,
and Estimated Percent Contribution of Each Source to
Observed Ambient Mn and Total Aerosol Mass, Based on Target
Transformation Factor Analysis 3-43
3-17 Number of National A1r Surveillance Network Stations within
Selected Annual Average Manganese A1r Concentration
Intervals, 1957-1969 3-61
x1
1794A 5/09/83
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LIST OF TABLES (cont.)
No. Title Page
3-18 National A1r Surveillance Network Stations with Annual
Average Manganese A1r Concentrations Greater Than
0.5 ug/m3 3-62
3-19 Average Manganese Concentration 1n Ambient A1r and Total
Suspended Partlculates (TSP) 1n Urban and Nonurban NASN
Sites, 1966-1967 3-64
3-20 Urban NASN Sites, 1970-1982: National Cumulative Frequency
Distributions of Quarterly Values for Manganese Concentration 3-66
3-21 Nonurban NASN Sites, 1970-1982: National Cumulative Frequency
Distributions of Quarterly Values for Manganese Concentration 3-67
3-22 Manganese Concentrations 1n A1r, Kanawha Valley Area,
West Virginia 3-68
3-23 Ambient A1r Sampling Data for Total Suspended Partlculates
and Manganese (1n ug/m3) 1n the Marietta, OH-Parkersburg, WV
Vicinity, 1965-1966 and 1982-1983 3-70
3-24 Concentrations of Trace Metals 1n A1r Measured at Three
Locations 1n New York City 3-71
3-25 Selected Dlchotomous Sampler Data on Manganese and Particle
Mass from 22 U.S. CH1es 1n 1980 3-74
3-26 Concentration of Manganese 1n Various Lake and River Waters 3-76
3-27 Mean Concentrations of Dissolved Manganese by Drainage Basin 3-77
3-28 Dissolved and Suspended Manganese 1n Five U.S. Rivers . . . 3-78
3-29 Cumulative Frequency Distribution of Manganese Concentration
1n Tap Waters Sampled 1n the HANES I Augmentation Survey of
Adults 3-80
3-30 Estimates of Human Inhalation Exp]osure to Manganese 1n
Ambient A1r 3-85
3-31 Dietary Intake of Manganese 1n the U.S 3-86
3-32 Intake of Manganese from Food by Children 3-88
4-1 Manganese 1n Human Tissues 4-7
4-2 Concentrations of Manganese 1n Liver, Kidney and Brain. . . 4-16
1794A 5/09/83
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LIST OF TABLES (cont.)
No.
5-1
5-2
6-1
6-2
6-3
6-4
6-5
6-6
6-7
6-8
6-9
6-10
6-11
7-1
7-2
7-3
9-1
A-l
TUle
Acute LDcQ Values for Manganese Compounds
Influence of Age on Manganese ToxIcUy 1n Rats: 10$$ Values
8 Days after a Single Oral Administration of MnCl2
Studies of Manganlsm 1n Humans and Exposure-Response
Relationship
Frequency of Abnormal Neurological Findings
Ferroalloy Workers with Neurological Signs by Level of
Exposure to Manganese
Neurotoxlc Effects of Manganese 1n Experimental Animals . .
Neurological Signs Induced by Manganese 1n Monkeys
Prevalence of Chronic Bronchitis 1n Groups of Workers
According to Smoking Status
Cumulative Incidence of Acute Respiratory Diseases During
the 3-Year Period
Summary of Human Studies of Respiratory Effects at Various
Levels of Exposure to Manganese
Respiratory Effects with Manganese Exposure: Intratracheal,
Intraperltoneal and High Dose Inhalation Exposures
Respiratory Effects with Manganese Exposure: Inhalation
Exposures at Low Doses
Pulmonary Physiology Data for Male and Female Monkeys After
Nine Months of Exposure
Pulmonary Tumors 1n Strain A Mice Treated with Manganese
Sulfate
Carc1nogen1dty of Manganese Powder, Manganese Dioxide and
Manganese Acetylacetonate 1n F344 Rats and Swiss Albino
Mice
Induction of Sarcomas 1n Rats by the Intramuscular
Injection of Manganese Dust
Studies of Manganese Inhalation 1n Animals -- Summary of
Effect Levels
Exposure Effect Information for Health Hazard Evaluation:
Human Equivalent Exposure Levels Estimated from Animal Data
Paqe
5-2
5-3
6-5
6-8
6-12
6-17
6-21
6-41
6-45
6-47
6-48
6-54
6-56
7-2
7-4
7-8
9-9
A-3
X111
1794A 5/09/83
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LIST OF FIGURES
No.
3-1
3-2
6-1
THle
The Global Cycles of Manganese
Concentration Factors for Manganese 1n Hudson River ....
Schematic Representation of the Mechanisms of Actions of
Manganese on the Central Dooam1nera1c Svstem
Page
3-49
3-59
6-27
x1v
1794A 5/12/83
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1. INTRODUCTION
The purpose of this document 1s to summarize the current knowledge of
the effects of exposure to environmental manganese upon human health.
Manganese 1s an essential trace element for all living organisms, and
chronic manganese toxldty from occupational exposure 1s well documented.
For this reason, the potential human health hazard from environmental
exposure must be evaluated. In order to assess the effects on human health,
the general properties, ambient levels and biological availability of
manganese from environmental media must be considered.
The rationale for structuring the document 1s based primarily on two
major Issues, exposure and response. The first portion of the document 1s
devoted to manganese 1n the environment: physical and chemical properties,
the monitoring of manganese 1n various media, natural and human-made
sources, the transport and distribution of manganese within environmental
media, and the levels of exposure. The second part 1s devoted to biological
responses 1n laboratory animals and humans Including metabolism, pharmaco-
klnetlcs, mechanisms of toxldty, as well as toxlcologlcal effects of
manganese.
This assessment document 1s based on original publications, although the
overall knowledge covered by a number of reviews and reports was also
considered. The references cited were selected to reflect the current state
of knowledge on those Issues which are most relevant for a health assessment
of manganese 1n the environment.
0202P 1-1 5/09/83
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2. SUMMARY AND CONCLUSIONS
2.1. SUMMARY OF EXPOSURE
Manganese 1s a ubiquitous element 1n the earth's crust, 1n water and 1n
partlculate matter 1n the atmosphere. In the ground state, manganese 1s a
gray-white metal resembling Iron, but harder and more brittle. Manganese
metal forms numerous alloys with Iron, aluminum and other metals.
There are numerous valence states for manganese, with the divalent form
giving the most stable salts and the tetravalent form giving the most stable
oxide. The chlorides, nitrates and sulfates of manganese (II) are highly
soluble 1n water, but the oxides, carbonates and hydroxides are only spar-
ingly soluble. The divalent compounds are stable 1n add solution, but are
readily oxidized 1n alkaline conditions. The heptavalent form 1s found only
1n oxy-compounds.
Sampling of manganese In ambient air may be carried out by any of the
methods used for collecting atmospheric partlculate matter. High-volume
samplers with glass fiber filters are widely used to measure total ambient
aerosol. If Information on particle size 1s desired the dlchotomous sampler
1s often used, which separately collects fine (<2.5 urn) and coarse
(>2.5 um) particles.
Water, soil and food are collected for manganese analysis by the usual
techniques Insuring representative sampling without contamination. Biologi-
cal materials such as urine, blood, tissues, hair, etc., are collected and
stored so as to prevent contamination by dust; no other special procedures
are required when sampling for manganese analysis.
Sample preparation and analysis 1s the same for manganese as for other
nonvolatile metals. Atomic absorption spectrophotometry, optical emission
spectrometry and X-ray fluorescence are commonly used. Detection limits for
3
manganese 1n air usually are as low as 0.002
0201P 2-1 5/06/83
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Very little manganese 1s mined 1n this country; some 1s mined domestic-
ally as low-grade ores, but most 1s Imported. Ferromanganese and sH1co-
manganese are ferroalloys produced by the smelting of manganese ore 1n an
electric furnace. Manganese metal 1s produced by add leaching of the ore,
precipitation of other metals, and electrolysis of the solution. Manganese
alloys and metal are then used to Introduce manganese Into steel or non-
ferrous alloys.
Metallurgy, especially steel making, accounts for -95% of United
States demand for manganese. Production of manganese alloys 1s declining,
since demand has diminished recently and Imports are Increasing. The
remaining 5-6% of manganese demand 1s for a number of compounds which are
Important 1n the chemical Industry and 1n battery manufacture.
Methylcyclopentadlenyl manganese trlcarbonyl (MMT) has been produced and
used 1n small quantities as a fuel additive since 1958. Major use as an
octane Improver 1n unleaded gasoline (at 0.125 g Mn/gal) began 1n 1974, but
was discontinued 1n 1978 due to adverse effects on catalytic converter
performance and hydrocarbon emissions. MMT continues to be used at ~0.05
g/gal In -20% of leaded gasoline.
Manganese 1s the 12th most abundant element and fifth most abundant
metal 1n the earth's crust. While manganese does not exist free 1n nature,
1t 1s a major constituent 1n at least 100 minerals and an accessory element
1n more than 200 others. Its concentration 1n various crustal components
and soils ranges from near zero to 7000 ug/g; a mean soil content of 560
y.g/g has been given. Crustal materials are an Important source of atmo-
spheric manganese due to natural and anthropogenic activities (e.g., agri-
culture, transportation, earth-moving) which suspend dusts and soils. The
resulting aerosols consist primarily of coarse particles (>2.5 vim)-
0201P 2-2 5/06/83
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Manganese 1s also released to the atmosphere by manufacturing processes.
Furnace emissions from manufacture of ferroalloys, Iron, and steel are a
major source of fine partlculate emissions with a high manganese content.
Fossil fuel combustion also results In manganese release. Coal fly ash 1s
about equal to soil 1n manganese content, but contains particles finer 1n
size. This 1s an Important manganese source because of the volume of coal
burned each year. Combustion of residual oil 1s less Important because of
Us lower mangnese content. About 15-30% of manganese combusted 1n MMT-
contalnlng gasoline Is emitted from the tailpipe.
The relative Importance of emission sources Influencing manganese
concentration at a given monitoring location can be estimated by chemical
mass balance studies. Studies 1n St. Louis and Denver suggest that crustal
sources are more Important 1n the coarse than 1n the fine aerosol fraction.
Conversely, combustion sources such as refuse Incineration and vehicle emis-
sions predominantly affect the fine fraction. In an area of steel manufac-
turing, the Influence of this process was seen 1n both the fine and coarse
fractions.
Atmospheric manganese 1s present 1n several forms. Coarse dusts contain
manganese as oxides, hydroxides or carbonates at low concentrations (<1 mg
Mn/g). Manganese from smelting or combustion processes 1s often present 1n
fine particles with high concentrations of manganese as oxides (up to 250
mg/g). Organic manganese usually 1s not present 1n detectable concentra-
tions.
Oxides of manganese are thought to undergo atmospheric reactions with
sulfur dioxide or nitrogen dioxide to give the divalent sulfate or nitrate
salts. Manganous sulfate has been shown to catalyze SO transformation to
sulfurlc add, but the manganese concentration necessary for a significant
catalytic effect has been disputed.
0201P 2-3 5/06/83
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Atmospheric manganese 1s transported by air currents until dry or wet
deposition occurs. In New York City, dry deposition occurred more quickly
for manganese than most other metals, because 1t tended to be present 1n
2
larger particles. Dry deposition of manganese averaged 300-670 ng/cm /
2
month, whereas wet deposition was -120 ng/cm /month. Over much of the
United States 1n 1966-1967, wet deposition of manganese ranged from <10-540
2
ng/cm /month. Near a ferromanganese plant 1n 1964-1965, dry deposition
2
was as high as 19,300 ng/cm /month.
In water or soil, manganese Is usually present as the divalent or tetra-
valent form. Divalent manganese 1s soluble and relatively stable 1n neutral
or acidic conditions. Manganese tends to be mobile 1n oxygen-poor soils and
1n the groundwater environment. Upon entering surface water, manganese 1s
oxidized and precipitated, primarily by bacterial action. If the sediments
are transported to a reducing environment such as lake bottom, however,
mlcroblal reduction can occur, causing re-release of divalent manganese to
3 4
the water column. Manganese 1s bloconcentrated (by a factor of 10 -10 )
2
1n lower organisms; however, the concentration factor decreases (10-10 )
as trophic level Increases. Thus blomagnlf 1cat1on of manganese does not
occur.
A rough assessment of trends 1n nationwide air sampling data Indicates
that manganese concentrations have declined during the period of record.
The arithmetic mean manganese concentration of urban air samples decreased
from 0.11 ug/m3 In 1953-1957 to 0.073 ug/m3 1n 1966-1967, and to
3
0.033 vig/m 1n 1982. In 1953-1957, the percentage of urban stations
T
with an annual average of >0.3 ug/m was ~10X. By 1969 these had
dropped to <4%, and since 1972 the number has been <1X.
0201P 2-4 5/06/83
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The highest manganese concentrations, with some observations exceeding
3
10 ug/m , were seen 1n the 1960s 1n areas of ferromanganese manufacture.
More recent measurements 1n these areas Indicated decreases of at least an
order of magnitude had occurred, although definitive studies were not
available.
Manganese 1s associated with both fine (<2.5 vim) and coarse
(>2.5 vim) particles, but the manganese concentration 1n each fraction 1s
highly variable. On the average, <16% of manganese 1n aerosol mass 1s found
1n fine particles; however, 1t 1s estimated that 1n some situations the fine
fraction could contain as much as 50%.
Manganese concentrations 1n nonpolluted freshwaters are usually <20
vig/i, but may exceed 1000 vig/8. where polluted. Concentrations 1n
groundwater typically are higher than 1n surface water. Concentrations
>1000 ug/i are found 1n some drinking waters, but ~95X of water
supplies contain manganese at <100 vg/fc- A median concentration of 4
y.g/9. for public supplies has been reported.
Total human exposure to manganese may be estimated from Information on
levels 1n air, water and diet. Inhaled particles can be deposited either
extrathoradcally, 1n the tracheobronchlal region, or 1n the alveoli. Time
required for particle clearance and probability of absorption Increases with
Increasing depth of deposition 1n the respiratory tract. Deposition of
manganese 1n the alveoli can be calculated from the ambient concentration
and the fraction present 1n fine particles. Thoracic (tracheobronchlal plus
alveolar) deposition 1s calculated from estimates of the manganese found 1n
particles <15 vun 1n size. Alveolar deposition of manganese at current
ambient levels 1s estimated as 0.072 vuj/day as an average and 6.6 vig/day
under high exposure conditions. Estimates of total thoracic deposition are
0201 P 2-5 5/06/83
-------
slightly higher; 0.26 jig/day (average) and 10.0 v.g/day (high). Alveolar
and total thoracic deposition under the high exposure conditions (10
3
vig/m ) of the 1960s were estimated to be 100 and 152 v-9/day, respec-
tively.
Diet 1s the main source of Ingested manganese. Average adult Intake has
been variously estimated at 2.3-5.5 mg/day. On a body-weight basis, expo-
sure Increases from 0.002-0.004 mg/kg/day 1n Infants to 0.06-0.08 mg/kg/day
1n adults. Drinking water usually comprises only a very small proportion of
total 1ngest1on exposure. The median Intake level via drinking water 1s
-0.008 mg/day, but can be as high as -2.0 mg/day for some water
supplies. The 1ngest1on of particles cleared from the respiratory tract 1s
an even smaller source, probably constituting no more than 0.01 mg/day under
the highest ambient exposure conditions currently observed.
2.2. SUMMARY OF BIOLOGICAL ROLE AND HEALTH EFFECTS
2.2.1. Biological Role. Manganese 1s widely distributed within the human
and animal body 1n constant concentrations which are characteristic for
Individual tissues and almost Independent of the species. The highest
values of manganese 1n humans are found 1n liver, kidney and endocrine
glands. Manganese has been shown to penetrate the blood-brain and placental
barriers. Animal data Indicate a higher manganese accumulation 1n suckling
animals, especially 1n the brain.
Manganese elimination from the body 1s accomplished mainly via feces.
Biliary excretion 1s predominant under normal conditions although excretion
via the pancreas and Intestinal wall are considered to be Important 1n
conditions of biliary obstruction or manganese overload. In humans and 1n
animals urinary excretion 1s low. The total body clearance of manganese 1n
humans can be described by a curve which 1s the sum of at least two exponen-
0201P 2-6 5/06/83
-------
tlal functions with half-times of 4 and 40 days, respectively. However, the
physical significance of the estimated half-times cannot be obtained from
this data.
Manganese metabolism 1s rigorously controlled by homeostatlc mechanisms.
The homeostatlc control 1s primarily exerted at the level of excretion; how-
ever, the site of gastrointestinal (GI) absorption may also be an Important
control point. The absorption, retention and excretion of manganese are
Interrelated and respond very efficiently to an Increase 1n manganese
concentration. The GI absorption depends not only on the amount Ingested
and tissue levels of manganese, but also on manganese b1oava1labH1ty and
Interaction with other metals. The Influence of tissue concentrations on
the excretory mechanism 1s still unknown.
It 1s generally accepted that under normal conditions 3-4% of orally
Ingested manganese 1s absorbed 1n man and other mammalian species. Gastro-
intestinal absorption of manganese and Iron may be competitive. This Inter-
action has a limited relevance to human risk assessment under normal condi-
tions. However, 1t does lead to the hypothesis that Iron-deficient Individ-
uals may be more sensitive to manganese than the normal Individual.
2.2.2. Toxldty. The acute toxldty of manganese 1s greater for soluble
compounds and via the parenteral route. Acute poisoning by manganese 1n
humans 1s very rare. Along with a number of other metals, freshly formed
manganese oxide fumes have been reported to cause metal fume fever.
The major systems affected by chronic exposure to manganese 1n humans
are the CNS and pulmonary systems. The neurological disorder known as
chronic manganese poisoning, or manganlsm, resulting from occupational
exposures to manganese dusts and fumes 1s well documented. Earlier studies
report advanced cases of manganlsm 1n various miners, but more recent
0201P 2-7 5/06/83
-------
studies report cases showing neurological symptoms and signs at much lower
exposure concentrations.
These reports Include no longitudinal studies and are therefore not
adequate to Identify a dose-response relationship, but do permit the Iden-
tification of the LOEL. The full clinical picture of chronic manganese
3
poisoning 1s reported less frequently at exposure levels below 5 mg/m .
The reports of a few early signs of manganlsm 1n workers exposed to 0.3-5
3 33
mg/m suggest 0.3 mg/m (300 i^g/m ) as a LOEL. The data available
3
for Identifying effect levels below 0.3 mg/m Is equivocal or Inadequate.
This 1s further complicated by the fact that good biological Indicators of
manganese exposure are not presently available. Also, there are neither
human nor animal data suggesting the rate of absorption of manganese through
the lung; therefore, extrapolating from other routes of exposure would be
difficult.
Only one animal study utilized Inhalation exposure to study neurotoxic-
1ty, resulting In no behavioral effects 1n monkeys or rats after 9 months
3
exposure to 11.6 ug/m Mn3°4- Unfortunately, this study did not
Include biochemical data nor levels of manganese 1n brain tissues relating
the neurotoxlc effects to the tissue levels of manganese 1n the body.
Chronic treatment of rats with MnCl 1n the drinking water throughout
development 1s associated with selective regional alteration of synaptosomal
dopamlne uptake but not of serotonin or noradrenaline uptake. The brain
regional manganese concentrations show dose-dependent Increases and in
treated animals, the changes In synaptosomal dopamlne uptake 1s associated
with decreased behavioral responses to amphetamine challenge. These
observations are consistent with the hypothesis that 1n chronic manganese
toxicity the central dopamlnerglc system 1s disturbed, providing a mechanis-
tic explanation for the extrapyramldal disturbances seen 1n human manganlsm.
0201 P 2-8 5/06/83
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The toxic effects of manganese on the pulmonary system vary 1n type and
severity. There are several reports of humans developing pneumonia after
occupational exposures to manganese at levels higher than the present TLV of
3
5 mg Mn/m . Chronic bronchitis has been reported to be more prevalent 1n
3 33
workers exposed to 0.4-16 mg/m , but below 0.04 mg/m (40 ug/ro )
respiratory symptoms were not Increased over controls. However, conclusions
about these exposure/response relationships are limited by the broad range
of exposure values. Also, the health effects of simultaneous exposures to
other toxic substances, such as silica, have also not been thoroughly
examined.
One study 1n schoolchildren supported an association between Increased
respiratory symptoms and exposure to the manganese dusts emitted from a
3
ferromanganese plant at 3-11 v-g/m . The study Involved several hundred
children, had a participation rate of over 97% and clearly documented
exposure patterns. It 1s plausible that exposure to manganese may Increase
susceptibility to pulmonary disease by disturbing the normal mechanism of
lung clearance.
Inhalation studies of pulmonary effects 1n animals show the occurrence
3
of acute respiratory effects when the level of exposure exceeds 20 mg/m
of MnO . Mice and monkeys exposed to Mn02 via Inhalation showed patho-
3
logical effects at 0.7 mg/m after 14 days of exposure. This represents
the lowest level at which adverse effects were observed after Inhalation
exposure to MnO . There 1s little data on toxldty after chronic exposure
3
to MnOp levels between 0.1 and 0.7 mg/m . Several studies do exist
3
where animals were exposed to ~0.1 mg/m MnO as Mn30, particle or
aerosols of resplrable particle size, an appropriate form for health risk
evaluation for airborne manganese. These studies have a variety of defi-
ciencies such as lack of description of pathological examination, small
0201P 2-9 5/06/83
-------
study size and short exposure period. The clustering of negative results
around this level suggests that major adverse effects such as gross patho-
logical changes are absent.
Reports of Impotence 1n a majority of patients with chronic manganese
poisoning are common, however, no other supporting human data are available.
Existing animal data addressing reproductive failure 1n males describe
long-term dietary exposure to manganese. Results show that dietary levels
up to 1004 ppm as MnS04»7H20 and up to 3550 ppm as Mn 0 were
almost without effect on reproductive performance. However, these and other
observations need to be verified using well-defined reproductive testing
protocols.
Although other effects of exposure to manganese have been reported 1n
animals, none have been observed consistently. In some cases the Implica-
tions for human health are uncertain.
Prior to the adoption of the International Agency for Research on Cancer
(IARC) criteria, the U.S. EPA Carcinogen Assessment Group judged manganese
to be a possible human carcinogen based on the mutagenlc properties and the
positive responses 1n mice and rats 1n two studies. However, the pathology
was Incomplete 1n these studies and no animal studies exist using long-term
exposure by feeding or by Inhalation. Therefore, using IARC criteria, the
available evidence for manganese carclnogenlclty would be rated as Inade-
quate 1n animals and no data are available for humans, placing manganese 1n
IARC Group 3.
Divalent manganese 1on has elicited mutagenlc effects 1n a wide variety
of mlcroblal systems, probably by substitution for magnesium 1on and Inter-
ference with DNA transcription. Attempts to demonstrate mutagenlc effects
of manganese 1n mammalian systems have failed to show significant activity.
0201P 2-10 5/06/83
-------
Two recent studies suggest that excess manganese during pregnancy affects
behavioral parameters, but there 1s Insufficient evidence to define manga-
nese as teratogenlc.
2.3. CONCLUSIONS
The effects of major concern to humans exposed to manganese are chronic
manganese poisoning and a range of pulmonary effects. The effects on the
CNS are Incapacitating and generally Irreversible 1n Its fully developed
3
form, and have been reported at manganese exposure levels above 5 mg/m .
3
There have been no reports of CNS effects below 0.3 mg/m exposure. Data
3
1s equivocal between 1 and 5 mg/m but suggest decreased prevalence.
3
Studies below 1 mg/m report some signs of the disease. There 1s little
supportive animal data.
The pulmonary effects Include pneumonia and chronic bronchitis at levels
which are also associated with neurological effects. An Increased preva-
lence of temporary respiratory symptoms and lower mean values on objective
3
tests of lung function were reported In children exposed to 3-11 v-g/m .
In comparison, studies of a smaller number of workers exposed to <40
3
ug/m resulted 1n the conclusion that symptoms were generally unrelated
to exposure to manganese. There are no data describing the effects of
manganese exposure 1n asthmatics or other sensitive Individuals.
Animal studies report Increased susceptlblHy to Infection and radio-
logical changes 1n the lungs associated with manganese exposure, thus quali-
tatively supporting the respiratory effect as the endpolnt of concern.
Respiratory symptoms occurred at lower levels than neurological symptoms and
are therefore considered to be the critical effect.
0201P 2-11 5/06/83
-------
3. GENERAL PROPERTIES AND BACKGROUND INFORMATION
3.1. PHYSICAL AND CHEMICAL PROPERTIES
Manganese 1s a ubiquitous element 1n the earth's crust, 1n water, and 1n
partlculate matter 1n the atmosphere. Manganese was recognized as a new
element by C.W. Scheele, Bergman and others, but 1t was first Isolated by
J.G. Gahn 1n 1774 on reducing the dioxide with carbon. Some ores have been
known and used since antiquity, e.g., pyroluslte (MnO ) 1n glass bleach-
Ing (Weast, 1980; Re1d1es, 1981).
Manganese (Mn) 1s a steel gray, lustrous, hard brittle metal, too
brittle to be used unalloyed. It exists 1n four allotroplc forms of which
the a-form Is stable below 710°C. Manganese has only one stable
natural Isotope, Mn. The manganese atom 1n the ground state has the
electronic configuration (Is2) (2s2) (2p6) (3s2) (3p6) (3d5)
p
(4s ) and six possible orientations of the 5/2 nuclear spin (Matr1card1
and Downing, 1981). Some physical properties of manganese are listed 1n
Table 3-1.
Manganese exists In 11 oxidation states from -3 to +7, Including 0,
5 2
since the outer electron levels, 3d 4s , can donate up to seven elec-
trons. The compounds most environmentally and economically Important are
those containing Mn2*, Mn4"1" and Mn7+. The Mn4* 1s significant
because of the Important oxide, MnO . The +2 compounds are stable 1n add
solution but are readily oxidized 1n alkaline medium. The +7 valence 1s
found only 1n oxy-compounds (Re1d1es, 1981). Normal oxidation potentials of
manganese couples are given 1n Table 3-2.
1797A 3-1 4/27/83
-------
TABLE 3-1
Physical Properties of Manganese*
Property Value
Atomic number 25
Atomic weight 54.9380
Density 7.43 at 20°C
Melting point 1244°C
Boiling point 1962°C
Specific heat 0.115 cal/g at 25.2°C
Moh's hardness 5.0
Solubility Soluble 1n dilute adds; reacts
slowly 1n hot or cold water.
*Source: Weast, 1980; Matr1card1 and Downing, 1981; Re1d1es, 1981
1797A 3-2 4/27/83
-------
TABLE 3-2
Normal Oxidation Potentials of Manganese Couples3
Oxidation
State
0,
+2,
+2,
+2,
+4,
+4,
+6,
o,
+2,
+2,
+4,
+4,
+6,
+2
+ 3
+4
+7
+6
+7
*7
+2
+3
+4
+6
+ 7
+7
Reaction
Add Solution
0.
Mn^ Mn + 2e
Mn2*^ Mn3+ + e
2+ b +
Mn + 2H~0 ^Mn02(py) + 4H + 2e
2+ +
Mn + 4H?0 ^ (Mn04) + 8H + 5e
2- +
Mn00 + 2H00^(MnO.) + 4H + 2e
c c. 1
Mn00(py)b + 2H00 ^ (MnO.)" + 4H+ + 3e
-------
3.1.1. Manganese Compounds. Manganese forms numerous alloys with Iron
(ferromanganese, slUcomanganese, Hadfleld manganese steel) and with other
metals like aluminum alloys, aluminum-bronzes, constantan, manganese-bronze,
Monel, nickel-silver, and nickel-chromium resistance alloys. Several
Important compounds of manganese are described below and 1n Table 3-3.
3.1.1.1. MANGANESE (I) COMPOUNDS —
3.1.1.1.1. Methylcyclopentadlenyl Manganese TMcarbonyl (MMT)
CH3C5H4Mn(CO)3 or MMT 1s a light amber liquid added to fuels as an
antiknock agent or smoke suppressant. It 1s formed by reaction of methyl-
cyclopentadlene with manganese carbonyl [Mn (CO) _].
3.1.1.2. MANGANESE (II) COMPOUNDS —
3.1.1.2.1. Manganous Carbonate — MnCO occurs naturally, but the
O
commercial product 1s made by precipitation from manganese sulfate solu-
tions. It 1s used 1n ferrHe production, animal feeds, ceramics, and as a
source of add soluble manganese.
3.1.1.2.2. Manganous Chloride — MnCl exists 1n anhydrous form and
as hydrate with 6, 4, or 2 water molecules. It 1s used as a starting mater-
ial for other manganese compounds and 1n anhydrous form as a flux 1n magnes-
ium metallurgy.
3.1.1.2.3. Manganese Ethyleneb1sd1th1ocarbamate — (CH NHCS^Mn
1s a yellow powder used under the name of "Maneb" as a fungicide. It 1s
produced by treating a solution of manganous chloride containing sodium
hydroxide and ethylenedlamlne with carbon dlsulflde and neutralizing the
resulting solution with acetic add.
3.1.1.2.4. Manganous Acetate ~ Mn(C ^O^ ^4H20 1s 1n
the form of pale red, transparent crystals. It 1s soluble 1n water and
alcohol. It 1s used as a mordant 1n dyeing and as a drier for paints and
varnishes.
1797A 3-4 5/03/83
-------
TABLE 3-3
Physical Properties of Some Manganese Compounds*
i
Ul
4/27/83
Name and
CAS Registry Valence
Number
Methylcyclopenta- +1
dlenyl manganese
tMcarbonyl (MMT)
[12108-13-3]
Manganous oxide +2
[1344-43-0]
Manganous +2
carbonate
[598-62-9]
Manganous +2
chloride
[7773-01-5]
Manganous +2
acetate
[15243-27-3]
Manganous +2
sulfate
[7785-87-7]
Trlmanganese +2, +3
tetraoxlde
[1317-35-7]
Manganese +4
dioxide
[1313-13-9]
Potassium +7
permanganate
[7722-64-7]
Chemical Molecular
Formula Weight
CH3c5H4Mn(c°)3 218.09
MnO 70.94
MnCOs 114.94
MnCl2 125.84
Mn(C2H302)2 • 41^0 245.08
MnS04 • H20 169.01
Mn304 228.81
Mn02 86.94
KMn04 158.04
Specific
Gravity
1.39(20°)
5.37(23°)
3.125
2.997
(25°)
1.589
3.25
4.64
5.026
2.703
(20°)
Melting Boiling
Point, - Point,
°C °C
1.5 233
1945
Decomposes
650 1190
Decomposes
850
1560
Decomposes
500-600
Decomposes
200-300
Solubility
Insoluble 1n H20. Soluble
1n most organic solvents
Insoluble 1n H20.
65 mg/a (25°C)
Soluble In dilute acid.
Insoluble In NH3 and
alcohol.
622 g/a (10°C)
1238 g/a (100°C)
Soluble 1n alcohol.
Insoluble 1n ether and NH3-
Soluble 1n cold H20 and
alcohol.
Soluble 1n one part cold and
0.6 part boiling water;
Insoluble In alcohol.
Insoluble 1n H20.
Insoluble 1n hot or cold
H20, HN03, or acetone.
Soluble In HC1.
28.3 g/a (0°C)
250 g/a (65°C)
Decomposes 1n alcohol.
Soluble In H2S04.
Very soluble In methyl
alcohol and acetone.
*Source: U.S. EPA. 1975; Re1d1es, 1981
-------
3.1.1.2.5. Manganous Oxide — MnO 1s found In nature as manganoslte
and 1s manufactured by reducing higher oxides with carbon monoxide or coke
or by thermal decomposition of manganous carbonate. It 1s a good starting
material for preparing other manganous salts and has some use 1n ferrltes,
1n welding, and as a nutrient 1n agricultural fertilizers.
3.1.1.2.6. Manganous Phosphate ~ Mn(PO) 1s made from car-
bonate and phosphoric add. It 1s used as an Ingredient of proprietary
solutions for phosphatlng Iron and steel.
3.1.1.2.7. Manganous Sulfate ~ MnSO »H 0 can be made by treat-
Ing any manganese compound with sulfurlc add. It Is also a co-product 1n
the manufacture of hydroqulnone. In pure state 1t 1s used as a reagent.
Its major use 1s as a nutrient 1n fertilizers and 1n animal feeds.
3.1.1.2.8. Manganese Soaps — Manganese(II) salts of fatty acids
(2-ethyl hexoate, Unoleate, naphthenate, oleate, reslnate, stearate, and
tallate) are used as catalysts for the oxidation and polymerization of oils
and as paint driers.
3.1.1.1.9. Other Manganese (II) Compounds — Other commercially
available Mn(II) compounds Include the acetate, borate, chromate, fluoride,
formate, gluconate, glycerophosphate, hydroxide or "hydrate", hypophosphlte,
nitrate, nitrite, perchlorate, sulflde, and sulflte.
3.1.1.3. MANGANESE (IV) COMPOUNDS —
3.1.1.3.1. Manganese Dioxide — MnO 1s the most Important Mn(IV)
compound and the most Important commercial compound of manganese. In nature
1t occurs as pyroluslte, the principal ore of manganese, as well as 1n
several other less common minerals. More than 90% of manganese dioxide 1s
used 1n the production of ferromanganese and other alloys and of manganese
metal. The rest 1s used for the production of dry cell batteries and chem-
icals, and as an oxldant 1n the manufacture of some dyes.
1797A 3-6 4/27/83
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Manganese dioxide 1s Insoluble 1n water. This property confers stabil-
ity, since the 1on Mn 1s unstable 1n solution. On heating, 1t forms
other oxides, Mn 0 , Mn 0 and MnO. Hydrated forms are obtained by
c. o o H
reduction of permanganates 1n basic solution. In add solution 1t 1s an
oxidizing agent. The classic example 1s the oxidation of HC1 which has been
a convenient means of chlorine generation both 1n the laboratory and 1n the
Weldon process for manufacturing chlorine commercially (Hay, 1967).
Mn02 + 4HC1 -> Mn4tCl4 + 2H20
Mn4+Cl4 -* Mn3*Cl3 + 1/2C12
warm
Mn3+Cl3 -* Mn2*Cl2 + 1/2C12
Manganous sulfate and oxygen are produced 1n hot sulfurlc add 1n the
presence of a little MnO as catalyst. Hydrogen fluoride reacts with manga-
nese dioxide at 400-500°C to produce manganous fluoride and oxygen (Hay,
1967).
Manganese dioxide can react with sulfur dioxide 1n two ways:
2. Alternatively, 1t can occur stepwlse:
2Mn0
2
Mn2(S03)3 -* MnS206 + MnS03
MnSOo + 1/20- -> MnSO.
O c. i
The end products of this series of reactions are Mn$206 (manganese
dlthlonate) and MnSO. (Hay, 1967). Nitrogen dioxide also reacts similarly
with MnOp to form manganous nitrate, Mn(N03)2 (Sullivan, 1969).
1797A 3-7 4/27/83
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3.1.1.4. MANGANESE (VII) COMPOUNDS —
3.1.1.4.1. Potassium Permanganate — KMnO. 1s an Important Indus-
trial chemical as well as an analytical reagent (Re1d1es, 1981). Its use 1s
based on Us oxidizing ability. It 1s used 1n the organic chemical Indus-
try, 1n the alkaline pickling process, and 1n cleaning preparatory for
plating. It 1s also used for water purification and odor abatement 1n
various Industrial wastes. Other permanganates, although less Important,
are also available commercially.
Manganese (VII) permanganates (almost always potassium permanganate) are
used 1n a host of oxidations Including reactions with both Inorganic and
organic compounds (Hay, 1967). In moderately alkaline solution, the oxidiz-
ing reaction 1s:
2KMn04 + HO -* 2KOH + 2MnO + 3(0)
In neutral solution,
2KMn04 + MgS04 (buffer) + H20 -» K2S04 + Mg(OH)2 + 2Mn02 + 3(0)
while 1n add solution 1t reacts as
2KMnO, + 3H0SO, -» K_SO. + 2MnS04 + 3H.O + 5(0)
4 c 4 d H 4 I
In organic reactions (Mn04)~ 1s a most versatile oxldant, the activ-
ity of which can be controlled to a great extent not only by the molecular
nature of the compound undergoing oxidation but also by the acidity or
alkalinity and other reaction conditions. It 1s potentially a more vigorous
oxldant than dlchromate.
3.2. SAMPLING AND ANALYTICAL METHODS
Determination procedures consist of three main steps: sampling, sample
preparation and analysis. In trace metal determination, sample preparation
often also Includes a preconcentratlon or a preseparatlon step.
1797A 3-8 4/27/83
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3.2.1. Sampling.
3.2.1.1. AIR — Virtually all of manganese present 1n air 1s Inor-
ganic, 1n the form of suspended partlculate matter, and 1s collected by
sampling procedures for airborne partlculates. Organic manganese compounds
1n the gas phase are not normally present 1n air 1n detectable concentra-
tions (see Section 3.5.2.1.), although sampling and analysis techniques have
been described (Ethyl Corporation, 1972; Coe et al., 1980). Therefore,
description of air sampling procedures will be limited to methods designed
for partlculates.
3.2.1.1.1. In-plant A1r — In the past, the 1mp1nger was widely used
for the sampling of partlculate air contaminants (ACGIH, 1958). However,
owing to a low efficiency for particles smaller than 1 urn 1n diameter
(Davles et al., 1951) and Impractical handling and transportation, the
1mp1nger has been replaced by filtering media: 1) glass fiber filters,
which have a low resistance to air flow, have high efficiency for submlcron
particles, and are hydrophoblc so that they can be weighed without trouble;
and 2) organic membrane filters, which are soluble 1n organic solvents and
strong adds. Electrostatic predpHators have also been used 1n the work-
Ing environment. They have a high collection efficiency for particles of
all sizes, but are less practical and versatile 1n field use than filters,
and cannot be used 1n potentially explosive atmospheres.
3.2.1.1.2. Ambient A1r — High-volume (HI-VOL) samplers are frequent-
ly used to collect samples of airborne particles from ambient air for trace
metal analysis. These samplers typically use glass fiber filters, 20x25 cm,
3
and collect particles from about 2500 m of air 1n 24 hours. Several
hundred samplers of this type are currently 1n use as part of the National
A1r Surveillance Networks (NASN), and thousands are 1n use by state and
1797A 3-9 4/27/83
-------
local agencies (Thompson, 1979; U.S. EPA, 1979a). Prior to 1977, filters
from the NASN were composited for analysis on a quarterly basis, but since
then Improved analytical efficiency has enabled analysis of Individual
filters (U.S. EPA, 1979a).
High-volume samplers with organic membrane filters of 10 cm diameter,
3
sampling 200 m of air over 24 hours, and low-volume samplers with mem-
3
brane filters of 2.5 cm diameter, sampling 25-30 m over a week, have also
been used (WHO, 1976; Sarlc, 1978). Manganese can be conveniently deter-
mined on both membranous and fibrous filters (Fugas, 1980); however, fibrous
filters should not be used when the method of analysis 1s x-ray fluorescence
(U.S. EPA, 1981c).
Particle size 1s an Important factor 1n determining human exposure to an
ambient aerosol (see Section 3.6.4.1.). High-volume samplers may sample
particles as large as 50-100 vim 1n diameter (Bernstein et al., 1976;
Thompson, 1979) and thus do not provide any specific Information on particle
size. A variety of samplers achieving some degree of particle size
discrimination have been used for ambient trace metal analyses, Including
cascade Impactors (Lee et al., 1972) and cyclones (Bernstein et al., 1976;
Bernstein and Rahn, 1979). However, dlchotomous samplers are now most
widely used for this purpose. Samplers of this type separate fine and
coarse particles by use of a virtual Impactor (Dzubay and Stevens, 1975).
The fine particle cut-off (D«-n), at which 50% of larger-diameter particles
are excluded, ranges from 2-3.5 v.m depending on the sampler used. A frac-
tlonlng Inlet also 1s often used to determine the upper size limit for the
coarse fraction; DS(, 1s normally set at 10, 15 or 20 urn (e.g., U.S. EPA,
1981a). Particles for metal analysis are typically collected on a teflon or
p
cellulose filter of ~1 vim pore size and -6-25 cm surface area
1797A 3-10 4/27/83
-------
(e.g., Lewis and Madas, 1980; Dzubay et al., 1982). Flow rates vary from
14-50 a/m1n, and sampling times from 2-24 hours (e.g., Stevens et al.,
1978).
3.2.1.1.3. Stationary Source Emissions -- Glass fiber filters are
used for sampling manganese particles 1n stacks, often 1n the form of a
filter thimble to Increase the sampling surface and thus reduce air flow
resistance. For low temperature flue gases (=100°C), membrane or
cellulose filters may be used as well. Sampling Is usually performed Iso-
klnetlcally, and the filter holder Is placed 1n the stack or heated during
sampling to prevent condensation. In the classical sampling train for the
collection of particles (36 FR 24876; U.S. EPA, 1978a), the filter holder 1s
followed by a series of Implngers for the collection of condensate 1n order
to measure moisture content and to protect the pump and the gas meter.
Implngers can be replaced by a condensor. Cascade Impactors are available
for collecting samples of particles by size from the stack (P1lat et al.,
1970) and are sometimes preceded by a cyclone to prevent the massing of
large particles on the first separation stage (Instrumentation for Environ-
mental Monitoring, 1975).
3.2.1.1.4. Mobile Source Emissions — Standard tests of motor vehicle
emissions measure only gaseous pollutants (CO, NO and hydrocarbons), but
for heavy duty vehicles, smoke measurements using optical methods are also
used (37 FR 24250). The only purpose of the filters 1n the sampling system
1s to remove particles from the gas stream. The composition, mostly lead
content and particle size, of automotive exhaust has been measured only
under experimental conditions (Ter Haar et al., 1972). The samples,
collected 1n large black polyethylene bags during a 7-mode Federal emission
1797A 3-11 5/03/83
-------
test cycle, were diluted 8 to 1 wHh dry air 1n order to prevent condensa-
tion, and a known volume of the mixture was sampled through a membrane
filter.
For particle size analysis, either microscopic counting of electrostatic
predpltator samples (Hlrschler and Gilbert, 1964) or size selective
sampling by cascade Impactor was used (Mueller et al., 1963). The samples
were collected from a tailpipe by a probe (Ter Haar et al., 1972) or else a
mixing tunnel was used for proportional sampling (Hab1b1, 1970).
3.2.1.2. WATER ~ The sampling of water and wastewater can be by grab
or composite sample (minimal portions 25 mfc). Samples are collected 1n
bottles of glass or plastic (U.S. EPA, 1973; King, 1971). Preparation of
bottles to prevent contamination 1s discussed by Moody and Llndstrom (1977),
and possible wall losses by Bond and Kelly (1977).
3.2.1.3. FOOD — According to the sampling objective, samples of food
consist of cooked, raw, or packed food. Plscator and Vouk (1979) described
three methods currently available for estimating Intake of metals via food
products:
1. To collect and analyze samples of single foodstuffs for the
metal, and then estimate the Ingested amount of metal.
2. To collect and analyze certain classes of food 1n the amounts
that are actually consumed and make estimates from that.
3. To collect and analyze duplicate samples of the meals people
have eaten during a certain period.
The first of the three methods 1s recommended by the Food and Agricul-
tural Organization/World Health Organization (FAO/WHO, 1977); the second
method has been used by the U.S. FDA (1978).
3.2.1.4. SOIL — Samples of soil are collected either area wide or
along a transect. The variability 1n the soil complex makes 1t desirable to
take paired samples.
1797A 3-12 4/27/83
-------
Profile samples are collected either by digging a hole at a sample site
and taking an undisturbed slice from the side of the hole, or layer by layer
to the depth desired. The samples are screened to remove organic matter,
stones, and lumps, and are thoroughly mixed. A more detailed description
can be found 1n Bear (1964).
3.2.1.5. BIOLOGICAL MATERIALS --
3.2.1.5.1. Urine — Samples of urine are collected either 1n glass
(Ajemlan and Whitman, 1969) or polyethylene bottles (Stoeppler et al., 1979)
with the addition of redistilled HC1 at pH 2, and are kept under refrigera-
tion before analysis. Preferably, 24-hour samples should be collected
(T1chy et al., 1971).
3,2.1.5.2. Blood -- Samples of blood are obtained by venlpuncture and
transferred to polyethylene tubes. If serum 1s used for further analysis,
blood 1s allowed to clot and serum 1s separated by centrlfugatlon (D'Amlco
and Klawans, 1976). If whole blood 1s analyzed, heparln 1s added (Tsalev et
al., 1977). This, however, can Introduce contamination according to Bethard
et al. (1964), who used citrate dextrose as a coagulant. Additional possi-
ble sources of contamination are discussed by Cotzlas et al. (1966).
3.2.1.5.3. Tissue and Organs — Tissue or organ samples should be
dissected with knives 1n a dust-free atmosphere, placed 1n a polyolefln
vessel, and stored deep frozen until analysis (Stoeppler et al., 1979).
3.2.1.5.4. Hair and Other Biological Samples — Samples of hair are
cut close to the scalp (Gibson and DeWolfe, 1979) and stored 1n polyethylene
bags.
Samples of nails (Hopps, 1977), teeth (Langmyhr et al., 1975), skin
(Parkinson et al., 1979), and sweat (Hopps, 1977) have also been used for
manganese analysis.
1797A 3-13 5/03/83
-------
3.2.2. Sample Preparation. While sampling 1s rather specific for various
environmental media, the procedures for sample preparation and analysis are
often the same. Unless a nondestructive method 1s used for analysis, sam-
ples have to be transformed first Into solution by dry, wet, or low tempera-
ture ashing and add digestion. The conventional ashing 1n a muffle furnace
results 1n loss of a number of trace elements (Thompson et al., 1970), but
manganese can be treated by any ashing procedure without an appreciable
loss. After digestion of the samples with nitric add, the add has to be
expelled, and manganese 1n the residue 1s dissolved 1n hydrochloric add.
Glass fiber filters are not destroyed In the ashing procedure; there-
fore, 1t 1s better to remove manganese by add extraction (Thompson et al.,
1970) 1n order to avoid filtration which 1s a source of wall losses 1n trace
metal analysis (Hrsak and Fugas, 1980). Extraction, with a mixture of
nitric and hydrochloric adds, may be carried out by refluxlng after ashing
of the sample (U.S. EPA, 1979a), or by son1f1cat1on In the adds at
100°C, without ashing. The latter method 1s currently used by the U.S.
EPA (1983a).
If small concentrations of manganese are present In a large volume of
sample {e.g., water or urine), 1t may become necessary to Increase the
concentration of manganese to a measurable level by reducing the volume of
the solution by evaporation. To avoid contamination, nonboHIng evaporation
1n Teflon tubes (Boutron and Martin, 1979) or "vapor filtration" through a
vapor-permeable membrane (U.S. EPA, 1978b) have been used. A simultaneous
Increase 1n the concentration of other substances present 1n the sample 1n
much higher concentrations may cause turbidity, copredpltaton, or other
type of Interference caused by the "matrix effect." In such cases a pre-
separatlon step 1s Indicated. It 1s usually based on chelatlon, either
1797A 3-14 4/27/83
-------
selective, e.g., with thlnoyltrlfluoroacetone (Sarlc, 1978) or nonselective,
as with 8-hydroxyqu1nol1ne (AJemlan and Whitman, 1969; KUnkhammer, 1980;
Vanderborght and Van Grleken, 1977) and cupferron (Van Ormer and Purdy,
1973; Buchet et al., 1976) or by 1on exchange on Chelex 100 (Lee et al.,
1977) or Dovex Al (R1ley and Taylor, 1968). Coprec1p1tat1on with dlethyl
dlthlocarbamate (Watanabe et al., 1972) or d1benzyld1th1ocarbamate (Under
et al., 1978) also has been applied for enrichment of samples as has
electrodeposltlon (Wundt et al., 1979). Radio-chemical separation 1s most
often used before the analysis of Irradiated samples (Cotzlas et al., 1966;
Hahn et al., 1968; Versleck et al., 1973).
Samples of plants, raw food, or hair have to be cleaned before further
treatment. Care should be taken not to contaminate the sample during this
operation. Detergents or solvents have been used for washing hair samples.
However, while surface contamination 1s being removed, weakly bound metals
also may be removed from hair. Hair washing procedures are discussed by
ChHtleborough (1980).
3.2.3. Analysis. The selection of available analytical methods for the
determination of manganese has Increased 1n recent years, and methods of
preference have changed.
Some 30 years ago colorlmetrlc (Standard Methods for the Examination of
Water and Wastewater, 1971) or spectrographlc (Thompson et al., 1970)
methods were used the most. Polarographlc methods had a number of support-
ers but never became very popular. Polarographlc and voltametrlc analyses
are now regaining some popularity since new techniques have been developed
with a high resolution and sensitivity, such as the pulsed stripping
technique (Flato, 1972). Colorlmetrlc methods are still used, especially 1n
water analysis, and are now coupled with an autoanalyzer (Crowther, 1978).
1797A 3-15 4/27/83
-------
The Introduction of atomic absorption spectrophotometry (AAS) 1n 1955
proved to be a turning point 1n analytical practice. Although many other
new and sophisticated methods have been developed, none has experienced such
a wide acceptance as AAS. The Introduction of Delves cups (Delves, 1970),
and fTameless techniques using the carbon rod (Matousek and Stevens, 1971)
and graphite furnace (Slavln et al., 1972), made 1t possible to analyze
m1crol1ter samples with little or no pretreatment, although with less
precision and at a higher cost.
DC arc optical emission spectrometry (OES) was used by U.S. EPA until
1976 for multi-elemental analysis of NASN high-volume samples collected on
glass fiber filters (U.S. EPA, 1979a). The method currently used for this
purpose 1s Inductively coupled argon plasma optical emission spectrometry
(ICAP) (U.S. EPA, 1983b). Since Instrumental detection limits are lower
than most blank filter analyses, the limits of discrimination are determined
mainly by filter characteristics. The limit of discrimination for manganese
on filters used by the NASN 1n 1975-1976 was -0.0025 ug/m3 (U.S. EPA,
1979a).
X-ray fluorescence (XRF) 1s also used 1n multi-element analysis
(G1lfr1ch et al., 1973). Problems Include particle size effect (Davlson et
al., 1974), self absorption (Dzubay and Nelson, 1975), and the preparation
of standards with a matrix matching that of the sample. This method 1s not
used with fibrous filters, but Is the most popular for use with membrane
filters, as are commonly used with dlchotomous samplers. Detection limits
2
of -20 ng/cm of filter surface area have been Indicated for manganese.
For a 24-hour sampling period with typical filters and flow rates, detection
limits of 0.002-0.007 ng/m In air are obtained (Ozubay and Stevens,
1975; Stevens et al., 1978).
1797A 3-16 4/27/83
-------
Neutron activation analysis (NAA) has been used for the determination of
manganese 1n various environmental media, mostly 1n multi-element analysis
(Robertson and Carpenter, 1974). NAA suffers from Interferences such as the
production of the same radlolsotope by another element or one with a close
radiation peak, but most of these can be eliminated by optimizing IrMda-
tlon, decay, and counting times. The method 1s sensitive, but more costly
and less frequently available than XRF (U.S. EPA, 1981c).
Both NAA and XRF are basically nondestructive methods of analysis, but
1f a greater sensitivity 1s required, a separation and preconcentratlon step
cannot be avoided for aqueous samples (Lee et al., 1977; Buono et al., 1975;
Watanabe et al., 1972; Under et al., 1978).
Instrumental detection limits for manganese by several analytical tech-
niques are shown 1n Table 3-4. Reported sensitivities for any method vary
depending on the type of Instrument, the preparation or enrichment of the
sample, and on the way of expressing the result. It 1s difficult to compare
the sensitivities claimed by researchers using various methods since the
result may be expressed as absolute amount, concentration per ml of final
solution, or per unit of measure of the medium from which the sample was
taken.
3.3. PRODUCTION AND USE
3.3.1. Production. The ferroalloy Industry uses manganese-bearing ore to
produce several manganese alloys and manganese metal. Production may be
carried out using a blast furnace, an electric arc furnace or electrolytic-
ally (Bacon, 1967; U.S. EPA, 1974; MatMcardl and Downing, 1981).
1797A 3-17 4/30/83
-------
TABLE 3-4
Relative Sensitivity of Some Important
Analytical Techniques for Manganese*
Analytical Method Detection Limit
(ng)
Neutron activation analysis 0.005
Optical emission spectroscopy (DC arc) 10
Atomic absorption spectrophotometry 0.5
Spark source mass spectrometry 0.05
'Source: U.S. EPA, 1975
1797A 3-18 4/27/83
-------
For blast furnace production of ferromanganese (an alloy of manganese
and Iron) the furnace 1s charged with a blend of ores, coke and limestone,
or dolomite, and operated at low blast pressures. The composition of the
charge 1s carefully controlled to decrease the slag production, minimize
dust losses, and allow uniform gas distribution throughout the furnace.
This 1s done by careful choice of the chemical composition of the charge as
well as the size distribution. High manganese recovery 1s favored by:
1) small slag volume, 2) a basic slag, 3) high blast temperatures, and
4) coarse ores. The limit of capacity 1s determined by the loss of manga-
nese by volatilization. Blast furnace production of ferromanganese was last
used 1n this country 1n 1977; production 1s now primarily by electric
submerged-arc furnace.
In submerged-arc furnace production, the charge, consisting of manganese
ore, coke and dolomite, 1s placed 1n the furnace by continuous or Intermit-
tent feed. Vertically suspended carbon electrodes extend down Into the
charge, and carbon reduction of the metallic oxides takes place around the
electrodes. Carbon monoxide gas 1s produced 1n large quantities, and rises
from the charge carrying entrained fume particles. Submerged-arc furnaces
may have open tops, may be partially sealed (mix-sealed), or completely
sealed. The open furnaces vent larger quantities of gas due to mixing of
air with the process gases.
SHIcomanganese 1s an alloy of manganese and Iron, also produced by
smelting of ore 1n an electric submerged-arc furnace. It differs from
standard ferromanganese 1n that the furnace charge contains large amounts of
quartz, and the resulting alloy 1s lower 1n carbon and higher 1n silicon.
For electrolytic production of h1gh-pur1ty manganese metal, the ore 1s
leached with sulfurlc add at pH 3 to form manganese sulfate. The solution
1797A 3-19 5/03/83
-------
1s adjusted to pH 6 by the addition of ammonia or calcined ore to preci-
pitate the Iron and aluminum. Arsenic, copper, zinc, lead, cobalt and
molybdenum are removed as sulfldes after the Introduction of hydrogen sul-
flde gas. Ferrous sulflde and air 1s added to remove colloidal sulfur,
colloidal metal sulfldes, and organic matter. The purified liquid 1s then
electrolyzed.
Manganese metal can also be produced via a fused-salt electrolysis pro-
cess. The process Is similar to the Hall method of producing aluminum. The
manganese ore 1s reduced to the manganese(II) level and charged to an elec-
trolytic cell containing molten calcium fluoride and lime. The manganese 1s
formed 1n a molten state.
A number of compounds of managanese also are commercially produced.
Manganese oxide (MnO) 1s produced by reductive roasting of ores high 1n
managanese dioxide (MnO ). MnO 1s an Important precursor of several other
commercially-produced compounds, Including electrolytic manganese dioxide, a
h1gh-pur1ty product formed by electrolysis of MnO. Potassium permanganate
1s produced by a liquid-phase oxidation of managanese dioxide ore with
potassium hydroxide, followed by electrolysis (Re1d1es, 1981). United
States production capacities for several compounds are shown 1n Table 3-5.
Manganese supply-demand relationships for the years 1969-1979 are given
1n Table 3-6. A small proportion of the manganese smelted 1n this country
Is mined domestically, the bulk 1s Imported. However, ore Imports have
declined recently since Imports of alloy and metal have Increased and over-
all demand for ferroalloys has decreased somewhat. Domestic production of
ferromanganese has declined steadily since 1965; slUcomanganese production
has also declined recently (Table 3-7).
1797A 3-20 5/03/83
-------
TABLE 3-5
Estimated United States Production, Capacity
and Use of Selected Manganese Compounds*
Product
Estimated
Formula U.S. Production
Capacity (mt/yr)
Use
Electrolytic man
ganese dioxide
High purity man-
ganese oxide
Manganese sulfate
Potassium per-
manganate
MnO
60% manganese oxide MnO
MnS04
Manganese chloride MnCl2
KMn04
18,000
9,000
36,000
68,000
3,000
14,000
Methylcyclopenta- CH3C5H4Mn(CO)3 500-1,000
dlenyl manganese
trlcarbonyl (MMT)
Dry-cell batteries;
ferrltes
H1gh-qual1ty ferrltes;
ceramics; Intermediate
for high purity Mn(II)
salts
Fertilizer; feed addi-
tive, Intermediate for
electrolytic manganese
metal and dioxide
Feed additive; ferti-
lizer; Intermediate for
many products
Metallurgy; MMT synthe-
sis; brick colorant;
dye; dry-cell batteries
Oxldant; catalyst; In-
termediate; water and
air purifier
Fuel additive
*Source: Adapted from Re1d1es, 1981
1797A
3-21
4/27/83
-------
TABLE 3-6
Manganese Supply-Demand Relationships, 1969-19793
(thousand short tons, manganese content)
OJ
i
ro
co
03
Mine production:
United States
Rest of world
Total
Domestic mines
Shipment of Government
stockpile exceses
Imports, ore
Imports, alloy and metal
Industry stocks, Jan. 1
Total U.S. supply
Distribution of U.S. supply:
Industry stocks, Dec. 31
Exports, ore
Exports, alloy and metal
Demand
1969
93
9.192
9,285
93
50
992
257
1.180
2,572
1,241
10
4
1.317
1970
66
8.978
9,044
66
140
847
238
1.241
2,532
1,175
10
20
1,327
1971
38
9.960
9,998
Components
38
118
938
212
1.175
2.481
1,281
25
5
1,170
1972
World
29
9.983
10,012
1973
Production
31
10.707
10,738
and Distribution of
29
218
793
305
1.281
2.626
1,241
12
7
1,366
31
242
722
336
1.241
2.572
978
29
11
1,554
1974
35
10.185
10,220
U.S. Supply
35
807
593
376
978
2,789
1,183
107
7
1,492
1975
19
10.791
10,810
19
309
766
346
1.183
2,623
1.359
125
6
1,133
1976
31
11.007
11,038
31
294
649
478
1.359
2,811
1,373
64
10
1,364
1977
27
9.547
9.574
27
358
454
481
1.373
2,693
1.092
69
9
1,523
1978
38
9.544
9,582
38
279
278
604
1.092
2,291
811
100
17
1.363
1979
31
10.487b
10,518b
31
264
244
708
811
2,058
749
29
30
1.250
U.S. Demand Pattern
Construction
Transportation
Machinery
Cans and containers
Appliances and equipment
011 and gas Industries
Chemicals
Batteries
Otherc
Total U.S. primary demand
268
253
185
62
51
43
37
20
398
1,317
260
226
176
73
51
42
37
20
442
1,327
252
261
175
71
51
46
35
19
260
1,170
236
239
171
58
51
44
50
18
499
1,366
325
340
229
72
68
63
54
18
385
1.554
317
315
245
79
68
69
65
18
316
1,492
249
260
185
59
47
64
52
16
201
1,133
238
298
186
63
51
53
47
18
410
1,364
240
300
188
60
53
63
61
18
540
1,523
279
317
216
60
58
74
61
18
280
1,363
291
296
217
61
59
70
59
17
180
1,250
aSource: DeHuff and Jones, 1980
Estimated
clncludes processing losses
-------
TABLE 3-7
Net United States Production
of Ferromanganese and S1l1comanganesea
Year
Ferromanganese
(103 short tons)
SlUcomanganese
(103 short tons)
1982
1981
1980
1979
1978
1977
1976
1975
1974
1973
1972
1971
1970
1969
1968
1967
1966
1965
1964
1963
1962
1961
1960
(120)b
193
189
317
273
334
483
576
544
683
801
760
835
852
880
941
946
1148
929
751
781
733
843
(75)b
173
188
165
142
120
129
143
196
184
153
165
193
223
284
246
253
--
203
152
136
120
101
aSource: U.S. Bureau of Mines (Jones, 1982; DeHuff and Jones, 1981;
DeHuff, 1961-1980)
Estimated gross production; exceeds net production (U.S. Bureau of Mines,
1983)
1797A
3-23
4/27/83
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3.3.2. Use. The principal use of manganese 1s 1n metallurgy, which
accounts for =95% of United States demand for all forms of manganese
(Re1d1es, 1981) and =99% of manganese alloys and metal (DeHuff and Jones,
1981). The majority (>90%) of metallurgical use 1s 1n steel production, for
which manganese 1s 1nd1spens1ble (Matr1card1 and Downing, 1981; Bacon,
1967). Its function 1s 3-fold: 1) 1t combines with sulfur, eliminating the
principal cause of hot-shortness; 2) 1t acts as a deoxldlzer or cleanser 1n
molten steel; 3) 1n certain steels 1t 1s used as an alloying element to
Improve the strength, toughness, and heat-treating characteristics of
structural and engineering steels.
Several different manganese alloys, as well as h1gh-pur1ty manganese
metal, are used to Introduce manganese Into steels, pig Iron, and some non-
ferrous alloys (Bacon, 1967). The various forms are listed 1n Table 3-8,
along with their composition and use.
A minor use of manganese metal, 1n various powdered forms, 1s 1n mili-
tary and civilian pyrotechnics and fireworks. It 1s used to produce ex-
tremely bright flares and lighting devices. Annual consumption for this
application may be on the order of several hundred tons per year.
A variety of compounds of manganese are used 1n the chemical Industry
and battery manufacture; these uses accounted for 4.7 and 1.4% of total
United States manganese demand 1n 1979 (see Table 3-6). Some major uses are
as follows: feed additives and fertilizers (MnO, MnSO,), colorants 1n
4
brick and tile manufacture (various oxides, MnClp), dry cell battery manu-
facture (electrolytic MnO,,, MnClp), chemical manufacture and processing
(KMn04, MnC03, MnCl2) and fuel additives (MMT) (see Table 3-5).
MMT was Introduced 1n 1958 as an antiknock fuel additive (U.S DHEW,
1962). This compound has been used at a concentration of 0.025 g Mn/gal 1n
1797A 3-24 5/03/83
-------
ID
~J
3>
TABLE 3-8
Commercial Forms of Manganese3
Name
Composition^
Use
High purity manganese
i
M
VI
Low-carbon ferromanganese
Medium-carbon ferromanganese
Standard ferromanganese
Low-Iron ferromanganese
Splegelelsen
99.5X manganese
0.15X (max) hydrogen
0.030X (max) sulfur
0.005% (max) Iron
0.005X (max) carbon
0.001X (max) phosphorus,
aluminum, silicon
CO
to
95-90X manganese
2.OX (max) silicon
0.07-0.75X carbon
0.2% (max) phosphorus
0.02X (max) sulfur
80-8SX manganese
1.25-1.SOX carbon
l.OX (max) silicon
0.3X (max) phosphorus
0.02X (max) sulfur
78-82X manganese
up to 7.5X carbon
1.2X (max) silicon
0.35X (max) phosphorus
0.05X (max) sulfur
85-90X manganese
7X carbon
3X silicon
2X Iron
16-19X manganese
6.5X carbon
1.0-3.OX silicon
0.08X (max) phosphorus
0.05X (max) sulfur
Ferrous metals:
free-machining steels
flat-rolled low-carbon steels
Non-ferrous metals (Improves strength, ductility and hot-rolling
properties)
aluminum alloys
aluminum-bronze
constantan
monel
everdur
nickel-chromium
nickel-silver
manganese-bronze for ship propellers
Stainless steels where low carbon content 1s essential
For use In steels with carbon specifications too low to permit use of
standard ferromanganese
Used 1n production of Bessemer, open-hearth and electric furnace steels
for forging, rolled products, and castings
Used 1n making alloys with non-ferrous metals such as aluminum, nickel,
and copper.
A white cast Iron with low phosphorus and sulfur, used for making alloy
additions and as a cleaning agent.
-------
TABLE 3-8 (cont.)
us
•—i
Name
Compos1t1onb
Use
VjO
I
S3
"MS" ferromanganese
"DQ" ferromanganese
Exothermic ferromanganese
Ferromanganese-slllcon
SHIcomanganese
Calclum-manganese-slHcone
Manganese-aluminum
master alloys
80-85X manganese
1.25-1.SOX carbon
0.35X silicon
86X manganese
0.45X carbon
0.40X silicon
0.17X phosphorus
63-66X manganese
28-30X silicon
0.08X (max) carbon
0.05X (max) phosphorus
65-68X manganese
18.5-21X slllcone
1.SOX carbon
0.2X (max) phosphorus
0.04X (max) sulfur
53-59X silicon
16-20X calcium
14-18X manganese
75X manganese
25X aluminum
Used for making screw-stock where high silicon content destroys
machining properties.
Used as a manganese additive to steels for drawing quality steel sheets.
Briquets when added to steel cause an exothermic reaction—used for
ladle additions of manganese to prevent chilling.
For partial slag reduction and manganese additions 1n the production of
the 300 series of stainless steels, for large manganese additions to the
200 series of stainless steels, and 1n nongraln-orlented silicon
electric steels and low-carbon, low-alloy steels as a ladle addition of
manganese and silicon.
Used In open-hearth steelmaklng practice as a blocking agent (I.e., to
prevent the reaction between carbon and oxygen) for engineering steels
with carbon content of 0.10-0.15X.
In high quality steel castings to Improve tensll strength, elongation,
and Impact strength.
Used 1n aluminum alloys to Impart strength, hardness, and stiffness.
PO
aSource: Bacon, 1967 and OeHuff, 1975
^Composition Is given for Grade A product; other grades will have the same Impurities, but 1n a higher percentage. The balance of each
composition necessary to make 100X 1s mainly Iron.
CO
CO
-------
fuel on and 0.08-0.5 g Mn/gal In turbine fuels, and has been used to a
small extent 1n leaded gasoline (Ter Haar et al., 1975). Production prior
to 1974 was =500 tons/year (=125 tons Mn/year) (P1ver, 1974). Beginning
1n 1974, MMT was used 1n unleaded gasoline at concentrations up to 0.125 g
Mn/gal; use 1n 1977 has been estimated at -12,000 tons/year (-3000 tons
Mn/year) (Vouk and P1ver, 1983). Some adverse effects of MMT on catalytic
converter performance and hydrocarbon emissions were reported (U.S. EPA,
1977b), and MMT use In unleaded gasoline was banned 1n October, 1978. The
ban continues 1n effect, except that MMT use at 0.031 g/gal was permitted
during a 4-month period 1n 1979, due to a shortage of unleaded fuel (44 FR
32281-32282). MMT continues to be used 1n =20% of leaded gasoline at
levels of =0.05 g Mn/gal, and 1s used 1n Canada 1n the majority of unlead-
ed gasolines at levels of up to 0.068 g Mn/gal (Hall, 1983). Options for
Us future use at low levels 1n United States unleaded gasoline continue to
be studied (Hall, 1983).
3.4. SOURCES OF MANGANESE IN THE ENVIRONMENT
3.4.1. Crustal Materials and Soils. Manganese 1s widely distributed 1n
the earth's crust. It 1s considered to be the 12th most abundant element
and fifth most abundant metal. The concentration of manganese 1n various
components of the earth's crust ranges from near zero to 7000 ug/g- A
rough estimate of the average concentration of manganese 1n the earth's
crust 1s about 1000 mg/kg (DeHuff, 1973). Tureklan and Wedepohl (1961)
suggested the following distribution of manganese, expressed 1n ug/g, for
the major units of the earth's crust:
1. Igneous rock: ultrabaslc, 1620; basaltic, 1500; hlgh-caldum
granitic, 540; low-calcium granitic, 390; and syenltlc, 850
2. Sedimentary rock: shales, 850; sandstones, essentially zero;
and carbonates, 1000
3. Deep-sea sediment: carbonate, 1000; and clay, 6700
1797A 3-27 4/27/83
-------
Hodgson (1963) reported concentrations of manganese 1n ug/g for various
types of rocks and for soil: 1000 1n earth's crust; 2000 1n basic rocks;
600 1n add rocks; 670 1n sedimentary rocks; 850 1n soils.
Manganese 1s a major constituent of at least 100 minerals and an access-
ory element 1n more than 200 others (Hewett, 1932). The most common manga-
nese minerals and the percentages of manganese contained therein are listed
1n Table 3-9.
Relatively little manganese 1s mined within the United States (S1tt1g,
1976). Manganese deposits are well-distributed through the southern Appa-
i
lachlan and Piedmont regions, the Batesvllle district of Arkansas and many
of the western states. These deposits have been exhausted 1n terms of mining
for profit at existing or appreciably higher prices. There are large
low-grade manganese deposits extending for miles along both sides of the
Missouri River 1n South Dakota and large low-grade deposits 1n the Cuyuna
Range of Minnesota, 1n the Artillery Mountains region of northwestern
Arizona, 1n the Batesvllle district of Arkansas, 1n Aroostok County 1n
Maine, and to a lesser extent 1n the Gaffney-K1ngs Mountain district of
North Carolina and South Carolina. Manganese ore (>35% Mn) 1s no longer
mined 1n the United States, but some manganlferous ore (5-35% Mn) 1s mined
1n Minnesota, New Mexico and South Carolina (DeHuff and Jones, 1980).
Researchers report various concentrations of manganese 1n different
types of soils. Swalne (1955) reported a range of 200-3000 y.g/g for total
content of manganese 1n most soils. Wright et al. (1955) studied virgin
profiles of four Canadian soil groups and reported a manganese content of
250-1380 ug/g. Swalne and Mitchell (1960) studied representative Scottish
soil and reported a range for total manganese of 50-7000 ug/g 1n a1r-dr1ed
soil. Shacklette et al. (1971) analyzed various soil samples 1n the United
1797A 3-28 4/27/83
-------
TABLE 3-9
Manganese Content of Selected Minerals*
Mineral
Pyroluslte
Manganlte
Hausmannite
RodochrosHe
Rhodonite
BraunHe
Pyrochrolte
Alabandlte
Formula
Mn02
MnO(OH)
Mn304
MnC03
MnS103
3Mn203, MnS103
Mn(OH)2
MnS
Manganese Content (%)
60-63
62
72
47
42
63
61
63
*Source: Hewett, 1932
1797A
3-29
4/27/83
-------
States and reported a range of manganese content from <1-7000 ug/g, with
an arithmetic mean of 560 v.g/9-
Crustal materials are entrained Into the atmosphere by a number of
natural and anthropogenic processes, and thus compose an Important fraction
of atmospheric partlculate. These processes Include vehicle suspension of
road dusts, wind erosion and suspension of soils (especially through agri-
culture or construction activities), and quarrying processes (Dzubay et al.,
1981). The resulting, mechanically-generated aerosols consist primarily of
coarse particles (>2.5 \im) (Dzubay, 1980). Since manganese 1s a typical
constituent of these dusts, some researchers have used this element as a
tracer to determine the degree of contributions from these sources 1n
ambient aerosol (Klelnman et al., 1980; Knelp et al., 1983).
Several other processes also result 1n the ejection of crustal materials
to the atmosphere; for example, the smelting of natural ores and the combus-
tion of fossil fuels. However, these differ from the above categories 1n
that much of the material 1s released 1n the form of fume or ash 1n the fine
particle range (<2.5 y.ro). In addition, these tend to be point sources
subject to control measures, whereas the above typically are not. These
Industrial and combustion processes will be discussed In Section 3.4.2. The
relative contributions of all sources to fine and coarse partlculate 1n
ambient air will then be discussed Section 3.4.3.
3.4.2. Industrial and Combustion Processes. Manganese 1s released to the
atmosphere during the manufacture of ferroalloys, Iron and steel, other
alloys, batteries, and chemical products. Combustion of fossil fuels also
results 1n release. Emissions from these sources 1n 1968 were estimated by
the U.S. EPA (1971), as shown 1n Table 3-10. This national Inventory
estimated that nearly half of all Industrial and combustlve emissions of
1797A 3-30 4/27/83
-------
TABLE 3-10
Sources and Estimated Atmospheric Emissions of Manganese 1n 1968a
30
v-o
VjJ
43.
CO
CO
Partlculate
Product/Process Emissions
(kg/mt product)
Mn metal/
electrolytic
Ferromanganese/
blast furnace
Ferromanganese/
electric furnace
SlUcomanganese/
electric furnace
Pig Iron/blast
furnace
Steel/open hearth
furnace
Steel/basic oxygen
furnace
Steel/electric
furnace
Cast Iron/cupola
furnace
Melding rods
Nonferrous alloys
Batteries
Chemicals and
miscellaneous
Mining
Coal combustion
Residual fuel oil
NA
205
NA
NA
75
4-10.5
23
3.5-5.5
11
NA
NA
NA
NA
NA
40-70
NA
Average or Control
Partlculate Predominant Efficiency
Mn Content Particle Size or Prevalence
(X) (vun) of Use (X)
NA
15-25
20-25
(33X Mn Oxide)
NA
0.5
0.5
3.2
(4.4X Mn304)
3.1
(4X MnO)
2
NA
NA
NA
NA
NA
0.02-0.03
NA
NA
0.3
<2
NA
NA
0.5
0.5-1.0
<5
NA
NA
NA
NA
NA
NA
NA
NA
NA
95
NA
NA
97
40
97
78
25
NA
NA
NA
NA
NA
75
10
Mn Emission Factor
(kg/mt product)
2.5
2.1
12
35
0.011
0.026
0.022
0.039
0.165
8b
6b
5b
5»
O.lb
0.0042
NA
Estimated 1968
1968 Volume Emissions
(103 mt product) (mt)
24
481
279
109
80,700
59.000
43,500
14,500
1 5 . 200
2.7b
9.1b
16. 3b
54b
43. 5b
462,000
669x10 bbl
295
1010
3330
3780
910
1506
962
562
2510
21.8
54.4
81.6
270
4.4
1950
6.4
Percent of
Total Emissions
1.7
5.9
19.3
21.9
5.3
8.7
5.6
3.2
14.5
0.1
0.3
0.5
1.6
N 0.03
11.3
0.04
aSource: Adapted from U.S. EPA, 1971
bOn a basis of tons manganese, not tons product
NA = Not available
-------
manganese were from ferroalloy manufacture, over one-third were from Iron
and steel manufacture, about one-tenth were from fossil fuel conbustlon, and
minor amounts (<2%) were generated by other processes. Since 1968, pro-
cesses, control measures, and production volumes have changed substantially
1n many categories. Thus the emissions estimates 1n Table 3-10 will be used
only as a basis for discussion; more recent emissions estimates are not
available. The most Important sources are discussed 1n the following
sections.
3.4.2.1. FERROALLOY MANUFACTURE — The manufacture of manganese
alloys and metal has been the major source of manganese emissions to the
atmosphere (see Table 3-10), and has been responsible for the highest
recorded ambient manganese concentrations (see Section 3.6.1.2.). Dust
varying from 3-100 um 1n size 1s emitted from crushing, screening, drying
and mixing of both raw materials (-0.3% loss) and product (-0.5% loss),
but the majority of pollution 1s from the furnace (U.S. EPA, 1981b).
Furnace partlculate emissions contain 15-25% manganese, primarily 1n the
form of oxides. Silicates are a second major constituent. Particle size 1s
predominantly fine (<2 v.m).
Total U.S. emissions of manganese from ferroalloy manufacture were
estimated at -8400 mt 1n 1968 (see Table 3-10) but current emissions are
probably much lower. Production of ferromanganese and slUcomanganese, the
major emission source, has declined substantially; combined 1981 production
was -31% of 1968 production, and 1982 production estimates showed substan-
tial further declines (see Table 3-7). Process emissions of manganese may
also be much lower than those Indicated 1n 1968. Blast furnaces, reportedly
the most prolific polluter of any metallurgical process when not controlled
(Wurts, 1959), have not been used since 1977 (Matr1card1 and Downing, 1981).
1797A 3-32 4/30/83
-------
In addition, more recent measurements Indicate lower emission factors for
controlled submerged-arc facilities (Table 3-11). Ambient air measurements
In the vicinity of ferromanganese manufacturing Indicate that recent manga-
nese levels were lower by about an order of magnitude than those recorded
during the mid-1960s (see Section 3.6.1.2.)-
3.4.2.2. IRON AND STEEL MANUFACTURE — There 1s considerable loss of
manganese 1n Iron and steel production. Manganese 1s lost to fume, slag or
other waste products at each stage of production; however, the most signifi-
cant loss 1s to fume and slag 1n the furnace. Partlculates from the furnace
tend to be submlcron 1n size. Table 3-10 Indicates that partlculate manga-
nese content (<5%) Is less than for ferromanganese manufacture, but total
emissions are comparable because of the larger production volume. Other
sources (U.S. EPA, 1981a) have listed a higher manganese content (8.7%) for
aerosol from a steel electric furnace (see Section 3.4.3.). Manganese
emissions 1n 1968 were estimated at -6500 mt, or -37% of total U.S.
emissions (see Table 3-10). Production levels have decreased somewhat; pig
Iron production 1n 1980 was 78% of 1968 levels, and 1980 steel production
was 85% of 1968 levels (DeHuff, 1961-1980; OeHuff and Jones, 1981).
3.4.2.3. FOSSIL FUEL COMBUSION — Manganese 1s emitted to the atmo-
sphere by the burning of coal and other fuels containing natural trace
levels of manganese. The use of manganese fuel additives constitutes an
additional source. The average and range for mang/artese concentration 1n
various fuels and preparations are shown 1n Table 3-12. The range of manga-
nese content 1n coal ash 1s presented 1n Table 3-13.
1797A 3-33 5/03/83
-------
US
—J
3>
TABLE 3-11
Estimated Manganese Emissions from Controlled Submerged-Arc Furnaces Producing Manganese Alloys
Furnace Type
Open
Open
\jj Open
-e-
Seml-sealed
Semi-sealed
Semi -sealed
Totally sealed
Product
slllcomanganese
slllcomanganese
high carbon
ferromanganese
slllcomanganese
high carbon
ferromanganese
high carbon
ferromanganese
slllcomanganese
Control Type
scrubber
scrubber
scrubber
scrubber
scrubber
scrubber
scrubber
Control Efficiency
(X)
99.1
94. Ob
97
>99.1b
>99.1b
98b
NA
Partlculate
Emission Factor
(kg/mt product)
0
3
0
0
0
0
0
.73
.25
.79
.05
.03
.16
.062
Manganese
Emission Factor
(kg Mn/mt product)
0
0
0
0
0
0
0
.15
.65
.16
.010
.015
.08
.012
U
U
U
U
U
U
U
Reference
.S.
.S.
.S.
.S.
.S.
.S.
.S.
EPA,
EPA.
EPA,
EPA.
EPA,
EPA,
EPA,
1971
1971
19816
1971
1971
1981b
1979b
aAssumes manganese content of partlculate Is 20X.
bDoes not Include losses during tapping of the metal.
rsj
-j
co
CO
-------
CD
TABLE 3-12
Manganese Concentrations of Coal, Fuel 011,
Crude 011, Gasoline, Fuel Additives and Motor 011*
co
I
CO
in
IV)
CO
CO
Samp 1 e
Coal
Residual fuel oil
Crude oil
Regular gasoline
Brand A
Brand B
Premium gasoline
Brand A
Brand B
Fuel additives
Gas treatment
Fuel-mix tune up
Engine tune up
Gas power booster
Gas treatment
Gasoline antifreeze
Gas booster
Carburetor tune up
Motor oil
Number
of Samples
76
20
20
10
9
10
8
3
3
3
3
3
3
6
3
4
Average
Concentration
37 ug/g
0.136 ug/g
0.031 ug/g
-------
TABLE 3-13
Manganese Content in Coal Ash*
Type of Coal Range of Content
(X)
Pennsylvania Anthracite 0.005-0.09
Texas, Colorado, North 0.01 -1.0
and South Dakota
West Virginia 0.012-0.18
Montana 0.33
Alabama 0.04-0.05
*Source: Abernathy et al., 1969
1797A 3-36 4/27/83
-------
Coal combustion was estimated to be the source of -11% of total manga-
nese emissions 1n 1968 (see Table 3-10). The emission factor assumed an
average manganese content of 26.4 ug/g 1n coal, and penetration to the
atmosphere of -1654 (U.S. EPA, 1971). U.S. consumption of coal 1n 1980 was
640.4x10 mt, an Increase of -39% over 1968 (Energy Information Adminis-
tration, 1980). However, recent measurements from coal-fired power plants
equipped with electrostatic predpHators (ESPs) showed manganese penetra-
tions of 0.07-0.13% for one plant, and 1.6% for another plant with partial
ESP malfunction (Ondov et al., 1979). Estimates of average penetrations for
the range of plants currently operating are not available.
While collection efficiencies may be high, some evidence Indicates that
metal concentrations are higher 1n the smaller-diameter particles which are
less efficiently collected. Analyses of s1ze-fract1oned fly-ash collected
from a coal-fired power plant predpHator showed that manganese concentra-
tions were highest (1090-1180 ug/g) 1n particles of 0.2-1.5 um, whereas
concentrations of 500-800 ug/g were found among particles of 3 to >140
urn (Smith et al., 1979). A similar trend but with lower concentrations
(150-470 ug/g, Increasing as particle size decreases) was found 1n air-
borne material not retained by a cyclonic predpUator In another coal-fired
power plant (Davlson et al., 1974). The elemental mass median diameter for
manganese for the two ESP-equ1pped plants described above was -2.3 um
for the more-efficient and -8.2 u"" for the less-efficient ESP (Ondov et
al., 1979).
The manganese content of petroleum 1s lower by >2 orders of magnitude
than that of coal (see Table 3-12). Therefore, regardless of changes 1n
residual fuel oil combustion and emission control practices, oil combustion
constitutes a minor source of ambient manganese.
1797A 3-37 4/30/83
-------
P1ver (1974) reported that MMT production prior to Us use In unleaded
fuel was -500 tons/year, or -125 tons as manganese. Vouk and P1ver
(1983) estimated that 1n 1977, during MMT use 1n unleaded fuels, 20% of the
9
110x10 gallons of gasoline consumed contained MMT at 0.125 g Mn/gal, or
-3000 tons as manganese. Estimates of the percentage of manganese emitted
from the tailpipe range from 15-30% of the amount burned (Ethyl Corporation,
1972; Plerson et al, 1978), resulting 1n an estimate of 450-900 tons of
manganese emitted per year during the peak of MMT use. The manganese 1s
emitted primarily as Mn 0 , 1n particles of 0.30-0.38 vim mass median
diameter (Ethyl Corporation, 1972). The manganese content of partlculate
from two automobiles burning gasoline containing MMT (at 0.125 g/gal) ranged
from 1.4-3.1%, and averaged 3.0% (Ethyl Corporation, 1973). Current use of
MMT at -0.05 g Mn/gal 1n -20% of leaded gasoline (Hall, 1983) results 1n
a substantially lower emissions estimate than that given for 1977.
3.4.3. Relative Importance of Manganese Sources at Several Locations as
Determined by Mass Balance and Enrichment Models. The availability of
Increasingly sensitive analytical techniques for determining the elemental
composition of ambient airborne partlculate matter has enabled the use of
statistical methods to Identify the most likely emission sources. Elemental
composition patterns for ambient partlculates at a "receptor" or monitoring
site can be compared with known or statistically constructed composition
patterns for particles from a number of sources. Using chemical mass
balance techniques, the total ambient aerosol mass and the mass of each
element at the receptor can then be apportioned among the sources (Cooper
and Watson, 1980; Alpert and Hopke, 1981; U.S. EPA, 1981a). The separation
of coarse (e.g., >2.5 vim) and fine particle fractions by a dlchotomous
1797A 3-38 4/27/83
-------
sampler can result 1n better resolution of sources (Ozubay, 1980; Alpert and
Hopke, 1981). Many applications of source apportionment techniques have
Included data on manganese.
In the Portland Aerosol Characterization Study, a priori determination
was made of the elemental composition of aerosols from several sources
(Table 3-14) (Cooper and Watson, 1980; U.S. EPA, 1981a). The manganese
component varied from 173 mg/g, for ferromanganese furnace emissions, to
"0 mg/g", for leaded automobile exhaust. The elemental compositions for
several sources (soil, road dust, asphalt production, rock crusher and coal
fly ash) were so similar that they could not readily be distinguished; the
manganese concentration of these aerosols varied only from 0.3-2 mg/g
(Cooper and Watson, 1980).
Dzubay (1980) used six source terms for apportioning Regional A1r Pollu-
tion Study (RAPS) data from dlchotomous samplers 1n St. Louis, Missouri.
Some of the terms used were composites, representing several natural and
anthropogenic processes which could not be distinguished. The crustal-shale
component Included soil or dust suspended by wind or human activities (e.g.,
vehicle traffic, earth-moving, argrlculture, etc.), partlculates from
quarrying or other manufacturing processes, and/or fly ash. The crustal-
Hmestone component Included suspended calc1um-r1ch soil, cement dust from
vehicles or cement manufacture, and/or other manufacturing processes. The
term for steel Industry emissions might also have Included natural or
anthropogenic suspension of Iron-rich soil. The elemental compositions for
source aerosols were assigned a^ priori. based on data from various studies.
The manganese component of each source, and the estimated contribution of
each source to ambient manganese and total aerosol mass are given for the
coarse particle fraction at one St. Louis receptor site (site 106) for
1797A 3-39 5/03/83
-------
TABLE 3-14
Manganese Concentration 1n Fine (<2.0 vim) and Coarse (2.0-20 urn)
Particle Fractions of Aerosols from Several Sources 1n the
Portland Aerosol Characterization Study*
Aerosol Source
Marine
Soil
Road dust
Leaded auto exhaust
Residual oil combustion
Distillate oil
Vegetative Burn 1
Vegetative Burn 2
Kraft recovery boiler
SulfHe recovery boiler
Hog fuel boiler
Aluminum processing
Steel electric furnace
Ferromanganese furnace
Carborundum
Glass furnace
Carbide furnace
Asphalt production
Rock crusher
Coal fly ash
Mn Concentration
Fine Particles
NR
2.0
1.23
0.0
0.46
0.14
1.2
0.47
0.3
0.54
5.1
0.11
87
173
0.35
0.021
0.42
2.0
0.8
0.3
(mq/q)
Coarse Particles
0.0
0.85
1.0
0.0
0.46
NR
1.2
0.47
5.2
0.54
2.9
0.0
87
173
0.29
0.031
0.36
NR
NR
NR
*Source: U.S. EPA, 1981a; Cooper and Watson, 1980
NR = Not reported
1797A
3-40
4/27/83
-------
August and September, 1976 (Table 3-15). Dzubay et al. (1981) used similar
source terms 1n an analysis of data for January, 1979, from a single dlcho-
tomous sampler 1n Denver, Colorado. These source apportionment data for
both fine and coarse particle fractions are also shown 1n Table 3-15. A
comparison of coarse particle sources for the St. Louis and Denver sites
shows that the proportion of manganese contributed by the crustal-shale
source was much greater In Denver, 1n the absence of the paint pigment and
steel sources found 1n St. Louis. Comparison of fine and coarse fractions
1n Denver shows that while crustal-shale was the predominant source of man-
ganese 1n coarse particles, vehicle exhaust evidently was the main manganese
source 1n fine particles.
Hopke and coworkers (Alpert and Hopke, 1981; L1u et al., 1982) applied
target transformation factor analysis (TTFA) to other subsets of the St.
Louis RAPS data. In TTFA, source aerosol composition 1s determined through
both a priori knowledge of source characteristics and a posteriori selection
and adjustment based on factor analysis and chemical element balance tech-
niques applied to the receptor data set. These source refinement methods
were applied Individually to fine and coarse data sets at RAPS site 112 for
July and August, 1976 (Table 3-16, part A), and to all 10 St. Louis RAPS
sites during a single week beginning July 31, 1976 (Table 3-16, part 8)
(Alpert and Hopke, 1981).
A direct comparison of the TTFA results with those of Dzubay (1980) for
St. Louis 1s not possible since the same data sets were not used. The stud-
ies evidently detected differences 1n aerosol sources among the sites. Site
106 (see Table 3-15) and several of the other sites (Table 3-16, part B) are
located In close proximity to Iron works and foundries, whereas site 112
(Table 3-16, part A) 1s not. These differences are reflected 1n the absence
1797A 3-41 4/27/83
-------
N>
TABLE 3-15
Manganese Concentration 1n Aerosols from Various Sources, and Estimated Percent Contribution of Each Source to Observed
Ambient Manganese and Total Aerosol Mass at Two Sites
Source
FINE PARTICLES**
Ammonium sulfate
Motor vehicle exhaust
Crustal-shale6
Crustal-Hmestone6
Road salt
Refuse Incineration
COARSE PARTICLES'1
Ammonium sulfate
Motor vehicle exhaust
Crustal-shale8
Crustal-Hmestone6
Paint pigment
Steele
Road salt
Refuse Incineration
Mn 1n Source
Aerosol (mg/g)
0.0
0.6
0.85
1.1
0.0
0.7
0.0
0.6
0.85
1.1
4.0
31.0
0.0
0.7
St. Louis. MO RAPS
Contribution to Ambient
Aerosol Mass (X)c
NR
NR
NR
NR
NI
NI
7.1
4.5
51.5
29.4
3.4
1.9
NI
NI
Site 106a
Contribution to
Ambient Mn (X)c
NR
NR
NR
NR
NI
NI
0.0
2.9
34.3
25.7
8.6
48.6
NI
NI
Denver. CO SHeb
Contribution to Ambient
Aerosol Mass (X)c
15.8
25.3
2.2
0.5
1.1
0.2
0.4
7.3
54.0
2.5
NI
NI
10.9
0.6
Contribution to
Ambient Mn (X)c
0
80
20
0
0
0
0
5.6
66.7
5.6
NI
NI
0
0
aDer1ved from Dzubay, 1980
bOer1ved from Dzubay et al., 1981
Percentages may not sura to 100X when model under- or overestimates Mn concentration or aerosol mass.
dSt. Louis study: fine <2.4 vm, coarse 2.4-20 vn. Denver study: fine <2.5 urn. coarse 2.5-15 um
^Composite of natural and anthropogenic sources; see text
NI » Not Included In analysis for this site; NR = not reported
00
OJ
-------
TABLE 3-16
ID
~J
3>
Manganese Concentration In Aerosols from Various Sources, and Estimated
Percent Contribution of Each Source to Observed Ambient Mn and Total
Aerosol Mass, Based on Target Transformation Factor Analysis.3
Source
Mn 1n Source
Aerosol (mg/g)
Contribution to Ambient
Aerosol Mass (%)
Contribution to
Ambient Mn (X)b
A. RAPS Site 112, St. Louis, MO, July and August, 1976
CO
I
CO
FINE FRACTION (<2.4 urn)
Motor vehicle
Sulfate
Fly ash/Soil
Paint
Refuse Incineration
Unknown
COARSE FRACTION (2.4-20
Soil
Limestone
Sulfate
Paint
0.0
0.0
0.7
4.8
8.6
NR
0.8
1.6
1.0
1.2
15
65
11
1
4
4
54
27
12
7
0.0
0.0
13.5
11.8
64.7
NR
38.5
38.5
10.3
7.7
oo
CO
B. 10 RAPS Sites, St. Louis, MO, Week of July 31, 1976
FINE FRACTION (<2.4 vm»)
Sulfate
Steel
Motor vehicle
Zinc/Lead smelter
Unknown
0.0
7.1
0.7
0.8
NR
84
7
6
2
1
0.0
83.3
6.7
4.2
NR
-------
10
TABLE 3-16 (cont.)
Source
Hn 1n Source
Aerosol (mg/g)
Contribution to Ambient
Aerosol Mass (X)
Contribution to
Ambient Mn (X)b
COARSE FRACTION (2.4-20 urn)
Son
Steel
Limestone
Sulfate
Soil/Fly ash
Unknown
1.1
23.0
0.0
1.7
0.0
NR
31
5
39
11
10
4
21.7
75.0
0.0
11.3
0.0
NR
CO
I
-p»
.£»
aDer1ved from Alpert and Hopke, 1981
Percentages do not sum to 100X because model slightly under- or overestimated Mn concentration.
NR = Not reported
00
CO
-------
of a resolvable steel source at the latter site. However, the refinement of
sources by TTFA results 1n certain Irregularities where a minor element such
as manganese 1s concerned. The attribution of coarse-fraction manganese to
a sulfate source term (Table 16) was acknowledged by the authors to be
Irregular. This result may be a sampling artifact (I.e., due to condensa-
tion of SOp on coarse Mn-conta1n1ng particles) or may result from "source
lumping" due to an Inability to resolve other minor, manganese-containing
sources. The absence of manganese from the limestone and soil/fly ash
source terms (Table 3-16, part 8) 1s also rather Implausible, and further
Indicates the deficiencies of this technique.
In source apportionment studies of partlculates 1n New York City, manga-
nese was used as a tracer for suspended dust and soils (Klelnman et al.,
1980; Knelp et al., 1983). Regression models were used to derive coeffic-
ients relating tracer mass 1n ambient air to mass of partlculates from the
traced source. Other sources which also undoubtedly contributed to airborne
manganese, such as vehicle emissions, fuel oil burning, and Incineration,
were traced by other elements. Since the manganese concentration 1n dust
and soil probably 1s relatively stable, changes 1n the manganese coefficient
over time are probably related (Inversely) to changes 1n relative contribu-
tions from nonsoll-related sources. From the period 1972-1973 to the period
1977-1978, the manganese coefficient ( + S.E.) for total suspended partlcu-
late (TSP) Increased from 4204-200 to 840+311, Indicating a substantial
reduction of manganese emissions from nonsoll sources. These changes would
be expected due to the elimination of MMT usuage 1n unleaded gasoline and
reduction of Incineration during this period (Klelnman et al., 1980; Knelp
et al., 1983). A concommltant reduction 1n mean TSP from 82+2 to 54+2
3
v.g/m was seen during this period. However, during the period
1797A 3-45 4/30/83
-------
1979-1980, a decrease 1n the manganese coefficient to 670+160 seemed to
Indicate Increasing nonsoll contributions, and was accompanied by an
3
Increase 1n mean TSP to 66^2 iig/m (Knelp et al., 1983).
A simpler method for making Inferences about partlculate sources from
receptor data Is by the use of an enrichment factor (EF) model. The ratio
of the concentration of the element 1n question to that of a reference
element 1s compared for an ambient aerosol and a background aerosol or
source material, to determine whether the element 1s enriched with respect
to the reference element (Cooper and Watson, 1980). The crustal contribu-
tion of manganese to ambient aerosols has been evaluated using aluminum as a
crustal reference element, as follows:
(Mn/Al) a1r
Crustal EF =
(Mn/Al)
crust
Values for elements arising exclusively from crustal material should be near
unity, although some variation would be expected due to natural variations
1n soil (see Section 3.4.1.). As mentioned previously, crustal material
suspended by natural processes 1s Indistinguishable by these methods from
crustal material suspended by human activities. However, values of crustal
EF for elements such as lead, which are highly enriched from noncrustal
4
sources, may be as high as 10 (Bernstein and Rahn, 1979; Lewis and
Madas, 1980).
Ouce et al. (1974) reported a crustal EF of 2.6 for manganese over the
Atlantic Ocean north of 30°N. Bernstein and Rahn (1979) reported the
elemental composition of fine (<2.5 um) and total aerosol from New York
City for August, 1976. They derived a crustal EF for manganese of 4.6, and
also reported EF values of 5.7, 0.56 and 0.54 for Philadelphia, Bermuda and
Tucson, respectively. Although the latter two values were lower by a factor
of 10, manganese was not considered to be enriched 1n the New York aerosol.
1797A 3-46 4/27/83
-------
However, these EF values were based on total aerosol analyses. Calculation
of EF for the fine particle fraction alone gives a value of 14.3, or =3
times higher.
Bernstein and Rahn (1979) used a crustal Mn:Al ratio of 0.011 to calcu-
late crustal EF for manganese. Very similar ratios are found by examining
the "crustal-shale" composition data used by Dzubay (1980) and Dzubay et al.
(1981), and the soil, road dust and rock-crusher aerosol composition data
reported by Cooper and Watson (1980). Using this ratio as a crustal refer-
ence, the EF model was applied to dlchotomous sampler data sets for St.
Louis, MO (Stevens et al., 1978; Dzubay, 1980; Alpert and Hopke, 1981),
Charleston, WV (Stevens et al., 1978; Lewis and Madas, 1980), Denver, CO
(Dzubay et al., 1981), Houston, TX (Dzubay et al., 1982) and several other
cities (Stevens et al., 1978). Crustal EF for the coarse aerosol fraction
(the lower size cut-off varying from 2.0-3.5 urn) ranged from 0.35-4.76
with an unweighted mean value of 1.9. For the fine fraction, values ranged
from 1.83-38.8, with a mean of 14.4. The ratio crustal EF (fine fraction):
crustal EF (coarse fraction), ranged from 2.02-28.9, with a mean of 8.1.
Thus, 1t can be Inferred by this rough Illustration that manganese 1n coarse
aerosol fractions tended to be associated with aluminum 1n ratios found 1n
crustal material. Lower relative concentrations of aluminum 1n fine frac-
tions Indicated a greater Influence of noncrustal manganese sources 1n fine
than In coarse particles In ambient aerosols.
The above conclusions were reached based on data sets which were
averaged over time and/or local geography. However, a single sample from
one St. Louis site (RAPS site 108) strongly Influenced by steel processing
showed an EF for the coarse fraction (16.9) slightly greater than that for
the fine fraction (15.6) (Dzubay, 1980). Therefore, Industrial processes
1797A 3-47 4/27/83
-------
may be expected to have local Influence on manganese levels 1n the coarse
particle fraction, but this Influence 1s likely to be less pervasive than
fine fraction enrichment, due to the more rapid deposition of the larger
particles (Klelnman et al., 1975).
3.5. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES
3.5.1. Principal Cycling Pathways and Compartments. Garrels et al.
(1975) presented the pre-human cycle and the present-day cycle of manganese
(Figure 3-1). Manganese, an element of low volatility, tends to settle out
near sources of pollution and to be of concern 1n local or regional environ-
mental problems. However, fine partlculate materials containing manganese
can be distributed world-wide. According to Garrels et al. (1975), the
major exchange of manganese between the atmosphere and the pre-human earth
surface was due to continental dust being swept Into the atmosphere by winds
and then falling back onto the earth's surface. Today this dust flux 1s
augmented by manganese emitted to the atmosphere In partlculate form by
Industrial activities. The total river flux of manganese to the ocean today
1s estimated to be nearly three times the pre-human flux. This Increase
represents principally an Increase 1n the rate of stripping the land's
14
surface from about 100x10 g/year pre-human to today's rate of about
14
225x10 g/year. Because this Increase 1n stripping reflects an Increase
1n the load of suspended solids to rivers from deforestation and agricultur-
al activities, and because manganese 1s concentrated 1n the ferric oxide
coatings on suspended material and 1n the suspended particles, the land-to-
ocean manganese flux Is higher today than 1n the past. Manganese 1n partlc-
ulate emissions from Industrial activities rivals the natural Input of con-
tinental dust to the atmosphere. Most partlculate manganese probably falls
out of the atmosphere near Industrial sources.
1797A 3-48 5/03/83
-------
us
PRE-MAN CYCLE
PRESENT DAY CYCLE
/ /
LAND
0000000
RIVERS
572
»
OCEANS
38000
I
CO
I
US
VOLCANISM
HATC ALTERATION
SEDIMENTATION
615
SEDIMENTS
I LOSS OK)) V
aEDIMENTAIION
(6)7
VOtCAMSM
MAFIC ALTERATION
FLUXES Kf g yr' ; RESERVOIR MASES »°g
00
CO
FIGURE 3-1
The Global Cycles of Manganese
Source: Garrels et al., 1975
-------
The mining of manganese ore has resulted 1n a net gain for the land
reservoir and a net loss from the sediment reservoir. There Is no evidence
of change over time 1n dissolved manganese 1n the oceanic reservoir (Garrels
et al., 1975).
3.5.2. Atmospheric Fate and Transport.
3.5.2.1. CHEMICAL FORMS PRESENT IN THE ATMOSPHERE — Soils, dust and
other crustal materials containing naturally-occurring manganese compounds
enter the atmosphere as a result of natural and anthropogenic processes (see
Section 3.4.1.). While a number of ores exist (see Table 3-9), the most
common forms of manganese 1n rocks and soils are oxides and hydroxides, of
oxidation states +2, +3 and +4, and manganese carbonate (Hem, 1970). These
are undoubtedly the most common manganese compounds 1n the coarse partlcu-
lates of crustal origin. Like soils, these particles usually contain manga-
nese at concentrations of <1 mg/g (<0.1%) (see Section 3.4.1. and Tables 14,
15 and 16).
The manganese emitted by metallurgical processes Is normally described
as consisting of oxides (see Section 3.4.2.). Manganese from combusted MMT
1s emitted primarily as Mn.,0. (Ethyl Corporation, 1972). Much of the
partlculate released from these processes Is 1n the fine range (<2.5 v-m).
Fine partlculate from fly ash usually 1s no more highly enriched 1n manga-
nese than are soils, but the fine particles arising from metallurgy and MMT
combustion are enriched, with manganese concentrations ranging from 14-250
mg/g (1.4-25%) (see Sections 3.4.2., 3.4.3. and Tables 3-10 and 3-14).
Minute amounts of organic manganese compounds may be present 1n ambient
air under certain conditions. Ethyl Corporation (1972) analyzed the exhaust
products of three cars operating on gasoline containing an abnormally high
level of MMT (1.25 g Mn/gal). About 0.1-0.5% of the manganese burned was
1797A 3-50 4/27/83
-------
emitted In organic form. However, these authors found that MMT was rapidly
photodegraded to Inorganic manganese 1n sunlight; estimated half-life was
10-15 seconds. They estimated that, for cars meeting 1975 emissions
standards and an MMT use rate of 0.125 g Mn/gal, ambient MMT concentration
would be 0.12-0.48 ng MMT/m3 (0.03-0.12 ng Mn/m3) 1f photodegradatlon
a 3
were neglected, and <0.048 ng MMT/m (<0.012 ng Mn/m ) 1f photodegrada-
tlon were considered (Ter Haar et al., 1975).
Coe et al. (1980) used gas chromatography-atomlc absorption spectrometry
to measure MMT levels 1n air 1n Canada, where MMT Is still 1n use 1n unlead-
3
ed fuels. With a detection limit of 0.1 ng MMT/m , they were unable to
detect MMT 1n samples of auto exhaust from unleaded gasoline (emission
3
control system unspecified). With a limit of 0.05 ng MMT/m , they could
not detect MMT on Toronto streets. MMT detected 1n an underground car park
3
at levels of 0.1-0,3 ng/m was presumed to arise from fuel evaporation or
spillage, rather than exhaust emissions (Coe et al., 1980).
3.5.2.2. ATOMSPHERIC REACTIONS — Except for the photodegradatlon of
MMT, very little Information 1s available on the atmospheric reactions of
manganese. Manganese dioxide can react with sulfur dioxide or nitrogen
dioxide to form manganous sulfate (MnSO.) and dlthlonate (MnS_0,) or
manganese nitrate [MnfNO,,)-], respectively (Hay, 1967; Schroeder, 1970).
Various oxides of manganese (MnO, Mn-O,,, MnO^), used as absorbants,
have been shown to combine with sulfur dioxide 1n heated flue gases (B1en-
stock and Field, 1960). The possibility of these reactions occurring In the
atmosphere has been recognized (Sullivan, 1969; P1ver, 1974) but occurrence
or reaction rates have not been demonstrated.
1797A 3-51 4/30/83
-------
It has been shown that aerosols of manganous sulfate can catalyze the
oxidation of atmospheric sulfur dioxide to sulfur trloxlde, thus promoting
the formation of sulfurlc add (Matteson et al., 1969; Sullivan, 1969;
P1ver, 1974):
MnSO, +2H-0
4 2
2S00 + 00 -2SO,, ^2H0SO,
c i. 3 24
It has been reported that under foggy conditions, an atmospheric manganese
concentration of 0.2 ug/m3 and a sulfur dioxide concentration of 1750
3 3
ug/m would result 1n a sulfurlc add formation rate of 25 ug/m /hr,
or a conversion rate of 1.4%/hr (Bracewell and Gall, 1967; Sullivan, 1969).
Extrapolations from the experimental data of Matteson et al. (1969) suggest
3 3
that at concentrations of 259 ug S02/m and 2 ug Mn/m , a rate of
~0.04%/hr would be observed (Wright et al., 1973).
A test was conducted to determine the catalytic effect of exhaust prod-
ucts from a car burning MMT-conta1n1ng fuel on the disappearance of SO,, 1n
ambient air (Wright et al., 1973). In the absence of manganese, at a rela-
tive humidity of 90-100% and an S02 concentration of 35 ug/m3, the
rate constant for S02 disappearance was 14%/hr. This unusually high rate
was attributed primarily to 1mpact1on on the black polyethylene bag In which
the experiment was conducted. Addition of exhaust to give a manganese
o
concentration of 4 ug/m , a level much higher than normally encountered
1n ambient air (see Section 3.6.1.), did not noticeably affect this rate,
although manganese concentrations >30 ug/m3 did Increase the rate
constant. On the other hand, addition of 20 ug/m of ammonia, an amount
probably about equal to the ammonia already present 1n ambient urban air,
caused the rate constant to double. The authors concluded that ambient
ammonia was therefore the rate-controlling factor for SO oxidation, and
1797A 3-52 4/30/83
-------
that addition of MMT to gasoline would have no measurable effect. However,
this conclusion with respect to manganese 1s weakened by the apparent magni-
tude of the container effect, and because the control contained no exhaust,
rather than manganese-free exhaust.
3.5.2.3. DRY AND WET DEPOSITION -- Atmospheric partlculate matter,
Including manganese, 1s transported by air currents until 1t 1s lost from
the atmosphere by either dry or wet deposition.
Dry deposition rate 1s strongly affected by particle size. Klelnman et
al. (1975) studied the deposition of nine metals 1n New York City. Particle
deposition velocity was calculated by comparing the amount deposited with
the air concentration Immediately above the collection surface. Deposition
velocity was lowest (1.1 cm/sec) for lead, which was mainly associated with
small particles [mass median aerodynamic diameter (MMAD) = 0.56 urn].
Manganese had the highest velocity (10.4 cm/sec), and a larger particle size
(MMAD = 1.3 \an). Dry deposition of manganese at three New York City sites
? 2
averaged 300-670 ng/cm /month and ranged from 24-1700 ng/cm /month.
Assuming total transfer of partlculates to runoff, dry deposition resulted
In an estimated manganese concentration In urban runoff of 39 vuj/i. or
about 120 kg/day discharged to New York Harbor (Klelnman et al., 1975).
By comparison, average wet deposition of manganese In New York reported-
p
ly was 120 ng/cm /month, stemming from a rainfall concentration of 19 ug
Mn/8, (Volchok and Bogen, 1973). Thus, manganese deposited 1n dustfall was
more than twice that In rainfall.
Manganese deposition 1n precipitation at ~30 stations throughout the
U.S. In September 1966-January 1967 was reported by Lazrus et al. (1970).
p
Amounts deposited ranged from undetectable (<10 ng/cm /month), for Mauna
1797A 3-53 4/30/83
-------
Loa, Hawaii; Amarlllo, Texas; and Tampa, Florida to levels of 200-300
2
ng/cm /month for Chicago, Illinois and Sault St. Marie, Michigan. An
2
unusually high value of 540 ng/cm /month was observed 1n Caribou, Maine.
The latter dty 1s located 1n AMstook County, an area of low-grade manga-
nese ore deposits. The average value was -80 ng/cm2/month, and the
average manganese concentration In precipitation was -12 ug/8. (Lazrus
et al., 1970).
None of the above measurements was made 1n the Immediate vicinity of a
major Industrial source. Dry deposition of manganese was measured 1n a
1965-1966 study of air pollution 1n the Kanawha Valley, West Virginia
(NAPCA, 1970). In the two communities nearest a ferromanganese plant,
2
manganese deposition averaged 19,300 and 2700 ng/cm /month, respectively.
2
Deposition 1n other locations 1n the valley ranged from 80-320 ng/cm /
month (see Section 3.6.1.2.).
3.5.3. Fate and Transport 1n Water and Soil.
3.5.3.1. CHEMICAL FORMS IN SOLUTION -- The aqueous chemistry of
manganese 1s complex, as manganese can be present 1n II, III, IV, VI and VII
oxidation states. Mn(II) and Mn (IV) are the oxidation states most commonly
found. In neutral and add aqueous solutions, the II state exists as the
hexaquo 1on, [Mn(H20)6]* , which 1s unstable with respect to oxidation
by 02 over the entire pH range of natural water (Morgan, 1967). The maxi-
mum concentration of soluble Mn* In many natural waters Is limited by the
solubility product of MnC03. With low alkal1nH1es and reducing condi-
tions 1n freshwaters, solubility may be restricted by high sulflde concen-
trations.
The possible chelatlng Influence of natural organic compounds 1n natural
waters was studied on a hypothetical multlmetal, mult1-!1gand system.
1797A 3-54 4/30/83
-------
Calculations were performed simultaneously by Morel and Morgan (1972) and
by Stumm and B1l1nsk1 (1972), and both concluded that a free manganese Ion
may be present as a predominant species even 1f complex-forming organic
matter 1s present.
In water or soil of pH >8 or 9, the soluble divalent manganese 1on 1s
chemically oxidized to the Insoluble tetravalent form. At pH <5.5, chemical
reduction of the tetravalent form takes place. However, the Interconverslon
of these forms which 1s commonly observed at Intermediate pH occurs only by
microblal mediation (Alexander, 1977; Konetzka, 1977).
Groundwater has different manganese equilibria than surface water
because of the oxygen-poor environment. Nlchol et al. (1967) suggested that
1n add, water-logged soils, manganese passes freely Into solution and
circulates In the groundwater. On entering stream waters with average pH
and biological oxidation potential (Eh)» manganese 1s precipitated, thus
giving rise to stream sediments enriched with manganese. Mitchell (1971)
also showed that the mobilization of manganese was greatly enhanced 1n add,
poorly drained podzollc soils and groundwaters. Josephson (1980) found that
manganese exists 1n a reduced state 1n groundwater and that 1t can be
readily leached from waste sites or from natural sources. High levels of
divalent manganese may also be found 1n add mine drainage (see Section
3.6.2.).
Various opinions exist regarding the dominant form of manganese 1n
seawater. According to Slllen (1961), the dominant form of manganese 1s
Mn(OH) or Mn(OH) . Moklevskaya (1961) and Spencer and Brewer (1971)
O T"
found that 1n water of the Black Sea, the dominant form of manganese was the
divalent form. Fukal and Huynh-Ngoc (1968) found that divalent manganese
remained 1n that form 1n seawater for a long period of time. According to
1797A 3-55 4/30/83
-------
Breck (1974), the main species are MnO? and/or Mn304- Ahrland (1975)
considered that dispersed Mn02(s) 1s predominant. Musan1-Marazov1c and
54
Pucar (1977) concluded that Mn Introduced 1n divalent form Into seawater
behaves as a cation.
3.5.3.2. MICROBIAL TRANSFORMATION -- Bacteria are Important agents 1n
determining the form and distribution of metals 1n the environment.
Alexander (1967) described how the availability of manganese 1n soil or
water 1s affected by microorganisms. Several processes can occur: release
of Inorganic manganese Ions during decomposition of organic material;
Immobilization of Ions by Incorporation Into mlcroblal tissue; oxidation of
manganese to a less available form; direct, enzymatic reduction of oxidized
manganese; or Indirect transformation (especially reduction) through changes
1n pH or E . Saxena and Howard (1977) also concluded that bacteria play a
major part 1n the modification, activation and detoxification of heavy
metals.
For example, manganese usually enters a lake 1n the Insoluble oxidized
form, which settles to the sediment. Manganese-reducing bacteria may be
active 1n the sediments, or manganese may be reduced by the lowering of pH
resulting from general mlcroblal activity (I.e., 0 consumption or the
production of addle metabolites) (Kuznetsov, 1970; Alexander, 1977). In
the first case the reduction 1s enzymatic; 1n the second 1t 1s nonenzymatlc.
Reduced manganese then diffuses upward 1n the sediment or Into the water
column. In Lake Pannus-Yarvl of the Karelian Isthmus (USSR), Iron- and
manganese-reducing bacteria are present 1n the upper 10 cm of the sediments.
Reduced manganese 1n the bottom waters of the profundal zone reaches 1.4
mg/8., whereas the total manganese concentration 1n the rest of the lake 1s
only 0.01 mg/a, (Kuznetsov, 1970).
1797A 3-56 4/30/83
-------
Manganese-oxidizing bacteria can be divided Into two functional groups.
The first are Included among the "Iron bacteria," or "that group of aerobic
bacteria which appear to utilize the oxidation of ferrous and/or manganous
Ions as an essential component 1n their metabolic functioning" (CulUmore
and McCann, 1977). These have been assumed to be chemoautotrophs, utilizing
energy from the reduction of manganese to carry out synthetic processes
(Kuznetsov, 1970), but others have questioned this conclusion (Alexander,
1977; Konetzka, 1977). The second group consists of heterotrophs possess-
ing a slime capsule that can absorb divalent manganese. Oxidation then
occurs within the sheath, which becomes Impregnated with the hydroxide
(Kuznetsov, 1970).
Divalent manganese entering the water column from the sediments 1s
precipitated by these organisms, usually 1n the form of hydroxides. This
leads to a repetition of the redox cycle. However, 1n lakes such as
Pannus-Yarvl where bottom currents carry the reduced manganese out of the
profundal zone and Into more shallow and highly oxygenated areas, microblal
oxidation 1n the sediments can lead to the formation of manganese lake ores
(Kuznetsov, 1970).
Bacterial oxidation of Mn * has also been Implicated 1n the formation
of manganese nodules on the ocean floor (Silver and Jasper, 1977). However,
this conclusion 1s far from certain, as some nodule-associated bacteria
catalyze manganese accretion via oxidation while others catalyze manganese
reduction (Ehrllch, 1972).
Iron bacteria can be a tremendous nuisance In water supply systems
because of their tendency to foul pipes and other surfaces with Iron or
manganese oxides. This problem Is especially acute 1n wells 1n many regions
of the world. Most study of conditions contributing to these problems has
focused on Iron rather than manganese, and the role of the latter remains
1797A 3-57 4/30/83
-------
poorly understood (Culllmore and McCann, 1977). Luthy (1964) stated that
0.05 mg Mn Vft 1s undesirable because of discoloration of the water, and
that measures for bacterial control should be taken at levels >0.15 mg
Mn /ft. Control measures Include sterilization of equipment before
drilling of wells, and treatment of affected systems by chlorlnatlon, acidi-
fication, or other antibacterial agents (CulUmore and McCann, 1977).
In the soil, microorganisms play an Important role 1n determining the
availability of manganese to plants. Several genera of bacteria and fungi
are capable of oxidizing soil manganese, many even under slightly add
conditions. Numerically, the manganese oxldlzers may constitute up to 5-15%
of the total viable mlcroflora. Addition of organic matter to soils can
Increase manganese oxidation by stimulating population Increase of these
groups (T1mon1n and Giles, 1952). Since the oxides are less available or
unavailable to plants, symptoms of manganese deficiency may result
(Alexander, 1977).
Regeneration of reduced manganese may be enzymatic or nonenzymatlc, as
1n water. The reduction proceeds more rapidly 1n poorly drained soils. In
such cases, manganese phytotoxldty may also occur (Alexander, 1977).
3.5.3.3. BIOCONCENTRATION — The tendency of a substance to be
concentrated 1n organisms will have an Important effect on Us ultimate
distribution 1n biological and nonblologlcal ecosystem compartments. Figure
3-2 shows an example of concentration factors for manganese 1n an estuarlne
system (Hudson River), determined by Lentsch et al. (1972). They observed
that filamentous algae have the greatest concentration factor, and the most
predatory organism has the lowest concentration factor. They also observed
that the higher organisms do not have higher concentration factors, as these
seem to be capable of regulating manganese. Thus, blomagnlf1cat1on or
Increasing accumulation with trophic level evidently was not occurring.
1797A 3-58 4/30/83
-------
03
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-------
3.6. ENVIRONMENTAL LEVELS AND EXPOSURE
3.6.1. A1r.
3.6.1.1. NATIONWIDE TRENDS -- In 1953, the U.S. PHS Initiated an air
sampling program 1n 17 cities. Some samples were analyzed Individually and
others as quarterly composites. Twelve nonurban samples collected 1n
1955-1956 at Point Woronzof, Alaska, showed an average manganese concentra-
tion of 0.01 ug/m3, with a maximum of 0.02 ug/m3 (U.S. DHEW, 1958).
Over 100 suburban samples collected at nine different locations 1n the
3
United States 1n 1954-1956 averaged 0.06 ug/m , with a maximum value of
3
0.50 ug/m 1n Kanawha County, West Virginia. Nearly 2000 urban samples
3
collected In 1953-1957 averaged 0.11 ug/m , with a maximum value of 9.29
3 3
at Cincinnati, Ohio 1n 1955. Concentrations >3.0 ug/m were
found 1n Anchorage, Alaska 1n 1954-1955, probably after volcanic eruption;
1n Philadelphia, Pennsylvania 1n 1954; and 1n Chattanooga, Tennessee 1n
1955-1956.
The National A1r Surveillance Network started analysis January 1, 1957,
at 26 randomly-selected stations 24 hours/day for 1 year. Comparison of
data from different years Involves problems because of changes 1n the
analytical methodology and the number and position of stations. However, an
examination of nationwide summaries of these data does permit a rough
assessment of national trends.
The data for all NASN sites for 1957-1969 are summarized 1n Table 3-17.
The sites are categorized Into four concentration ranges. Since urban and
nonurban data are not segregated and the majority of sites fall Into the low
3
range (<0.099 ug/m ), this display serves primarily to show the number
of urban sites with particularly high ambient manganese concentrations. A
comparison of 1957-1963 data with post-1963 data shows a clear decline 1n
3
the percentage of sites with concentrations >0.100 ug/m • Table 3-18
1797A 3-60 5/03/83
-------
TABLE 3-17
Number of National A1r Surveillance Network Stations within
Selected Annual Average Manganese A1r Concentration Intervals, 1957-1969*
Number and Percent of Stations
by A1r Concentration Interval, ng/m3
(percent shown 1n parentheses)
Year
1957-1963
1964
1965
1966
1967
1968
1969
1957-1969
<0.099
76
(59.4)
68
(73.1)
132
(84.1)
113
(88.3)
121
(85.2)
126
(86.9)
169
(80.9)
805
(80.4)
0.100-0.199
29
(22.7)
12
(12.9)
14
(8.9)
8
(6.3)
13
(9.2)
11
(7.6)
23
(11.0)
no
(11.0)
0.200-0.299
10
(7.8)
6
(6.5)
5
(3.2)
4
(3.1)
4
(2.8)
2
(1.4)
9
(4.3)
40
(4.0)
>0.300
13
(10.2)
7
(7.5)
6
(3.8)
3
(2-3)
4
(2.8)
6
(4.1)
8
(3.8)
47
(4.7)
Total
128
(100)
93
(100)
157
(100)
128
(100)
142
(100)
145
(100)
209
(100)
1002
(100)
*Source: NASN, 1957-1969
1797A
3-61
5/03/83
-------
TABLE 3-18
National A1r Surveillance Network Stations with
Annual Average Manganese A1r Concentrations
Greater Than 0.5
Year
1958
1959
1960
1961
1963
1964
1965
1966
1967
1968
1969
Station
Charleston, WV
Johnstown, PA
Canton, OH
Gary, IN
Canton, OH
Philadelphia, PA
Johnstown, PA
Philadelphia, PA
Charleston, WV
Johnstown, PA
Philadelphia, PA
Lynchburg, VA
Charleston, WV
Niagara Falls, NY
Knoxvllle, TN
Johnstown, PA
Niagara Falls, NY
Johnstown, PA
Philadelphia, PA
Manganese
Average
0.61
2.50
0.72
0.97
0.57
0.70
1.44
0.62
1.33
2.45
0.72
1.71
0.60
0.66
0.81
3.27
0.66
1.77
0.50
Concentration, i
Maximum
Quarterly
1.10
5.40
1.10
NR
NR
NR
NR
NR
NR
3.90
1.70
2.50
1.70
1.30
1.50
NR
1.30
2.10
1.30
ng/ir?
Maximum
24-hour
7.10
7.80
2.20
3.10
2.90
>10.00
6.90
3.70
>10.00
NR
NR
NR
NR
NR
NR
14.00
NR
NR
NR
*Source: NASN, 1957-1969
NR = Not reported
1797A
3-62
5/03/83
-------
gives NASN sites for which average concentrations were >0.5
Higher concentrations for shorter average times may be of considerable
significance 1n the evaluation of the potential biological effects of
3
airborne manganese. Several 24-hour values >10 v-g/m were observed
during this time period (see Table 3-18).
A comparison of urban and nonurban NASN data for 1966-1967 was provided
by McMullen et al. (1970). Urban samples showed an arithmetic mean manga-
o
nese concentration of 0.073 ug/m , while the mean for nonurban samples
3
decreased from 0.026 to 0.005 ug/m with Increasing remoteness of the
monitoring site from urban areas (Table 3-19). While this decrease of
manganese concentration primarily reflects a decrease 1n total suspended
partlculates, percent manganese 1n TSP mass also decreased with Increasing
remoteness (McMullen et al., 1970).
An examination of NASN data for the early 1970s shows a further decline
1n ambient manganese levels at urban sites, and Indicates some reduction at
nonurban sites as well. The U.S. EPA (1977a) reported that the median (50th
percentlle) value of annual average manganese concentrations for 92 urban
3 3
sites declined from 0.040 ug/m 1n 1965 to 0.016 v.g/m In 1974.
When urban values for the period 1970-1971 were compared to those for
1973-1974, a 50% decline was observed 1n both the 50th and 90th percentlle
values for manganese, Indicating a reduction by about half 1n both median
and extreme levels. During this same Interval, the reductions 1n TSP at
these percentlles were only 4% and 13%, respectively, Indicating that this
reduction was not simply related to a general Improvement 1n air quality.
The trend for manganese was thought to be attributable to controls 1n the
metals Industry. Data examined for 16 nonurban sites were also said to
Indicate a downward trend for manganese, but this conclusion was described
as tenuous (U.S. EPA, 1977a).
1797A 3-63 5/03/83
-------
TABLE 3-19
Average Manganese Concentration 1n Ambient A1r and Total
Suspended Partlculates (TSP) 1n Urban and Nonurban NASN Sites, 1966-1967*
Stations
TSP Mn Mn/TSP
Type Number (ug/m3) (ug/m3) (X)
Urban 217 102 0.073 0.07
Nonurban
Proximate
Intermediate
Remote
Total nonurban
5
15
10
30
45
40
21
34.5
0.026
0.012
0.005
0.012
0.06
0.03
0.02
0.03
*Adapted from McMullen et a!., 1970
1797A 3-64 4/29/83
-------
The frequency distributions of quarterly analytical values for manganese
at all urban and nonurban NASN sites for the years 1970-1982 are given 1n
Table 3-20 and 3-21, respectively. Prior to 1977, quarterly values were
based on single analyses of filter composites (U.S. EPA, 1979a). Since
1977, Individual filters were analyzed. Therefore, to permit comparison of
these data with the earlier data, quarterly arithmetic means of all values
for each site were used to simulate quarterly composite values 1n the
frequency distributions (Barrows, 1983). A rigorous trend analysis of these
data 1s not possible due to changes 1n sites and methodology. Decreases
over the period are Indicated, however, both 1n median and extreme concen-
trations, for both urban and rural areas.
3.6.1.2. AREA STUDIES — Pollution problems and trends can also be
characterized on a more local scale. A few area studies 1n which ambient
manganese concentrations are given will be discussed. In 1964-1965, a study
was undertaken of air pollution 1n the Kanawha Valley, West Virginia (NAPCA,
1970). Average TSP levels for sites 1n the area ranged from 132-413
3 3
ng/m , compared to the national urban average of 100 v.g/m (Table
3-22). Yearly average suspended manganese concentrations were as high as
3
8.3 ug/m , with quarterly composite samples ranging up to 11.0 and 13.0
3
ug/m for the Smlthers and Montgomery communities, respectively. The
major manganese source was a ferromanganese plant, with additional contribu-
tions from a large coal-burning Industrial steam-generation plant (NAPCA,
1970). However, NASN data collected 11 years later (1976) 1n two Kanawha
Valley communities (although not necessarily the same sampling sites) Indi-
cate decreases of an order of magnitude 1n ambient manganese concentration
(see lable 3-22; U.S. EPA, 1979a).
1797A 3-65 5/03/83
-------
US
TABLE 3-20
Urban NASN Sites, 1970-1982: National Cumulative Frequency Distributions of Quarterly Values
for Manganese Concentration (ug/ni3)3*''
i
er>
-p>
•x
ro
CO
CO
Percentlles
Year
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
Numberc
795
716
708
559
594
695
670
741
568
429
437
477
309
Minimum
L0«
LD
LD
LD
LD
LD
LD
0.0051
0.0043
0.0022
0.0030
0.0040
0.0031
10
0.02
0.02
0.01
0.01
0.01
0.01
0.01
0.017
0.016
0.011
0.009
0.011
0.011
30
0.03
0.04
0.02
0.02
0.02
0.02
0.02
0.025
0.025
0.017
0.015
0.017
0.017
50
0.04
0.05
0.03
0.02
0.02
0.03
0.03
0.032
0.034
0.025
0.021
0.024
0.023
70
0.06
0.07
0.04
0.04
0.04
0.04
0.04
0.045
0.043
0.035
0.031
0.033
0.032
90
0.15
0.16
0.09
0.07
0.07
0.07
0.08
0.077
0.088
0.073
0.063
0.059
0.063
95
0.23
0.24
0.12
0.11
0.11
0.10
0.12
0.100
o.ni
0.102
0.093
0.084
0.081
99
0.49
0.46
0.22
0.29
0.21
0.18
0.27
0.297
0.185
0.158
0.133
0.138
0.170
Maximum
2.10
1.95
0.86
0.56
0.35
0.72
0.74
0.632
0.300
0.448
0.141
0.303
0.661
Arithmetic
Mean
0.07
0.08
0.04
0.04
0.04
0.04
0.04
0.045
0.043
0.035
0.030
0.032
0.033
Standard
Deviation
0.12
0.11
0.06
0.05
0.04
0.04
0.05
0.051
0.035
0.039
0.026
0.030
0.047
Geometric
Mean
0.04
0.05
0.03
0.02
0.02
0.02
0.03
0.034
0.034
0.026
0.022
0.025
0.024
Standard
Deviation
3.13
2.81
2.76
2.72
2.39
2.49
2.60
2.486
2.043
2.443
2.111
2.214
2.846
aSource of 1970-1976 data: U.S. EPA, 1979a
bSource of 1977-1982 data: Barrows, 1983
cNumber of quarterly site values. From 1-4 quarterly values were available per site.
dL1m1ts of discrimination (LO) for 1970-1976 were =0.0025 ug/m3, but varied among years. LD for 1977-1982 ranged from 0.00042-0.0024
vg/m3.
-------
TABLE 3-21
us
— J
3»
Nonurban NASN Sites,
1970-1982: National Cumulative Frequency Distributions
for Manganese Concentration (vg/m3)a»b
PercentHes
Year
1970
1971
1972
1973
1974
^ 1975
S 1976
1977
1978
1979
1980
1981
1982
Number0
124
97
137
100
79
98
98
126
65
44
35
43
33
Minimum
LD<1
LD
LD
LD
LD
LD
LD
LO
0.0011
LD
LD
LD
LD
10
0.003
0.003
LD
LD
LD
LD
LO
0.003
0.003
0.002
LD
0.003
0.001
30
0.006
0.009
LD
LD
0.001
0.004
0.005
0.005
0.006
0.004
0.004
0.004
0.003
50
0.012
0.013
0.003
0.002
0.004
0.006
0.007
0.009
0.008
0.005
0.005
0.006
0.005
70
0.018
0.022
0.007
0.004
0.007
0.009
0.010
0.012
0.010
0.007
0.007
0.009
0.007
90
0.035
0.032
0.016
0.011
0.017
0.014
0.025
0.021
0.015
0.011
0.014
0.015
0.009
95
0.041
0.041
0.029
0.022
0.023
0.018
0.030
0.030
0.018
0.015
0.018
0.021
0.009
99
0.066
0.064
0.039
0.030
0.027
0.031
0.036
0.049
0.030
0.024
0.019
0.025
0.015
Maximum
0.068
0.102
0.046
0.030
0.033
0.040
0.046
0.122
0.036
0.024
0.019
0.025
0.015
of Quarterly Values
Arithmetic
Mean
0.015
0.018
0.007
0.004
0.006
0.007
0.010
0.012
0.009
0.006
0.007
0.008
0.005
Standard
Deviation
0.013
0.015
0.009
0.005
0.007
0.007
0.009
0.013
0.006
0.006
0.005
0.006
0.003
Geometric
Mean
0.012
0.013
0.003
0.002
0.004
0.015
0.010
0.008
0.007
0.005
0.005
0.007
0.004
Standard
Deviation
2.11
2.09
2.81
2.79
2.52
2.19
2.21
2.468
1.810
1.862
1.970
1.897
1.807
o
CO
oo
os
aSource of 1970-1976 data: U.S. EPA, 1979a
••Source of 1977-1982 data: Barrows, 1983
cNumber of quarterly site values. From 1-4 quarterly values were available per site.
dL1m1ts of discrimination (LO) for 1970-1976 were =0.0025 ug/m3, but varied among years. LO for 1977-1982 ranged from 0.00042-0.0024
vg/m3.
NR = Not reported
-------
TABLE 3-22
Manganese Concentrations 1n A1r, Kanawha Valley Area, West Virginia*
I
C^
C»
Sampling Site
and Site Number
Falls View (1)
SmUhers (5)
Montgomery (6)
Cedar Grove (7)
Mar met (11)
Kanawha City (13)
Charleston (15)
West Charleston (17)
North Charleston,
West (19)
South Charleston,
East (20)
Ounbar (22)
St. Albans (24)
NHro (25)
NHro, West (27)
TSP
(WJ/m3)
Study Period
Average
179
347
413
235
242
287
189
209
241
298
199
223
179
132
Fall Winter
1964 1964-1965
3.40
11.00 6.50
13.00
4.20 3.50
3.60
3.30 1.10
0.91
0.96
0.52
2.00 0.26
0.24
0.43 0.44
0.59 0.28
0.08
Suspended Manganese (ug/m3) Settled Manganese
Quarterly Composites (nq/cm2/month)
Spring Summer Study Period Yearly Averageb Study Period
1965 1965 Average 1976 Average
4.50 3.00 8.30 19,300
2,700
1.80 0.32 2.45 130
110
0.53 0.27 1.30 80
0.07
240
0.23 0.17 0.67 0.04 320
0.06 0.06 0.25 80
0.10 0.09 0.27 90
aSource: NAPCA, 1970
bSource: U.S. EPA, 1979a. NASN data, not necessarily same sampling locations.
oo
CO
-------
A nearby region along the Ohio River between Marietta, Ohio and Parkers-
burg, West Virginia was studied during the period 1965-1966 (U.S. DHEW,
1967). A1r quality 1n this area was Influenced by a large plant producing
manganese metals and alloys. Sampling of ambient participate using a direc-
tional sampler or during different wind directions showed that for sites
both north (Marietta) and south of the plant (Vienna, Parkersburg), ambient
manganese concentration was always substantially higher when the wind was
blowing from the direction of the plant (Table 3-23). The trend for TSP was
3
not nearly so clear, however. Manganese levels as high as 11.4 ug/m
were observed 1n 24-hour samples downwind of the plant. At one site, a
composite of samples collected by a directional sampler selective for wind
o
direction showed manganese levels 10 times higher for the 90 sector
o
toward the plant (4.1 v.q/m ) than for the remaining 270° sector
3
(0.4 ug/m ). Recent unpublished monitoring data for two of these sites
have been provided by the current operator of the manganese plant (Moore,
1983a,b). The mean and range of at least 14 24-hour samples during the
winter (December 2-February 4) of 1982-1983 Indicate substantial reductions
(by roughly an order of magnitude) 1n manganese when compared with data from
the earlier study (see Table 3-23). TSP levels were also reduced. Manga-
nese production rates at this plant during the recent sampling period were
reported to be 60-70% of those for 1965-1966 (Moore, 1983b).
Ambient manganese levels 1n New York City are substantially lower than
those 1n areas Influenced by the manganese metal and alloy manufacturing
Industry. However, trends can be noted here as well. Data of Klelnman et
al. (1980) for NYU Medical Center and a location 1n the Bronx show substan-
tial reductions 1n annual averages for manganese and several other metals
during the years 1968-1975 (Table 3-24). The greatest decrease was observed
1797A 3-69 5/03/83
-------
1C
•—I
TABLE 3-23
Ambient A1r Sampling Data for Total Suspended Participates and Manganese (1n
1965-19663 and 1982-1983°
1n the Marietta. OH-Parkersburg, WV Vicinity,
Site
Vienna
Outc
Marietta (Central)
Marietta (West)
Parkersburg (Central)
Nov.
TSP
257d
309d
1876
3. 1965*
Mn
1.6d
11. 4d
0.29e
Nov. 27.
TSP
121d
204d
8ie
1965a
Mn
1.6d
6.6d
0.0C
Jan. 15.
TSP
196d
54d
67^
124d
19663
Mn
3.4d
O.ld
O.le
0.7d
Jan. 25.
TSP
278d
128d
155e
219d
19663
Mn
2.0d
0.2d
O.le
0.7d
Composite,
Jan. 11-31. 1966a
TSP Hn
197 4.1
63 0.4
132 0.6
134 0.7
Mean (Range),
Dec. 1982-Feb. 1983b
TSP Hn
47 (12-97) 0.14 (0.03-0.56)
32 (20-48) 0.13 (0.03-0.51)
aSource: U.S. DHEW. 1967
°Source: Unpublished data of El kern Metals Co., Marietta, OH (Moore, 1983b)
C01rect1onal sampler; "In": 90° sector toward ferromanganese plant; "Out": remaining 270° sector
dS1te was downwind of ferromanganese plant during sampling period
eS1te was upwind of ferromanganese plant during sampling period
00
-------
TABLE 3-24
Concentrations of Trace Metals 1n A1r Measured at
Three Locations In New York City* (ng/m3)
Element
Cd
Cr
Cu
Fe
K
Mn
Na
N1
Pb
V
Zn
TSP (ng/m )
Element
Cd
Cr
Cu
Fe
K
Mn
Na
N1
Pb
V
Zn
1969
10.0
33.0
526
NR
NR
89.0
NR
1390
2110
874
670
134
1968
14.0
49.0
133
NR
NR
54.0
NR
150
3820
1230
730
New York Un1
1972
6.0
11.9
63.0
1490
240
27.5
1130
30.7
1370
68.9
380
82
Bronx
1969
9.0
23.0
115
NR
NR
40.0
NR
122
2760
795
1120
verslty Medical
1973
7.1
8.9
55.7
1580
358
28.1
1990
45.0
1240
86.0
311
80
, New York
1972
4.0
7.0
60.0
1940
NR
29.0
NR
210
2000
53.0
304
Center
1974
6.0
10.8
46.8
1410
371
23.1
604
45.4
1400
72.6
338
71
1975
4.2
8.5
43.9
1010
99.1
19.8
800
35.2
1070
38.8
294
52
1973
3.5
5.3
52.5
1440
NR
30.2
NR
311
1580
80.0
289
*Source: Klelnman et al., 1980
NR = Not reported
1797A
3-71
5/03/83
-------
over the years 1968-1972. TSP levels measured at the Medical Center showed
that the decrease was concomitant with a decrease 1n TSP.
3.6.1.3. PARTICLE SIZE — Techniques for accurately characterizing
particle-size distributions for trace metals 1n ambient partlculate matter
have been available and Improving since about 1970. Lee et al. (1972) used
cascade Impactors to achieve a size fractlonatlon of ambient aerosols 1n six
United States cities during 1970. Their data showed that, on an annual
average, 45-62% of ambient manganese was 1n particles of <2 vim diameter.
Bernstein and Rahn (1979) used a size-selective cyclone sampler to fraction-
ate New York CHy urban aerosol during 2 weeks of sampling 1n August, 1976.
In these samples, 64-68% of manganese was found 1n particles of <2.5 vim
diameter. Manganese was blmodally distributed, with a peak 1n the
0.5-1.5 v-m fraction, a nadir 1n the 1.5-2.5 vim fraction, and a second
peak 1n the 2.5-3.5 y.m fraction. A single week of sampling with this
device 1n November, 1974, had shown only the latter (2.5-3.5 >im) peak
(Bernstein et al., 1976).
More recent data tend to Indicate that less of the ambient manganese 1s
found 1n fine particles. Dlchotomous samplers, which segregate particles
Into fine and coarse fractions, have been used widely since about 1975.
Davis et al. (unpublished manuscript) performed analyses of 104 selected
filter pairs from dlchotomous samples collected 1n 22 geographically diverse
cities 1n the United States during 1980. The size classes were <2.5 vm
(fine) and 2.5-15 >im (coarse). Filters with a high level of total
partlculate were selected to facilitate analysis. Therefore, the sample has
some bias, and the concentrations are not representative. However, this was
considered an excellent data base for examining relative amounts of manga-
nese 1n fine and coarse aerosol.
1797A 3-72 5/03/83
-------
Table 3-25 shows that the manganese concentration (1n mg/g) 1n particles
of each fraction 1s highly variable, but tends to be higher 1n the coarse
particles. Since coarse particle mass also tends to be greater, the overall
precentage of manganese found 1n fine particles tends to be <50% of the
total measured; the average for this study was 28%.
The total partlculate measured by the dlchotomous sampler (DS) with a
15 urn size-selective Inlet 1s less than the TSP measured by high-volume
samplers. The ratio DSrTSP has been measured for samples where TSP 1s >55
3
ug/m (Pace and Frank, 1983). Ninety percent of all values for the
ratio were between 0.36 and 0.76; the mean was 0.56. The ratio 1s somewhat
higher when TSP 1s lower. If manganese 1s assumed to be distributed fairly
evenly over particle mass for particles of different sizes, then this ratio
can be used to compare dlchotomous-sampler manganese with high-volume-
sampler manganese. The percentage of manganese present 1n the fine fraction
would then have an average of 28% x 56%, or 16%, of the total measured.
However, since the manganese concentration (1n mg/g) 1n coarse particles
tends to be higher than 1n fine particles, this average 1s probably too high.
This Indicates that only a small percentage of the manganese measured by
the high-volume sampler usually 1s present In the fine fraction. However,
It should be noted that of the 22 cities examined 1n this study, the dty
3
(Akron, OH) with the highest manganese concentration (0.129 y.g/m ) also
had the highest percentage 1n the fine fraction (66%). Therefore, 1n high-
exposure situations the relative amount 1n the fine fraction may be large.
If the DS:TSP ratio was also high (e.g., 0.76), the percentage could be as
high as 66% x 76%, or 50%.
1797A 3-73 5/03/83
-------
TABLE 3-25
Selected Olchotomous Sampler Data on Manganese and Particle Mass
from 22 U.S. Cities 1n 1980a
Manganese
aSource: Davis et al., unpublished manuscript
''Particle size: fine, <2.5 um; coarse, 2.5-15
GAr1thmet1c mean by city
Particle Mass
Parameter1*
A1r concentration (ng/m^)
Fine
Coarse
Total
Particle concentration (mg/g)
Fine
Coarse
Percent mass 1n fine fraction
Meant
0.016
0.030
0.046
0.50
0.70
28
Range
0.001-0.085
0.003-0.078
0.006-0.129
0.029-2.36
0.27-1.75
3-66
Meanc
28.7
44.6
73.3
—
41
Range
9.7-57.1
8.2-105.6
36.0-140.4
::
15-78
1797A
3-74
4/29/83
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3.6.2. Water. Natural concentrations of manganese 1n seawater are
reported to vary from 0.4-10 v-Q/i (U.S. EPA, 1975). Kopp and Kroner
(1969) studied trace metals 1n United States freshwaters and generalized
that "1n most natural waters, the concentration of manganese 1s <20
iig/ft". In surface freshwaters, background levels are frequently
exceeded due to human activities. Manganese concentration ranges 1n various
United States lakes and rivers, some heavily polluted, are given 1n
Table 3-26.
Kopp and Kroner (1969) summarized trace-element data for 1577 water sam-
ples collected over the contiguous United States and Alaska from 1962-1967,
under the water quality surveillance program of the Federal Water Pollution
Control Administration (FWPCA). Dissolved manganese was detected 1n 810 of
1577 samples; the mean concentrations of dissolved manganese for 16 drainage
basins are shown 1n Table 3-27.
Manganese oxides are common constituents of suspended materials and
frequently comprise >0.1% (>1000 iig/g) of riverine sediments (Hem, 1970).
A comparison of suspended and dissolved manganese 1n Table 3-28 shows that,
1n river systems, the amount 1n suspension normally exceeds the amount 1n
solution. Exceptions to this pattern are the Allegheny and Monongahela
Rivers, which are characterized by add mine drainage {Kopp and Kroner,
1969).
Manganese levels 1n groundwaters frequently are much higher than 1n
surface waters because the more add and reducing conditions which prevail
In the sub-surface environment promote dissolution of manganese oxides.
Manganese concentrations as high as 9600 v-g/fi- 1n add groundwater
(pH=4.0) and 1300 v.g/8. 1n neutral groundwater (pH=7.0) have been
reported (Hem, 1970).
1797A 3-75 5/03/83
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TABLE 3-26
Concentration of Manganese 1n Various Lake
and River Waters
Locality
Concentration
Range (v.q/9.)
Reference
Wisconsin Lakes
Mississippi River
Llnsley Pond, Connecticut
Maine Lakes
Yukon River, Alaska
Mississippi River
Southeastern Missouri
Streams
3-25
80-120
50-250
0.02-87.5
181
12-185
10-2420
Juday et al., 1938
W1ebe, 1930
Hutchlnson, 1957
Klelnkopf, 1960
Durum and Haffty, 1963
Durum and Haffty, 1963
Gale et al., 1973
1797A
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4/29/83
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TABLE 3-27
Mean Concentrations of Dissolved Manganese by Drainage Basin*
Drainage Basin ug Mn/ft
Northeast 3.5
North Atlantic 2.7
Southeast 2.8
Tennessee River 3.7
Ohio River 232.0
Lake Erie 138.0
Upper Mississippi 9.8
Western Great Lakes 2.3
Missouri River 13.8
Southwest-lower Mississippi 9.0
Colorado River 12.0
Western Gulf 10.0
Pacific Northwest 2.8
California 2.8
Great Basin 7.8
Alaska 18.0
*Source: Adapted from Kopp and Kroner, 1969
1797A 3-77 4/29/83
-------
co
I
TABLE 3-28
Dissolved and Suspended Manganese 1n Five U.S. Rivers*
Location
Delaware River
At Martins Creek, PA
At Trenton, NJ
At Philadelphia, PA
Allegheny River
At Pittsburgh, PA
Monongahela River
At Pittsburgh, PA
Ohio River
Below Addlson, OH
Kanawha River
At W1nf1eld Dam, WV
Detection
Frequency
(X)
40
27
31
60
93
51
87
Dissolved
Mean of
Positive Values
(ug/D
2.9
3.2
4.2
>1000
607
57
44
Detection
Frequency
(X)
93
100
100
100
87
100
100
Suspended
Mean of
Positive Values
OS
CO
-------
In a 1962 U.S. Geological Survey study of public water supplies of the
100 largest dtles 1n the United States, Durfor and Becker (1964) reported
manganese concentrations of up to 2500 iig/ft for treated water. Of these
water supplies, 97% contained concentrations below 100 vuj/8.- A U.S.
Public Health Service (U.S. PHS) community water survey 1n 1969 examined
2595 samples of tap water from 969 community water supplies (U.S. DHEW,
1970). The maximum concentration of manganese was 1320 ug/S., but 91.9%
of samples and 91% of supplies did not exceed 50 ug/i-
As part of the first Health and Nutrition Examination Study (HANES I
Augmentation Survey of Adults), conducted 1n 1974-1975, tap water samples
from public and private water supplies of 35 urban and rural, randomly
chosen sampling areas were analyzed for trace metals (U.S. DHEW, 1978).
Unpublished data for manganese (Table 3-29) Indicate that higher manganese
concentrations can be found 1n private wells than 1n public water supplies
(Greathouse, 1983). Manganese concentration at the 95th percentlle was 3
times higher 1n private (228 U9/&) than 1n public supplies (78
ug/fc). The median level for private supplies was below detection limits
while that for public supplies was 4 ug/&; however, since the detection
limit was calcium dependent (U.S. EPA, 1978b) and may have been higher for
private waters, the median levels may not be comparable to one another.
3.6.3. Food. Manganese concentrations were measured 1n foods from the
United States (Schroeder et al., 1966; Baetz and Kenner, 1975; Wong et al.,
1978), Great Britain (Wenlock et al., 1979) and New Zealand (Guthrle, 1975).
Concentrations varied widely among food groups, within food groups, and even
for a given food type. Concentrations 1n various grains and cereals In the
United States ranged from 1.17-30.76 y.g/g. Manganese concentrations for
unpolished rice were given as 2.08 (United States), 32.5 (New Zealand) and
1797A 3-79 5/03/83
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TABLE 3-29
Cumulative Frequency Distribution of Manganese Concentration
1n Tap Waters Sampled 1n the HANES I Augmentation Survey of Adults*
Supply Type
Public
Private
Number
2853
596
25
NO
NO
50
4
NO
Percentl
75
13
34
les (ug/S
90
36
121
,,
95
78
228
99
295
977
*Source: Unpublished EPA data (Greathouse, 1983)
NO = Less than detection limits (see text)
1797A 3-80 4/29/83
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40 ug/g (Great Britain). Most non-cheese dairy products contained
<1 v-g/g, but cheeses varied widely. Swiss cheese 1n the United States was
reported to contain 1.32 and 17.2 vig/g, respectively, by two different
authors. Most meat, poultry and fish contained manganese at <2 yxj/g.
Most fresh fruits contained <2 uQ/g. but bananas and canned fruits ranged
from this level to 19 and 10 v.g/g, respectively. The manganese content of
various vegetables ranged from 0.14-12 ug/g. Most nuts contained from
7-35 ng/g, and certain spices (cloves, ginger, sage) contained >200
ug/g. Thus, 1t 1s obvious that wide differences 1n manganese Intake can
exist for people with differing or even with similar food habits.
3.6.4. Human Exposure. Data on manganese levels 1n air, water and food
can be used to estimate human exposure to manganese. No attempt has been
made 1n this document to project numbers of Individuals subject to given
exposure levels. Rather, manganese Intakes characteristic of an "average"
and a "high" level of exposure are estimated. These estimates are presented
solely as a rough basis for comparison with the Information on health
effects 1n the following chapters.
3.6.4.1. INHALATION — The degree of Intake or absorption associated
with human Inhalation exposure to an aerosol Is highly dependent upon
particle size. Particles of diameter >100 um can be Inhaled, but few of
those larger than =15 >im are likely to reach the thoracic region (U.S.
EPA, 1982b). Insoluble particles deposited 1n the extrathoraclc region are
usually cleared to the esophagus within minutes, offering little opportunity
for absorption of toxic constituents by the respiratory tract (although
absorption by the digestive tract 1s possible; see Section 3.6.4.2.).
Particles of smaller diameter may be deposited 1n the thoracic (I.e.,
tracheobronchlal and alveolar) regions, to a degree which 1s dependent on
1797A 3-81 5/03/83
-------
type of breathing (I.e., oral or nasal), breathing flow rate, and particle
characteristics. Insoluble particles deposited 1n the tracheobronchlal
region normally are cleared within hours, whereas those deposited 1n the
alveolar region would be expected to remain for weeks, months or longer
(U.S. EPA, 1982b).
Particles of =10 vim are almost all deposited extrathoradcally
during nasal breathing. During mouth breathing =35% are deposited trache-
obronchlally, but still practically none reach the alveoli. As particle
size decreases, the fractions reaching the thoracic region and passing to
the alveoli Increase. Alveolar deposition 1s greatest (=25-65%) for
particles 1n the range of 2-4 vim. Nearly all particles smaller than
2 |im reach the alveoli, but many (=50-80%) remain suspended and are
exhaled (U.S. EPA, 1982). However, some conventions conservatively assume
that none 1s exhaled; thus, >80% of particles smaller than 2 urn are
considered to be deposited 1n the alveoli, and for particles =4-10 urn,
<30% are alveolar and >50% are deposited 1n the tracheobronchlal region (Ad
Hoc Working Group of Technical Committee !46-A1r Quality, International
Standards Organization, 1981).
Data collected by dlchotomous sampler are roughly amenable to exposure
estimates. The extrathoradc fraction 1s approximately excluded by an upper
size cut-off, usually =05 vun. Thus, all aerosol sampled 1s assumed to
reach the thoracic region. The coarse aerosol from the dlchotomous sampler
1s generally taken to represent the tracheobronchlal fraction, and the fine
aerosol to be the alveolar fraction (Dzubay and Stevens, 1975). This
assumption 1s a reasonable approximation 1f all particles reaching the
alveoli are assumed to be deposited, as mentioned above. In actuality, as
also has been discussed, the mode of the alveolar deposition curve 1s at
1797A 3-82 5/09/83
-------
2-4 vro, and Is usually divided by the size cut between fine and coarse
fractions. However, for the purposes of this document, the conservative and
simplifying assumptions will be made that the fine fraction 1s 100% deposit-
ed In the alveoli, and the coarse fraction 1s 100% deposited 1n the tracheo-
bronchlal region.
The NASN monitoring data were collected using high-volume samplers,
which sample 50% of particles of 30 v-m and some particles of up to 100
Vim (Pace and Frank, 1983). Dlchotomous sampler data from around the
country Indicate that of the manganese sampled (particles 0-15 um), an
average of -28% and a maximum of ~66% 1s 1n the fine (<2.5 \m)
fraction (Davis et al., unpublished manuscript; see Section 3.6.1.3.)- The
dlchotomous sampler collects an average of -56% and a maximum of ~76% of
the TSP collected by the high-volume sampler (Pace and Frank, 1983; see
Section 3.6.1.3.). Assuming similar percentages for manganese, and assuming
3
dally Inhalation of 20 m of air, human Inhalation exposure to manganese
can be estimated from NASN data as follows:
3
Alveolar deposition (ug/day) = Ambient concentration (v.q/m )
X Flne/DS X DS/TSP X 20 m3/day
3
Total thoracic deposition (ug/day) = Ambient concentration (vig/m )
X DS/TSP X 20 m3/day
where Flne/DS = Fine-fraction manganese/total dlchotomous-sampler manganese
and DS/TSP = Dlchotomous-sampler part1culate/h1gh-volume-sampler partlcu-
late. Both alveolar and total thoracic deposition are estimated since both
could have some role 1n causing adverse effects. Both average and maximum
values for ambient concentration, Flne/DS, and DS/TSP are used for estimat-
ing average and maximum exposures.
1797A 3-83 5/03/83
-------
The most recent (1982) ambient air monitoring data for the urban United
o
States show a median quarterly manganese level of 0.023 ug/m , and a
3
high quarterly value of 0.661 y.g/m (see Table 3-20). Ambient levels
3
reaching ~10 y.g/m were observed near sites of manganese alloy manu-
facture during the 1960s (U.S. DHEW. 1967; NAPCA, 1970). These levels are
of Interest because they are relatively recent and could have had some
bearing on health studies conducted during or subsequent to that period.
However, such levels evidently are no longer occurring 1n ambient air.
Exposure estimates derived from these data are presented 1n Table 3-30.
Alveolar deposition of manganese at current ambient levels 1s estimated as
0.072 iig/day (average) and 6.6 ug/day (high). Estimates of total thor-
acic deposition are slightly higher. Alveolar and total thoracic deposition
under high exposure conditions 1n the 1960s were estimated to be as high as
100 and 152 ug/day, respectively.
3.6.4.2. INGESTION — Humans Ingest manganese from three main
sources: diet, drinking water and Inhaled particles cleared from the
respiratory tract.
No recommended dally allowance has been established for manganese,
although 1t 1s recognized as essential (U.S. FDA, 1978). Various estimates
have been made of average dally dietary Intake of manganese by adults 1n the
United States (Table 3-31); most recently, average consumption was estimated
by the U.S. FDA (1978). This estimate was based on a market basket survey
of 117 frequently eaten foods (the "Total Diet — Adult") collected 1n 1976
1n four United States geographic regions. The diet, Including drinking
water, was analyzed for several minerals, Including manganese. Results
expressed 1n terms of caloric Intake were 1.28 mg Mn/1000 Calories. At the
3000 Calorie/day Intake recommended for a 15 to 18-year-old male, average
1797A 3-84 5/03/83
-------
1C
TABLE 3-30
Estimates of Human Inhalation Exposure to Manganese 1n Ambient A1r*
w
1
03
tn
Exposure Type
1982 average
1982 high
1960s high
Deposition Site
alveolar
total thoracic
alveolar
total thoracic
alveolar
total thoracic
Ambient Concentration
(ug/m3)
0.023
0.023
0.661
0.661
10
10
Fine/OS
0.28
—
0.66
--
0.66
—
DS/TSP
0.56
0.56
0.76
0.76
0.76
0.76
Inhalation
(m3/day)
20
20
20
20
20
20
Exposure
(ug/day)
0.072
0.26
6.6
10.0
100
152
*See text for explanation and qualifications.
fO
V.
oo
-------
TABLE 3-31
Dietary Intake of Manganese 1n the U.S.
Group
Average Dally Intake
(mg)
Reference
Adults, college women
Adults
Adults, males
Adolescents (15-18 years),
males
3.7
2.3-2.4
3.3-5.5
3.8
North et al., 1960
Schroeder et al., 1966
Upton et al., 1969
U.S. FDA, 1978
1797A
3-86
5/03/83
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manganese Intake would be 3.8 mg/day. Assuming a body weight of 70 kg, this
amounts to an Intake of -0.054 mg/kg/day. It should be kept 1n mind that
substantial variability 1n real Intake levels 1s expected, as discussed 1n
Section 3.6.3. The dally Intake of manganese by bottle and breast-fed
Infants 1s much lower because of the low concentrations of manganese In both
breast and cow's milk (Table 3-32). Manganese Intake Increases with age, as
the type of feeding changes, from 0.002-0.004 mg/kg/day 1n Infants, to
0.06-0.08 mg/kg/day 1n children.
In public water supplies, the median manganese concentration at the tap
1s 4 >ig/8. (see Table 3-29). Assuming dally adult consumption of 2 8,
of water, 1t 1s apparent that the resulting manganese Intake of 0.008 mg/day
was a very small contribution to the above "Total Diet" estimate of 3.8
mg/day. On the other hand, manganese concentration at the 99th percentlle
1n private wells was 977 jig/8., and therefore 1t should be recognized
that In extreme Instances the drinking water contribution (=2.0 mg/day)
could be substantial. This contribution could be even more substantial for
small children consuming 1 9,/day (~1 mg Mn/day), when compared with
dietary Intakes for children (see Table 3-32). In most cases, however,
drinking water 1s not a significant contributor to manganese 1ngest1on when
compared to diet.
Clearance of particles from the respiratory tract 1s an even smaller
source. Even assuming 100% deposition and clearance to the gut of Inhaled
partlculate manganese, current ambient exposure (see Table 3-30) results 1n
0.00026 mg/day (average) or 0.010 mg/day (high). High ambient exposures
during the 1960s could have resulted 1n the 1ngest1on of -0.15 mg/day.
1797A 3-87 5/03/83
-------
TABLE 3-32
Intake of Manganese from Food by Children
oo
CO
o
10
oo
CO
Age
1 week
0-3 months
1 month
1 month
3-4 months
5-6 months
3-5 years
7-9 years
10-13 years
3 months-8 years
9-12 years
Type of Feeding
NR
NR
breast milk
cow's milk
mixed feeding
mixed feeding plus
cow's milk
mixed feeding
mixed feeding
mixed feeding
mixed feeding
Institutional diet
Dally Intake
of Mn 1n mg
0.0064
NR
0.011
0.024
0.2
0.4
1.4
1.7
2.2
NR
2.0
Dally Intake
of Mn In mg/kg
Body Weight
0.002
0.002-0.004
NR
NR
NR
NR
0.08
NR
0.06
0.06
NR
Reference
Wlddowson, 1969
Belz, 1960
McLeod and Robinson, 1972
McLeod and Robinson, 1972
McLeod and Robinson, 1972
McLeod and Robinson, 1972
Schlage and Wortberg, 1972
Belz, 1960
Schlage and Wortberg, 1972
Alexander et al. , 1974
Murthy et al., 1971
NR = Not reported
-------
Therefore, for all practical purposes, Ingestlon of manganese 1s deter-
mined solely by diet. Estimates for average exposure range from 2.3-5.5
(see Table 3-31), but some variability should be expected due to the widely
varying manganese content of foodstuffs.
3.7. SUMMARY OF GENERAL PROPERTIES AND BACKGROUND INFORMATION
3.7.1. Chemical and Physical Properties. Manganese 1s a ubiquitous
element 1n the earth's crust, 1n water and 1n partlculate matter 1n the
atmosphere. In the ground state, manganese 1s a gray-white metal resembling
Iron, but harder and more brittle. Manganese metal forms numerous alloys
with Iron, aluminum and other metals (Matrlcardl and Downing, 1981).
There are numerous valence states for manganese, with the divalent form
giving the most stable salts and the tetravalent form giving the most stable
oxide. The chlorides, nitrates and sulfates of manganese (II) are highly
soluble 1n water, but the oxides, carbonates and hydroxides are only
sparingly soluble. The divalent compounds are stable 1n add solution, but
are readily oxidized 1n alkaline conditions. The heptavalent form 1s found
only 1n oxy-compounds (Re1d1es, 1981).
3.7.2. Sampling and Analysis. Sampling of manganese 1n ambient air may
be carried out by any of the methods used for collecting atmospheric
partlculate matter. High-volume samplers with glass fiber filters are
widely used by the NASN and by state and local agencies (Thompson, 1979).
3
These samplers usually filter -2500 m of air 1n a 24-hour sampling
period. High-volume samplers may also be operated with filters composed of
organic membrane.
If Information on particle size 1s desired, other types of sampling
devices are used. Currently, the type most widely used 1s the dlchotomous
sampler, which separately collects fine (<2.5 um) and coarse (>2.5 vim)
1797A 3-89 5/03/83
-------
particles. The upper size limit of coarse particles may be set at 10, 15 or
20 urn by a size-selective Inlet. Particles are usua>ly collected on
teflon filters, and sampling time varies from 2-24 hours (Dzubay and
Stevens, 1975; U.S. EPA, 1981a).
Sampling of source emissions presents special problems related to gas
temperature and flow rate, which affect choice of filtering medium, sampling
rate and sampling equipment. Isok1net1c or equivalent flow rate Into the
sampling probe Insures representative sampling; membrane filters are not
used at high temperatures; and collection of condensate after the filter may
also be necessary to prevent complications. Automobile exhaust may be
diluted with air to prevent condensation In the sampling train.
Water, soil and food are collected for manganese analysis by the usual
techniques Insuring representative sampling without contamination. Biologi-
cal materials such as urine, blood, tissues, hair, etc., are collected and
stored so as to prevent contamination by dust; no other special procedures
are required when sampling for manganese analysis.
Sample preparation prior to analysis 1s necessary unless a non-destruc-
tive analytical technique 1s used. Solid samples may be add digested, with
or without prior ashing of organic matter. Extraction of partlculate from
glass fiber filters 1s done by Bonification 1n heated, mixed add without
ashing (U.S. EPA, 1983a).
Manganese 1n an aqueous sample may be preconcentrated by evaporation of
the liquid (Boutron and Martin, 1979). If other Interfering substances are
present, however, a preseparatlon step may be required. Preseparatlon may
be accomplished by chelatlon, 1on exchange or copredpHatlon.
1797A 3-90 5/03/83
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One of the most popular analytical techniques for metals Including
manganese 1s atomic absorption spectrophotometry (AAS). Optical emission
spectrometry (OES) has been used for analysis of metals from glass fiber
filters; Inductively coupled argon plasma (ICAP) 1s the excitation method
currently used by EPA with this technique (U.S. EPA, 1983b).
The above are destructive methods. Non-destructive analytical tech-
niques used 1n multi-elemental analysis are X-ray fluorescence (XRF) and
neutron activation analysis (NAA). XRF Is the most commonly used method for
analysis of partlcultes on membrane filters.
The detedon limits for any technique vary according to sampling method,
sample preparation and analytical method. Detection limits for manganese 1n
3
air are as low as 0.002 ug/m (Dzubay and Stevens, 1975; U.S. EPA,
1979a).
3.7.3. Production and Use. Very Uttle manganese 1s mined 1n this
country; some 1s mined domestically as low-grade ores, but most 1s Imported.
Manganese alloys, manganese metal and many compounds of manganese are pro-
duced and used 1n the United States, however. Ferromanganese and sH1co-
manganese are ferroalloys produced by the smelting of manganese ore 1n an
electric furnace (Matrlcardl and Downing, 1981). Manganese metal 1s
produced by add leaching of the ore, precipitation of other metals and
electrolysis of the solution. Manganese alloys and metal are then used to
Introduce manganese Into steel or nonferrous alloys.
Metallurgy, especially steel making, accounts for -95% of United
States demand for manganese (Reldles, 1981). Ferromanganese production has
decreased from 1148xl03 tons in 1965 to <120xl03 tons 1n 1982. SIHco-
3 3
manganese production has decreased from 284x10 tons 1n 1968 to <75xlO
tons 1n 1982. Demand for these products has diminished recently and Imports
are Increasing (Jones, 1982; OeHuff and Jones, 1981; DeHuff, 1961-1980).
1797A 3-91 5/03/83
-------
The remaining 5-6% of manganese demand 1s for a number of compounds which
are Important 1n the chemical Industry and 1n battery manufacture.
Manganous oxide (MnO), produced by reduction of manganese dioxide ore, 1s an
Important precursor for compounds used as feed additives, fertilizers,
colorants and chemical Intermediates. Electrolytic MnOp, also produced
from MnO, 1s used 1n dry-cell battery manufacture. Potassium permanganate,
produced by oxidation of MnO ore, 1s an Important oxidizing agent and
catalyst (Reldles, 1981).
Methylcyclopentadlenyl manganese trlcarbonyl (MMT) has been produced and
used 1n small quantities as a fuel additive since 1958. Major use as an
octane Improver 1n unleaded gasoline (at 0.125 g Mn/gal) began In 1974, but
was discontinued 1n 1978 due to adverse effects on catalytic converter
performance and hydrocarbon emissions (U.S. EPA, 1977b). MMT continues to
be used at -0.05 g/gal 1n -20% of leaded gasoline (Hall, 1983).
3.7.4. Sources of Manganese 1n the Environment. Manganese 1s the 12th
most abundant element and fifth most abundant metal 1n the earth's crust.
While manganese does not exist free 1n nature, 1t 1s a major constituent 1n
at least 100 minerals and an accessory element In more than 200 others
(Hewett, 1932). Its concentration 1n various crustal components and soils
ranges from near zero to 7000 ug/g; a mean soil content of 560 ug/g has
been given (Shacklette et al., 1971). Crustal materials are an Important
source of atmospheric manganese due to natural and anthropogenic activi-
ties (e.g., agriculture, transportation, earth-moving) which suspend dusts
and soils. The resulting aerosols consist primarily of coarse particles
(>2.5 y.m) (Ozubay, 1980; Dzubay et al., 1981).
1797A 3-92 5/03/83
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Manganese 1s also released to the atmosphere by manufacturing processes.
Ferromanganese furnace emissions are composed mainly of fine partlculate
(<2.5 y.m) with a high manganese content (15-25%). Ferroalloy manufacture
was the largest manganese emission source 1n 1968 (U.S. EPA, 1971). Current
estimates are not available, but control technology has Improved and produc-
tion volume has diminished. Iron and steel manufacture Is also an Important
manganese source. Manganese content of emitted particles 1s lower
(0.5-8.7%), but overall production volume Is greater than for manganese-
containing ferroalloys.
Fossil fuel combustion also results 1n manganese release. The manganese
content of coal 1s 5-80 ug/g (U.S. EPA, 1975). Fly ash Is about equal to
soil 1n manganese content (150-1200 ug/g), but contains particles finer 1n
size. This 1s an Important manganese source because of the volume of coal
burned each year. Combustion of residual oil 1s less Important because of
Its lower mangnese content. About 15-30% of manganese combusted In MMT-
contalnlng gasoline 1s emitted from the tailpipe.
The relative Importance of emission sources Influencing manganese con-
centration at a given monitoring location can be estimated by chemical mass
balance studies. Studies 1n St. Louis and Denver suggest that crustal
sources are more Important 1n the coarse than 1n the fine aerosol fraction.
Conversely, combustion sources such as refuse Incineration and vehicle emis-
sions predominantly affect the fine fraction. In an area of steel manufac-
turing, the Influence of this process was seen 1n both the fine and coarse
fractions (Dzubay, 1980; Dzubay et al., 1981; Alpert and Hopke, 1981; L1u et
a!., 1982).
1797A 3-93 5/03/83
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Another means of determining the Influence of noncrustal sources 1s to
compare the ratio of manganese and aluminum 1n an aerosol with that 1n
soils. The derived enrichment factor (EF) Indicates the magnitude of Influ-
ences from noncrustal sources. In most areas EF for coarse aerosols 1s near
unity, Indicating crustal origin, but EF for the fine fraction 1s substan-
tially higher, Indicating a greater Influence from noncrustal sources of
emission.
3.7.5. Environmental Fate and Transport Processes. A general overview of
man's Impact on the geochemlcal cycling of manganese shows a nearly doubled
flux from the land to the atmosphere due to Industrial emissions, and a
tripled flux from land to oceans, via rivers, due to soil loss from agricul-
ture and deforestation (Garrels et al., 1975).
Atmospheric manganese 1s present 1n several forms. Coarse dusts contain
manganese as oxides, hydroxides or carbonates at low concentrations (<1 mg
Mn/g). Manganese from smelting or combustion processes 1s often present 1n
fine particles with high concentrations of manganese as oxides (up to 250
mg/g). Organic manganese usually 1s not present 1n detectable concentra-
tions (Coe et al., 1980).
Oxides of manganese are thought to undergo atmospheric reactions with
sulfur dioxide or nitrogen dioxide to give the divalent sulfate or nitrate
salts (Sullivan, 1969). Manganous sulfate has been shown to catalyze SO
transformation to sulfurlc add, but the manganese concentration necessary
for a significant catalytic effect has been disputed (Wright et al., 1973;
P1ver, 1974).
Atmospheric manganese 1s transported by air currents until dry or wet
deposition occurs. In New York City, dry deposition occurred more quickly
for manganese than most other metals, because H tended to be present In
1797A 3-94 5/03/83
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2
larger particles. Dry deposition of manganese averaged 300-670 ng/cm /
2
month, whereas wet deposition was ~120 ng/cm /month (Klelnman et al.,
1975; Volchok and Bogen, 1973). Over much of the United States 1n
2
1966-1967, wet deposition of manganese ranged from <10-540 ng/cm /month
(Lazrus et al., 1970). Near a ferromanganese plant 1n 1964-1965, dry
deposition was as high as 19,300 ng/cm2/month (NAPCA, 1970).
In water or soil, manganese 1s usually present as the divalent or tetra-
valent form. Divalent manganese (present as the hexaquo 1on) 1s soluble and
relatively stable 1n neutral or acidic conditions. Chemical oxidation to
the Insoluble tetravalent form takes place only at a pH above 8 or 9, and
chemical reduction of the tetravalent form occurs only at pH <5.5. At
Intermediate pH, 1nterconvers1on occurs only by mlcroblal mediation
(Alexander, 1977).
Manganese tends to be mobile In oxygen-poor soils and 1n the groundwater
environment (Mitchell, 1971). Upon entering surface water, manganese 1s
oxidized and precipitated, primarily by bacterial action. If the sediments
are transported to a reducing environment such as lake bottom, however,
mlcroblal reduction can occur, causing re-release of divalent manganese to
the water column (Kuznetsov, 1970).
The concentration of manganese 1n lower organisms 1s much higher (by a
3 4
factor of 10 -10 ) than In the surrounding water. However, the concen-
2
tratlon factor Is lower (10-10 ) as trophic level Increases, Indicating
that the element 1s metabollcally regulated. Thus blomagnlf1cat1on of
manganese does not occur (Lentsch et al., 1972).
3.7.6. Environmental Levels and Exposure. Nationwide air sampling has
been conducted In some form since 1953 (U.S. DREW, 1958). Analytical
methodology has Improved and monitoring stations have changed, complicating
1797A 3-95 5/03/83
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any analysis of trends In manganese concentration. However, H 1s evident
that manganese concentrations 1n ambient air have declined during the period
of record. The arithmetic mean manganese concentration of urban samples was
0.11 vig/m3 1n 1953-1957 (U.S. DHEW, 1958), 0.073 ug/m3 1n 1966-1967
(McMullen et al., 1970), and decreased to 0.033 ug/m3 by 1982 (Barrows,
1983). In 1953-1957, the percentage of urban stations with an annual
3
average of >0.3 v-9/m was ~10%. By 1969 these had dropped to <4%, and
since 1972 the number has been <1%.
The highest manganese concentrations, with some observations exceeding
3
10 ug/m , were seen 1n the 1960s 1n areas of ferromanganese manufacture
(NAPCA, 1970; U.S. DHEW, 1967). More recent measurements 1n these areas
Indicated decreases of at least an order of magnitude had occurred, although
definitive studies were not available.
In most cases where comparable data on total suspended partlculate (TSP)
were available, decreases 1n TSP also occurred, but were usually smaller 1n
magnitude than those for manganese. This would suggest that the observed
reductions 1n manganese were more than a simple reflection of TSP Improve-
ments, Indicating specific reductions of manganese emissions.
Techniques for characterizing particle-size distributions for trace
metals 1n ambient aerosol are only recently available. Studies Indicate
that manganese 1s associated with both fine (<2.5 y.m) and coarse
(>2.5 y.m) particles (Bernstein and Rahn, 1979). The manganese concentra-
tion In each fraction 1s highly variable. On the average, <16% of manganese
1n aerosol mass 1s found 1n fine particles; however, 1t 1s estimated that 1n
some situations the fine fraction could contain as much as 50%.
1797A 3-96 5/03/83
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Manganese concentrations 1n nonpolluted freshwaters are usually <20
, but may exceed 1000 ug/& where polluted. The amount of
manga- nese 1n suspension exceeds the amount 1n solution, except where add
mine drainage 1s prevalent (Kopp and Kroner, 1969). Concentrations 1n
ground- water typically are higher than In surface water (Hem, 1970).
Three surveys of United States drinking water supplies have provided
data on manganese concentration (Durfor and Becker, 1964; U.S. DHEW, 1970;
Greathouse, 1983). Although concentrations >1000 vig/8, are found 1n
some, notably private, water supplies, -95% of all supplies contain manga-
nese at <100 ug/fc- A median concentration of 4 iig/fc for public
supplies has been reported (Greathouse, 1983).
Total human exposure to manganese may be estimated from Information on
levels 1n air, water and diet. Inhaled particles can be deposited either
extrathoradcally, 1n the tracheobronchlal region, or 1n the alveoli. Time
required for particle clearance and probability of absorption Increases with
Increasing depth of deposition 1n the respiratory tract (U.S. EPA, 1982).
Deposition of manganese 1n the alveoli can be calculated from the ambient
concentration and the fraction present 1n fine particles. Thoracic
(tracheobronchlal plus alveolar) deposition 1s calculated from estimates of
the manganese found 1n particles <15 um 1n size. Alveolar deposition of
manganese at current ambient levels 1s estimated as 0.072 v-9/day as an
average and 6.6 ug/day under high exposure conditions. Estimates of total
thoracic deposition are slightly higher; 0.26 vig/day (average) and 10.0
lig/day (high). Alveolar and total thoracic deposition under the high
3
exposure conditions (10 vig/m ) of the 1960s were estimated to be 100 and
152 ug/day, respectively.
1797A 3-97 5/09/83
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Diet 1s the main source of Ingested manganese. Average adult Intake has
been variously estimated at 2.3-5.5 mg/day. On a body-weight basis, expo-
sure Increases from 0.002-0.004 mg/kg/day 1n Infants to 0.06-0.08 mg/kg/day
1n adults. Drinking water usually comprises only a very small proportion of
total 1ngest1on exposure. The median Intake level via drinking water 1s
~0.008 mg/day, but can be as high as -2.0 mg/day for some water
supplies. The 1ngest1on of particles cleared from the respiratory tract 1s
an even smaller source, probably constituting no more than 0.01 mg/day under
the highest ambient exposure conditions currently observed.
1797A 3-98 5/03/83
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4. BIOLOGICAL ROLE AND PHARMACOKINETICS
4.1. BIOLOGICAL ROLE OF MANGANESE
Manganese was shown to be essential for growth and reproduction 1n rats
and mice as early as 1931 (Kemmerer et al., 1931; Orent and McCollum, 1931).
Later 1t was demonstrated that manganese prevented a skeletal abnormality 1n
chickens called perosls (Wllgus et al., 1936). Although manganese has been
shown to be essential for many species of animals, as yet there are no
well-defined occurrences of manganese deficiency 1n humans (Prasad, 1978).
4.1.1. Biochemical Role. Extensive Information 1s available on the
Interaction between manganese and proteins (Leach and Lllburn, 1978; Utter,
1976; Prasad, 1978). The relationship between manganese and enzymes can be
classified Into two categories, metalloenzymes and metal-enzyme complexes
(Leach, 1976). The first category of enzymes 1s very limited, while the
enzymes that can be activated are numerous.
Glycosyl transferases are Important enzymes 1n the synthesis of poly-
saccharldes and glycoprotelns, and most of these enzymes require manganese
for normal activity (Leach, 1971, 1976).
There 1s substantial experimental evidence that an Impairment 1n glycos-
amlnoglycan metabolism 1s associated with several symptoms of manganese
deficiency (Leach and Lllburn, 1978).
The most extensively studied manganese metalloenzyme 1s pyruvate car-
boxylase (Scrutton et al., 1972). Magnesium was found to replace manganese
as the bound metal to pyruvate carboxylase Isolated from manganese-deficient
chicks.
4.1.2. Manganese Deficiency. Manganese deficiency has been demonstrated
1n mice, rats, rabbits and guinea pigs. The main manifestations of manga-
1804A 4-1 4/29/83
-------
nese deficiency are those associated with skeletal abnormalities, Impaired
growth, ataxla of the newborn, and defects 1n I1p1d and carbohydrate
metabolism.
The skeletal abnormalities of manganese deficiency are described as
abnormally fragile bones, with shortening and bowing of the forelegs 1n
mice, rats and rabbits (Amdur et al., 1945; Ellis et al., 1947; Plumlee et
a!., 1956). This disease 1s known as perosls 1n chickens.
Manganese deficiency during pregnancy 1n rats and guinea pigs produces a
congenital defect In the young characterized by ataxla {Hurley, 1968; Ever-
son et al., 1959). This defect 1s usually associated with loss of equilib-
rium, Increased susceptibility to stimuli, head retraction and tremors.
4.1.3. Manganese Requirements. The minimum dally requirements of manga-
nese for laboratory animals vary with the species and genetic strain of
animal, the composition of diet and the criteria of adequacy employed.
Mice, rats and rabbits are unable to grow normally on milk diets
containing 0.1-0.2 ppm manganese. The minimum requlrment for manganese 1n
the diet of mice has not been established, but diets containing 50 mg/kg
manganese were adequate for growth and development of several genetic
strains (Hurley and Ther1ault-Bell, 1974). Although the requirement of
manganese for development and growth has not been adequately studied,
Holtkamp and H111 (1950) concluded that 50 ppm manganese In diet 1s optimum
for rats.
4.1.4. Summary. Although manganese has been shown to be essential for
many species of animals, as yet there are no well-defined occurrences of
manganese deficiency 1n humans. Manganese deficiency has been demonstrated
1n mice, rats, rabbits and guinea pigs. The main manifestations of manga-
nese deficiency are those associated with skeletal abnormalities, Impaired
1804A 4-2 05/06/83
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growth, ataxla of the newborn, and defects 1n I1p1d and carbohydrate metabo-
lism. Although the dally requirement of manganese for development and
growth has not been adequately studied, 1t was accepted that diets contain-
ing 50 mg/kg manganese are adequate for most of the laboratory animals (MAS,
1978).
4.2. COMPOUND DISPOSITION AND RELEVANT PHARMACOKINETICS
4.2.1. Absorption. The main route of manganese absorption 1s the gastro-
intestinal (GI) tract. Absorption through the lung 1s considered to be an
additional route 1n occupatlonally exposed workers and 1n residents living
1n Industrialized areas with higher ambient air concentrations of manganese.
Skin absorption of Inorganic manganese 1s not considered to occur to a
significant extent.
4.2.1.1. GASTROINTESTINAL ABSORPTION — Food 1s generally the main
source of manganese. Therefore, the GI tract 1s the portal of entry of
manganese and the absorption from the GI tract 1s the first step 1n manga-
nese metabolism. Human and animal studies show that on an average ~3% or
less of a single dose of radlolabeled manganese 1s absorbed from the GI
tract Irrespective of the amount of stable carrier.
4.2.1.1.1. Human Studies — Mena et al. (1969) studied manganese
absorption 1n 11 healthy fasted human subjects by administering 100 uC1 of
4MnCl? with 200 ug stable 55MnCl2 as a carrier. On the basis of
whole body counts performed dally for 2 weeks the absorption of Mn was
calculated to be an average of -3%. Similar absorption values were
obtained 1n six healthy manganese miners (-3%) and six ex-miners with
chronic manganese poisoning (-4%). These values could be an underestimate
of the absorption because enterohepatlc circulation was not taken Into
account but the authors considered this to be Insignificant.
1804A 4-3 4/29/83
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4.2.1.1.2. Animal Studies — In an early study using rats Greenberg
et al. (1943) estimated that 3-4% of a single oral dose containing 0.1 mg of
54
Mn labeled manganese (as chloride) was absorbed from the Intestine.
54
This estimation was made on the basis of differences 1n biliary Mn
excretion after parenteral and oral administration. Pollack et al. (1965)
54
reported 2.5-3.5% absorption of a single oral dose of Mn (as chloride
with 5 v.moles stable carrier) 1n fasted rats. They measured whole-body
and gut-free carcass radioactivity 6 hours after administration. The
fraction apparently absorbed (I.e., the gut-free carcass retention) could be
an underestimate due to the excretion Into the Intestine. Similarly, Rabar
(1976) and Kostlal et al. (1978) reported a 0.05% whole-body retention value
54
6 days after a single oral dose of Mn (as chloride-carrier free) 1n
postweanlng nonfasted rats. The very low value observed 1n their experi-
ments can be explained by considerable loss of the absorbed manganese
through endogenous fecal excretion within 6 days after administration. It
should also be mentioned that higher values obtained 1n other studies might
be due to administration of the Isotope to fasted animals.
Little 1s known about mechanisms Involved 1n manganese absorption. The
IP. vitro experiments performed by C1krt and Vostal (1969) show that manga-
nese absorption 1s likely to occur 1n the small as well as 1n the large
Intestine. However, whereas manganese 1s actively transported 1n the small
Intestine, there 1s only simple diffusion 1n large Intestine. Miller et al.
(1972) found that 1n calves the upper sections of the small Intestine absorb
54
far more Mn than the lower sections. Manganese excreted Into the Intes-
tine (biliary excretion being the most Important) 1s known to enter the
enterohepatlc circulation. C1krt (1973) showed that manganese excreted 1n
the bile 1s 1n a form more easily absorbed than manganese dlchloMde. He
1804A 4-4 4/29/83
-------
found that the Intraduodenal uptake of biliary excreted manganese was about
35%, whereas only 15% of an equivalent dose of manganese dlchlorlde adminis-
tered Intraduodenally was absorbed.
4.2.1.2. RESPIRATORY ABSORPTION — There are no quantitative data on
absorption rates for Inhaled manganese either 1n humans or 1n animals. It
1s assumed that some basic principles considered by the Task Group on Metal
Accumulation (TGMA, 1973) can be applied to Inhaled metals 1n general. Only
particles small enough (usually several tenths of yon) to reach the alveo-
lar lining are likely to be absorbed directly Into the blood. An unspeci-
fied fraction of the metal Initially deposited 1n the lung 1s expected to be
removed by mucocllllary clearance and consecutively swallowed, thus under-
going gastrointestinal absorption processes.
4.2.1.2.1. Human Studies — Mena et al. (1969) performed an Inhala-
tion study In 21 human subjects exposed for 10 minutes either to a nebulized
54
aqueous solution of MnCl- (7 normal controls and 10 exposed working
54
miners) or to a nebulized aqueous suspension of Mn?°3 ^ exposed
miners). The estimated mean particle size of the droplets delivered through
the nebulizer was 1 v.m. They found that about 40-70% (average 60%) of the
radioactivity Initially located 1n the lung was recovered 1n the feces
collected within 4 days after administration. The fate of manganese oxide
was Identical to that of the chloride. On the basis of regional radio-
activity measurements over different parts of the thoracic and abdominal
cavities the authors assumed that the GI tract was a portal of entry for the
Inhaled manganese. However, as stated by the authors themselves, absorption
of the Inhaled manganese directly from the lung cannot be excluded. The
authors' assumption seems to be highly speculative and experimental data
presented are Incomplete. Fecal excretion 1s the main route of manganese
1804A 4-5 05/06/83
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excretion and regional measurements Indicating the movement of the Isotope
through the body do not provide data concerning the direction of movement of
the Isotope through the Intestinal wall (I.e., whether 1t 1s being absorbed
or excreted).
4.2.1.2.2. Animal Studies ~ Pertinent data regarding manganese
absorption from the lung 1n animals could not be located 1n the available
literature.
4.2.2. Distribution and Normal Tissue Levels. Distribution 1s the term
used to describe the uptake of the absorbed manganese by various tissues and
organs 1n pharmacoklnetlc studies after a single or repeated administration
of the radioactive tracer. Such data are almost always obtained In animal
studies. Human studies (generally post-mortem analyses of various organs
and tissues) reflect the body and organ burden as a consequence of the
long-term (Hfespan) Intake of this essential element.
4.2.2.1. HUMAN STUDIES ~ A normal 70 kg man has a total of 12-20 mg
manganese 1n the body (Cotzlas, 1958; WHO, 1981). Sumlno et al. (1975)
found ~8 mg manganese 1n a group of 30 Japanese cadavers (15 males .and 15
females, -40 years old with an average weight of 55 kg). Muscles con-
tained -30%, liver -20%, and the digestive tract -15% of the total
amount. Manganese tissue levels 1n normal humans from three different
studies (Kehoe et al., 1940; Upton and Cook, 1963; Sumlno et al., 1975) are
presented 1n Table 4-1 (WHO, 1981). Although some differences between these
studies are obvious (probably due to different analytical techniques used)
the highest concentrations were found In liver and pancreas (~1 vuj Mn/g
wet weight or more). Kidney concentrations were between 0.6 and 0.9 y.9/9-
Lowest concentrations were found 1n brain, heart, lung, Intestine and gonads
(usually between 0.2 and 0.3>ig/g), with extremely low concentrations
(<0.10 ug/g) 1n muscles, bone, fat tissue and spleen.
1804A 4-6 05/06/83
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CO
o
TABLE 4-1
Manganese In Human Tissues (ug Mn/g wet weight)
ro
oo
to
Kehoe et al., 1940
Tissue (emission spectroscopy)
Aorta
Brain 0.30
Fat
Heart 0.32
Intestine 0.35
Kidney 0.60
Liver 2.05
Lung 0.22
Muscle
Ovary
Pancreas
Spleen
Testes
Trachea
R1b
Tipton and Cook, 1963
(emission spectroscopy)
0.11
0.27
--
0.23
--
0.90
1.30
0.24
0.06
0.18
1.10
0.11
0.14
0.14
— _
Sumino et al., 1975
(atomic absorption)
--
0.25
0.07
0.21
—
0.56
1.00
0.22
0.09
0.19
0.77
0.08
0.20
0.20
0.06
-------
In spHe of appreciable Individual variations of manganese concentra-
tions 1n the liver, there 1s little variation from one part of the liver to
another (Perry et al., 1973). Normal brain concentrations 1n adults up to
0.6 y.g Mn/g wet weight were reported (Fischer and Uelgert, 1977). Larsen
et al. (1979) studied the topographical distribution of manganese (As and Se
as well) 1n normal human brain tissue. Manganese was found to be associated
with the dry matter of brain tissue and, related to dry weight, equal con-
centrations were found 1n white and grey matter. They also found signifi-
cant differences between 24 different brain regions studied. Mean values
were within the range from 0.133-0.449 ug Mn/g wet weight, with highest
values observed 1n the basal ganglia (I.e., nucleus caudatus, globus
palUdus and putamen). Similar results with highest concentrations 1n the
basal ganglia were also reported by Smeyers-Verbeke et al. (1976).
The levels 1n biological fluids (blood and urine particularly) will be
discussed 1n Section 4.2.5.1. concerning their significance 1n relation to
exposure.
4.2.2.2. ANIMAL STUDIES — Distribution studies 1n mice (Kato, 1963),
rats (Dastur et al., 1969) and monkeys (Dastur et al., 1971) show a high
uptake of radioactive manganese by liver, kidneys and endocrine glands, and
only minor amounts In brain and bone.
When mice were exposed to MnO by Inhalation 1n concentrations of 5.6
3
and 8.9 mg/m and particle size of 3 vim for 2 hours dally for 8 and 15
days, respectively, the highest concentrations of manganese were found 1n
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) (Mourl, 1973). After
1ntraper1toneal administration of radioactive manganese to rats, the highest
concentrations were found 1n the suprarenal, pituitary, liver and kidney
1804A 4-8 05/06/83
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tissue (Dastur et al., 1969). The uptake by glandular structures was also
high 1n monkeys after 1ntraper1toneal Injection of radioactive manganese
(Dastur et al., 1971).
Scheuhammer and Cherlan (1981) studied regional distribution of manga-
nese 1n brains of male rats. Two groups of six animals each were given
dally 1.p. Injections of either 3 mg Mn/kg as MnCl_»4H20_ or an
equal volume of 0.9% NaCl for 30 days. Of the thirteen regions examined,
the highest concentrations 1n normal rats were 1n hypothalamus, colUcull,
olfactory bulbs and mldbraln. In treated rats all brain regions showed an
Increase, the greatest being 1n the corpus stMatum which Increased from
~1.7 to 8.8 mg/kg dry weight. On a percentage basis the highest Increase
was 1n the corpus callosum, 1300%. This study demonstrated that under these
conditions manganese 1s taken up by strlatal, mldbraln and thalanrtc regions
at a greater rate than other brain areas. Thus, manganese 1s selectively
concentrated 1n areas of the extrapyramldal system, which may explain the
signs and symptoms of manganlsm.
In the portal blood most of the manganese may become bound to a
a -macroglobulln and removed from the blood very efficiently by the
liver. A small proportion becomes bound to transferrln, and enters the
circulation system to be transported to the tissues. This oxidation step
may be performed by ceruloplasmln (Gibbons et al., 1976). Within a cell,
manganese 1s sequestered by mitochondria (Maynard and Cotzlas, 1955).
Tissues rich In mitochondria (liver, kidneys, pancreas) contain higher
levels of manganese (Kato, 1963).
The early work of Fore and Morton (1952) showed the constancy of
manganese concentrations 1n different organs for a large number of species.
1804A 4-9 05/06/83
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From their data It 1s apparent that bones, liver, kidneys and some endocrine
'j
glands (pituitary In particular) carry higher manganese concentrations
(1.2-3.3 ng Mn/g wet weight) than other organs and tissues (0.18-0.65
V.g/g). Brain concentration was 0.40 vig/g and this value 1s 1n agreement
with human values already discussed.
4.2.3. Excretion. Manganese 1s almost totally excreted via feces 1n
humans and animals (Newberne, 1973; WHO, 1981). Amounts of manganese
excreted via urine, sweat and milk are negligible compared to fecal excre-
tion. Variable excretion 1s assumed to be the main mechanism 1n manganese
homeostasls (see Section 4.2.5.).
4.2.3.1. HUMAN STUDIES — Quantitative data concerning manganese
excretion 1n humans are not available (WHO, 1981). Urinary excretion 1s low
Indicating that only a small fraction of the absorbed manganese 1s excreted
via that route. Concentrations In urine 1n unexposed and exposed people
will be discussed In Section 4.2.5.1.
4.2.3.2. ANIMAL STUDIES — Animal studies clearly show that manganese
1s eliminated from the body mainly via feces. Greenberg and Campbell (1940)
54
reported that 90.7% of a single 1ntraper1toneal dose of 1 mg Mn to rats
was found 1n the feces within 3 days after administration. In a subsequent
study Greenberg et al. (1943) Injected 1ntraper1toneally 0.01 or 0.1 mg of
54
Mn to rats and found that 27.1 and 37.3% of the respective dose was
collected 1n the bile within 48 hours. After Intravenous administration of
0.6 >ig of manganese dlchlorlde 1n rats 12% of the Injected dose was
excreted Into the bile within 3 hours (T1chy et al., 1973) and 27% within 24
hours (C1krt, 1972).
Adklns et al. (1980a) studied retention and subsequent clearance of
manganese after 2-hour Inhalation exposure of Charles River CD-I mice to 1.8
1804A 4-10 05/06/83
-------
3
mg Mn/m as Mn»0. aerosol, with average mass median diameter ~1.4
um. Seven data points were obtained 1n 24 hours, each for a group of six
mice. The exponential curve fit to the data Indicated that -47, 27 and
14% of the manganese remained 4, 6 and 24 hours after exposure, respectively.
Klaassen (1974) estimated the biliary excretion of manganese 1n rats,
rabbits and dogs after Intravenous doses of 0.3, 1.0, 3.0 and 10.0 mg/kg.
At the three lower doses the concentration of manganese 1n bile was 100-200
times higher than 1n the plasma. Excretion Into the bile Increased as the
dose Increased. However, after a dose of 10 mg/kg there was no further
Increase 1n excretion of manganese Into the bile, and a maximum excretion
rate of ==8.5 ]ig/m1n/kg was attained. This Indicates that a saturable
active transport mechanism may exist for manganese.
Although biliary excretion 1s particularly Important 1n adjusting the
manganese body load, bile 1s not the exclusive route of manganese excretion.
Under ordinary conditions, the bile 1s the main route of excretion and
represents the principal regulatory mechanism, but experiments 1n animals
show conclusively that manganese 1s also excreted through the Intestinal
wall (Bertlnchamps and Cotzlas, 1958; Kato, 1963; PapavaslHou et al.,
1966). In rats there 1s some evidence for the excretion of manganese
through the Intestinal wall Into the duodenum, jejunum and, to a lesser
extent, the terminal 1leum (Bertlnchamps et al., 1966; C1krt, 1973). In
dogs manganese 1s also excreted to some extent 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 auxiliary
GI routes may Increase 1n the presence of biliary obstruction or with over-
loading of manganese (Bertlnchamps et al., 1966; PapavaslHou et al., 1966).
1804A 4-11 4/29/83
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Urinary excretion Is low. Klaassen (1974) found that 1n rats 5 days
after Intravenous dosing 99% of administered manganese was eliminated 1n
feces and only 0.1% In urine. Biliary obstruction or overloading with
manganese did not Increase the urinary excretion (PapavaslHou et al.,
1966). Moreover, the authors found that animals with rectal obstruction did
54
not excrete measurable quantities of Mn via urine within the 5-day
observation period. Only after Injection of EDTA (ethylene dlamlnetetra-
acetlc add) did urinary excretion become predominant for 24 hours, after
which time fecal elimination was resumed (Kosal and Boyle, 1956; Maynard and
F1nk, 1956).
4.2.4. Biological Half-time.
4.2.4.1. HUMAN STUDIES — Mahoney and Small (1968) showed that the
disappearance rate of labeled manganese from the body of three normal human
subjects can be described by a mathematical expression which 1s the sum of
two exponential functions. Each of these processes can be characterized by
a "half-time", one of which was 4 days and another which was 39 days. About
70% of the Injected manganese was excreted via the slower pathway. In three
other subjects with a higher oral Intake of manganese, a higher rate of
elimination was observed.
Cotzlas et al. (1968) studied the tissue clearance of manganese 1n three
groups of humans: healthy subjects, healthy manganese miners and miners
removed from manganese exposure but with chronic manganese poisoning. After
54
a single Mn Injection they found a different total body turnover of the
label for the three groups: 37.5, 15 and 28 days, respectively. Regional
determination of radioactivity of the liver, head and thigh showed differ-
ences among various body areas and differences among groups. The corre-
sponding turnover times for the three groups were: 1n the liver 25, 13 and
26 days; In the head 54, 37 and 62 days; and 1n the thigh 57, 39 and 48 days.
1804A 4-12 05/06/83
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4.2.4.2. ANIHAL STUDIES — Brltton and Cotzlas (1966) reported a two-
component whole body clearance rate for manganese 1n mice. The half-time of
the fast component was 10 days and of the slow component, 50 days. A
10-fold Increase 1n the dietary Intake of manganese decreased the half-times
of the Isotope by about 50%. The effect of dietary manganese levels on the
terminal elimination of manganese 1n mice was studied by Suzuki (1974). The
animals received an aqueous solution of manganese chloride 1n concentrations
ranging from 20-2000 mg/4 for 30 days before radlomanganese administra-
tion. The whole body clearance half-time was estimated at about 6 days 1n
the lowest concentration group. It decreased to 3 days at a manganese
concentration of 100 mg/9. and to about 1 day 1n animals receiving 2000
mg/8.. The half-time of manganese In the brain was found to be longer than
for the whole body. This was also shown for rats (Oastur et al., 1969) and
for monkeys (Dastur et al., 1971). In rats the half-time 1n the whole body
was estimated to be 14 days, and 1n the brain 1t could not be determined
during the observation period of 34 days. In monkeys the half-time 1n the
brain could not be determined after 278 days of observation, while the whole
body half-time was estimated to be 95 days.
4.2.5. Homeostasls. As pointed out by Rehnberg et al. (1980), the normal
human adult effectively maintains tissue manganese at stable levels despite
large variations In manganese Intake. Although some workers maintain that
this homeostatlc mechanism 1s based on controlled excretion (Brltton and
Cotzlas, 1966; Hughes et al., 1966; Leach, 1976), a critical review of the
evidence reveals that manganese homeostasls 1s regulated at the level of
absorption (Abrams et al., 1976a,b) as well as at the level of excretion.
1804A 4-13 05/06/83
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For Instance, Lasslter et al. (1974) have provided evidence that the dietary
manganese level has a greater effect on manganese absorption than on excre-
tion of endogenous manganese and that both variable excretion and absorption
play Important roles 1n manganese homeostasls. In addition, manganese
absorption 1n rats 1s related to the dietary manganese level (Abrams et al.,
54
1976a,b). In these experiments Mn absorption and metabolism were
studied 1n rats fed diets containing 4 ppm (basal), 1000 ppm and 2000 ppm of
54
unlabeled manganese several days prior to a single oral dose of Mn. At
54
different time Intervals after oral administration, the Mn concentration
was determined 1n various tissues. Four hours after administration all
54
tissues from rats fed the basal diet continued to have higher Mn concen-
tration than tissues of rats given higher unlabeled manganese 1n diet. The
54
effect of dietary manganese on tissue Mn concentration following oral
dosing Indicates that variable absorption 1s an Important factor 1n manga-
nese homeostasls (Abrams et al., 1976b). From 4-24 hours after administra-
tion of low and high manganese diets to rats, the relative difference 1n
54
Mn concentration Increased 1n many tissues. This confirms that higher
54
levels of unlabeled dietary manganese accelerates Mn turnover after
absorption and tissue deposition. Suzuki (1974) reported an Intestinal
54
absorption of only 0.5-1.97% of Mn 1n mice prefed diets having levels of
54
MnOp ranging from 20-2000 mg/kg. The retention of Mn observed In the
whole body was Inversely proportional to the dietary manganese level.
Absorbed manganese is almost totally excreted via the Intestinal wall by
several routes, and these routes are interdependent and combined to provide
an efficient homeostatlc mechanism. Robert (1883) and Cohn (1884) are cited
by von Oettingen (1935) as the first to observe that manganese, after large
injected doses, was mainly excreted in the feces and only traces appeared In
1804A 4-14 4/29/83
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urine. Subsequent experiments with rats at a lower level (a 1 mg dose)
showed that 90% of the 1ntraper1toneally admlnstered dose appeared 1n the
feces within 3 days (Greenberg and Campbell, 1940).
IntraperHoneal administration of 0.01 mg manganese to rats resulted 1n
the biliary excretion of 27% of the dose within 48 hours; a dose of 0.1 mg
resulted 1n 37% appearing 1n the bile (Greenberg et al., 1943). Klaassen
(1974) estimated the biliary excretion of manganese 1n rats, rabbits and
dogs after Intravenous doses of 0.3, 1.0, 3.0 and 10.0 mg/kg. At the three
lower doses, the concentration of manganese 1n bile was 100-200 times higher
than that 1n the plasma. Excretion Into the bile Increased as the dose
Increased. However, after a dose of 10 mg/kg, there was no further Increase
1n excretion of manganese Into the bile, and a maximum excretion rate of
-8.5 vig/m1n/kg was attained. This finding Indicates that an apparent
maximum transport rate may exist for manganese. Aut1ss1er et al. (1982)
recently demonstrated that the IntraperHoneal administration of the same
high dose of manganese (10 mg MnCl?/kg bw) for a period of 4 months
resulted 1n Increased brain accumulation of manganese 1n rats. This manga-
nese treatment gave rise to significant Increases In the concentrations of
manganese 1n brain stem (359%), corpus strlatum (243%), hypothalamus (138%)
and "rest of the brain" (119%).
The efficient operation of the homeostatlc mechanism 1s also reflected
by the fact that tissue manganese accumulation differs depending on the
routes of administration of this metal. Thus, the results of Aut1ss1er et
al. (1982) contrast with those of Chan et al. (1981) and Rehnberg et al.
(1982). The results from Rehnberg et al. (1982), summarized 1n Table 4-2,
demonstrate that the dose-related Increases In manganese levels In brain and
1804A 4-15 4/29/83
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CD
o
r\j
vo
CO
03
TABLE 4-2
Concentrations of Manganese 1n Liver, Kidney and 8ra1na
wet weight)
Manganese
Concentrat1onb
(ppm)
50
400
1100
3550
24
2.1
4.0
6.7
17.0
40
2.0
2.6
2.8
4.6
60
2.1
2.6
2.5
3.5
Liver
100
(days)
2.2
2.7
2.6
3.3
115
2.0
2.5
2.4
3.1
135
2.8
3.7
3.4
4.7
224
2.9
3.0
3.4
4.0
24
0.6
0.9
1.5
2.6
40
1.3
1.3
1.4
2.0
60
1.0
1.1
1.2
1.2
Kidney
100
(days)
0.8
1.1
1.0
1.0
115
0.6
0.7
0.8
0.9
135
0.9
1.2
1.2
1.5
224
1.0
1.2
1.2
1.2
24
0.5
0.8
1.4
2.7
40
0.5
0.6
0.7
1.1
Brain
60 100 130
(days)
0.4 0.4
0.5 0.4
0.6 0.4
0.7 0.5
224
0.4
0.4
0.4
0.5
aAdapted from Rehnberg et a!., 1982
bMn304 1n diet
-------
kidney resulting from chronic feeding with manganese varying from 50-3550
ppm were not quite as high as one might anticipate. Chan et al. (1981) only
observed a small Increase (31%) 1n brain manganese concentration 1n rats
exposed to 278 ppm Hn as MnCl 1n the drinking water for over 2 years.
Liver values were up 45%.
The concentrations of manganese 1n the liver are probably related to the
specific mechanism of biliary excretion of manganese. Klaassen (1974)
demonstrated that manganese 1s excreted Into the bile against a concentra-
tion gradient. On the other hand, T1chy and C1krt (1972) suggested that
manganese may be transferred from plasma Into the bile by passive transfer
followed by a nonenzymatlc complex formation 1n the bile. However, 1n
contrast to bile, plasma and liver contain Ugands with higher affinity for
manganese (Klaassen, 1974). Thus, the transfer of manganese from plasma to
bile may be mediated by an active mechanism.
Although normally biliary excretion 1s particularly Important 1n regu-
lating the body burden of manganese, this route of excretion 1s by no means
exclusive. This 1s because experiments In animals and humans conclusively
demonstrate that manganese 1s also excreted through the Intestinal wall
(Bertlnchamps and Cotzlas, 1958; Kato, 1963; PapavaslHou et al., 1966;
Wassermann and Mlhall, 1964). For Instance, there 1s some Indication of
manganese excretion through the rat Intestinal wall Into the duodenum, the
jejunum and, to a lesser extent, the terminal 1leum (Bertlnchamps et al.,
1966; C1krt, 1972). Both of these routes of excretion contribute signifi-
cantly toward the homeostasls of tissue contents of manganese. In addition,
manganese 1s also excreted to some extent with the pancreatic juice (Burnett
et al., 1952); manganese excretion by auxiliary GI routes may Increase 1n
the presence of biliary obstruction or with manganese overloading (Bertln-
champs et al., 1966; PapavaslHou et al., 1966).
1804A 4-17 05/06/83
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4.2.5.1. LEVELS IN BIOLOGICAL FLUIDS AND BIOLOGICAL INDICATORS OF
EXPOSURE — Concentrations of the metal In biological media have been
studied as Indicators of exposure. The correlations between the manganese
contents 1n blood and urine and the findings of neurological symptoms and
signs have also been examined. Manganese concentrations 1n body fluids have
not, however, proven to be reliable Indicators of exposure.
The mean concentration of manganese 1n the urine of nonexposed people 1s
usually estimated to be between 1 and 8 v-9/fc, but values up to 21
V.g/8. have been reported (Hor1uch1 et al., 1967; T1chy et al., 1971).
Tanaka and Lleben (1969) have shown that a rough correlation may exist
between mean urinary levels and average occupational air concentrations of
manganese, but 1n Individual cases the correlation 1s poor. Hor1uch1 et al.
(1967) and Chandra et al. (1981) have also associated Increased mean urine
manganese levels with Increased levels of manganese 1n the air.
Recent studies that used neutron activation and electrothermal atomic
absorption analytic procedures have shown that the average normal concentra-
tion of manganese 1n whole blood 1s 0.7-1.2 ixg/100 m&, and that manga-
nese concentration 1s much higher In the erythrocytes than 1n plasma or
serum (Cotzlas et al., 1966; Cotzlas and Papavas1l1ou, 1962; Papavas1l1ou
and Cotzlas, 1961; PapavaslHou et al., 1966; MuzzarelH and Rocchettl,
1975; Buchet et al., 1976; Tsalev et al., 1977; Z1elhu1s et al., 1978; Olehy
et al., 1966). The average manganese blood level 1n exposed workers seems
to be of the same order as that In nonexposed persons, but some observations
Indicate that heavy exposures to manganese may Increase the level of manga-
nese 1n the blood. Tsalev et al. (1977) found that workers exposed to
3
=1 mg of manganese dust/m of air, for a period of 1-10 years, had blood
1804A 4-18 4/29/83
-------
levels of manganese averaging 11-16 ]ig/A compared to a mean level of 10
iig/9. 1n nonexposed persons. Variations In plasma manganese concentra-
tions 1n women may be associated with hormonal changes (Hagenfeldt et a!.,
1973). Slight seasonal (HoMuchl et al., 1967) and diurnal (Sabadas, 1969)
variations 1n blood manganese concentrations (lower during summer, autumn
and at night) have also been reported. Manganese concentrations did not
differ among adult age groups (Hor1uch1 et al., 1967) and several studies
Indicate that there 1s no difference 1n the concentration of manganese 1n
the blood of men and women (HoMuchl et al., 1967; Zhernakova, 1967; Mahoney
et al., 1969; Versleck et al., 1974).
There 1s only one study Indicating a correlation between the manganese
blood and urine levels and the findings of neurological symptoms and signs
(Horluchl et al., 1970). Using the results of medical examinations per-
formed 1n three groups of workers employed 1n crushing manganese ore, manu-
facturing dry-cell batteries and electrodes, Hor1guch1 et al. (1966), found
a tendency toward anemia as determined from the specific gravity of whole
blood, a decrease 1n white blood cell count, and an Increase 1n neurological
findings. A significant association was reported (p<0.05) between the urine
manganese level and the neurological findings for all the groups taken
together. In the manganese ore-crushing workers (the group with the highest
mean exposure), a significant association was determined between manganese
levels 1n the whole blood and urine and 1n the neurological findings. Other
Investigators reported that the manganese of blood 1s unrelated to clinical
neurological findings (Rodler, 1955; Penalver, 1955).
The determination of manganese 1n feces has been recommended as a group
test for the evaluation of the level of occupational exposure to manganese
»
(J1ndr1chova, 1969). Manganese content 1n hair 1s normally below 4 mg/kg
1804A 4-19 4/29/83
-------
(Eads and Lambdln, 1973). There 1s as yet no consensus on other biological
materials which could be used to monitor manganese exposure. Chandra et al.
(1974) suggested using serum calcium to diagnose early exposure, and subse-
quently found an Increase 1n calcium 1n exposed welders (Chandra et al.,
1981).
4.2.6. Summary. On the basis of human (Mena et al., 1969) and animal
data (Pollack et al., 1965; Kostlal et al., 1978) H 1s generally accepted
that -3% or less of a single oral dose of manganese 1s absorbed from the
GI tract under normal conditions. There are neither human nor animal data
suggesting the rate of absorption of manganese through the lung.
Manganese 1s widely distributed within the body 1n constant concentra-
tions which are characteristic for Individual tissues and almost Independent
of the species (Fore and Morton, 1952). The concentration of manganese
present 1n Individual tissues, particularly 1n the blood, remains remarkably
constant 1n spite of some rapid phases 1n manganese transport. The average
normal level of manganese 1n whole blood of humans 1s 7-12 y.g/8., while
the manganese levels In serum are normally distributed around a mean value
of 0.5-0.6 u.g/8, (Versleck and Cornells, 1980). The highest values of
manganese In humans are found 1n liver, kidney and endocrine glands which do
not exceed 2 ug/g wet weight of tissue. Manganese penetrates the blood-
brain and placental barrier. Animal data Indicate a higher manganese accu-
mulation 1n suckling animals, especially 1n the brain (Kostlal et al., 1978).
Fecal excretion 1s the most Important way of manganese elimination from
the body. Biliary excretion 1s predominant under normal conditions
(Klaassen, 1974) although excretion via pancreatic juice and Intestinal wall
are considered to be Important 1n conditions of biliary obstruction or
manganese overload (PapavaslHou et al., 1966). In humans and 1n animals
urinary excretion 1s low (Klaassen, 1974).
1804A 4-20 05/06/83
-------
The total body clearance of manganese 1n humans can be described by a
curve which 1s the sum of at least two exponential functions with half-times
of 4 and 40 days, respectively. However, the physical significances of the
estimated half-times cannot be obtained from this data.
Manganese metabolism 1s rigorously controlled by homeostatlc mechanisms.
The homeostatlc control 1s primarily exerted at the level of excretion;
however, the site of GI absorption may also be an Important control point.
The absorption, retention and excretion of manganese are closely linked and
Interrelated and respond very efficiently to an Increase 1n manganese
concentration. The GI absorption depends not only on the amount Ingested
and tissue levels of manganese, but also on manganese b1oava1labH1ty and
Interaction with other metals. The way tissue concentrations Influence the
excretory mechanism 1s still unknown. B1le Is the most Important route of
excretion.
4.3. SYNERGISTIC/ANTAGONISTIC FACTORS
The way 1n which the body normally handles manganese 1s affected by the
age of the Individual and by the status of other metals 1n the body. The
effect of Iron stores has been the subject of several studies.
4.3.1. Interaction with Metals.
4.3.1.1. HUMAN STUDIES — Thomson et al. (1971) studied the Intesti-
nal transport system for manganese and Iron 1n subjects with three different
levels of Iron stores: those with normal Iron stores, patients with Iron
deficiency, and patients with endogenous Iron overload. Administration of
manganese by a duodenal sonde 1n these patients showed that the rate of
absorption was Increased 1n Iron-deficient patients and that this enhanced
absorption could be Inhibited by addition of Iron.
1804A 4-21 4/29/83
-------
Recent balance studies performed 1n humans showed no effect of dietary
calcium on manganese balance. Price and Bunce (1972) studied the Influence
of calcium Intake (300-1300 mg dally) on the balance of several essential
elements Including manganese 1n 7- to 9-year-old girls. The researchers
concluded that the calcium Intake 1n this study had no effect on manganese
balances.
4.3.1.2. ANIMAL STUDIES — Considerable Investigation has been made
of the relationship between Iron and manganese. The addition of manganese
to diets of several species of animals depleted of Iron resulted 1n
depressed hemoglobin levels. WHgus and Patton (1939) reported that
addition of ferric citrate to the diet accentuated the severity of perosls.
Matrone et al. (1959) found that excessive manganese 1n the diet (2000 ppm)
depressed hemoglobin formation 1n both rabbits (-88% of control levels)
and baby pigs (-50% of control levels). The minimal level of manganese 1n
the diet that Interfered with hemoglobin formation was estimated to be 50
and 125 ppm, respectively.
The Interaction of Iron and manganese metabolism 1n rats was also
studied by Dlez-Ewald et al. (1968). When Iron absorption was Increased 1n
Iron deficiency, manganese absorption was also Increased. Decreased Iron
absorption 1n Iron loaded animals was associated with decreased manganese
absorption. The body compensated for changes In manganese absorption by
Increasing manganese excretion 1n Iron-deficient states and decreasing
manganese excretion In Iron loaded states.
Kostlal et al. (1980) found that Increasing the Iron content of milk
54
decreased the whole body retention of orally administered Mn by a factor
of 10 1n rats fed milk with or without 100 ppm Iron additive. Thomson and
Valberg (1972) and Thomson et al. (1971) studied the Interrelationship of
1804A 4-22 05/06/83
-------
the Intestinal transport system for manganese and Iron by using the
technique of open-ended duodenal loops 1n control and Iron-deficient rats.
They found that manganese competes with Iron and cobalt 1n the process of
uptake from the lumen Into the mucosal cells and 1n the transfer across the
mucosa Into the body.
Manganese Interaction with other elements such as Zn, Cu, Cr, Co, Cd,
N1, In, Rh and Se have also been described (Doyle and Pfander, 1975; Jacobs
et al., 1978; Burch et al., 1975; Schroeder et al., 1974; Schroeder and
Nason, 1976). Most of these Interactions occurred at the level of gastro-
intestinal absorption and under specific conditions, I.e. the concentrations
of other nonessentlal elements exceeded the normal levels by several orders
of magnitude. These Interactions are not discussed because of their limited
relevance to evaluating the human health risk of manganese Inhalation.
4.3.2. Effect of Age.
4.3.2.1. HUMAN STUDIES -- Several studies Indicate that age 1s an
Important factor 1n manganese absorption and retention starting with the
fetal stage through adult life. Studies by Schroeder et al. (1966) and
Wlddowson et al. (1972) confirm that human placenta! transfer of manganese
takes place.
In contrast to some other essential metals, manganese levels 1n the
fetus and newborn are similar to adult levels (Fischer and Vlelgert, 1977;
Casey and Robinson, 1978). The exception seems to be bone, where fetal
concentration 1s higher than 1n the adult (Casey and Robinson, 1978; Sumlno
et al., 1975). In fetal liver and kidney, concentrations of -0.94 and
0.45 mg/kg have been found (Casey and Robinson, 1978). In the newborn,
corresponding values were 0.52 and 0.48 mg/kg, respectively (Fischer and
1804A 4-23 05/06/83
-------
Welgert, 1977). Wlddowson et al. (1972) reported that there was no consis-
tent change In the liver with age 1n 30 fetuses from 20 weeks of gestation
to full term but that generally manganese concentrations 1n full-term livers
were 7-9% higher than concentrations 1n adult livers.
In contrast to many other trace metals, manganese does not accumulate
significantly 1n the lungs with age (Newberne, 1973). In lungs of both the
adult and the fetus, average concentrations of -0.2 mg/kg manganese have
been reported (Schroeder et al., 1966; Sumlno et al., 1975; Casey and
Robinson, 1978).
Data reported by Fischer and Welgert (1977) Indicate a tendency to
decreasing renal manganese levels above age 50. Data reported by Schroeder
et al. (1966) show a difference between subjects 20-49 and 50-59 years of
age. Anke and Schneider (1974) report a slightly higher mean concentration
of manganese In females than 1n males.
Several studies Indicate that manganese penetrates the placental barrier
and that manganese Is more uniformly distributed 1n fetal than 1n adult
tissues (Koshlda et al., 1963; Onoda et al., 1978). Koshlda found that
fetal tissue concentrations of manganese except kidney and liver were higher
than concentrations of comparable adult tissue. Onoda et al. (1978) found,
however, that all measured fetal tissues (Including kidney and liver) had
higher concentrations of manganese. At a later embryonic stage manganese
accumulation takes place parallel to ossification (Koshlda et al., 1963).
4.3.2.2. ANIMAL STUDIES — Rabar (1976) and Kostlal et al. (1978)
observed much higher manganese absorption 1n artificially fed suckling rats
54
than in adult animals. Absorption of Mn in older animals fed on milk
diet was also higher (6.4%) than 1n rats on control diet (0.05%) but never
as high as 1n newborn rats. These results Indicate that both age and milk
1804A 4-24 4/29/83
-------
diet cause very high absorption (40%) of manganese In the Immature. The
addition of manganese to milk decreased the percentage of absorption of
54
Mn In both suckling and adult rats, Indicating the existence of a
homeostatlc control mechanism 1n neonates which, however, seemed to be less
effective 1n newborns.
Miller et al. (1975) found that neonatal mice did not excrete manganese
for the first 17-18 days of life, although absorption as well as distribu-
tion, tissue accumulation and mltochondrlal accumulation of elemental
manganese was vigorous. This suggested an Initially avid accumulation of
manganese that was supplied 1n trace amounts 1n the mouse milk (54 ng/mi).
The presence of high absorption coupled with the absence of excretion
resulted 1n a marked rise of tissue manganese 1n the neonates from an
exceedingly low to a very high level.
Ihe tissue accumulation 1n the brain was particularly Impressive as the
brain can be susceptible to both manganese poisoning and deficiency. Miller
and Cotzlas (1977) noticed an absence of manganese excretion during the
first 18 days of life 1n neonatal rats and kittens. However, when lactatlng
mothers were given drinking water with concentrations of manganese ranging
from 40-40,000 mg/ft, the lactation barrier appeared to give adequate pro-
tection to the young. When the level exceeded 280 mg/9., newborn animals
Initiated excretion before the 16th day of life. The neonates showed a
greater accumulation 1n the brain than their mothers, whereas the Increase
In liver concentrations was proportional to the concentrations found 1n the
liver of their mothers.
Kostlal et al. (1978) found a difference between 54Mn distribution 1n
the newborn as compared to older rats. Most striking was the 34 times
higher manganese uptake 1n the brain of 6-day-old sucklings as compared to
1804A 4-25 4/29/83
-------
adult females. These findings suggest that the neonatal brain may be at a
higher risk of reaching abnormal concentrations than are other tissues.
Rehnberg et al. (I960) found that the tissue distribution of manganese oxide
In preweanllng rats after oral exposure was: liver > brain » kidney >
t
testes at 18-21 days of age. Subsequent studies of longer duration (Rehn-
berg et al., 1981, 1982) gave similar results and Indicated the dietary Iron
deficiency caused a greater accumulation of tissue manganese. These authors
concluded that maximum manganese oral absorption and retention 1n rats
occurs during the preweanllng period. CahUl et al. (1980) found that
preweanllng rats retained up to 12 times more manganese when the chloride
was Ingested compared to the oxide.
4.3.3. Summary. It 1s generally accepted that under normal conditions
3-4% of orally Ingested manganese 1s absorbed 1n man (Mena et al., 1969) and
other mammalian species (Pollack et al., 1965). Gastrointestinal absorption
of manganese and Iron may be competitive (Mena et al., 1969; Kostlal et al.,
1980). This Interaction has a limited relevance to human risk assessment
under normal conditions. However, 1t does lead to the hypothesis that Iron-
deficient Individuals may be more sensitive to manganese than the normal
Individual.
Evidence 1s accumulating that during mammalian development manganese
absorption and retention are markedly Increased (Kostlal et al., 1978)
giving rise to Increased tissue accumulation of manganese (Cahlll et al.,
1980; Chan et al., 1983).
Manganese does penetrate the blood-brain barrier and the placenta!
barrier. Studies 1n animals Indicate a higher manganese concentration 1n
suckling animals, especially In the brain (Kostlal et al., 1978).
1804A 4-26 05/06/83
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5. TOXIC EFFECTS AFTER ACUTE EXPOSURE
5.1. ANIMAL STUDIES
The average median lethal doses (LIL-) observed 1n different animal
experiments are presented 1n Table 5-1. These data Indicate some variance
among LD doses reported by different researchers, which may be attrib-
uted to the specific experimental design used (I.e., route of exposure,
chemical form, animal species, or even age of animals). Generally, oral
doses are much less toxic than parenteral doses. The average LDV- values
range from 400-830 mg Mn/kg for oral administration of soluble manganese
compounds and from 38-64 mg Mn/kg for parenteral Injection. These data also
show that the toxldty of manganese varies with the chemical form admin-
istered to animals. It has been suggested that catlonlc manganese forms are
more toxic than the anlonlc forms and that the bivalent cation 1s ~3 times
more toxic than a trlvalent cation (U.S. EPA, 1975). Although the permanga-
nate anlons are strong oxidizing agents which show some caustic action, they
are relatively less toxic than the catlonlc forms. Obviously, Insoluble
manganese oxide Is less toxic than several of the soluble compounds (Hoi-
brook et al., 1975). However, as seen from Table 5-1, 1t 1s very difficult
to conclude from the data how the type of manganese 1on Influences Its tox-
1c1ty. Comparative 1ntraper1toneal toxldty studies have shown that manga-
nese 1s less toxic than many other metals (Franz, 1962; Blenvenu et al.,
1963).
Kostlal et al. (1978) found that age plays an Important role 1n the
pharmacoklnetlcs and toxldty of heavy metals. The highest oral toxldty of
manganese was found In the oldest and youngest groups of rats, as Indicated
1n Table 5-2. In 3- and 6-week-old rats a sharp decrease 1n toxldty was
noted when compared to sucklings; LD__ values were Increased by a factor
0591B 5-1 05/06/83
-------
o
LTI
TABLE 5-1
Acute 1050 Values for Manganese Compounds
in
i
r\j
(\3
00
CO
Compound Valence
Manganese 2+
chloMde
Manganese 2+
acetate
Potassium 7+
permanganate
Manganese 4+
dloxlde
Manganese 2+
sulfate
Manganese 2+
nltrate
Manganese 2+
chloride
Exposure
Route
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
l.p.
1.p.
l.p.
1.p.
1.p.
Animal
mouse
rat
guinea pig
rat
rat
rat
mouse
rat
guinea pig
rat
mouse
mouse
mouse
mouse
rat
LD50
(mg Mn/kg)
450
425
400
410
475
836
750
750
810
7400
44
64
56
53
38
Reference
S1gan and VUvlckaja,
S1gan and VHvlckaja,
S1gan and Vltvlckaja,
Holbrook et al., 1975
Kostlal et al., 1978
Smyth et al., 1969
Sigan and Vltvlckaja,
S1gan and VHvlckaja,
Sigan and Vltvlckaja,
Holbrook et al., 1975
Blenvenu et al. , 1963
Yamamoto and Suzuki,
Yamamoto and Suzuki,
Franz, 1962
Holbrook et al.. 1975
1971
1971
1971
1971
1971
1971
1969
1969
-------
TABLE 5-2
Influence of Age on Manganese ToxIcUy In Rats:
LD5o Values 8 Days after a Single Oral
Administration of MnCl?*
Average and Range of
Age 1n Weeks MnCl2 • 4H20
2 804 (735-897)
3 1860 (1655-2009)
6 1712 (1553-1887)
18 850 (775-957)
54 619 (564-702)
LDso (mg/kg) Values
Actual Mn Dose
223 (204-249)
516 (459-557)
475 (431-524)
236 (215-265)
171 (156-194)
'Source: Kostlal et al., 1978
0591B
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4/21/83
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of 2-3. In adult rats toxldty Increased again and reached values 1n the
oldest animals similar to those of suckling rats. The researchers suggested
that older rats might be more susceptible to metal toxldty due to a general
decrease 1n adaptive responsiveness, which 1s characteristic of the aging
process. It Is difficult to evaluate the contribution of aging because the
animals were only about 1 year old. Increased toxldty 1n suckling rats
might occur as a result of higher Intestinal manganese absorption and higher
body retention, observed earlier by some authors (see Chapter 4).
5.2. HUMAN STUDIES
Acute poisoning by manganese 1s very rare. It may occur In exceptional
circumstances such as accidental or Intentional 1ngest1on of large amounts
of manganese compounds. Dagll et al. (1973) described a case where exten-
sive damage to the distal stomach, resulting In pylorlc stenosis, occurred 2
hours after Ingestlon of potassium permanganate (10 tablets of 300 mg
each). Mahomedy et al. (1975) reported two cases of lethal methemoglobl-
nemla Induced by potassium permanganate prescribed by African witch doctors.
Manganese, along with other metals such as zinc, copper, magnesium,
aluminum, antimony, Iron, nickel, selenium, silver and tin, has been
reported to cause metal fume fever 1n humans. Metal fume fever 1s an acute
effect of occupational exposure to freshly formed metal oxide fumes of
resplrable particle size. The symptoms are similar to those of Influenza
consisting of fever, chills, sweating, nausea, and cough. The syndrome
begins 4-12 hours after sufficient exposure and usually lasts for 24 hours
without causing any permanent damage. The mechanisms are not fully under-
stood (Plscator, 1976).
0591B 5-4 4/26/83
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5.3. SUMMARY
The average LD observed 1n different animal experiments Indicates
that the oral dose values range from 400-830 mg Mn/kg of soluble manganese
compounds, much higher than the 38-64 mg Mn/kg for parenteral Injection.
The toxldty of manganese varies with the chemical form 1n which 1t 1s
administered to animals. Acute poisoning by manganese 1n humans 1s very
rare. It may occur following accidental or Intentional 1ngest1on of large
amounts of manganese compounds. Along with a number of other metals,
freshly formed manganese oxide fumes have been reported to cause metal fume
fever.
0591B 5-5 05/06/83
-------
>EPA
United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
EPA-600/8-83-013
June 1983
External Review Draft
lfr 2.
Research and Development
Health Assessment
Document for
Manganese
Part 2 of 2
Review
Draft
(Do Not
Cite or Quote)
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its
technical accuracy and policy implications.
-------
EPA-600/8-83-013
External Review Draft
DRAFT
Do not dte or quote
HEALTH ASSESSMENT DOCUMENT
FOR
MANGANESE
Notice
This document 1s a preliminary draft. It has not been
formally released by EPA and should not at this stage be
construed to represent Agency policy. It 1s being circu-
lated for comment on Us technical accuracy and policy Im-
plications.
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
Project Managers: Dr. Linda S. Erdrelch
Dr. Oerry F. Stara
U.S. !""• '•'.-•
r
-------
DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products does
not constitute endorsement or recommendation for use.
U,S,
11
1794A 5/06/83
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PREFACE
The Office of Health and Environmental Assessment of the Office of
Research and Development has prepared this Health Assessment Document (HAD)
at the request of the Office of A1r Quality Planning and Standards (OAQPS).
Manganese 1s one of several metals and associated compounds emitted to the
ambient air which are currently being studied by the Environmental Protec-
tion Agency to determine whether they should be regulated as hazardous air
pollutants under the Clean A1r Act.
A Multimedia Health Assessment for Manganese had been drafted 1n 1979 to
evaluate the health effects of manganese. The original document has since
been modified 1n scope and emphasis and updated. This HAD 1s designed to be
used by OAQPS for decision making.
In the development of this assessment document, the scientific litera-
ture has been Inventoried, key studies have been evaluated and summaries arid
conclusions have been directed at qualitatively Identifying the toxic
effects of manganese. Observed effect levels and dose-response relation-
ships are discussed where appropriate 1n order to Identify the critical
effect and to place adverse health reponses In perspective with observed
environmental levels.
111
1794A
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LIST OF AUTHORS, CONTRIBUTORS AND REVIEWERS
Dr. D1nko Kello (author)
Institute for Medical Research
Zagreb, Yugoslavia
Mr. Randall J.F. Bruins (author)
ECAO-C1n, U.S. Environmental Protection Agency
Dr. Linda S. Erdrelch (author, document manager)
ECAO-C1n, U.S. Environmental Protection Agency
Dr. Jerry F. Stara (document manager)
ECAO-C1n, U.S. Environmental Protection Agency
Dr. Steven J. Bosch
Syracuse Research Corporation
Syracuse, NY
Dr. Tom Clarkson
University of Rochester
Rochester, NY
Dr. Herb Cornish
School of Public Health
University of Michigan
Ann Arbor, MI
Dr. Michael Dourson, ECAO-C1n
U.S. Environmental Protection Agency
Dr. D. Anthony Gray
Syracuse Research Corporation
Syracuse, NY
Dr. Paul Hammond
University of Cincinnati
Cincinnati, OH
Dr. Rolf Hartung
School of Public Health
University of Michigan
Ann Arbor, MI
Dr. Bernard Haberman
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, DC
Dr. T.J. Knelp
NYU Medical Center
Tuxedo, NY
1v
1794A 5/11/83
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Or. James La1
Burke Rehabilitation Center
Dementia Research
White Plains, NY
Mr. C.A. Hall
Ethyl Corporation
Ferndale, MI
Dr. Fred Moore
Elklns Metal Company
Marietta, OH
Dr. Debdas Mukerjee, ECAO-C1n
U.S. Environmental Protection Agency
Dr. Nancy Pate
U.S. Environmental Protection Agency
Office of A1r Quality Planning and Standards
Research Triangle Park, NC
Dr. W. Bruce Pelrano, ECAO-C1n
U.S. Environmental Protection Agency
Dr. wnilam Pepelko, ECAO-C1n
U.S. Environmental Protection Agency
Dr. Mangus Plscator
School of Public Health
University of Pittsburgh
Pittsburgh, PA
Dr. Ivan Rabar
Institute for Medical Research
Zagreb, Yugoslavia
Dr. Marco Sarlc
Institute for Medical Research
Zagreb, Yugoslavia
Dr. Samuel Shlbko
Contaminants and Nat. Toxic. Evaluation Branch
Division of Toxicology, Food and Drug Administration
Washington, DC
Dr. Ellen Sllbergeld
Environmental Defense Fund
Washington, DC
Dr. Melvyn Tochman
John Hopkins Hospital
Baltimore, MD
1794A 5/11/83
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Dr. Otto Weber
Institute for Medical Research
Zagreb, Yugoslavia
Or. David Well
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, NC
Dr. James WUhey
Food Directorate, Bureau of Chemical Safety
Ottawa, Ontario
Special Acknowledgement: Technical Services and Support Staff, ECAO-C1n
U.S. Environmental Protection Agency
v1
1794A 5/11/83
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1-1
2. SUMMARY AND CONCLUSIONS 2-1
2.1. SUMMARY OF EXPOSURE 2-1
2.2. SUMMARY OF BIOLOGICAL ROLE AND HEALTH EFFECTS 2-6
2.2.1. Biological Role 2-6
2.2.2. Toxldty 2-7
2.3. CONCLUSIONS 2-11
3. GENERAL PROPERTIES AND BACKGROUND INFORMATION 3-1
3.1. PHYSICAL AND CHEMICAL PROPERTIES 3-1
3.1.1. Manganese Compounds 3-4
3.2. SAMPLING AND ANALYTICAL METHODS 3-8
3.2.1. Sampling 3-9
3.2.2. Sample Preparation 3-14
3.?.3. Analysis 3-H
3.3. PRODUCTION AND USE 3-17
3.3.1. Production 3-17
3.3.2. Use 3-24
3.4. SOURCES OF MANGANESE IN THE ENVIRONMENT 3-27
3.4.1. Crustal Materials and Soils 3-27
3.4.2. Industrial and Combustion Processes 3-30
3.4.3. Relative Importance of Manganese Sources at
Several Locations as Determined by Mass Balance
and Enrichment Models 3-38
3.5. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES 3-48
3.5.1. Principal Cycling Pathways and Compartments . . . 3-48
3.5.2. Atmospheric Fate and Transport 3-50
3.5.3. Fate and Transport 1n Water and Soil 3-54
3.6. ENVIRONMENTAL LEVELS AND EXPOSURE 3-60
3.6.1. A1r 3-60
3.6.2. Water 3-75
3.6.3. Food 3-79
3.6.4. Human Exposure 3-81
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3.7. SUMMARY OF GENERAL PROPERTIES AND BACKGROUND INFORMATION.
Page
3-89
3.7.1. Chemical and Physical Properties 3-89
3.7.2. Sampling and Analysis 3-89
3.7.3. Production and Use 3-91
3.7.4. Sources of Manganese 1n the Environment 3-92
3.7.5. Environmental Fate and Transport Processes. . . . 3-94
3.7.6. Environmental Levels and Exposure 3-95
4. BIOLOGICAL ROLE AND PHARMACOKINETICS 4-1
4.1. BIOLOGICAL ROLE OF MANGANESE 4-1
4.1.1. Biochemical Role 4-1
4.1.2. Manganese Deficiency 4-1
4.1.3. Manganese Requirements 4-2
4.1.4. Summary 4-2
4.2. COMPOUND DISPOSITION AND RELEVANT PHARMACOKINETICS. ... 4-3
4.2.1. Absorption 4-3
4.2.2. Distribution and Normal Tissue Levels 1-6
4.2.3. Excretion 4 10
4.2.4. Biological Half-time 4-12
4.2.5. Homeostasls 4-13
4.2.6. Summary 4-20
4.3. SYNERGISTIC/ANTAGONISTIC FACTORS 4-21
4.3.1. Interaction with Metals 4-21
4.3.2. Effect of Age 4-23
4.3.3. Summary 4-26
5. TOXIC EFFECTS AFTER ACUTE EXPOSURE 5-1
5.1. ANIMAL STUDIES 5-1
5.2. HUMAN STUDIES 5-4
5.3. SUMMARY 5-5
6. TOXIC EFFECTS AFTER CHRONIC EXPOSURE 6-1
6.1. NEUROTOXIC EFFECTS — HUMAN STUDIES 6-1
6.1.1. Case Reports and Ep1dem1olog1c Studies 6-3
6.1.2. Pathology of Manganese Poisoning 6-14
6.1.3. Summary 6-14
1794A
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Page
6.2. NEUROTOXIC EFFECTS — ANIMAL STUDIES ........... 6-15
6.2.1. Mechanism of Manganese Neurotox1c1ty ....... 6-23
6.2.2. Altered Neurotransmltter Metabolism ....... 6-25
6.2.3. Summary ..................... 6-35
6.3. LUNG EFFECTS ....................... 6-36
6.3.1. Human Studies .................. 6-36
6.3.2. Animal Studies .................. 6-46
6.4. REPRODUCTIVE EFFECTS ................... 6-58
6.4.1. Human Studies .................. 6-58
6.4.2. Animal Studies .................. 6-58
6.4.3. Summary ..................... 6-61
6.5. HEMATOLOGIC EFFECTS ................... 6-62
6.5.1. Human Studies .................. 6-62
6.5.2. Animal Studies .................. 6-63
6.5.3. Summary ..................... 6-G4
6.6. CAROJOVASCUIAR SYSTFM EFFECTS .............. 6 65
6.6.1. Human Studies .................. 6-65
6.6.2. Animal Studies .................. 6-66
6.6.3. Summary ..................... 6-66
6.7. BIOCHEMICAL EFFECTS ................... 6-66
6.7.1. Human Studies .................. 6-66
6.7.2. Animal Studies .................. 6-67
6.7.3. Summary ..................... 6-68
6.8. DIGESTIVE SYSTEM EFFECTS ................. 6-68
6.8.1. Gastrointestinal Tract Effects .......... 6-68
6.8.2. Liver Effects .................. 6-69
6.8.3. Summary ........... .......... 6-71
CARCINOGENICITY ........................ 7-1
7.1. ANIMAL STUDIES ...................... 7-1
7.2. HUMAN STUDIES ...................... 7-7
7.3. SUMMARY ......................... 7-10
1x
1794A 5/09/83
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Page
8. MUTAGENICITY AND TERATOGENICITY 8-1
8.1. MUTAGENICITY 8-1
8.1.1. Tests for Gene Mutations 8-1
8.1.2. Tests for Chromosomal Damage 8-1
8.1.3. Tests for Other Genetic Damage 8-1
8.2. TERATOGENICITY 8-3
8.3. SUMMARY 8-4
9. EFFECTS OF CONCERN AND HEALTH HAZARD EVALUATION 9-1
9.1. EXISTING GUIDELINES, RECOMMENDATIONS AND STANDARDS. ... 9-1
9.1.1. A1r 9-1
9.1.2. Water 9-1
9.2. SUMMARY OF TOXICITY 9-2
9.3. SPECIAL GROUPS AT RISK 9-5
9.4. EFFECTS OF MAJOR CONCERN AND EXPOSURE/RESPONSE INFORMATION 9-7
9.4.1. Effects of Major Concern 9-7
9.4.2. Exposure/Response Information 9-7
9.5. HEALTH HAZARD EVALUATION 9-11
9.5.1. Critical Effect and Effect Levels 9-11
10. REFERENCES 10-1
APPENDIX: ESTIMATING HUMAN EQUIVALENT INTAKE LEVELS FROM ANIMAL
STUDIES A-l
1794A 5/09/83
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LIST OF TABLES
No. Title Page
3-1 Physical Properties of Manganese 3-2
3-2 Normal Oxidation Potentials of Manganese Couples 3-3
3-3 Physical Properties of Some Manganese Compounds 3-5
3-4 Relative Sensitivity of Some Important Analytical Techniques
for Manganese 3_18
3-5 Estimated United States Production, Capacity and Use of
Selected Manganese Compounds 3-21
3-6 Manganese Supply-Demand Relationships, 1969-1979 3-22
3-7 Net United States Production of Ferromanganse and
SHIcomanganese 3-23
3-8 Commercial Forms of Manganese 3-25
3-9 Manganese Content of Selected Minerals 3-29
3-10 Sources and Estimated Atmospheric Emissions of Manganese
1n 1968 ! . . . . 3-31
3-11 Estimated Manganese Emissions from Controlled Submerged-Arc
Furnaces Producing Manganese Alloys 3-34
3-12 Manganese Concentrations of Coal, Fuel 011, Crude 011,
Gasoline, Fuel Additives and Motor 011 3-35
3-13 Manganese Content 1n Coal Ash 3-36
3-14 Manganese Concentration 1n Fine (<2.0 um) and Coarse
(2.0-20 urn) Particle Fractions of Aerosols from Several
Sources 1n the Portland Aerosol Characterization Study. . . 3-40
3-15 Manganese Concentrations 1n Aerosols from Various Sources,
and Estimated Percent Contribution of Each Source to Observed
Ambient Manganese and Total Aerosol Mass at Two Sites . . . 3-42
3-16 Manganese Concentrations In Aerosols from Various Sources,
and Estimated Percent Contribution of Each Source to
Observed Ambient Mn and Total Aerosol Mass, Based on Target
Transformation Factor Analysis 3-43
3-17 Number of National A1r Surveillance Network Stations within
Selected Annual Average Manganese A1r Concentration
Intervals, 1957-1969 3_61
xl
1794A 5/09/83
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LIST OF TABLES (cont.)
No. TUIe Page
3-18 National A1r Surveillance Network Stations with Annual
Average Manganese A1r Concentrations Greater Than
0.5 ug/m3 ............... . ......... 3-62
3-19 Average Manganese Concentration 1n Ambient A1r and Total
Suspended Partlculates (TSP) 1n Urban and Nonurban NASN
Sites, 1966-1967 ...................... 3-64
3-20 Urban NASN Sites, 1970-1982: National Cumulative Frequency
Distributions of Quarterly Values for Manganese Concentration 3-66
3-21 Nonurban NASN Sites, 1970-1982: National Cumulative Frequency
Distributions of Quarterly Values for Manganese Concentration 3-67
3-22 Manganese Concentrations 1n A1r, Kanawha Valley Area,
West Virginia ....................... 3-68
3-23 Ambient A1r Sampling Data for Total Suspended Partlculates
and Manganese (1n ng/m3) 1n the Marietta, OH-Parkersburg, WV
Vicinity, 1965-1966 and 1982 1933 ............. 3 70
3-?4 Concpnt rat Ions of Trace Metals in A1r Measured at Three
Locations In New York City ................. 3-71
3-25 Selected Dlchotomous Sampler Data on Manganese and Particle
Mass from 22 U.S. Cities In 1980 .............. 3-74
3-26 Concentration of Manganese 1n Various Lake and River Waters 3-76
3-27 Mean Concentrations of Dissolved Manganese by Drainage Basin 3-77
3-28 Dissolved and Suspended Manganese 1n Five U.S. Rivers . . . 3-78
3-29 Cumulative Frequency Distribution of Manganese Concentration
1n Tap Waters Sampled 1n the HANES I Augmentation Survey of
Adults ........................... 3-80
3-30 Estimates of Human Inhalation Exp]osure to Manganese 1n
Ambient A1r ........................ 3-85
3-31 Dietary Intake of Manganese 1n the U.S ........... 3-86
3-32 Intake of Manganese from Food by Children ......... 3-88
4-1 Manganese 1n Human Tissues ......... . ....... 4-7
4-2 Concentrations of Manganese 1n Liver, Kidney and Brain. . . 4-16
1794A 5/09/83
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LIST OF TABLES (cont.)
No. TUIe Page
5-1 Acute LOgQ Values for Manganese Compounds ......... 5-2
5-2 Influence of Age on Manganese ToxIcHy 1n Rats: LD5Q Values
8 Days after a Single Oral Administration of MnCl2 ..... 5-3
6-1 Studies of Manganlsm 1n Humans and Exposure-Response
Relationship ........................ 6-5
6-2 Frequency of Abnormal Neurological Findings ........ 6-8
6-3 Ferroalloy Workers with Neurological Signs by Level of
Exposure to Manganese ................... 6-12
6-4 Neurotoxlc Effects of Manganese 1n Experimental Animals . . 6-17
6-5 Neurological Signs Induced by Manganese In Monkeys ..... 6-21
6-6 Prevalence of Chronic Bronchitis In Groups of Workers
According to Smoking Status ................ 6-41
6-7 Cumulative Incidence of Acute Respiratory Diseases During
thp 3-Year Period ..................... f> **?
6-8 Summary of Human Studies of Respiratory Effects at Various
Levels of Exposure to Manganese .............. 6-47
6-9 Respiratory Effects with Manganese Exposure: Intratracheal ,
Intraperltoneal and High Dose Inhalation Exposures ..... 6-48
6-10 Respiratory Effects with Manganese Exposure: Inhalation
Exposures at Low Doses ................... 6-54
6-11 Pulmonary Physiology Data for Male and Female Monkeys After
Nine Months of Exposure .................. 6-56
7-1 Pulmonary Tumors 1n Strain A Mice Treated with Manganese
Sulfate .......................... 7-2
7-2 Carc1nogen1c1ty of Manganese Powder, Manganese Dioxide and
Manganese Acetylacetonate 1n F344 Rats and Swiss Albino
Mice ............................ 7-4
7-3 Induction of Sarcomas 1n Rats by the Intramuscular
Injection of Manganese Dust ................ 7-8
9-1 Studies of Manganese Inhalation 1n Animals — Summary of
Effect Levels ....................... 9-9
A-l Exposure Effect Information for Health Hazard Evaluation:
Human Equivalent Exposure Levels Estimated from Animal Data A-3
1794A 5/09/83
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LIST OF FIGURES
No. TUIe Page
3-1 The Global Cycles of Manganese 3-49
3-2 Concentration Factors for Manganese 1n Hudson River .... 3-59
6-1 Schematic Representation of the Mechanisms of Actions of
Manganese on the Central Dopam1nerg1c System 6-27
x1 v
1794A 5/12/83
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6. TOXIC EFFECTS AFTER CHRONIC EXPOSURE
6.1. NEUROTOXIC EFFECTS - HUMAN STUDIES
The effect of manganese on the CNS 1s a serious adverse effect and 1s
often known as manganlsm. According to Voss (1939) there were 152 cases of
manganlsm described 1n the literature prior to 1935. By 1943, Falrhall and
Neal (1943) found 353 cases of manganese poisoning. Subsequently, reports
of at least 200 additional cases of manganlsm have been published.
The signs and symptoms of chronic manganese poisoning have been de-
scribed 1n detail several times (FUnn et al., 1940; Ansola et al., 1944a,b;
Penalver, 1955; Rodler, 1955; Schuler et al., 1957; Chandra et al., 1974).
This poisoning can result from exposure to manganese aerosols after only a
few months (Ansola et al., 1944b), although H usually results from expo-
sures of 2-3 years or longer. It has been suggested that damage 1s revers-
ible 1f the patient 1s removed from exposure at an early stage. On the
other hand, Barbeau et al. (1976) observed that signs and symptoms persisted
and even worsened several months after exposure had ceased. This finding 1s
corroborated by Cotzlas et al. (1968) who reported that the presence of
elevated tissue manganese concentrations was not necessary for the confirma-
tion of poisoning. A person who has recovered from manganese poisoning
seems to be prone to contracting the Illness again.
The classical clinical picture of the disease had been divided Into
three phases on the basis of reports from the United States, Morocco and
Cuba by Cotzlas (1962):
1. Prodromal Phase. The disease begins Insidiously with anorexia,
asthenia, and occasionally psychotic behavior. Severe somnolence
followed by Insomnia 1s often found early 1n the disease. Headache and
leucopenla may further confuse the differential diagnosis between
manganlsm and viral encephalitis.
1803A 6-1 5/06/83
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2. Onset of the Extrapyramldal Disease. Clumsy articulation overlaps
encephalHIc manifestations 1n the prodromal phase, often resulting 1n
muteness. A mask-like face and general clumsiness with loss of skilled
movement are characteristic.
3. Established Manganlsm. Fully developed manganlsm causes severe rigidity
with the extremities showing the "cogwheel" phenomenon. Tremors may
occur which become exaggerated by emotion, stress, fatigue or trauma.
Indifference occurs, Interrupted by spasmodic laughter or by crying
spells. Similarly, an autonomlc disturbance manifested by excessive
salivation and sweating may become apparent.
Symptoms and signs of chronic manganese poisoning have often been com-
pared to Parkinson's disease, but certain differences should be noted.
Tremor, for example, 1s frequently an Intention tremor 1n manganlsm and not
the resting tremor that 1s typical for Parklnsonlsm (Klawans et al., 1970).
Barbeau et al. (1976) provide a revised description suggesting that chronic
manganese poisoning Is a better model of dystonla than of Parkinson's dis-
ease. These authors base such an assumption on the observations that some
form of dystonla, defined as a postural Instability of complementary muscle
groups, Is an almost obligatory feature of the manganlsm. They think 1t
probable that the minor manifestations of dystonla and torticollis were not
properly described 1n many papers. They also point out that the tremor
observed 1n some of the patients with manganese poisoning Is quite different
from that seen 1n Parkinson's disease. In their opinion 1t has much more of
an attHudlnal or flapping quality resembling that seen 1n Wilson's disease
or, for that matter, 1n dystonla musculorum deformans. Barbeau et al.
(1976) present a further argument to separate chronic manganese poisoning
from Parklnsonlsm based on the pathological findings: the classical flnd-
1803A 6-2 5/06/83
-------
1ngs 1n Parkinson's disease are deplgmentatlon and loss of cells 1n the sub-
stantla nlgra, locus caerulesus, and dorsal nucleus of the vagus with Uttle
damage to the stMatum or palUdum. In chronic manganese poisoning there 1s
no appreciable destruction of the substantla nlgra; the lesions are found
mainly within the stMatum and palUdum.
On the basis of the clinical similarity to Park1nson1sm, established
manganlsm has shown some Improvement after treatment with levadopa (Mena et
al., 1970; Rosenstock et al., 1971), confirming the depletion of the dopa-
mlnerglc system (Cotzlas et al., 1976).
A more specific description of the earlier stages of this disorder has
appeared 1n conjunction with a report of cases 1n the United States {Cook
et al., 1974). Symptoms were consistent with the literature except for the
absence of "manganese psychosis." The most characteristic signs were the
various gait disorders. Six cases showed similarity 1n the earliest symp-
toms: somnolence, 1ncoord1nat1on, speech disorder, gait difficulty, and
Imbalance. Postural tremor and tremors at rest were seen 1n four of the six
cases. In no case was this tremor the only symptom and all four had slurred
speech, asthenia and somnolence.
6.1.1. Case Reports and Ep1dem1olog1c Studies. Reports of cases of man-
ganlsm and the associated clinical descriptions have established that expo-
sure to manganese can cause chronic manganese poisoning 1n some Individuals.
In order to establish levels of exposure at which effects do not occur 1t 1s
necessary to have data with clearly described levels of exposures (Including
specific compound and particle size). The number and selection of Individ-
uals exposed and studied should be clearly defined Including data on the
duration of exposure. Although there has been a good deal of occupational
exposure to manganese, this type of dose/response data Is not available.
1803A 6-3 5/06/83
-------
There are, however, many reports of cases of manganlsm Including a few In
which an Identified exposed group has been examined for early signs of the
disease. The studies which have been reviewed with the goal of Identifying
the no-observed-effect level (NOEL) are discussed. However, the cross-
sectional approach of most of the studies Introduces selection biases,
Including the concern that disabled Individuals may have been lost from the
work force and excluded from the studies. Despite these limitations, there
are human studies which, taken together, define a range of lowest-observed-
effect levels (LOEL).
Manganlsm has been described 1n workers 1n ore crushing and packing
mills, 1n the ferroalloy production, In the use of manganese alloys 1n the
steel Industry, 1n the manufacture of dry cell batteries, and 1n welding rod
manufacture. Exposure typically Involved manganese oxides but Information
on manganese concentrations and the occurrence of other chemicals at working
places was usually limited. Few studies dealt with the particle size dis-
tribution of manganese aerosols.
Most of the described cases of manganlsm occurred 1n manganese mines.
The reported poisonings were among Huelva miners 1n Spain (Dantln Gallego,
1935, 1944), S1na1 miners (Nazlf, 1936; Scander and Sallam, 1936), miners
from Glessen 1n Germany (Buttner and Lenz, 1937), Moroccan miners (Baader,
1939; Rodler and Rodler, 1949), Chilean miners (Ansola et al., 1944a,b),
Cuban miners (Garcia Avlla and Penalver, 1953), Suceova miners 1n Rumania
(Wassermann et al., 1954), Mexican miners (Roldan, 1956), USSR miners
(Khazan et al., 1956; Khavtasl, 1958), Japanese miners (Suzuki et al.,
1960), and Indian miners (Balanl et al., 1967).
Table 6-1 contains a summary of those studies with corresponding expo-
sure data and a description or response frequency for CNS Involvement 1n
1803A 6-4 5/06/83
-------
TABLE 6-1
o
VjO
Type of Exposure
Ore crushing mill/dust
Manganese mine
Manganese mine; dusts
Manganese mine
Industrial plants
Dry-cell battery
Industry; dusts
i
vn Ferromanganese produc-
tion and processing
ferromanganese In-
dustry
Ferromanganese In-
dustry: electric
furnace workers
en
O
o> Ferromanganese plant,
^5 dust and fumes
Chemical
(particle size)
oxides, mostly
Hn02 (NR)
NR
NR (90% <5 u)
oxides (NR)
NR
65% Mn02 (NR)
ferromanganese,
small amounts
of MnO, Hn304
(95% <5 u)
and/or
100% Mn oxides,
mainly Mn304
(<2 w)
NR
(0.5-6 VL;
mostly 4.5)
NR (<1.5 u)
NR
Exposure Level
(mg Mn/nr)
10-30
30-180
62.5-250
250-450
1.5-16b
<5
5-30
6.8-42.2b
2.1-12.9
and/or
0.12-13.3
0.06-4.9
3.2-8.6
0.30-20.44
Duration of Exposure
3.3 yr average
178 days
~1 mo to 10 yr
8.2 yr average
(9 mo to 16 yr)
NR
7.5 yr average
{1-16 yr, cases)
8-26 yr 1n five cases
12 yr
(12 hr/day)
8.5+6.8 yr
27% <4 yr
9.8% >20 yr
Number Affected/
Number Studied
0/9
11/25
12/72
NR
15/83
0/38
7/117
8/36
5/71
26/160
40/100
62/369
Pathological Reference
Findings8
none Fllnn et al., 1941C
44% manganlsm
manganlsm Ansola et al., 1944a,b
150 cases manganlsm Rodler, 1955
manganlsm Schuler et al., 1957
none Tanaka and Lleben, 1969
6% manganlsm
22.2% manganlsm Emara et al., 1971
psychosis
7% manganlsm Smyth et al.. 1973
30% subjective symp- Suzuki et al., 1973a
toms; 2% "health dis-
orders due to manga-
nlsm"; symptoms In-
creased with number of
years of employment
40% subjective symp- Suzuki et al., 1973b
toms; 8-10% single
neurological signs,
e.g. , tremor of
fingers
16.8% slight neuro- Sarlc et al., 1977C
logical signs, e.g..
tremor at rest, patho-
logical reflexes
-------
TABLE 6-1 (cont.)
CO
Q , _^___
Oi
•** Type of Exposure
Control I electrode
plant
Control II aluminum
rolling rail!
(ambient levels)
Welding fumes
Chemical Exposure Level Duration of Exposure
(particle size) (mg Mn/m3)
0.002-0.030 NR
(emissions from
ferromanganese
plant)
<0.07 ug/m3 NR
NR 0.44-0.99d 20.2 (mean yr) (10-31)
0.5-0.8d 21.9 (mean yr) (2-32)
0.88-2.6d 14.1 (mean yr) (6-27)
Number Affected/
Number Studied
"n/190
0/204
5/20
10/20
9/20
Pathological
Findings3
5.8X neurological
findings
none
25X slight neurologi-
cal signs (brisk deep
reflexes)
SOX
45X
Reference
Sarlc et al., 1977
Sarlc et al., 1977
Chandra et al.. 1981
Percentage 1s given If sample has been selected such that the rate can be considered an estimate of prevalence
bRange of averages for different areas or workstations sampled
cSee also Tables 6-2 and 6-3
dln workers breathing zone
NR = Not reported
tn
X.
o
oo
to
-------
workers occupatlonally exposed to manganese by Inhalation. These studies
are presented 1n chronological order. The earlier ones 1n particular have
several limitations due 1n part to the fact that they were designed to
obtain clinical Information rather than Incidence or prevalence rates.
Generally the exposure data covers a broad range and does not Include par-
ticle size or chemical characterization. In some cases exposures change
over time (e.g., Fllnn et al., 1941; Smyth et al., 1973). The selection and
composition of the exposed group may not be adequately described or may be
based on high exposure. None of these studies employs a standard cohort
design. Duration of exposure 1s sometimes presented only for diagnosed
cases, and the endpolnts differ among studies. Percentages reported 1n the
table reflect prevalence of the pathological findings 1n the group as
described. While the use of this Information for obtaining a dose-response
association Is limited quantitatively, 1t does show evidence of effects 1n
humans and can be used to define a range of LOELs.
FUnn et al. (1941) examined 34 manganese exposed workers representing
all of the exposed Individuals from the same ore crushing mill. The authors
described the 23 workers without chronic manganese poisoning as exposed but
not affected. However, Table 6-2 shows that these workers had some neuro-
logical findings which might be Indicative of early manganlsm. The average
exposure for those affected was 5.3 years and for the exposed workers unaf-
fected was 2.4 years. No case of manganlsm was detected 1n nine workers
o
exposed to average manganese concentrations of 10-30 mg/m 1n two manga-
nese ore crushing mills (FUnn et al., 1940). The lowest average manganese
o
concentration at which the disease was found was 30 mg/m . However, only
two of these nine men were exposed for more than 3 years. Although the
entire exposed group was examined, the numbers are small and exposures too
short to define 16-30 mg/m as a NOEL.
1803A 6-7 5/06/83
-------
CO
o
to
3»
C"
CO
in
o
CT>
v>
CO
OS
Total examined
Tremor of tongue
Gait disturbances
Speech disturbances
Tremor of extremities
Muscular weakness
Intention tremor of hands
Abnormal reflexes
Masked fades
Sensitive achllles tendon
Abnormal handwriting
Spasm of extremities
Lateral nystagmus, slight
Abnormal psyche
Frequency
Affected
91
90b
73
55
55
45
45
45
36
27
18
18
18
1 HDLI
of Abnormal
Percentage
Nonaffected
35
0
0
22
0
17
35
0
4
0
0
17
4
: v-c
Neurological
Nonexposed
19
0
0
0
0
0
31
0
0
0
0
0
0
Findings3
Affected
11
10
9b
8
6
6
5
5
5
4
3
2
2
2
Number of Cases
Nonaffected
23
8
0
0
5
0
4
8
0
1
0
0
4
1
Nonexposed
16
3
0
0
0
0
0
5
0
0
0
0
0
0
Source: Fllnn et al., 1941
'Excluding Case No. 64 who was too weak to walk normally due to a previous Illness
-------
In 1955, Rodler reported 150 cases of manganlsm from three Moroccan
mines. Underground workers engaged 1n drilling blast holes ran a high risk
of developing manganese poisoning; 132 of 150 cases occurred among workers
using the drills and the other cases were laborers who worked nearby. Con-
centrations of manganese were usually very high In the mines from which
cases of manganlsm were reported. The manganese concentration 1n the air 1n
3
the Immediate vicinity of rock drilling 1n Moroccan mines was =450 mg/m
3
1n one mine and =250 mg/m 1n another. Analyses of the ores Indicated
that toxldty was not strictly related to manganese content; most of the
cases of manganlsm resulted from exposure to an ore from one mine that was
less oxidized than the ores from the other mines. In two reports from
Chilean mines (Ansola et al., 1944a,b; Schuler et al., 1957) the concentra-
3
tlons of manganese In the air varied from 62.5-250 mg/m and from an aver-
3
age of 1.5-16 mg/m , respectively. Schuler et al. (1957) observed that
the Introduction of pneumatic drilling and the associated Increase 1n dust
led to outbreaks of manganlsm. The Investigators did not examine all of the
workers and stated that their study was not designed to provide Incidence.
data. The total number examined was =83 and the procedure for selecting
them was not described. Therefore, prevalence rate was not applicable.
Emara et al. (1971) studied 36 workers exposed to manganese dioxide dust
1n a factory manufacturing dry batteries. Average concentrations ranged
3
from 6.8-42.2 mg Mn/m 1n four areas. Eight workers (22%) exhibited symp-
toms of manganlsm. Concentrations at the main working areas of three of the
3
cases ranged from 6.2-7.2 mg/m . Cases had been working 1-16 years prior
to diagnosis of chronic manganese poisoning.
After an Industrial hygiene survey Identified certain plants 1n Pennsyl-
vania as having manganese exposures above the threshold limit value (TLV) of
1803A 6-9 5/06/83
-------
3
5 mg/m , Tanaka and Lleben (1969) selected factories with and without such
exposures, and examined workers 1n the selected factories. All four plants
processing manganese ore or ferromanganese had samples above the TLV as did
60% of chemical manufacturing plants. Neurological screening of 117 workers
3
from the factories where exposures >5 mg/m had been detected (81% of
those exposed) revealed seven cases with "definite signs and symptoms of
manganese poisoning." This study does not support a lack of effect at expo-
3
sures <5 mg/m due to lack of standardized examination procedures, expla-
nation of selection patterns, details on Industrial exposures, duration of
exposure, and the small, unrepresentative sample 1n the low exposure group.
The only exposure levels presented were for the two case histories described.
Smyth et al. (1973) performed repeated sampling and analysis of the man-
ganese concentration around 15 work positions 1n a ferromanganese alloy pro-
cessing plant. They selected 71 employees for study who were exposed dally
1n areas Involving these work positions. Another group of 71 unexposed male
employees matched by age and length of plant service were selected as con-
trols. The weighted average concentrations for manganese 1n air ranged from
o 3
0.12-13.3 mg/m for fumes and from 2.1-12.9 mg/m for manganese dust.
Five exposed Individuals and no controls had signs suggestive of early man-
ganlsm. Three of these cases had several classical signs such as masked
fades, but the other two had only loss of associated arm movements bilater-
ally. The detailed exposures by position were not explained on a case by
case basis and therefore could not be associated with each Individual.
Exposure duration In the five cases ranged from 8-26 years although 1t 1s
not known when signs of manganlsm first appeared. Thus, all cases were
exposed to the high average dust concentrations which had been recorded 1n
3
previous years (30 mg/m ). The authors reported a poor correlation
between manganese exposure and manganese excretion In the urine.
1803A 6-10 5/06/83
-------
3
Sarlc et al. (1977) compared 369 workers exposed to 0.3-20 mg Mn/m at
a ferroalloy plant to two other groups; 190 workers at an electrode plant
3 3
exposed to 0.002-0.03 mg/m (2-30 p.g/m ) and 204 workers at an aluml-
3
num rolling mill exposed to ambient levels <0.0001 mg/m (<0.10
3
v.g/m )• Neurological examinations were given to 95% of all workers.
Prevalence of neurological signs was 17% 1n workers 1n the ferroalloy plant,
compared to 6% and 0% of workers 1n the electrode and aluminum plant,
respectively. The most prevalent symptom, tremor at rest, cannot be defi-
nitely attributed to exposure to manganese. There was no apparent associa-
tion of neurological symptoms with smoking habit. The ferroalloy workers
were further categorized Into three groups by mean manganese concentrations
33 3
at working places: <5 mg/m , 9-11 mg/m , and 16-20 mg/m . In addi-
tion to manganese compounds, carbon monoxide, carbon dioxide and coal dust
were also present. Table 6-3 summarizes neurological signs observed 1n
these groups. These data suggest that slight neurological disturbances may
3
occur at exposures <5 mg/m and seem to be more prevalent at higher expo-
sures. Although analysis of the effect by duration of exposure was Incom-
plete, reducing the usefullness of this study for obtaining dose-response
data, 1t does help to establish a range for a LOEL.
Chandra et al. (1981) reported on three groups of 20 welders each
3
exposed to levels <3 mg/m compared to 20 controls. The welders were
exposed to manganese released from manganese-coated electrodes as well as
from materials being welded. The materials being welded were stated to be
mainly steel; no data were given on exposure to other metals. The groups
came from a heavy engineering shop, a railway workshop, and a ship repair
shop. Many workers had been employed for >10 years. Means of airborne
manganese were stated to average 0.31, 0.57 and 1.75 mg/m with slightly
1803A 6-11 5/06/83
-------
00
o
CO
lABLt 0-J
* Ferroalloy Workers with Neurological Signs by Level of Exposure to Manganese3
Signs
Cogwheel phenomenon
Difficulty 1n Initiating voluntary movements
^ Pathological reflexes
"^ Tremor at rest
Pathological reflexes and tremor at rest
Cogwheel phenomenon and tremor at rest
Cogwheel phenomenon and pathological reflexes
Total
aAdapted from Sarlc et al., 1977
Mean Manganese Concentrations
0.301-4.933 9.480-11.062
(N = 268) (N = 17)
1 0
2 0
6 1
42 2
3 0
0 0
0 0
54 (20.1%) 3 (17.6%)
at Working Places (mg/m3)
16.347-20.442
(N = 18)
0
0
1
2
0
1
1
5 (27.8%)
Total
(N = 303)b
62 (16. 8X)
bTotal number examined was 369. The authors state 1n a footnote that "1n 66 workers with a mean manga-
nese exposure of 0.469-1.056 mg/m3 no neurological signs were found". It seems that these should be
<£ Included 1n the low exposure group 1n this table, 1n which case the prevalence of signs for this group is
S l&X.
oo
CO
-------
higher ranges 1n the workers' breathing zone. No data were given on
particle size, but H can be assumed that both fumes and small particles
were Inhaled. Positive neurological signs were reported to occur 1n the
form of brisk deep reflexes of the arms and legs and tremors of the hand and
tongue 1n 25, 50 and 45% 1n these three groups respectively, whereas none of
the controls showed such effects. No details of the neurological examina-
tion were presented. The mean exposure times of these groups were 20, 21
and 14 years, respectively. No statistical analysis or analysis by
person-years of exposure was presented.
Sabnls et al. (1966) assessed average dally exposure to manganese 1n a
ferromanganese alloy factory 1n India. The dally average weighted exposures
3
were <2.3 mg/m for all workers 1n the factory, although maximum levels
3
were recorded up to 10 mg/m . The medical officer of the factory reported
that he had observed neither acute nor chronic cases of manganese poisoning
among the workers. A 11st of subjective symptoms of manganlsm was prepared
for the medical officer who stated that no worker had reported such symp-
toms, but this 11st was not Included 1n their report. This data cannot be
used to Identify a NOEL because no clinical examinations were performed.
Other reports suggest that signs of manganlsm can be Identified 1n Individ-
uals not experiencing symptoms (e.g., Smyth et al., 1973).
Sabnls et al. (1966) relate 1n their report that manganese poisoning had
3
occurred 1n a nearby factory. High levels of 8.8 and 8.4 mg/m occurred
3
at operations here compared to 2.7 and 2.3 mg/m recorded 1n the ferro-
manganese alloy factory which had no reports of poisoning. Duration of
exposure was not reported at either factory. The authors concluded that 6
3
mg/m (the standard In effect at that time) was unsafe and that dally
3
weighted exposures up to 2.3 mg/m were safe.
1803A 6-13 5/06/83
-------
While the above studies do not show a clear dose-response relationship,
they do support the association of neurological symptoms and signs with
exposure to manganese.
6.1.2. Pathology of Manganese Poisoning. Pathologic findings observed at
autopsy have ranged from absence of morphologic changes, through specific
lesions of the basal ganglia (extrapyramldal system), to generalized pathol-
ogy of both the central and peripheral nervous systems (Casamajor, 1913;
Ashlzawa, 1927; Canavan et al., 1934; Stadler, 1936; Trendtel, 1936; Voss,
1939, 1941; Fllnn et al., 1941; Ardld and Torrente, 1949; Parnltzke and
Pfelffer, 1954; Bernhelmer et al., 1973; Barbeau et al., 1976). The most
extensive degenerative changes have been found 1n the corpus strlatum of the
basal ganglia (caudate nucleus, putamen and palUdum) and evidence Indicates
that the palUdum may be preferentially damaged.
6.1.3. Summary. An Important effect of chronic exposure to manganese 1s
the chronic manganese poisoning resulting from occupational exposures to
manganese dusts after only a few months of exposure, although other cases
develop only after many years. Earlier studies report advanced cases of
manganlsm (1n various miners), but more recent studies report cases showing
neurological symptoms and a few signs where the exposure was at much lower
concentrations.
The human studies are not adequate to Identify a dose-response relation-
ship, but do permit the Identification of the LOEL. The full clinical
picture of chronic manganese poisoning Is reported less frequently at expo-
sure levels below 5 mg/m (Sarlc et al., 1977; Chandra et al., 1981;
Tanaka and Lleben, 1969; Sabnls et al., 1966). The studies reporting
effects at the levels reported by Chandra et al. (1981) and of Sarlc et al.
(1977) describe effects which cannot be definitely attributed to manganese.
1803A 6-14 5/06/83
-------
Sarlc et al. (1977) report tremor at rest as the major effect on workers 1n
the electrode plant exposed to 2-30 ug/m (0.002-0.03 mg/m ). The
3
prevalence of a few signs In workers exposed to 0.3-5 mg/m (Sarlc et al.,
3 3
1977) and 0.4-2.6 mg/m (Chandra et al., 1981) suggest 0.3 mg/m (300
3
ug/m ) as a LOEL. The data available for Identifying effect levels
below this level 1s equivocal or Inadequate. This 1s further complicated by
the fact that good biological Indicators of manganese exposure are not
presently available. Consequently, studies directed toward clearly defining
the dose-effect relationship will undoubtedly facilitate a more realistic
estimate of the risk to developing manganlsm.
The broad exposure ranges, the Incomplete descriptions of chemical form
and particle size are Insufficient to relate response to exposure character-
istics. The exposure data reported by Smyth et al. (1973) suggests that
ferromanganese fumes may have a smaller particle size than the dusts and
^
thus more resplrable particles.
In order to obtain definitive dose response data, a cohort study 1s
needed, Including documented clinical examinations, more accurate exposure
characterization as well as exposure data on Individuals. All members of
the cohort should be followed for neurological signs for at least 20 years
and numbers lost to follow up should be clearly reported.
6.2. NEUROTOXIC EFFECTS - ANIMAL STUDIES
The wide range of ep1dem1olog1cal studies Indicates that the clinical
manifestations, observed morphological lesions and biochemical changes
described 1n chronic manganese Intoxication closely resemble those that
occur 1n other extrapyramldal disorders, notably Park1nson1sm. The exact
mechanism of biochemical changes 1s still debated, as 1s the role of manga-
nese 1n the extrapyramldal syndrome 1n exposed workers (Barbeau et al.,
1803A 6-15 5/06/83
-------
1976; WHO, 1981). Such controversy regarding the neurological component of
chronic manganese Intoxication 1n exposed workers prompted a wide range of
animal studies focused on the neurotoxlc effects of this metal.
Most of the earlier neurologic studies 1n animals utilized the paren-
teral or respiratory route of administration. Table 6-4 summarizes some of
the more recent data on neurological effects. An 1n-depth analysis of all
available animal data suggests no accurate dose-response relationship for
neurological effects of chronic manganese exposure can be assessed since the
methodology and reported values vary significantly among Investigators. For
Instance, very few of the early studies reported brain levels of manganese
(Pentschew et al., 1963; Neff et al., 1969; Mustafa and Chandra, 1971;
Bonllla and D1ez-Ewald, 1974; SHaramayya et al., 1974). In some of the
more recent studies where the brain manganese levels are reported, the
results obtained by different workers do not always agree. In some studies
(Chandara et al., 1979a; Chandra and Shukla, 1981) the brain manganese con-
centrations were reportedly an order of magnitude higher than those obtained
by most workers (Underwood, 1977; Bonllla, 1978, 1980; Deskln et al., 1981a;
Chan et al., 1981; La1 et al., 1981b, 1983c). Furthermore, 1n recent
studies by the same group (Chandra et al., 1979b; Murthy et al., 1981) the
brain manganese levels are reportedly different from values 1n their other
studies (Chandra et al., 1979a; Chandra and Shukla, 1981).
The available evidence obtained with small laboratory animals Indicates
that rats may display some of the neuroblochemlcal changes associated with
manganlsm 1n humans but they do not exhibit the wide range of behavioral
manifestations described 1n primates (Chandra and Srlvastava, 1970; Chandra
et al., 1979a,b; Singh et al., 1974, 1975; Shukla and Chandra, 1976, 1977;
SHaramayya et al., 1974). In addition, some studies have found clinical
1803A 6-16 5/09/83
-------
TABLE 6-4
___ iivwi v i>w A i v. k i i ^v i J vi i iai italic j c 111 i. *vpci iiii^iibui mil IIKI i 3
o
CO
3>
Dose (mq Mn/kq)
Species
Rat
Rat
Rat
Rat
Rat
Rat
Rabbit
>
i Rhesus
^' monkey
Squirrel
monkey
Monkey
Rats and
monkeys
Compound
MnCl2 4H20
MnCl2 4H20
MnCl2 4H20
MnCl2 4H20
HnCl2 4H20
MnCl2 4H20
Mn02
Mn02
Hn02
Mn02
Mn304
Route
Single
l.p. 2.2
1.p. 2.2
1.p. 2.2
1.p. 4.2
1.p. 4.0
l.p. 4.2
1.t. 169.0
1.m. 125,
220
s.c. 250.0
s.c. 39.5
79.0
158.0
Inhalation
Total
535
401
268
189
120
63
169
345b
50QC
355d
711d
1422d
11.6*
112. 5e
1152. Oe
Duration
1n Months
8
6
4
1.5
1
1
24
9
14
3
2
1.5
1
9
CNS Abnormality3
Behavioral H1stolog1cal Biochemical
+ NS NS
+ NS
NS NS +
NS NS +
4- +
- + 4-
t- + +•
+ NS NS
f t NS
,
+ - NS
t - NS
+ - NS
NS
Reference
Roussel and Renaud, 1977
Chandra and Srlvastava, 1970
SUaramayya et al., 1974
Shukla and Chandra. 1977
Chandra et al.. 1979b
Shukla and Chandra, 1976
Chandra, 1972
Pentschew et al.. 1963
Neff et al.. 1969
Suzuki et al.. 1975
UlMch et al., 1979a,b,c
aNS - Not studied
bDoses 2 months apart. Each dose was spread over eight Injection sites.
C0oses 1 month apart
dN1ne weekly doses
eCont1nuous 24 hours/day exposure. Units are 1n v-g Mn/m^.
CO
CO
-------
features of the extrapyramldal disease 1n most of the exposed animals, a
scattered neuronal degeneration 1n the cerebral and cerebellar cortex
(Chandra and SMvastava, 1970; Chandra et al., 1979b; Shukla and Chandra,
1976), but only occasionally some changes 1n the basal ganglia of the extra-
pyramidal system (Chandra, 1972). Consequently, with the exception of
Intratracheally exposed rabbits described below (Mustafa and Chandra, 1971,
1972; Chandra, 1972), studies with animals did not find the characteristic
clinical features of the extrapyramldal disease of manganlsm described
earlier 1n exposed workers.
It 1s probable that the signs of extrapyramldal disease are so subtle 1n
some species that they cannot be noticed without special procedures. There-
fore, Roussel and Renaud (1977) performed a study to determine If the human
sleep disturbances observed 1n Parkinson's disease and 1n chronic manganese
poisoning appear 1n the rat after chronic manganese Intoxication. They
found alteration of the sleep-wake cycle 1n rats exposed 1ntraper1toneally
to 2.2 mg Mn/kg bw dally for 8 months. Chronic manganese Intoxication 1n
this experiment created an Increase 1n slow-wave sleep and a decrease In
paradoxical sleep by modification of the length of the phases. However,
these changes can be attributed to disturbances 1n cortical activity rather
than to lesions of the extrapyramldal system.
Experiments with rats Indicate that a dally 1ntraper1toneal administra-
tion of 2-4 mg Mn/kg bw produces neuronal degeneration 1n the cerebral and
cerebellar cortex and that a period of up to 120 days appears to be a
threshold for the appearance of microscopic lesions (Chandra and Srlvastava,
1970; Shukla and Chandra, 1976, 1977). These experiments also demonstrate
that the maximum number of degenerated neurons Is present when the amount of
manganese 1n the brain 1s at maximum, thus Indicating that the extent of
1803A 6-18 5/06/83
-------
damage to brain cells 1s directly related to the amount of manganese present
(Chandra and Srlvastava, 1970; Shukla and Chandra, 1977). Iron deficiency
1n the presence of treatment with manganese results 1n the highest levels of
manganese on rat brain tissue. Some other studies have shown that biochemi-
cal changes (e.g., decreased activity of sucdnlc add dehydrogenase,
Increased activity of monoamlne oxldase) may appear earlier than hlstologl-
cal alteration of the brain, I.e., even 30 days after the beginning of man-
ganese exposure (SHaramayya et al., 1974; Shukla and Chandra, 1976, 1977;
Chandra et al., 1979a,b). However, from all these experiments performed on
rats, 1t appears that the threshold for the appearance of microscopic
lesions and biochemical changes 1s when the manganese 1n the brain reaches a
level of =4-5 ug/9 of dry tissue (Singh et al., 1979).
Mustafa and Chandra (1971, 1972), and Chandra (1972) carried out an
extensive study on rabbits Intratracheally Inoculated with 400 mg of MnO ,
corresponding to =170 mg Mn/kg bw. After a period of 18-24 months, the
Inoculated rabbits developed paralysis of the hind limbs. The animals also
showed a widespread neuronal loss and neuronal degeneration 1n the cerebral
cortex, caudate nucleus, putamen, substantla nlgra and cerebellar cortex.
There was a marked decrease 1n brain catecholamlnes, particularly noreplne-
phrlne and dopamlne, and a reduction 1n the activity of some enzymes 1n the
manganese-dosed animals as compared with controls.
Primates are a better experimental animal than rodents for studying the
neurological manifestation of manganese Intoxication. Several studies with
manganese dioxide-exposed monkeys have been performed (Mella, 1924; Neff et
al., 1969; Pentschew et al., 1963; Suzuki et al., 1975), but all were con-
ducted under Inadequate experimental conditions (small numbers of animals
were exposed to large, widely spaced doses of manganese by nonnatural
1803A 6-19 5/06/83
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routes) (see Table 6-4). However, these exposures did consistently produce
extrapyramldal symptoms (excitability, Intention tremors, rigidity 1n the
extremities) and/or histologlcal lesions (damage to the putamen, caudate,
subthalamlc nucleus, and palUdum) that were remarkably similar to those
described 1n cases of human manganlsm. Suzuki et al. (1975) administered
subcutaneous Injections of 0, 0.25, 0.5 and 1.0 g MnO once a week for 9
weeks and found that the time of appearance of neurological symptoms and
manganese tissue concentrations 1n monkeys were proportional to cumulative
dose (Table 6-5). Although the severity of symptoms was not dose-related,
symptoms appeared earlier when higher doses were administered.
In contrast to the experiments described above, Ulrlch et al.
(1979a,b,c) observed no neurological or other pathological changes 1n groups
of 8 squirrel monkeys and 30 Sprague-Dawley rats exposed to Mn00, aero-
o 4
3
sol at 11.6, 112.5 or 1152 ug Mn/m 24 hours/day (equivalent aerodynamic
diameters =0.11 u). These three exposure groups and a control were
exposed for 9 months and those not sacrificed observed for 6 additional
months. No exposure-related effects on 11mb tremor or electromyographlc
activity were observed, although the techniques used to measure these
parameters were described as sensitive enough to demonstrate differences 1f
present. The authors report that there were no clinical signs of toxldty,
but no details of the examination were presented. The report of histo-
loglcal examination of brain tissue was vague, claiming "no degenerative
changes upon special staining." There was no biochemical analysis. These
results Indicate that large amounts of manganese may be required to produce
extrapyramldal effects, since manganese levels 1n the blood of the monkeys
exposed to the highest concentration were five times higher than 1n the con-
trols after 9 months of exposure. Brain manganese levels were not reported.
1803A 6-20 5/06/83
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TABLE 6-5
Neurological Signs Induced by Manganese 1n Monkeys*
Single Dose
mg Mn (mg/kg)b 0
Time In Weeks and
246
Cumulative
8
Dose (mg Mn)
10 12
14
158 (39.5) 0 316 632 948 1264 1422
Tremor, excitability,
chorelform movement, con-
tracture of hand
316 (79) 0 632 1264 1896 2528 2844
Tremor, excitability, chorelform
movement, contracture of hand
632 (158) 0 1264 2528 3792 5056 5688
Tremor, excitability, chorelform movement
contracture of hand
aSource: Adapted from Suzuki et al., 1975
bDose per body weight not reported. Monkeys weighed 3.5-4.5 kg. Estimates
are based on 4.0 kg animal.
1803A 6-21 5/06/83
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The chronic toxldty of orally-administered manganese has not been ade-
quately studied, but the available reports strongly suggest that 1t 1s very
difficult, 1f not Impossible, to produce the characteristic signs of extra-
pyramidal neurological disease 1n laboratory animals exposed via drinking
water or food. Rats seem to be unaffected by dietary Intakes as high as
2000 ppm (Wassermann and Wassermann, 1977). Klmura et al. (1978) reported
that feeding with 2000 ppm of manganese chloride (564 ppm Mn) resulted 1n a
slight decrease of the brain serotonin. Bonllla and 01ez-Ewald (1974)
exposed rats to 5000 ppm of manganese chloride (2180 ppm Mn) 1n drinking
water, corresponding to =306 mg Mn/kg bw. Despite the high manganese
Intake, none of the animals developed signs of extrapyramldal neurologic
disease, such as muscular rigidity, tremor or paralysis of the limbs.
H1stopatholog1cal observation of the caudate nucleus revealed only moderate
pyknosls of some neurons, and treated animals showed significant decreases
1n brain concentrations of dopamlne and homovanllUc add. Bonllla
(1978a,b) found an Increase 1n the concentration of Y-am1nobutyr1c add In
the brains of rats that were exposed to 10,000 ppm MnCl2 1n the drinking
water (=600 mg Mn/kg bw) for 2 months.
Several recent experiments have been conducted to evaluate the effects
of prolonged oral exposure to husmanlte, manganous manganic oxide
(Mn0OJ, the major residue produced by heating MMT. The effect of
o 4
chronic manganese oxide 1ngest1on 1n rats maintained on a normal Iron diet
(240 ppm Fe) and on a low Iron diet (20 ppm Fe) was studied by Carter et al.
(1980), Rehnberg et al. (1980, 1981, 1982) and Laskey et al. (1982). Ani-
mals were exposed to four different levels of Mn30. 1n their diet, 50,
400, 1100 and 3550 ppm manganese, corresponding to 2.25, 18, 50 and 160 mg
Mn/kg bw, respectively. Animals treated with manganese and maintained on a
1803A 6-22 5/09/83
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normal Iron diet or on a low Iron diet did not develop signs of extra-
pyramidal neurologic disease, such as muscular rigidity, tremor or paralysis
of the limbs. Recently, however, they have Indicated (Gray and Laskey,
1980) that chronic dietary exposure to 1050 pptn manganese, corresponding to
2=140 mg/kg bw over a period of 2 months, alters reactive locomotor activ-
ity (RLA) 1n mice. However, 1t 1s not clear whether the reduction 1n RLA 1s
a result of reproductive dysfunction or a direct result from the action of
manganese on the brain.
Biochemical changes 1n the brains of rats exposed to 4.4 mg Mn/kg bw 1n
their drinking water have been described {Singh et al., 1979), and similar
exposure to 0.28 mg Mn/kg bw reportedly produced neuronal degeneration 1n
the cerebral and cerebellar cortex of growing rats (Chandra and Shukla,
1978). Although dietary levels of manganese 1n the above studies were not
reported, 1t 1s unlikely that the described changes are attributable to man-
ganese exposure. It 1s Important to note that the above doses are generally
below the dietary level of -20-30 mg Mn/kg bw that has been found to be
optimal for development and growth 1n rats (Holtkamp and H111, 1950; H111
and Holtkamp, 1954), and below the dally requirement for rats of 50 mg Mn/kg
of diet (3-6 mg Mn/kg/day bw) that was recently recommended by the NAS
(1978). Other recent studies relating biochemical changes 1n the brain to
administration of manganese are discussed 1n the following section.
6.2.1. Mechanism of Manganese Neurotox1c1ty. After some five decades of
research 1n this field, the mechanisms underlying the neurotoxldty of
manganese and the pathogenesls of manganese encephalopathy have not been
definitively elucidated. Several major factors contribute toward this lack
of basic Information. (1) The biological roles of this metal are not fully
understood; similarly, there 1s an absence of a clear understanding of the
1803A 6-23 5/06/83
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pharmacoklnetlcs, the homeostatlc mechanisms as well as the deficiency -
sufficiency - toxldty continuum of manganese. (2) The dose-effect rela-
tionship 1n manganese encephalopathy has not been systematically or ade-
quately Investigated; Important variables such as the age, the species, the
various forms of manganese and the routes of administration of manganese
must be more seriously considered. (3) The neuroep1dem1olog1cal data of
human manganese encephalopathy are Inadequate: the provision of complete
data will undoubtedly generate new Ideas and theories concerning the neuro-
toxlc mechanisms underlying this syndrome (Sllbergeld, 1982). However,
despite the shortcomings just discussed, more recent studies employing ani-
mal models of this disease have provided some Interesting and useful Infor-
mation such that a state-of-the-art evaluation of the possible and plausible
mechanisms underlying the neurotoxlc effects of manganese can be attempted.
Since the dietary requirements of this metal for man and animals are rela-
tively high (>40 ppm) (Underwood, 1977), the following discussion focuses
primarily (although not exclusively) on studies where the administered
manganese levels exceed the dietary requirement by at least two orders of
magnitude.
A number of hypothetical mechanisms have been proposed to account for
the neurotoxlc effects of manganese causing the pathological and neuro-
logical changes 1n the CNS during manganese encephalopathy. However, when
these mechanisms are considered within the framework of neurochemlcal con-
cepts, they can be grouped Into two broad categories: 1) those that direct-
ly Implicate altered neurotransmltter metabolism, and 2) those that do not
directly Involve dysfunctions of neurotransmltter systems, but also do not
preclude the latter as being secondary, Indirect or side effects.
1803A 6-24 5/06/83
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6.2.2. Altered NeurotransmUter Metabolism.
6.2.2.1. EARLY PHASE OF RESEARCH IMPLICATING DISTURBANCES OF THE CEN-
TRAL MONOAMINERGIC SYSTEMS — Early neuropathologlcal and Mstologlcal
findings reveal certain neuronal degenerative changes 1n the basal ganglia,
the subthalamlc nuclei and less frequently 1n other brain regions 1n chronic
manganese encephalopathy (Pentschew et al., 1963). From the more recent
mapping studies (Ungerstedt, 1971) of the central monoamlnergic systems 1n
the mammalian CNS, 1t 1s apparent that some, 1f not most, of the neuronal
degenerative alterations 1n manganese encephalopathy occur 1n the anatomical
locations of these monoamlnergic pathways. Studies 1n human manganlsm as
well as 1n animal models of this disease Indicate that the levels of mono-
amines such as dopamlne, noradrenallne and serotonin (and some of their
metabolites) 1n the basal ganglia are decreased (Neff et al., 1969; Mustafa
and Chandra, 1971; Cotzlas et al., 1971). Since these changes 1n the levels
of monoamlnes also occur 1n Park1nson1sm and since the clinical signs and
symptoms of chronic manganese encephalopathy show many similarities with
Park1nson1sm, the hypothesis that the dysfunction of the central monoamlner-
gic systems (particularly the dopamlnerglc system) was the underlying patho-
physlologlcal mechanism of chronic manganese encephalopathy was first pro-
posed (Cotzlas et al., 1971). Consistent with this hypothesis was the
observation that treatment of patients with L-dopa, a classical ant1-Park1n-
sonlan drug, alleviates the symptoms of this disease (Mena et al., 1970).
6.2.2.2. RECENT STUDIES THAT SUPPORT THE HYPOTHESIS THAT THE CENTRAL
DOPAMINERGIC SYSTEM IS DISTURBED IN CHRONIC MANGANESE TOXICITY — Since the
central dopamlnerglc system plays a key role 1n the normal functions of the
basal ganglia, and dysfunctions of the basal ganglia are clearly discernible
1n chronic manganese encephalopathy, the proposal that a major, 1f not the
1803A 6-25 5/06/83
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major, neurotoxlc effect of manganese Involves disturbances of the central
dopamlnerglc system appears most reasonable. Furthermore, the observations
that 1n the human brain the manganese concentrations 1n the basal ganglia
are higher than those 1n other regions (Curzon, 1975) and that 1n manga-
nese-poisoned animals this brain region accumulates more manganese than
other regions (La1 et al., 1981b, 1983a,c; Scheuhammer and Cherlan, 1981;
Chan et al., 1983) are consistent with this hypothesis. Despite the concen-
sus that the central dopamlnerglc system 1s disturbed 1n experimental manga-
nese neuro1ntox1cat1on, the precise details of the temporal, qualitative as
well as the quantitative aspects of the disturbances are stm controver-
sial. Nonetheless, from a critical evaluation of recent studies, both
published and unpublished, the following scheme, Identifying the sites at
which the regulation of central dopamlne metabolism 1s affected 1n manganese
toxldty (and hence the possible mechanisms of action of manganese) can be
arrived at (Figure 6-1). The key feature of this hypothetical scheme 1s
that any alterations of dopamlne synthesis, release, re-uptake and
metabolism ultimately lead to changes 1n dopamlne turnover. Furthermore,
the changes 1n the steady-state levels of dopamlne will give rise to altera-
tions of the Interactions of dopamlne with Us receptors and hence the
alterations of the subsequent receptor-mediated events (changes 1n Ion
channels and cylcase activities).
Since tyroslne hydroxylase (TOH) catalyses the rate-limiting step 1n
brain catecholamlne biosynthesis, the changes 1n brain dopamlne (DA) concen-
trations 1n manganese neurotoxldty could simply reflect the changes 1n the
activities of this enzyme. However, there 1s evidence that the decreased
TOH activity, observed ex-v1vo 1n manganese-poisoned animals, cannot be
1803A 6-26 5/09/83
-------
Tyroslne
re-uptake
Changes*
1n Ion
channels
TOH+ -
release*
DA
Turnover
metabolism by MAO*
re-uptake
Behavioral output
**
**
Acute
behavioral
changes
(Mn psychosis)
**
Chronic
Extrapyramldal
signs & symptoms
FIGURE 6-1
Schematic Representation of the Mechanisms of Actions of Manganese
on the Central Dopam1nerg1c System
1803A
6-27
5/06/83
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attributed to the direct effect of the metal on this enzyme since Deskln et
al. (1981b) did not find any Inhibition of TOH activity by 1 mM Mn2+. In
young male rats chronically treated with MnCl »4H 0 (1 mg/m8. 1n the
drinking water) strlatal dopamlne level 1s Initially Increased and, upon
more chronic treatment with this manganese salt, 1s decreased (Chandra and
Shukla, 1981). In adult male rats chronically treated with MnCl (10
mg/mfc 1n the drinking water) TOH activities 1n neostMatum, mldbraln,
hypothalamus and hippocampus, but not 1n frontal cortex and cerebellum, are
Increased 1n the first few months of treatment (Bonllla, 1980). However,
upon more chronic treatment with MnCl , TOH activities are decreased 1n
the neostrlatum but Us activities 1n the other brain regions are essenti-
ally the same as values 1n control animals (Bonllla, 1980). Thus 1n manga-
nese-treated rats the changes 1n brain TOH activities closely parallel the
fluctuations of brain dopamlne levels (Bonllla, 1980; Chandra and Shukla,
1981). However, manganese administration by oral gavage 1n the form of
MnCl2»4H20 at doses of 1, 10 and 20 ug Mn/g bw/day In rat pups
during postnatal development for 24 days gives rise to dose-dependent
decreases 1n TOH activities, dopamlne levels and dopamlne turnover 1n the
hypothalamus (Deskln et al., 1981a). Furthermore, the dose-dependent
changes (decreases at the lowest dose but Increases at the higher doses) 1n
tyroslne hydroxylase activities closely parallel the dose-related changes 1n
dopamlne levels 1n the stMatum of these manganese-treated rat pups (Deskln
et al., 1981a). Employing a different route of adm1n1strat1n of manganese
(1 mg MnCl2«4H20 per 100 g/day 1.p.), Aut1ss1er et al. (1982) also
found decreases 1n straltal dopamlne and dopamlne turnover 1n rats 4 months
after such treatment.
1803A 6-28 5/06/83
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Changes 1n steady-state levels of dopamlne can also be accounted for by
mechanisms that Interfere with the release and re-uptake processes at the
nerve endings. For Instance, chronic manganese treatment (1 mg
MnCl »4H?0 per mi of drinking water) throughout brain development
leads to transient, age-dependent but definite decreases 1n dopamlne uptake
by synaptosomes Isolated from strlatum, hypothalamus or mldbraln but not
from the cerebral cortex (La1 et al., 1982a, 1983b). These results are
compatible with the observations that admlnlstratln of MnCl »4H 0
(1 mg/mS. of drinking water) throughout development gives rise to Increased
accumulation of this metal 1n all the brain regions studied, with the excep-
tion of the cerebral cortex (La1 et al., 1981b), and that the in vitro
Inhibitory effects of manganese on dopamlne uptake by synaptosomes vary
depending on the brain region from which the synaptosomes are Isolated (La1
et al., 1981c). However, the jm vivo effects of chronic manganese treatment
on ex-v1vo synaptosomal dopamlne uptake vary depending on the dose, since
treatment with a higher dose of MnCl »4H 0 (10 mg/m2. of drinking
water) leads to Increased (rather than decreased) synaptosomal dopamlne
uptake measured ex-v1vo (Leung et al., 1982b). In comparison with Us
effects on synaptosomal dopamlne uptake, the effects of manganese on
dopamlne release have not been extensively studied, although a recent study
by Daniels et al. (1981) reveals that dopamlne release by the rat stMatal
slice preparation 1s stimulated by 5 y.M Mn *.
Another mechanism by which manganese can Influence the steady-state
dopamlne levels 1n the brain 1s through Us actions on dopamlne metabolism
(breakdown). The key enzyme Involved 1n this process 1s monoamlne oxldase
(MAO). In earlier studies by Chandra and co-workers (SHaramayya et al.,
1974; Chandra and Shukla, 1978), Increased brain activities of MAO 1n
1803A 6-29 5/06/83
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manganese-treated rats were reported. More recently, Chandra and Shukla
(1981) found that the striatal MAO activities are only increased during the
initial phase of chronic manganese treatment. Others have reported that
brain MAO activities in manganese-treated rats show both increases and
decreases (Deskin et al., 1981a) or remain unchanged (Kimura et al., 1978;
Autissier et al., 1982). However, it is important to point out that, since
MAO in brain and other tissues exists in multiple forms (Lai et al., 1980),
none of the studies so far discussed (Sitaramayya et al., 1974; Chandra and
Shukla, 1978, 1981; Kimura et al., 1978; Deskin et al., 1981a; Autissier et
al., 1982) set out to address the effects of manganese on the heterogeneity
of MAO. The studies of Lai and co-workers (Leung et al., 1981, 1982a; Lai
et al., 1982b; Lai, 1983) were aimed at just trying to resolve the latter
question employing specific substrates (serotonin being type A MAO substrate
and benzylamine type B MAO substrate) and inhibitors (clorgyline being
type A MAO inhibitor and deprenyl type B MAO inhibitor). In rats chron-
ically treated with MnCl2'4H20 (1 mg/nu of drinking water) through-
out development until adulthood, only type A MAO activity in the cerebellum
is slightly decreased (Leung et al., 1981). In these treated rats, type A
MAO activities in all the other brain regions, type B MAO activities in all
the brain regions as well as the type A to type B MAO activity ratios in all
the brain regions remain unchanged. Furthermore, the development of type A
and type B MAO activities in the whole brain of rats treated with
MnCl2'4H20 (either 1 or 10 mg/mjl of drinking water) has also been
found to be unaltered (Leung et al., 1982a). On the other hand, the same
study reveals that both hepatic type A and type B MAO activities in treated
animals are increased after 10-15 days of postnatal life. In contrast with
the apparent lack of effects of manganese on the A and B forms of brain MAO
1803A 6-30 5/09/83
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during development, Hfespan treatment of rats with
(1 mg/mft, of drinking water for over 2 years) exerts a modulatory effect on
the age-related changes of the heterogeneity of brain MAO (Leung et al.,
1981). For example, consider the age-related decreases 1n type A MAO and
dopam1ne-ox1d1z1ng activities 1n strlatum and mldbraln of manganese-treated
rats. In these rats, the other effects are age-related Increases 1n the
rates of oxidation of serotonin, benzylamlne and dopamlne 1n the cerebellum
not observed 1n control rats (Leung et al., 1981). These results support
the hypothesis that chronic manganese encephalopathy may act differentially
upon the developing and aging nervous system (La1 et al., 1981a, 1983b;
Leung et al., 1981, 1982a; SUbergeld, 1982).
In human amphetamine addiction, the psychotic behavior closely resembles
schizophrenia (Iversen and Iversen, 1975). Neuroleptlcs that are potent
alleviators of the primary symptoms of schizophrenia are good antagonists of
CNS dopamlne receptors (Iversen and Iversen, 1975). An Interesting and
enlightening parallel can be drawn between the above two observations and
the signs, symptoms and the pathophyslology of chronic human manganlsm.
Since chronic manganese encephalopathy commences with a phase of psychotic
behavior ("locura manganlca" or "manganese madness") (Cotzlas et al., 1971;
Barbeau et al., 1976) resembling that of schizophrenia and amphetamine psy-
chosis, and alterations of the central dopamlnerglc receptor functions have
been Implicated 1n the pathophyslology of the latter two syndromes, 1t 1s
reasonable to hypothesize that one of the neurotoxlc mechanisms of manganese
may be Us effect on these receptors. Several groups of researchers have
speculated and proposed that some of the transient neurochemlcal changes
during the Initial stages of chronic and very long-term manganese neuro-
1ntox1cat1on 1n animals could be viewed as pathophyslologlcal parallels to
1803A 6-31 5/06/83
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the Initial manifestation of psychotic behavior 1n human manganlsm (Bonllla,
1980; Chandra and Shukla, 1981; La1 et al., 19836,c). There 1s some evi-
dence that manganese exerts definite effects on the dopamlne receptors. The
binding of agonist and antagonist to dopamlne receptors 1s potently enhanced
by manganous Ions (Usdln et al., 1980). Intraperltoneal administration of
MnCl (10 or 15 mg/kg bw/day) to rats for 15 days results 1n Increased
binding of the dopamlne antagonist splroperldol to straltal membranes (Seth
et al., 1981). Moreover, manganese also stimulates brain adenylate cyclase
activity in vitro (Walton and Baldessar1n1, 1976). Recently Bonllla (1983)
found that strlatal adenylate cyclase activity 1s markedly decreased 1n rats
exposed to 2.5, 5 and 10 mg Mn (as MnCl.) per mi of drinking water for 8
months. In addition, the cyclase activity 1n the treated animals does not
respond to stimulation by dopamlne (Bonllla, 1983). In rats chronically
treated with MnCl »4H 0 (10 mg/mfc of drinking water) throughout
development, the Increases 1n open-field behavior elicited with Intraperl-
toneal amphetamine administration (1 mg/kg bw) are far less marked (Leung et
al., 1982b).
6.2.2.3. IMPLICATIONS OF THE ALTERED METABOLISM OF OTHER NEUROTRANS-
MITTERS IN MECHANISMS OF MANGANESE NEUROTOXICITY —
6.2.2.3.1. GABAerglc Systems — In rats treated with MnCl2 (10
mg/mfc of drinking water) for 2 months, the caudate GABA level 1s Increased
markedly although the activities of glutamlc add decarboxylase (GAD), the
rate-limiting enzyme responsible for GABA synthesis, and GABA-transam1nase,
the enzyme which metabolizes GABA, remain unchanged (Bonllla, 1978a).
Employing a developmental rat model of chronic manganese encephalopathy
(1 mg MnCl «4H 0 per ml of drinking water throughout development),
La1 et al. (1981a) demonstrated that chronic manganese toxldty does not
1803A 6-32 5/06/83
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alter the brain regional activities of GAD: these results confirm those
obtained by Bonllla (1978a,b) 1n the rat caudate. Short-term 1ntraper1to-
neal treatment with Mn (15 mg MnCl /kg bw/day for 15 days) gives rise to a
small decrease 1n cerebellar GABA binding (Seth et al., 1981).
6.2.2.3.2. Chol1nerg1c System — Since the pathophyslology of manga-
nese encephalopathy and that of Parklnsonlsm show certain similarities
(Cotzlas et al., 1971) and the chollnergic system may be Implicated 1n the
pathogenesls of Parklnsonlsm (Erlckson, 1978), several systematic studies
have been Initiated to Investigate the possibility that the neurotoxic
effects of manganese also Involve the chollnergic mechanism (La1 et al.,
1981a, 1982a,c; Bonllla and Martinez, 1981). In adult rats chronically
treated with MnCl »4H 0 (1 mg/m8. of drinking water) throughout
development, the activities of ChAT, the enzyme that catalyses the synthesis
of acetylchollne, decrease slightly 1n cerebellum and mldbraln whereas the
activities of this enzyme 1n the other brain regions as well as the activi-
ties of AChE, the enzyme that catalyses the metabolism of acetylchollne,
remain unaltered 1n all the brain regions studied (La1 et al., 1981a).
However, 1n rats treated similarly (La1 et al., 1982a, 1983b), chollne
uptake by hypothalamlc synaptosomes shows an Initial decrease (at postnatal
ages between 70 and 90 days) and a subsequent Increase (at postnatal ages
between 100 and 120 days). On the other hand, chronic treatment with two
doses of MnCl «4H 0 (1 and 10 mg/ma, of drinking water) throughout
development does not give rise to any marked changes 1n the brain regional
development of AChE activities (La1 et al., 1982c). Bonllla and Martinez
(1981) studied the activities of ChAT and AChE 1n different brain regions 1n
adult rats treated with 10 mg MnCl per mi of drinking water for 1-8
months and found virtually no changes 1n the activities of these enzymes.
1803A 6-33 5/09/83
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The results of Bonllla and Matlnez (1981) and those of Glanutsos and Murray
(1982) are compatible with those of La1 et al. (1981a, 1982c).
6.2.2.3.3. Other NeurotransmUter Systems — Although the lack of
systematic studies precludes any critical and accurate assessment of the
possible roles of other neurotransmltters 1n the pathogenesls and patho-
physlology of the neurotoxlc effects of manganese, there 1s some Indication
that the noradrenerglc system may also be Implicated (Chandra et al., 1979c;
Chandra and Shukla, 1981; Aut1ss1er et al., 1982).
6.2.2.4. MECHANISMS THAT DO NOT DIRECTLY IMPLICATE NEUROTRANSMIT-
TERS — Recently three other hypotheses have been advanced to account for
the possible mechanisms underlying the neurotoxlc effects of manganese.
Although these hypotheses are presently somewhat speculative 1n nature, they
provide Important theoretical frameworks upon which current and future
studies are designed.
6.2.2.4.1. Free-rad1cal-roed1ated Neuronal Degeneration — This mech-
anism has been proposed by Donaldson (1981, 1982) to account for neuronal
degeneration observed 1n chronic manganese encephalopathy and other neuronal
degenerative diseases. The central theme centers upon the observation that
manganese greatly potentiates dopamlne autoxldatlon with the resultant gen-
eration of free radicals (e.g., superoxlde anlon, hydrogen peroxide and
hydroxyl radicals) giving rise to degenerative changes (Donaldson, 1981;
Donaldson et al., 1981, 1982).
6.2.2.4.2. Autoxldatlon of Amines to Qulnones Enhanced by Manga-
nese — This hypothesis proposes that Increased concentrations of dopamlne
could result 1n autoxldatlon to qulnones and liberation of free radicals:
both types of reaction products are cytotoxlc and could readily give rise to
neuronal degeneration (Graham, 1978; Graham et al., 1978). Furthermore,
manganese enhances this autoxldatlon process (Graham, 1983).
1803A 6-34 5/06/83
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6.2.2.4.3. Interactions with Other Essential Metals — Interactions
of manganese with other metals can occur during Increased cellular accumula-
tion of manganese 1n chronic manganese toxldty (La1 et al., 1981b). The
Increased cellular manganese could either substitute for other metals (par-
ticularly divalent metal Ions) 1n their normal capacity (La1 et al., 1983d)
or antagonize other metals (e.g., manganese 1s a potent Ca antagonist).
Under both of these conditions, altered metabolic or cellular regulation may
be the predicted result (La1, 1983; La1 et al., 1983d,e).
6.2.3. Summary. The available results suggest that an accurate dose-
response relationship for Inhalation exposure and neurotoxldty 1s unobtain-
able at present. This 1s largely due to the fact that criteria for end-
points of effects and routes of admlnsterlng manganese differ 1n various
studies. The single study using Inhalation exposure, Ulrlch et al.
(1979a,b,c), reports no behavioral effects after 9 months exposure to 11.6
3
y.g/m Mn«0A. Unfortunately, this study did not Include biochemical
«3 ^
data nor levels of manganese 1n brain tissues. Since there are as yet no
good biological Indicators of manganese exposure, relating the effects to
the tissue levels of manganese would represent a state-of-the-art approach.
Despite these shortcomings, evidence 1s accumulating that one of the key
neurotoxlc effects of manganese 1s the disturbance of brain neurotransmltter
metabolism.
Chronic exposure of adult rabbits (Mustafa and Chandra, 1972), monkeys
(Neff et al., 1969) and rats (Bonllla and 01ez-Ewald, 1974) to different
manganese compounds gives rise to decreases 1n brain levels of monoamlnes,
particularly dopamlne. More recent studies Indicate that chronic treatment
of rats with MnCl 1n the drinking water throughout development 1s asso-
ciated with selective regional alteration of synaptosomal dopamlne uptake
1803A 6-35 5/06/83
-------
but not of serotonin or noradrenallne uptake (La1 et al., 1982b). In the
latter studies, the brain regional manganese concentrations show dose-
dependent Increases (Chan et al., 1981, 1983) and 1n animals treated with
the higher manganese dose, the changes 1n synaptosomal dopamlne uptake 1s
associated with decreased behavioral responses to amphetamine challenge
(Leung et al., 1982a). All these observations are consistent with the
notion that 1n chronic manganese toxldty the central dopamlnerglc system 1s
disturbed. This hypothesis provides a mechanistic explanation for the
extrapyramldal disturbances seen 1n human manganlsm.
Results of studies with the rat also strongly suggest that age may play
a role 1n the dose-effect relationship 1n manganese neurotoxldty (La1 et
al., 1981a,b, 1983b; Leung et al., 1981, 1982b). These results suggest that
the developing and the aging brain show different susceptibility toward the
toxic effects of manganese.
6.3. LUNG EFFECTS
6.341. Human Studies. The concept of "manganese pneumonia" (manganese
pneumonltls) has been based mainly on ep1dem1olog1cal observations. An
association between exposure to manganese and a high rate of pneumonia was
first suspected by Brezlna (1921), who reported that 5 of 10 workers died of
croupous pneumonia within 27 months In an Italian pyroluslte mill. Baader
(1932) first ascribed the high Incidence of pneumonia among workers making
dry cell batteries to manganese. On the basis of his observations as well
as upon the reports of Brezlna (1921), Schopper (1930), Bubarev (1931),
Frelse (1933), Oantln Gallego (1935), and V1gl1an1 (1937), Baader (1937)
concluded that pneumonia should be regarded as an occupational disease among
manganese workers.
1803A 6-36 5/06/83
-------
Lloyd-Davles (1946) reported the Incidence of manganese pneumonia 1n the
manufacture of potassium permanganate. The Incidence of this disease among
the workers employed over the period 1938-1945 averaged 26 per 1000, com-
pared to an average of 0.73 per 1000 1n a control group. All cases were
diagnosed as lobar or bronchopneumonla. The Impression was that the temper-
ature and general condition of the patient responded more slowly than usual
to treatment with sulfonamldes. The possible causal relationship to manga-
nese was not suspected until subsequent Inquiry. Workers also complained of
symptoms of bronchitis and Irritation of the nasopharynx. Manganese concen-
trations 1n air, calculated from the MnO content of dust, were between
3
0.1 and 13.7 mg/m . Approximately 80% of the particles were <0.2 u 1n
size and nearly all particles were <1 y..
Lloyd-Davles and Harding (1949) reported that this high Incidence of
manganese pneumonltls had been maintained. On the basis of the results of
chemotherapy the authors thought 1t unlikely, with the exception of one
case, that bacterial Infection played a primary role 1n producing the con-
solidation that was unquestionably present 1n the lung. They concluded that
manganese dust 1n suitable particle size Introduced Into the respiratory
system will, without the presence of other factors, cause pneumonltls.
A high Incidence of pneumonia associated with manganese exposure has
also been reported by other researchers. Heine (1943) found a high Inci-
dence of pneumonia among workers 1n an alloy producing plant 1n Aachen,
Germany, during the period 1939-1941. However, more careful analysis of the
data revealed that during two periods (1936-1938 and 1939-1941) there was no
correlation between high Incidence of pneumonia and high concentration of
manganese 1n the air 1n different parts of the factory. Heine concluded
that factors other than manganese, such as draft, weather conditions and
malnutrition, were predisposing factors for the development of pneumonia.
1803A 6-37 5/06/83
-------
Rodler (1955) discussed manganese pneumopathles 1n a study of manganese
poisoning 1n Moroccan miners. Cauvln (1943) had already pointed out the
prevalence of pneumonltls associated with the high death rate 1n miners 1n
Morocco during the winter of 1939-1940 and 1947. Rodler did not consider
manganese to be the sole etlologlcal factor, but possibly a factor which
aggravated difficulties resulting from the war, poor housing and sanitation.
Problems 1n obtaining X-ray films and necropsies lead Rodler to conclude 1t
was uncertain whether one was dealing with an ordinary pulmonary Infection
complication aggravated by manganese, or subacute edema, the pulmonary
manifestation of a toxic state.
A higher rate of pneumonia was also reported 1n basic-slag workers
(Jotten et al., 1939). Pneumonia was considered an occupational disease
related to the processing, bagging and loading of Thomas slag obtained in
the Thomas process of making steel. The Thomas slag contained 6-8% manga-
nese. Baader (1937) assumed manganese and Thomas-slag pneumonia to be sim-
ilar and the chest symptoms to be caused primarily by the manganese In the
slag.
Wassermann and Mlhall (1961) studied manganese miners, coal miners and
forest workers, all working 1n comparable geographical areas during the
period 1957-1959. The Incidence of bronchopneumonla and pneumonia was
26-33/1000 for manganese miners, 0.8-3.0/1000 for coal miners, and
4.8-24/1000 for forest workers. Within each year rates for manganese miners
were higher than for other groups. In the manganese mine the concentrations
3
of the dust were 28-840 mg/m , and the concentration of manganese ranged
3
from 2-200 mg Mn/m depending on workplace. Particles contained 12-30%
manganese and the range of particles <5 u was 34-81%. Silicon dioxide was
1803A 6-38 5/06/83
-------
also present. Measurements showed manganese concentrations of 55 and 78
3
mg/m 1n respiratory zones of workers at two different positions. Radio-
logical examinations showed that 25% of the 820 miners had radiological
modifications of varying degrees of severity, characterized by diffuse pul-
monary flbrosls and the presence of nodules. Evidence of manganlsm was
reported 1n 19 workers (2%). Definitive evidence of flbrotlc or other
specific lung changes has rarely been reported with occupational exposure to
manganese aerosols because radiological examinations were not performed.
Flbrotlc changes observed by Buttner and Lenz (1937) were almost certainly
due to the 20% silica present 1n dust from the Glessen pyroluslte (MnO )
mines. Manganocon1os1s was confirmed or suspected 1n 21% of all of the
miners and the percentage Increased with age and duration of work 1n the
mines.
Van Beukerlng (1966) performed a study from 1963-1965 1n a manganese
mine and an Iron mine 1n South Africa and found a pneumonia Incidence of
8.08% 1n over 3000 manganese miners and 5.10% 1n over 1000 Iron miners. No
chronic manganlsm was observed. Sarlc and Luc1c-Pala1c (1977) studied three
groups of workers to determine whether long-term exposure to manganese may
contribute to the development of symptoms of chronic lung disease. The
3
level of manganese exposure was reported as 0.4-16.35 mg/m for workers 1n
3
the production of ferroalloys, 5-40 vig/m for workers 1n the electrode
3
plant and 0.05-0.007 ing/m for the workers 1n the aluminum rolling
mill. The latter 1s low ambient exposure and 1s considered a control
group. The prevalence rate of chronic bronchitis and the respiratory symp-
toms of phlegm and wheezing was compared 1n smokers and nonsmokers 1n the
group of ferroalloy workers and 1n the control groups. Chronic bronchitis
was defined as bringing up phlegm 1n the morning and during the day and/or
1803A 6-39 5/06/83
-------
night for at least three winter months 1n the last 2 years or longer. Table
6-6 shows that chronic bronchitis was highest 1n smokers 1n the high expo-
sure group. The percentage of chronic bronchitis associated with the objec-
tive finding of reduced forced vital capacity was 5X (7/143) 1n smokers 1n
the alloy plant, greater than 1n any of the other groups (0 or 1 1n each
group, hence no statistical testing was appropriate). The rate of respira-
tory symptoms among smokers did not show an exposure-response association
among the group. The tendency for the rate of respiratory symptoms to
Increase with the extent of the smoking habit was most pronounced 1n the
group of workers 1n the production of manganese alloys. On the basis of
these results, the authors suggest a possible synerglsm between airborne
manganese and smoking habit 1n the occurrence of respiratory symptoms.
However, the results do not support synerglsm because there 1s no consistent
Increase 1n symptoms among the group. Further, percentages appear to be
additive, but data 1s not sufficient to support this.
Several reports suggest an Influence of manganese on the rate of pneu-
monia and other respiratory ailments among Inhabitants living 1n the vicin-
ity of a ferromanganese factory. In two of these three studies the ambient
!
atmosphere was visibly polluted with dusts, suggesting simultaneous exposure
to other contaminants; therefore, effects cannot be definitely attributed to
manganese. In 1939, Elstad reported a high rate of lobar pneumonia among
the residents of Sauda, a small Norwegian town, after the opening of a man-
ganese ore smelting works 1n 1923. Data about manganese concentration 1n
air from Sauda are not reliable because only one measurement was made. The
report Indicates that manganese was contained 1n visible clouds of brown
smoke polluting the atmosphere and the dry matter 1n the smoke was found to
contain silica. From 1924-1935, lobar pneumonia accounted for 3.65% of all
1803A 6-40 5/06/83
-------
TABLE 6-6
Prevalence of Chronic Bronchitis 1n Groups of Workers
According to Smoking Statusa«D
Exposure to
Manganese
Smokers
Non-smokers
Totalc
Manganese Alloy
Production
(0.4-16.4 mq/m3)
Number %
46/143 32.2
14/169 8.3
64/369 17.3
Electrode plant
(5-40 uq/m3)
Number %
14/69 20.3
11/102 10.8
28/190 14.7
Aluminum
Rolling Mill
(0.05-0.07 uq/m3)
Number
17/94
4/81
25/204
«
18.1
2.0
12.3
aAdapted from Sarlc and Luclc-Palalc, 1977
^Statistical analysis 1n original publication 1s multiple t-tests. This
was considered Inappropriate and 1s therefore not presented.
cThe denominators do not total 369 because data for 57 past smokers are
not Included.
1803A 6-41 5/06/83
-------
deaths 1n all of Norway and 32.3X of all deaths 1n Sauda, although the dis-
ease had been Infrequent 1n the community until the operation of the plant.
Pneumonia attacked Inhabitants of the community as well as workers of the
plant. Men working at the factory had a SOX higher mortality due to lobar
pneumonia than men employed elsewhere. The number of pneumonia cases and
deaths varied with the tonnage of manganese alloy produced. The occurrence
and types of pneumococd 1n Sauda did not differ from the rest of Norway.
Nogawa et al. (1973) studied subjective symptoms and ventllatory func-
tion 1n 1258 junior high school students housed 1n a school 100 m from a
ferromanganese plant and 1n a similar group of 648 students housed 7 km
away. Manganese dustfall measured monthly for 3 years averaged 200
2
kg/km /month 1n the vicinity of the plant compared to 20-fold lower levels
measured at four other points elsewhere 1n town. This dustfall level 1s
Indicative of a relatively high ambient air concentration, comparable to
3
about 3-11 vig/m based on Information 1n Table 3-22. Atmospheric
concentration of manganese 100 m from the plant was measured by a high
3
volume air sampler at 4.04 vig/m . The author cites a previous report of
3
a 5-day average of 6.7 v.g/m at a point 300 m from the plant.
Data on subjective symptoms and medical history of the student and
family were obtained by the British Medical Research Council questionnaire
for which the response rate was over 9854 1n each school. Of the 30 Hems
the following were reported to have higher prevalence In students from the
school near the factory: presence of sputum 1n winter on arising, presence
of sputum 1n summer, wheezing, clogged nose, frequent colds, and all six
Items referring to symptoms of the throat. These were reported to be
statistically significant at p<0.05 but the test used was not specified.
1803A 6-42 5/06/83
-------
The authors addressed several Issues which could affect reliability of
results. Since ventilation function was related to stature, they compared
the stature of students 1n the two schools and found no difference suffi-
cient to bias results. They noted that the exposure values at the two
schools could distinguish among the two groups because students at the pol-
luted school lived within 1500 m of the plant whereas students from the con-
trol school lived at least 5 km from the plant. Furthermore, data on
schoolchildren are far less likely to be biased by smoking habit and occu-
pational exposure than data on adults. Students from the school near the
factory had a higher prevalence of past history of pneumonia. No chronic
bronchitis was reported at either school. Objective tests of lung function
were measured by the same methods and the same Inspectors at both schools
with a 91% response rate. Students from the school 1n the polluted area had
lower mean values than students of the control school for forced expiratory
volume analyzed by sex and grade. Mean values for the one-second capacity,
one-second ratio and maximum expiratory flow were also lower 1n the school
1n the polluted area.
In a follow-up study performed after dust collectors had been Installed
1n the factory to reduce the manganese dustfall, the Investigators examined
respiratory resistance and respiratory symptoms (Kagam1mor1 et al., 1973).
The authors concluded that the respiratory symptoms of students 1n the pol-
luted area Improved after manganese exhaust diminished.
In a study on the effect of a-1r polluted with manganese 1n the vicinity
of a plant smelting pig Iron and ferromanganese, Ookuchaev and Skvortsova
(1962) examined clinical histories of 1200 children up to 16 years of age.
Manganese concentrations 1n air within a distance <1 km from the plant
3
fluctuated from 0.002-0.262 mg/m . Residents within 0.5 km of the plant
1803A 6-43 5/06/83
-------
complained of visible black dust which accumulated 1n the homes. Wash water
from children's hands contained 38.8 mg Mn/m2 of skin area. Managenese
was found 1n 62*/4 of nasal mucosa smears from 700 children. Roentgenologlcal
examinations showed pulmonary changes 1n 75% of the children, many of tuber-
culous etiology or other residuals of past disease. However, H 1s not
clear how many children were examined nor how Incidents were diagnosed or
scored. The authors' report of Increased Inflammatory processes of the
respiratory passages due to manganese 1s not quantitatively supported.
Sarlc et al. (1975) studied acute respiratory diseases 1n a town con-
taminated by a ferromanganese plant. Table 6-7 shows the 3-year cumulative
Incidence of acute bronchitis (and per1bronchH1s) 1n three exposure zones
of the town of 31,000 Inhabitants. The authors report the differences 1n
the first three rows to be significant but multiple t-tests performed are
not appropriate for frequency data and there 1s no exposure/response
effect. The rate of pneumonia 1n the population of the town did not vary by
pollution zone, nor did 1t show the expected difference between summer and
winter periods. Because the concentrations of manganese 1n the ambient air
were higher 1n summer than 1n winter, the question was raised whether the
expected difference was masked by respiratory disease associated with
observed seasonal variations 1n the level of manganese. Incidence rates
were presented by age, but rates by zone were not age-adjusted. Locations
of the workers' homes were not given but workers represented only a small
percent of the population since only 100 lived 1n the town (Saric, 1983).
The authors also stressed the fact that 1n this study some other potentially
relevant factors may not have been sufficiently controlled.
1803A 6-44 5/06/83
-------
TABLE 6-7
Cumulative Incidence of Acute Respiratory Diseases During
the 3-Year Period*
Mn Concentration
(ug/m3)
Acute bronchitis
and perlbronchltls
Winter
Summer
Pneumonia
Winter
Summer
0.27-0.44
I (N=8690)
Number %
474 5.5
296 3.4
47 0.5
39 0.4
0.18-0.25
II (N=17105)
Number %
1125 6.6
698 4.1
84 0.5
93 0.5
0.05-0.07
III (N=5296)
Number
2261
141
17
19
«
4.3
2.7
0.3
0.4
*Adapted from Sarlc et al., 1975
1803A
6-45
5/06/83
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6.3.1.1. SUMMARY — The studies of occupational exposures support the
association of pulmonary effects and exposure to manganese. Most of these
exposures range higher than the present limit 1n the United States for occu-
3
patlonal exposure, 5 mg Mn/m , so they provide little Information on the
possible effects of exposures to ambient levels. These studies were exam-
ined to determine 1f exposure levels could be associated with a severity of
respiratory effects. However, conclusions about these exposure/response
relationships are limited because exposure values often cover a broad range
and pulmonary endpolnts may not be clearly described or vary among studies.
The health effects of simultaneous exposures have also not been thoroughly
examined; for example, exposure to silica may account for some of the more
dramatic Increases 1n pneumonia.
Table 6-8 summarizes those studies which report levels of exposure to
manganese. The study 1n schoolchildren (Nogawa et al., 1973) was suf-
ficiently well documented to support an association between the Increased
respiratory symptoms 1n children and exposure to the dusts containing manga-
nese from the emissions of the ferromanganese plant at the reported exposure
3
levels (3-11 v.g/m ). It 1s plausible that exposure to manganese may
Increase susceptibility to pulmonary disease by disturbing the normal mech-
anism of lung clearance. Uncertainties regarding manganese as an etlo-
loglcal factor 1n the development of pulmonary diseases (I.e., pneumonia)
among workers prompted the animal studies described 1n the next section.
6.3.2. Animal Studies. Studies with animals (Table 6-9) have helped
clarify the effect of manganese on the lungs. These findings suggest that a
primary Inflammatory reaction of limited duration, without the presence of
pathogenic bacteria, may occur 1n the lung after exposure to manganese.
1803A 6-46 5/06/83
-------
CD
O
CO
TABLE 6-8
Summary of Human Studies of Respiratory Effects at Various Levels of Exposure to Manganese
i
-F*.
Type of Exposure
Manganese miners
(Roumanla)
Exposure Level Chemical/
Particle Size
2-220 mg/m3 34-81X smaller
than 5 u --
various work-
places.
Some S102.
Number Response
820 Increased frequency of pneumonia compared
to coal miners and forest workers.
Radiological modifications 1n lungs of
25X of miners. 2X manganlsm.
Reference
Wassermann and
M1ha1l, 1961
Manufacture of potassium
permanganate; workers
(England)
Manganese alloy workers
and worker controls
(Yugoslavia)
Emissions from ferromanga-
nese plant; school-
children (Japan)
Emissions from manganese
alloy plant; town resi-
dents (Yugoslavia)
0.1-13.7 mg/m3
Mn02/80X <2 u
I 0.4-16.0 mg/m3 NR
II 5-40 ug/m2 NR
III 0.05-0.07 ug/m3 NR
3-11 ug/m3 vs. NR
10 to 45-fold
lower
0.27-0.44 ug/m3 NR
0.18-0.25 ug/m3 NR
0.05-0.07 ug/m3 NR
NR Increased Incidence of "pneumonia" 1n
workers averaged 26 vs. 0.73/1000 In
controls. Increased frequency of
bronchitis.
369 Increased prevalence of chronic bronchitis
190 1n group I. Particularly 1n smokers.
204 Respiratory symptoms did not vary with
exposure to manganese
1,235 Increased prevalence of respiratory
640 symptoms (e.g., sputum, wheezing, sore
throat). Lower mean values 1n objective
tests of lung function. No chronic
bronchitis 1n either school.
8,690 Incidence rate of acute bronchitis higher
17,105 1n zone II: Inconclusive.
5,296
Lloyd-Oavles, 1946
Sarlc and
Ludc-Palalc, 1977
Nogawa et al., 1973
Sarlc et al., 1975
en
O
-v
CO
CO
All workers were males; race not given.
NR = Not reported
-------
TABLE 6-9
oo
o
Respiratory Effects with Manganese Exposure:
Intratracheal, IntraperHoneal and High Dose Inhalation Exposures
Species
Compound
Concentration
Effects by Exposure Type
Exposure
Hn
Only
Bacteria
Bacteria
Only
Results
Reference
Rabbit
MnO?
NR
Nice
MnOj
NR
i
-C-
c»
Mice
tn
\
O
CD
OS
Mice
ferro-
manganese
Mn02
NR
NR
1 hr/day/39+20 day
1 hr/day/29 day
Guinea pig
Guinea pig
ferro-
manganese
ferro-
manganese
2350 mg/m3
2350 mg/m3
8 hr/day/
6 mo
8 hr/day/
7.5 mo
NS
15 m1n/day/
31-102 days
2.70 or 120 m1n/
day/15-21 days
Rabbits Infected with pneumococd
after 39 days. Bronchial lesions
with leukocyte and lymphocyte Infil-
tration noted h1stolog1cally In Mn
and Mn + Bacteria groups. Highest
mortality 1n Mn + Bacteria group.
No pathological changes 1n Bacteria
group.
+ More severe bronchopneumonic changes
observed 1n mice that were first
Immunized with killed pneumococd
than 1n mice exposed to Mn02 plus
viable pneumococd without prior
Immunization. No bronchopneumonic
changes 1n Mn only group.
NS No hlstopathologlcal changes 1n
lungs.
NS Guinea pigs Infected with pneu-
mococd. Mortality rate similar
1n unexposed, unexposed plus Im-
munized, exposed, and exposed plus
Immunized.
+ No significant difference 1n mor-
tality rate (=OOOX) between In-
fected unexposed and Infected ex-
posed mice. Mortality rates were
30-40X lower among Immunized than
among nonImmunized animals.
+ Mice Infected with pneumococd and/
or Streptococcus hemolytlcus.
Hlstologlcal changes (slight to In-
tense mononuclear Interstitial In-
filtration of bronchi, bronchial
and alveolar epithelium edema) de-
pended on length of exposure. Ex-
posed animals did not show Increased
susceptibility to pneumococcus.
Jotten et al., 1939
Jotten et al., 1939
Heine. 1943
Heine, 1943
Heine, 1943
Lloyd-Davles, 1946
-------
TABLE 6-9 (cont.)
CO
o —
Species Compound Concentration Exposure
Rat Mn02 10 mg single 1ntra-
solutlon trachea!
Rat HnCl2 50 mg single 1ntra-
tracheal
o-. Rat HnCl2 5 mg single 1ntra-
' tracheal
Effects by Exposure Type
Mn Mn + Bacteria Results
Only Bacteria Only
t NS NS Rats killed at Intervals from 1 hr-
18 mo postlnJecUon. Inflammatory
response within 15 m1n (bronchlolar
epithelial changes) to 24 hr (mono-
nuclear reaction 1n the Inter-
stitial tissue). Subsequently,
widespread pneumonia and a granulo-
matous reaction sometimes developed.
+ NS NS Rats killed at Intervals from sev-
eral minutes to 8 days postlnjec-
tlon. Death due to gross pulmonary
edema within a few minutes, but
lung histology normal.
+ NS NS Rats killed as above (50 mg). Death
due to pulmonary edema In 1/3 of the
Reference
Lloyd-Davles and
Harding, 1949
Lloyd-Davles and
Harding, 1949
Lloyd-Davles and
Harding, 1949
Guinea pig
50 mg
Intratracheal
en
•x
o
CO
CO
Monkey
Monkey
Mice
Mice
Mn02
Mn02
Mn02
3 mg/m3 22 hr/day/5 mo
0.7 mg/m3 22 hr/day/5 mo
3 mg/m3
0.7 mg/m3
22 hr/day/2 wk
22 hr/day/2 wk
NS
NS
NS
NS
rats within 1 hr. Alveoli normal 1n
survivors after 1 wk, but mucosal
cells 1n the bronchial epithelium
remained abnormal.
+ Simultaneous Inoculation of Mn and
Candida alblcans. Inflammatory re-
action developed earlier, was more
Intense and widespread, and eventu-
ally produced more flbrosls (>120
days) 1n the Mn * Bacteria group.
NS Pulmonary congestion.
NS Pulmonary changes were less severe
and appeared later than 1n 3 mg/m3
exposure.
NS Inflammatory changes were generally
reversible after 2 mo, at which
time desquamatlon of the bronchial
epithelium was observed.
NS Same pulmonary changes as In the
3 mg/m3 mice.
Za1d1 et al., 1973
Nlshlyama et al.,
1975
Nlshlyama et al..
1975
Nlshlyama et al.,
1975
Nlshlyama et al.,
1975
-------
TABLE 6-9 (cont.)
CD
O
Gi
Species
Compound
Concentration
Exposure
Effects by Exposure Type
Mn Hn + Bacteria
Only Bacteria Only
Results
Reference
Guinea pig
Mice
50 mg
109 mg/m3
single Intra-
tracheal
1-3 hr/day/
1-4 days
NS
i
in
o
Rat
50 mg
Intratracheal
NS
Guinea pig
22 mg/m3
24 hr
NS Hn particles were not phagocytlzed
until 30 days postlnjectlon. De-
generative changes In the macro-
phages, Infiltration of eoslnophlls,
and some retlculHIs at >90 days.
+ Mice Infected with Klebslella pneu-
monia within 1-5 hr after final 3-hr
exposure. Inflammatory response
was most marked after the 4th expo-
sure to Mn only, but no deaths.
Mortality was 2-fold higher In the
Mn + Bacteria group than In the
bacteria only group, and mortality
was greatest In animals with long-
est Intervals between MnO? exposure
and bacterial challenge.
NS Most of the animals showed normal
pulmonary histology after 30 days,
although some had nodules of dust,
macrophages and thin retlculln
fiber. Enzyme activities from lung
fractions normal.
Initial depression of number and
phagocytlc capacity of macrophages
and bacterial clearance mechanism,
but nearly all Mn02 was cleared from
the lungs by 7 days postexposure.
The Inflammatory reaction was more
pronounced In the lungs challenged
with bacteria, but tissue histology
was normal.
Shanker et al., 1976
Malgetter et al.,
1976
Singh et al., 1977
Bergstrora, 1977
NS = Not studied; NR = Not reported
o
cr
CO
-------
H1stolog1cal examination of lung tissue from animals exposed to manganese by
Inhalation Indicates that slight to Intense leukocyte Infiltration char-
acterizes the acute pulmonary responses (Jotten et al., 1939; Lloyd-Davles,
1946; Malgetter et al., 1976; Bergstrom, 1977). Since other clear-cut
hlstologlcal findings have not been observed 1n acute manganese exposure,
Bergstrom (1977) suggests that the acute pulmonary effects may have been
overlooked 1n the early Inhalation studies based only on hlstologlcal evalu-
ation (Heine, 1943). Bergstrom (1977) also notes that the occurrence of a
primary Inflammatory reaction 1s consistent with the Ineffectiveness of
usual antibiotics used for pneumonia treatment 1n the acute phase after
MnO exposure.
The available experimental evidence Indicates that 1t 1s unlikely that
exposure to manganese could be solely responsible for the development of the
serious pathological changes 1n the lungs (e.g., bronchopneumonla or pneumo-
n1t1s, chronic Inflammatory effects such as flbrosls); Instead, 1t 1s likely
that susceptibility to Infection 1s Increased. Table 6-9 shows the pulmon-
ary effects of exposure to manganese with and without simultaneous exposure
to bacteria. Since the pulmonary reaction after exposure to manganese 1s
more pronounced 1n lungs challenged with bacteria (Jotten et al., 1939;
Heine, 1943; Lloyd-Davles, 1946; Za1d1 et al., 1973; Malgetter et al., 1976;
Bergstrom, 1977), and because sufficient evidence Indicates that exposure to
manganese has a depressive effect on the number and phagocytlc capacity of
alveolar macrophages (Waters et al., 1975; Graham et al., 1975; Shanker et
al., 1976; Bergstrom, 1977), the serious pathological changes should prob-
ably be attributed to decreased resistance to respiratory Infection and the
presence of pathogenic bacteria. The results of the study by Jotten et al.
(1939) with Immunized mice further suggest that manganese may Interfere with
1803A 6-51 5/06/83
-------
some 1mmunolog1cal mechanism, rendering the animals more susceptible to
Infections. Consequently, some of the earlier observed cases of manganese
pneumonia might have had a bacterial genesis, particularly among population
groups whose exposure to manganese was low and risk of airborne Infection
was high.
The experimental data on the pulmonary toxldty of manganese 1n Table
6-9 consists of studies at high doses of short duration and often using
Intratracheal administration, therefore not showing a consistent dose-
response relationship. For example, Singh et al. (1977) reported that an
Intratracheal Inoculation of 50 mg MnO did not produce significant
biochemical or pathohlstologlcal changes 1n the lung tissue, although one of
the authors observed 1n his earlier Investigations that MnO alone pro-
duced flbrotlc reaction under exactly the same experimental conditions
(Za1d1 et al., 1973; Shanker et al., 1976). In other studies pathomorpho-
loglcal changes were observed 1n the lung tissue of experimental animals
after Intratracheal Inoculation of 10 mg MnO (Lloyd-Davles and Harding,
1949; Levlna and Robacevskaja, 1955), and even after 5 mg MnCK (Lloyd-
Davles and Harding, 1949). However, 1t 1s reasonable to conclude that the
usually rapid lung clearance of Inhaled manganese (Malgetter et al., 1976;
Bergstrom, 1977) 1s Ineffective 1n the Intratracheal Inoculation, so that an
amount of 5 mg manganese 1s sufficient to Induce local lesions 1n the lung.
Although Inhalation studies represent a much better experimental model
for studying pulmonary effects, the results obtained are still Insufficient
for estimating accurate dose-response relationships for Inhalation exposure
to manganese. For example, Heine (1943) found no pathological changes 1n
3
the lungs of guinea pigs exposed to 2350 mg/m ferromanganese dust 8
hours/day for up to 200 days. Further, 1n experiments on rats exposed to
3
150 mg MnO^/m for up to 15 months, no signs of pneumonia were observed.
1803A 6-52 5/06/83
-------
Table 6-10 contains more recent Inhalation studies administering lower
doses and using longer time periods; hence, these studies are more useful
for delineating effects at level near ambient exposures.
A series of Inhalation studies reporting acute exposures to Mn 0
o A-
aerosol are supportive of the pulmonary toxldty of manganese (Adklns et
al., 1980a,b,c). Charles River CD-I mice (4-8/group) were exposed for 2
3
hours to Mn.,0. aerosol 1n concentrations ranging from 0-2.9 mg Hn/m .
Dry/wet ratios of tissue weight were examined as an Index of edema and the
results were not considered to be biologically significant (Adklns et al.,
1980a). Another experiment was designed to examine the suppression of
pulmonary defense mechanisms after acute Inhalation exposure to manganese.
3
Exposure of groups of 22-195 mice for 2 hours to 897 ug Mn/m signifi-
cantly reduced the total number of mlcrocytlc pulmonary cells (p<0.01,
t-test), but did not affect the differential cell count (macrophages, PMNs,
lymphocytes). Reduction 1n phagocytlc capability was not statistically
significant (Adklns et al., 1980b).
Adklns et al. 1980c also exposed 20-80 mice/group to Mn_0
O *r
3
(0.22-2.65 mg/m ) and subsequently to airborne Streptococcus pyogenes.
Animals exposed to manganese showed higher mortality rates than Infected
3
control animals (at 0.38 mg Mn/m a 7.5% mortality Increase was within 95%
confidence limits). These results support the concept that a primary
Inflammatory reaction to manganese can occur 1n the respiratory tract after
exposure to manganese, causing a decrease 1n the resistance to respiratory
Infections.
UlMch et al. (1979a,b,c) exposed Sprague-Dawley rats (30/group) and
squirrel monkeys (8/group) to Mn00, aerosol at concentrations of 11.6,
J 4
3
11.25 and 1152 ug Mn/m for 24 hours/day, 7 days/week for 9 months.
1803A 6-53 5/06/83
-------
TABLE 6-10
Respiratory Effects with Manganese Exposure: Inhalation Exposures at Low Doses
CD
O
CO
3>
Species
Mice, Charles
River, CD-I
(20-195/group)
Mice. Charles
River, CD-I
(20-41/group)
Rats, Sprague-
er> Dawley (30/group)
^Monkeys, squirrel
•**• (8/group)
Monkeys, Rhesus
(7 exposed,
5 controls)
Monkey, Rhesus
A) 3 exposed
8) 2 exposed
Rats
(74/group)
Hamsters, golden
^ (60/group)
^
Compound
Mn30-4
aerosol
Nn304
aerosol
Mn304
partlculate
""304
partlculate
Mn02
dust
Automotive
emissions
containing
Mn
Effects
Concentration Exposure Mn Mn +
(particle size) Only Bacteria
897 ug/m3 2 hr - NS
(1-3 um)
220-2650 ug/m3 2 hr NS ++
(1-3 um)
Control 24 hr/day, - NS
1 1 . 6 ug 9 mo
112.5 ug
1152 ug
(<2 um)
100 ug/m3 24 hr/day - NS
to 66 wk
22 hr/day, * NS
A) 3000 ug/m3 10 mo
B) 700 ug/m3
117-131 ug/m3 8 hr/day, - NS
(0.3 um) plus 56 day
other partlcu-
late and gases
Bacteria Comments Reference
Only
NS Normal cell concentration (macro- Adklns et al.,
phages, PMNs, lymphocytes). No 1980b
Increase 1n extracellular protein
(no edema). No effect on phago-
cytlc capability.
«• (Bacteria only - control) Adklns et al..
Mean mortality rate Increases 1980c
over controls as Mn concentration
Increases. Enhanced growth of
streptococci over controls.
NS No exposure related gross or UlMch et al.,
microscopic alterations or effects 1979a,b,c
on mechanical or ventllatory prop-
erties of the lung. (No exposure
related effect on EM6 or 11mb
tremor .
NS No abnormal changes seen on gross Coulston and
or microscopic examinations. In- Griffin, 1977
crease of Mn In lung. 8/12 had
acarlasls.
NS Inflammatory changes earlier 1n A Suzuki et al.,
than B; granular rather than In- 1978
f1ltrat1ve shadows. After 10 mo
hyperplasla of lymphold tissue,
pulmonary emphysema. Deposits of
dust 1n macrophages.
NS No gross or microscopic changes Moore et al..
In the lung. 1975
o
\NS = Not studied
00
CO
-------
Although blood and tissue levels of manganese were elevated 1n both species
at the high dose after 9 months, significant exposure-related effects were
not reported 1n either species by neurologic, histopathologic, organ weight,
pulmonary function or hematologlc observations. The Investigators evaluated
pulmonary physiology data for the 4 exposure groups at 5 points 1n time but
the report presents only the mean percent of preexposure values after 9
months of exposure (Table 6-11). Few statistically significant differences
were found using the Mann-Whitney U test. Mean value showed Increased
airway resistance 1n some of the exposed groups. The authors conclude that
there were no time-related effects or trends attributable to manganese
exposure, but the data to support this are not displayed. However, there
are limitations 1n this study. It 1s not clear which two groups were com-
pared statistically, which 1s partlculararly confusing since there are 4
groups 1n the experiment. Data over time 1s not presented and numbers of
animals tested are small. The authors state that lungs were free of Inflam-
matory and/or degenerative changes but do not describe the scope of the
microscopic examination. Serum biochemical evaluations showed some evidence
3
of hypophosphatemla 1n the male rats exposed to 1152 ug Mn/m , but the
toxlcologlc significance of this finding 1s uncertain. The amount of manga-
nese present 1n the diets of the animals was not stated.
3
Coulston and Griffin (1977) exposed 7 rhesus monkeys to 100 ug Mn/m
as partlculate Mn 0 due to combustion of MMT for 6, 12 or 15 months.
*5 T"
The conclusion states that there were no abnormalities on gross or micro-
scopic examinations. However, no objective measures of pulmonary function
were reported. Per1bronch1olH1s and pneumonltls was reported 1n associa-
tion with Infection to mites (acarlasls) 1n 6 of 7 exposed monkeys, and a
statistically significant Increase 1n manganese 1n the lungs was reported 1n
2 controls.
1803A 6-55 5/06/83
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TABLE 6-11
Pulmonary Physiology Data for Male
and Female Monkeys After Nine Months of Exposure*
Evaluation
Group
Mean Percent Of
Pre-Exposure Values
Males (n=4) Females (n=4)
Respiratory rate
Vy (tidal volume)
MV
R (pulmonary flow
resistance)
Cdyn (dynamic
compliance)
N (1% N2)
I control
II 11.6 vig
III 11.25 vig
IV 1152 vig
I
II
III
IV
I
II
III
IV
I
II
III
IV
I
II
III
IV
I
- Ir
III
IV
( I
Mean + SEM b
134 + 31
88 + 9
175 + 32
157 + 32
90 + 4
141 + 33C
98 + 16
94 i 11
122+30
124 + 29
160 + 22
143 + 29
209 + 125
104 + 9
365 + 83
257 + 124
91 + 33
125+45
54 + 10
123+23
103 + 12
116 + 23
105 + 2
74 + 7
Mean + SEM
150 + 14
106 + 10
149 + 9
143 + 14
115 + 15
104 + 14
185 + 36
100 + 24
205 + 30
116 + 19
272 + 46
136+27
80 + 35
204 + 45
99 + 39
308 + 272
106 + 23
74 + 13
153 + 43
92 + 33
192 + 20
95 + 10
156 + 28
73 + 11
aAdapted from Ulrlch et al., 1979c
bThe authors state that the Mann-Whitney U was used for statistical com-
parisons, and the standard error of the mean 1s presented to provide some
Index of the variability.
cp = 0.028
1803A
6-56
5/06/83
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Moore et al. (1975) studied chronic exposure to automobile emissions
from the combustion of gasoline with MMT additive. The average concentra-
3
tlon was 117 ixg Mn/m over 56 days, 8 hours/day. No gross or micro-
scopic changes were seen 1n lungs of exposed animals. (For a review of the
toxicology of MMT see Stara et al.. 1973).
6.3.2.1. SUMMARY — Information from earlier studies on the pulmonary
toxldty of manganese 1s Incomplete and sometimes contradictory, particular-
ly In respect to the exposure-response relationship. Some pathomorphologl-
cal changes 1n the lung tissue of experimental animals were observed after
Intratracheal Inoculation of 10 mg MnO or after 5 mg MnCK (Lloyd-
Davles and Harding, 1949).
Inhalation studies represent much better experimental models for study-
Ing pulmonary effects. Experimental evidence Indicate that acute resplra-
3
tory effects appear when the level of exposure exceeds 20 mg/m of MnO?
(Bergstrom, 1977; Malgetter et al., 1976). Although studies of toxldty
after chronic exposure have deficiencies which limit their use for delineat-
ing exposure-response levels, several studies exist 1n which experimental
animals were exposed to MnO as Mn30. particle or aerosols of resplrable
particle size, an appropriate form for health risk evaluation for airborne
manganese. Suzuki et al. (1978) reports positive radlologlc findings after
10 months of exposure to manganese dioxide dust at higher levels, 0.7
3
mg/m , and Adklns et al. (1980c) report Increased mortality from Infection
3
1n mice at =0.4 mg/m .
Table 6-10 shows the two studies 1n which the lowest levels of exposure
to manganese occurred (Ulrlch et al., 1979a,b,c; Coulston and Griffin,
1977). These report no effect due to the exposure, but the latter, 1n
particular, had deficiencies which reduce confidence 1n the negative
1803A 6-57 5/06/83
-------
results. The existence of three negative studies 1n this range supports a
lack of gross toxic effect at this level.
6.4. REPRODUCTIVE EFFECTS
6.4.1. Human Studies. Impaired sexual behavior 1n workers showing symp-
toms of manganlsm has often been reported. Diminished Hbldo or Impotence
have been the most common symptoms (Penalver, 1955; Mena et al., 1967; Emara
et al., 1971; Chandra et al., 1974; Cook et al., 1974). Rodler (1955)
reported Impotence 1n -80% of his patients, although this symptom can be
preceded by a short phase of sexual stimulation. Emara et al. (1971)
reported one case of hypersexualUy which was not followed by diminished
libido.
6.4.2. Animal Studies. Influence of manganese exposure on sexual behav-
ior 1n experimental animals has not been reported 1n the literature. How-
ever, studies have been done on hlstologlcal, biochemical and/or mor-
phological changes. Chandra (1971) reported that 1.p. administered MnCl
(8 mg/kg bw dally) 1n rats caused no hlstologlcal changes 1n seminiferous
tubules for up to 90 days of exposure. Marked degenerative changes In these
tubules did occur after 150 and 180 days of exposure. The affected tubules
(~50%) showed marked depletion or absence of spermatlds and spermatocytes
and a number of degenerated spermatogenlc cells. Chandra and colleagues
Initiated a series of experiments 1n rats Injected 1.p. with 6 mg Mn/kg bw
dally (as MnSO »4H,.0) 1n order to elucidate the mechanism of testlcu-
4 c
lar damage (Singh et al., 1974, 1975; Tandon et al., 1975; Chandra et al.,
1975). The exposure periods were from 25-30 days. The number of tubules
showing degenerative changes was less (~10X) than 1n the study by Chandra
(1971). The rest of the tubules and Interstitial tissue showed no morpho-
logical changes. Degenerative changes were accompanied by a decrease 1n the
activity of some enzymes, such as sucdnlc and lactic dehydrogenases (SDH
1803A 6-58 5/06/83
-------
and LDH), and add phosphatase (AP), and an Increase 1n manganese concentra-
tion 1n the testes. The authors explained their hlstologlcal findings as
manganese-Induced Inhibition of enzymes Involved 1n energy metabolism of the
cells. Simultaneous administration of zinc had a beneficial effect, but
various chelatlng agents failed to Improve morphological changes.
In another experiment 1n rats, Shukla and Chandra (1977) administered
MnCl »4H 0 1.p. (15 mg/kg bw dally) for 15, 30 or 45 days. An In-
crease 1n manganese concentration 1n brain, liver and testes was accompanied
by a decrease 1n nonproteln sulfhydryls, and a reduction 1n activity of
glucose-6-phosphate dehydrogenase and glutathlone reductase. This was
explained by possible reduction of cystelne content of the tissues due to
formation of manganese-cystelne complex and Us excretion from the body.
Oral administration of MnCl_»4H_0 (50 ug/kg bw dally) to rats for
180 days did not Induce chromosomal damage 1n the bone marrow or spermato-
gonlal cells (D1ksh1th and Chandra, 1978). In this experiment, however, the
dally oral dose was at least 500 times lower than the recommended dally
dietary Intake of manganese. This makes 1t very difficult to evaluate these
data.
In rabbits a single Intratracheal Injection of MnO (250 mg/kg bw,
particle size <5 v.m) resulted 1n marked destruction and calcification of
the seminiferous tubules at 8 months after exposure (Chandra et al.,
1973a). There was extensive desquamatlon and cytolysls of various elements
of the epithelium with markedly degenerated spermatocytes and spermatlds.
Females kept with experimental males did not become pregnant, but no details
on the reproductive performance testing procedure were given. Similar to
results observed 1n rat experiments, the activities of some enzymes were
significantly reduced (ATPase, SOH and AP). Seth et al. (1973) using the
1803A 6-59 5/06/83
-------
same experimental design 1n rabbits, showed that degenerative changes 1n
~10-20% of seminiferous tubules were present at 2 months after exposure
and gradually Increased showing severe changes at 8 months.
In an attempt to Investigate whether the early hlstochemlcal effects of
manganese on testlcular enzymes occur prior to morphological changes, Imam
and Chandra (1975) administered MnCl »4H 0 1.v. to rabbits (3.5 mg/kg
bw dally) for up to 30 days. Manganese Inhibited SDH activity 1n semi-
niferous tubules 5 days after the beginning of exposure, when morphological
alterations were not apparent. They demonstrated that manganese affects the
germinal function of testlcular tissue without disturbing steroldogenesls,
and reached the same conclusion on manganese-Induced disturbances 1n energy
metabolism as 1n rat experiments.
Jarvlnen and Ahlstrom (1975) exposed female rats to manganese 1n diet
from weaning for 8 weeks and during pregnancy. MnSO.»7H_0 was the
dietary additive and final manganese concentrations In the diet were 4, 24,
54, 154, 504 and 1004 mg Mn/kg. Exposed animals had normal reproductive
performance. No gross malformations or bone structure anomalies were
observed 1n the fetuses. Body weights, dry matter and ash contents were
also not affected by dietary exposure to manganese of their dams. At higher
manganese levels (104, 504 and 1004 ppm) there was an Increase 1n whole body
content of manganese 1n fetuses as well as 1n livers of their dams, but no
Increase 1n Hver manganese was found In nonpregnant females.
Epstein et al. (1972) used a modified dominant lethal assay for 174 test
agents. MnCl was Injected 1.p. to male ICR/Ha Swiss mice (20 or 100
mg/kg bw). Animals were mated for eight consecutive weeks and the authors
classified MnCl as an agent producing early fetal deaths and prelmplanta-
tlon losses within control limits. In a similar study using dominant lethal
1803A 6-60 5/06/83
-------
test procedures 3orgenson et al. (1978) administered MnS04 to male rats by
single or multiple gavages at three dosage levels (levels not mentioned),
and concluded that MnSO, was not mutagenlc to the rat.
4
Gray and Laskey (1980) Investigated the reproductive development associ-
ated with chronic dietary exposure to manganese. Male mice (CD-I) were
exposed to 1050 ppm Mn as Mn 0 1n a casein diet from day 15 of lacta-
*J *T
tlon to 90 days of age. Wet weights of preputlal glands, seminal vesicles
and testes measured at 58, 73 and 90 days of age were lower 1n exposed than
1n control animals. Body and liver weights were not affected. Reproductive
performance was not tested 1n this study.
Laskey et al. (1982) designed a follow-up study 1n rats to evaluate the
effects of dietary manganese exposure and concurrent Iron deficiency on
reproductive development. Long-Evans rats were exposed beginning on day 2
of mothers' gestation through 224 days of age to 0, 350, 1050 and 3500 ppm
manganese added as Mn«0 (average particle size 1.02 vim) to a normal
(240 iig Fe/g; 50 ug Mn/g) and an Iron-deficient (20 vig Fe/g; 50 ug
Mn/g) diet. Testes weights were not affected, but of particular Interest
was the manganese dose-related decrease 1n serum testosterone concentration
without a concomitant Increase 1n serum LH concentration. Fertility, mea-
sured as percent pregnant, was reduced 1n females at 3500 ppm (females were
mated with males from the same dosage group). Although this difference was
statistically significant compared to controls, all other reproductive
parameters (Utter s1zef/ number, of ovulatlons, resorptlons and prelmplanta-
tlon deaths, as well as fetal weights) were within control values 1n all
manganese-treated groups.
6.4.3. Summary. Except for reports of Impotence 1n patients with chronic
manganese poisoning, human data are largely lacking.
1803A 6-61 5/06/83
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Existing animal data are most concerned with possible reproductive
failure 1n males. Chandra and co-workers suggested that the changes 1n
testes occur prior to changes 1n brain. However, with the exception of one
study on rabbits (Chandra et al., 1973a), reproductive performance was not
tested. These results, however, were obtained using parenteral routes of
exposure, thus being of limited value 1n predicting reproductive hazards of
Ingested or Inhaled manganese.
The few remaining studies are not 1n agreement with the Chandra stud-
ies. They show that manganese 1s not likely to Influence reproductive
parameters. The most accurate studies describing long-term dietary exposure
to manganese show that dietary levels up to 1004 ppm (Jarvlnen and Ahlstrom,
1975) as MnSO »7H 0 and up to 3550 ppm (Laskey et al., 1982) as
Mn 0. were almost without effect on reproductive performance. However,
O T"
some observations 1n all these studies need to be verified using well-
defined reproductive testing protocols.
6.5. HEMATOLOGIC EFFECTS
6.5.1. Human Studies. Reports about the effect of manganese on human
blood and hemoglobin show conflicting results. The studies are difficult to
compare because of variations 1n exposure and stage of disease or effect.
Keslc and Hausler (1954) reviewed these data and suggested that many authors
had not considered the variability 1n normal Individuals.
Keslc and Hausler (1954) reported hematologlcal data comparing 52
exposed miners without symptoms of poisoning to 60 sawmill workers of sim-
ilar age and social conditions. The miners had higher mean levels of eryth-
rocytes, 4.5x10" compared to 4.3x10" . Mean hemoglobin levels were
higher 1n miners, 15.03 compared to 14.19 g, and mean monocyte levels were
lower (6.4 vs. 7.8%).
1803A 6-62 5/06/83
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In a study on Industrial manganese poisoning, FUnn et al. (1941) found
a low white cell count 1n a group of 23 workers exposed to manganese. The
average white cell count was 5380 for the workers as compared to 7850 and
7560 for the two control groups. Seven of the 11 affected men had a white
cell count <5000 and, of these, three men had a count <4000. In general,
leucopenla became more pronounced with the progress of the disease.
Chandra et al. (1974) reported lower erythrocyte counts (RBCs) and lower
hemoglobin concentrations 1n 12 cases diagnosed as manganese poisoning com-
pared to 20 controls. Both cases and controls were under age 38; 3 cases
were mild, 8 moderate, and 1 severe according to the system of Rodler
e o
(1955). The RBC levels ranged from 3.5-4.8x10" /mm , and controls from
5.0-5.6xlO~6/mm3. Hemoglobin levels for cases and controls were 11-14.5
g/100 m& and 15-17 g/100 mi, respectively. Total white blood cell
3
counts ranged from 7000-11,000/mm 1n both groups with a normal percentage
of white cell forms.
Paternl (1954) claimed that small doses of manganese had a stimulatory
effect on erythropolesls. From other findings encountered 1n chronic manga-
nese poisoning, 1t was presumed that large amounts of manganese caused
depression of both erythropolesls and granulocyte formation (Cotzlas, 1958).
Rodler (1955) also reported a change 1n white-cell count 1n 52% of patients
with manganlsm, with a relative Increase of lymphocytes and a decrease 1n
the number of polymorphonuclear cells. Details and a comparison group are
lacking.
6.5.2. Animal Studies. Animal studies have confirmed some of the ob-
served hematologlcal effects 1n humans. For example, Baxter et al. (1965)
found that hematocrlt and mean corpuscular volume were significantly In-
creased 1n rats receiving 150 mg Mn/kg bw subcutaneously, while serum cal-
1803A 6-63 5/06/83
-------
dum and Iron were markedly depressed. Blood volume was unchanged; serum
magnesium, chloride, and phosphorus showed significant Increases. Similar
findings were reported by Oo1 (1959), who exposed rabbits to MnO 1n
specially designed Inhalation chambers. Both erythrocyte count and hemo-
globin content tended to Increase. The leukocyte count changed more exten-
sively with a relative Increase of lymphocytes. Matrone et al. (1959) found
that 2000 ppm of manganese 1n the diet depressed hemoglobin formation 1n
both rabbits and baby pigs. They estimated that the minimal level of manga-
nese 1n the diet that Interfered with hemoglobin formation was between 50
and 125 ppm. Similarly, Hartman et al. (1955) showed that 2000 ppm of
manganese 1n the diet Interfered with hemoglobin regeneration 1n lambs.
Carter et al. (1980) exposed two groups of Long-Evans rats to four
levels of manganese as Mn 0 at 50 ppm (normal dietary level), 400, 1100
O T"
and 3550 ppm. One group was maintained on a normal diet, the other on an
Iron-deficient diet. After exposure to Mn 0 during the prenatal and
O *r
postnatal period, no changes In red blood cell count, mean cell volume, or
hematocrlt were related to manganese dose 1n the normal low-Iron group.
Young animals, 24-100 days of age, on low-Iron diets developed mlcrocytlc
anemia related to manganese dose.
6.5.3. Summary. Reports of hematologlcal effects are conflicting, but
Increased hemoglobin values and erythrocyte counts have been associated with
human (Keslc and Hausler, 1954) and animal (Baxter et al., 1965) exposures
to high levels of manganese. Young animals maintained on a low-Iron diet
and receiving manganese treatment during the prenatal and postnatal periods
may develop a mlcrocystlc anemia (Carter et al., 1980).
1803A 6-64 5/06/83
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6.6. CARDIOVASCULAR SYSTEM EFFECTS
6.6.1. Human Studies. Sarlc and Hrustlc (1975) measured blood pressure
1n three groups of workers aged 20-59 to observe the effect of exposure to
airborne manganese. The dlastoUc and systolic blood pressure of 367
exposed workers from a ferromanganese plant were compared to 189 workers 1n
electrode production within the same plant not directly exposed to manga-
nese, and 203 workers 1n a light metal plant unexposed to manganese.
Seventy-five percent of exposed workers had been exposed for more than 4
years. The mean concentration of manganese for work sites with manganese
3
alloy varied from 0.39-20.44 mg/m . At sites for electrode production,
3
the concentrations varied from 0.002-0.30 mg/m .
Workers 1n the manganese alloy plant had the lowest mean systolic blood
pressure (130.8) followed by electrode plant workers (133.6) and the light
metal plant workers (138.7). The same trend occurred 1n each of four
10-year age groups and 1n all workers excluding hypertensives. The lowest
mean dlastoUc pressure was 1n workers In the light metal plant, followed by
the manganese alloy plant workers and then those from the electrode plant.
This was observed also for each age group except the oldest and was also
seen when hypertensives were excluded. All of the comparisons were signifi-
cant at the 0.05 or 0.01 level, but since multiple t-tests were performed,
this should be Interpreted with caution. It has to be noted that although
the mean body weight 1n the compared groups did not differ, a detailed
analysis of the body bulk 1n relation to the blood pressure values was not
performed. As stated by the authors, other risk factors also may have been
Insufficiently controlled. Sarlc (1978) suggests that the differences found
1n the behavior of systolic and dlastoUc blood pressure 1n those occupa-
tional ly exposed to manganese may Indicate an action of manganese Ions on
the myocardium.
1803A 6-65 5/06/83
-------
6.6.2. Animal Studies. In rats, Klmura et al. (1978) found that dietary
exposure to 564 ppm manganese produced a significant Increase 1n the level
of blood serotonin and a decrease In blood pressure. The researchers at-
tributed the final marked decrease of blood pressure to the elevated concen-
tration of serotonin 1n the blood, probably released from different tissues.
6.6.3. Summary. Manganese exposure has elicited decreases 1n systolic
blood pressure 1n humans (Sarlc and Hrustlc, 1975) and 1n animals (Klmura et
al., 1978). This latter finding was attributed to the elevated concentra-
tion of serotonin 1n the blood.
6.7. BIOCHEMICAL EFFECTS
6.7.1. Human Studies. Rodler (1955) reported diminished excretion of
!7-ketostero1ds 1n 81% of the patients with chronic manganese poisoning and
an Increase 1n basal metabolism 1n 57% of the cases with manganlsm. These
conclusions are reported with no supporting data.
Jonderko et al. (1971) compared a group of manganese-exposed workers who
did not exhibit symptoms or signs of Intoxication with a control group of 45
workers. The exposed workers had lower levels of magnesium, hemoglobin, and
reduced glutathlone, while calcium and cholesterol levels were Increased.
In an evaluation of the effects of manganese exposure on the development of
atherosclerosis, several variables were compared between 110 workers 1n a
steel mill and 80 nonexposed controls (Jonderko et al., 1973). Workers were
exposed for an average of 9 years to values of manganese that were 1.3-50
times above the maximum allowable concentration. The English abstract pub-
lished with this study reported statistically significant Increases 1n mean
cholesterol, 3-l1poprote1ns and total Upoprotelns, as well as Increased
Incidences of hypertension and atherosclerosis 1n the exposed group. How-
ever, there 1s no stratification or other control for confounding variables
1803A 6-66 5/06/83
-------
such as smoking or obesity. The Information available from table headings
and the abstract did not describe exposure levels or age distribution and
the statistical test was not named 1n English.
Jonderko et al. (1974) also examined a group of 34 Iron-manganese plant
workers during employment and 2-4 years after cessation of occupational
exposure. When compared with a group of 45 control subjects, Jonderko found
slight changes with a tendency to normalization after exposure ceased 1n a
number of biochemical parameters, Including lactate dehydrogenase, alanlne
and asparaglne amlnotransferase, cholesterol, and glutathlone levels. Hemo-
globin concentration 1n the followed workers also Increased from 12.6 during
employment to 13.9 1n the follow-up.
In a clinical and biochemical study conducted 1n 12 cases of suspected
manganese poisoning, Chandra et al. (1974) reported a statistically signifi-
cant Increase 1n serum calcium and adenoslne deamlnase levels 1n cases of
mild and moderate grades of poisoning, and particularly 1n a case of severe
poisoning, compared with values In normal volunteers. They suggest that
serum calcium levels be used to delect manyanese poisoning 1n the early
stages.
6.7.2. Animal Studies. Intratracheal administration of 400 mg Mn02/kg
bw to rats caused a significant decrease 1n the levels of serum alkaline
phosphatase and Inorganic phosphate, and an Increase 1n calcium (Chandra et
al., 1973b). Similar observations were reported by Jonderko (1965). Rab-
bits Injected Intramuscularly with 3.5 mg Mn/kg bw showed a distinct In-
crease of serum calcium and a decrease of Inorganic phosphorus. However,
the mechanism of hypercalcaemla and hypophosphataemla 1n manganese toxldty
was not clear because no gross or microscopic abnormalities were observed 1n
parathyroids and bones of exposed rats (Chandra et al., 1973b).
1803A 6-67 5/06/83
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Chandra and Imam (1975) studied the effect of Intravenously administered
2.5 mg MnCl /kg bw on the rabbit adrenal cortex. An Increase 1n the
cholesterol content and marked degenerative changes 1n the zona glomeruloza
and zona fasdculata were observed after a period of 2 months. Three months
after the beginning of exposure, the damaging effect of manganese on the
adrenal cortex was even more marked.
6.7.3. Summary. Effects of manganese exposure on the biochemical param-
eters Include an Increase 1n serum calcium, adenoslne deamlnase, choles-
terol, total I1p1ds and 3-Hpoprote1ns 1n workers occupatlonally exposed
to manganese (Jonderko et al., 1974). A diminished excretion of 17-keto-
sterolds has been reported 1n patients with chronic manganese poisoning.
Animal experiments demonstrate a decrease 1n the levels of serum alkaline
phosphatase and Inorganic phosphate, and an Increase 1n calcium 1n manganese
toxldty (Chandra et al., 1973b).
6.8. DIGESTIVE SYSTEM EFFECTS
6.8.1. Gastrointestinal Tract Effects. The paucity of data and the
controversy regarding the doses used In the available studies cause great
difficulty 1n assessing toxic effects of manganese on the GI tract. For
example, Chandra and Imam (1973) described significant hlstochemlcal and
hlstologlcal alterations 1n the GI mucosa of guinea pigs exposed orally to
=4.4 mg Mn/kg bw for a period of 30 days. However, an amount of =4 mg
Mn/kg bw has been recommended by the NAS (1973) as a minimum requirement for
guinea pigs. Even though no specific effort was directed to determine the
minimum manganese dally requirements, Everson et al. (1959) reported a diet
to be adequate with the presence of 40 ppm manganese. Further, Shrader and
Everson (1968) reported that manganese supplementation (125 ppm for 2
months) completely reversed the reduced glucose utilization caused by
congenital manganese deficiency.
1803A 6-68 5/06/83
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6.8.2. Liver Effects. The liver plays a significant role 1n manganese
metabolism, and the biliary route 1s very Important for the removal of man-
ganese from the body. Over 99% of an Intravenous dose excreted by the rat
appeared 1n the feces (Klaassen, 1974). However, manganese has produced
1ntrahepat1c cholestasls 1n rats, with large doses causing both functional
and morphological alterations (WHzleben et al., 1968; WHzleben, 1972). An
Intravenous dose of 55-60 mg/kg bw manganese caused necrosis 1n rat liver
and other ultrastructural alterations resembling some of those seen 1n human
cholestasls Induced by drugs (WHzleben, 1969). When manganese overload was
followed by Infusion of b1!1rub1n, the lesions were even more severe
(WHzleben, 1971, 1972), depending upon the dose of bH1rub1n (Boyce and
WHzleben, 1973).
Klaassen (1974) reported that no alteration 1n the bile flow was ob-
served 1n rats even at the relatively high Intravenous dose of 10 mg Mn/kg
bw. However, when blUrubln was administered Immediately after manganese
Injection, there was an almost complete cessation of bile flow, even at
small doses of manganese (3 mg Mn/kg) which are not cholestatlc when given
alone. The researcher suggested the possibility that blUrubln may form a
chelate with manganese which precipitates and obstructs the biliary tree.
De Lamlrande and Plaa (1978, 1979a,b) showed In a series of experiments
on rats that both manganese and blUrubln are essential for the Induction of
cholestasls. Small noncholestatic doses of each resulted 1n cholestasls
when given together, but the order and time of Injection were critical.
These observations suggest that the manganese-b1l1rub1n Interaction might
depend on the presence of short-lived Intermediate compounds during the pro-
cess of manganese biliary excretion.
1803A 6-69 5/06/83
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In an attempt to study the ultrastructural changes 1n the liver using
doses known to be nontoxlc, Wassermann and Wassermann (1977) gave rats
drinking water with an extra dosage of 200 ppm MnCl . The ultrastructural
changes found were an Increased amount of rough endoplasmlc retlculum, a
proliferated smooth endoplasmlc retlculum, prominent Golgl apparatuses and
the occurrence of multiple rough endoplasmlc dsternae, which may be Inter-
preted as an adaptation process to Increased exposure to MnCl .
Various biochemical or hlstologlcal changes 1n the liver were reported
1n a number of studies, mainly as side effects 1n the experiments where
neurological, respiratory, or reproductive effects of manganese were Inves-
tigated. Chandra and Tandon (1973) and Shukla et al. (1978) reported some
biochemical and hlstopathologlcal alterations 1n the livers of rats given
orally 2.8 or 4.4 mg Mn/kg bw. However, as was stressed earlier (see Sec-
tion 4.3.2.3.), the administered doses were too low to be considered toxic
to rats. Thus, the rats on manganese-supplemented diets (564 ppm manganese)
did not manifest abnormalities 1n the liver, and the liver monoamlne oxldase
activity remained the same as 1n the control group of animals (Klmura et
al., 1978).
Parenteral administration of manganese sulfate 1n a dose of 6 mg Mn/kg
bw did not significantly affect the enzyme activity 1n the liver of exposed
rats, 1n spite of a significant accumulation of this metal 1n the liver
(Singh et al., 1974, 1975). Only the activity of succlnlc dehydrogenase and
lactate dehydrogenase decreased to a considerable extent. Some pathomor-
phologlcal alterations were observed 1n the liver of the treated animals,
where some of the sections showed mild congestion of central veins and
adjacent sinusoids. Minute areas of focal necrosis were noticed throughout
the section.
1803A 6-70 5/06/83
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Microscopic examination of the liver In monkeys exposed parenterally to
relatively high doses of manganese showed only mild changes. In monkeys
receiving 345 mg Mn/kg bw, Pentschew et al. (1963) found only hemoslderosis
of the Kupffer cells. Neff et al. (1969) described only variable, often
mild, vacuolar changes 1n the liver cells of the monkeys subcutaneously
Injected with 500 mg Mn/kg bw. Finally, Suzuki et al. (1975) reported that
an Irregular arrangement of hepatic cords and lymphocytlc Infiltration of
GUsson's capsules were seen 1n two monkeys receiving the highest doses,
totaling 5680 mg Mn/kg bw over a period of 9 consecutive weeks.
6.8.3. Summary. The lack of data and the controversy over the doses used
1n the available studies cause difficulty 1n assessing toxic effects of man-
ganese on the Intestine. On the other hand, more data are available about
the hepatotoxlc effects of manganese. The liver plays a significant role 1n
manganese metabolism, and the biliary route 1s very Important for the
removal of manganese from the body. Over 99% of the Intravenous dose was
excreted by the rat 1n the feces. Manganese has been described as an agent
that produces Intrahepatlc cholestasls, large doses causing both functional
and morphological alterations. An Intravenous dose of manganese at a con-
centration of 55-60 mg/kg bw of the rat caused necrosis 1n the liver and
other ultrastructural alterations resembling some of those seen 1n human
cholestasls Induced by drugs (WHzleben, 1969). Microscopic examination of
the liver 1n monkeys exposed parenterally to relatively high doses of manga-
nese showed only mild changes, for example, hemoslderosis of the Kupffer
cells.
1803A 6-71 5/06/83
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7. CARCINOGENICITY
7.1. ANIMAL STUDIES
Manganese sulfate 1n sodium chloride has been tested for carcinogenic
activity 1n the Strain A mouse lung tumor system (Stoner et al., 1976). In
this study, Strain A/Strong mice of both sexes, 6-8 weeks old, were Injected
1ntraper1toneally 3 times/week for a total of 22 Injections. Three dose
levels were employed that represented the maximum tolerated dose, a 1:2
dilution and a 1:5 dilution of the maximum tolerated dose. Twenty mice were
used at each dose level (10/sex) Including vehicle (saline) and positive
(urethan) controls. Mice were sacrificed 30 weeks after the first Injec-
tion, and the frequency of lung tumors 1n each test group was statistically
compared with that 1n the vehicle-treated controls using the student t test.
The Interpretation of the lung tumor data 1n the Strain A mouse 1s some-
what unusual 1n that certain specific criteria should be met before a com-
pound 1s considered positive (Sh1mk1n and Stoner, 1975):
1. A significant Increase 1n the mean number of lung tumors 1n
test animals, preferably >l/mouse, should be obtained;
2. A dose-response relationship should be evident.
3. The mean number of lung tumors 1n control mice should be con-
sistent with the anticipated Incidence of spontaneous tumors
for untreated strain A mice.
The results obtained by Stoner et al. (1976) are summarized 1n Table 7-1.
These data Indicate that the above criteria were not conclusively met for
the establishment of a positive response. A slight but statistically sig-
nificant Increase 1n the number of pulmonary adenomas per mouse was associ-
ated with administration of the high dose. The response was somewhat ele-
vated at the other doses, but was not statistically significant. Overall,
H can be concluded that the results of this experiment are suggestive of
carcinogenic activity.
0199P 7-1 4/28/83
-------
TABLE 7-1
10
ig Pulmonary Tumors 1n Strain A Mice Treated with Manganese Sul
fate3
Total Dose
Group
Untreated control
Solvent control
(0.85X NaCl)
Treated
^ Treated
Treated
20 mg urethan6
mg MnS04/kg
0
0
132
330
660
0
mg Mn/kg
0
0
42.9
107.2
214.4
0
Mortality
1/20
1/20
1/20
0/20
2/20
2/20
Mice with
Lung Tumors (54)
6/19
7/19
7/19
7/20
12/18
18/18
(31)
(37)
(37)
(35)
(67)
(TOO)
Average Number
Tumors/Mouse^
0.28+0.07
0.42+0.10
0.47+0.11
0.65+0.15
1 . 20+0 . 49
21.6+2.81
PC
NA
NA
NS
NS
0.05d
NR
PO
oo
CO
CO
aSource: Stoner et al., 1976
bX+S.E.
^Student t test
dF1sher Exact Test p = 0.068
eS1ngle 1ntraper1toneal Injection
NA = Not applicable; NS = Not significant; NR = Not reported
-------
DIPaolo (1964) Injected DBA/1 mice subcutaneously or IntraperHoneally
wHh 0.1 ml of a 154 MnCl~ aqueous solution twice weekly for 6 months.
Control mice were Injected with water. Mice were sacrificed as they became
moribund or at 18 months of age. Sixty-seven percent (24/36) and 41%
(16/39) of the mice treated subcutaneously and 1ntraper1toneally, respec-
tively, had lymphosarcomas; the Incidence 1n controls was 24% (16/66).
Tumors appeared earlier 1n the treated groups than 1n the control group, but
statistically significant differences 1n the number of other tumors (e.g.,
mammary adenocarclnomas, leukemlas, Injection site tumors) did not occur.
The results of this study were published 1n abstract form, and additional
details regarding experimental design or results were not given. Therefore,
a thorough evaluation of the results 1s not possible.
Furst (1978) evaluated the carclnogenldty of manganese powder and
MnO_ 1n F344 rats and Swiss mice, and manganese (II) acetylacetonate (MAA)
1n F344 rats. The test materials were suspended 1n trloctanoln, and admin-
istered Intramuscularly (1.m.) or by gavage as follows. Groups of 25 rats
of each sex were administered 10 mg manganese (1.m.) per month for 9 months,
10 mg Mn02 (1.m.) per month for 9 months, 50 mg MAA (1.m.) per month for 6
months, or 10 mg manganese (gavage) twice per month for 12 months. Groups
of 25 female mice were administered single 10 mg doses of manganese powder,
6 doses of 3 mg MnO_, or 6 doses of 5 mg MnO via 1.m. Injection, but
the frequencies of Injection In these experiments were not stated. Complete
necropsies were performed on all animals and obvious growths, suspicious
tissues, lungs and livers were examined h1stolog1cally. The duration of the
experiments were not specifically stated, but were Implied to be 2 years 1n
the rat experiments. As summarized 1n Table 7-2, no difference 1n tumor
Incidence was noted between treated and control animals with respect to
0199P 7-3 4/28/83
-------
TABLE 7-2
Carclnogenlctty of Manganese Powder, Manganese Dioxide and Manganese Acetylacetonate
In F344 Rats and Swiss Albino Mice3
Compound0 Species
TrlglyceMde control rat
Manganese powder rat
Manganese acetylacetonate rat
TMglyceMde control rat
Manganese dioxide rat
Trlglycerlde control rat
Manganese powder rat
Trlglycerlde control mouse
Manganese powder mouse
Treatment
Route Schedulec
1 .m. 0.2 ml/month x
12 months
1 .m. 10 rag/month x
9 months
l.m. 50 Big/month x
6 months
l.m. 0.2 ml/month x
12 months
l.m. 10 ing/month x
9 months
oral 0.5 ml, twice
monthly x 12
months
oral 10 rog, twice
monthly x 12 months
l.m. 0.2 ml/Injection x
3 Injections
1 .m. 10 mg (single
Injection)
Total
Dose Tumor Type
2.4 mi lymphomas/leukemla
f Ibrosarcomasd
90 mg lymphomas/leukemla
Mbrosarcomas
300 mg lymphomas/leukemla
flbrosarcomas
other sarcomas
2.4 ml lymphomas/leukemla
flbrosarcomas
90 mg lymphomas/leukemla
flbrosarcomas
12.5 ml lymphomas/leukemla
flbrosarcomas
240 mg lymphomas/leukemla
flbrosarcomas
0.6 mi leukemia
lymphomas
10 mg leukemia
lymphomas
Incidence
(males) (females)
1/25
1/25
3/25
3/25
2/25
13/25e
3/259
0/25
0/25
0/25
0/25
3/25
0/25
0/25
0/25
NT
NT
NT
NT
3/25
1/25
5/25
0/25
2/25
6/25f
4/25
0/25
3/25
0/25
3/25
0/25
0/25
0/25
2/25
1/25
6/25
1/25
IV)
oo
GO
CO
-------
Table 7-2 (cont.)
1C
-o
Treatment Total
Compound" Species Route Schedule0 Dose
Tr1glycer1de control mouse 1.m. 0.2 ml/Injection x 24 ml
12 Injections"
Manganese dioxide mouse l.m. 3 mg/1nject1on x 15 mg
6 injections"
Manganese dioxide mouse l.m. 5 mg/lnjectlon x 30 mg
6 Injections"
Incidence
Tumor Type
leukemia
lymphomas
leukemia
lymphomas
leukemia
lymphomas
(males)
NT
NT
NT
NT
NT
NT
(females)
2/25
0/25
4/25
1/25
1/25
2/25
I
in
aSource: Furst. 1978
bCompounds suspended 1n 0.2 ml (l.m.) or 0.05 ml (gavage) trloctanoln
C0urat1on of experiments was not stated, but was Implied to be 2 years In the rat studies. The average weights of the treated and control
mice ranged from 22-25 g at the start of the experiments to 33-39 g at the end of the experiments.
^Injection site Hbrosarcoma
eF1sher Exact Test p = 0.002
fF1sher Exact Test p = 0.049
Slncldence Includes 2 rhabdomyosarcomas and 1 myxosarcoma
"Intervals between Injections not stated
NT = Not tested
CD
CO
CO
-------
manganese powder and MnOp. In contrast, a statistically significant
number of fIbrosarcomas {10 tumors 1n 25 male rats, p = 0.002; 6 tumors 1n
25 female rats, p = 0.049) developed at the Injection site 1n the rats given
MAA as compared to vehicle controls; the mean latency period was 17 months.
However, the results of the assay with the organomanganese compound (MAA)
cannot necessarily be extrapolated to pure manganese or other Inorganic
manganese compounds. Furst (1978) commmented that MAA suspended well 1n the
vehicle, and that the carcinogenic effect may therefore be Inconsistent with
foreign-body cardnogenesls. Further, 1t 1s doubtful whether these results
have any relevance to exposure to Inorganic manganese through Inhalation.
In June 1980, the Executive Committee of the National Toxicology Program
Included manganese sulfate 1n the 11st of priority chemicals for testing the
toxlcologlc and carcinogenic effects. Prechronlc testing of manganese sul-
fate 1n Fisher 344 rats and B6C3F, mice administered via their feed began
during March 1982 [National Cancer Institute (NCI), 1982].
Intraperltoneal Injection of another organomanganese compound, methyl-
cyclopentadlenyl manganese (MMT) (80 mg/kg), produced cell proliferation 1n
the lungs of female A/J mice (WHschl et al., 1981). When mice (30/group)
were treated with single Injections of urethan (500 mg/kg) followed 1 week
later by 6 weekly Injections of 80 mg/kg MMT, lung tumor formation was not
enhanced when compared with urethan treated controls. Weekly Injections of
MMT alone did not Increase the Incidence of spontaneously occurring lung
tumors.
Sunderman et al. (1974, 1976) also reported that 1.m. administration of
manganese did not Induce Injection site tumors 1n Fischer rats. Single 1.m.
Injections of 0.5 mi of penicillin suspensions containing manganese dust
0199P 7-6 5/06/83
-------
were admlnstered at the dosages specified 1n Table 7-3, and Incidences of
local sarcomas were tabulated after 2 years. The results of other
similarly-designed experiments 1n these studies Indicated that addition of
equlmolar amounts of manganese dust to nickel subsulflde (N1~S_) dust
significantly depressed N13S2-1nduced tumor1genes1s. Subsequent work by
the same group of Investigators (Sunderman et al., 1980) showed that, under
the same experimental conditions, manganese dust also Inhibited local sar-
coma Induction by benzo(a)pyrene.
7.2. HUMAN STUDIES
There are numerous ep1dem1olog1cal studies designed to evaluate the
chronic effects of manganese, such as CNS abnormalities or pneumonia, but
none have attempted to relate manganese exposure to cancer mortality or
Incidence. To assess the relationship between manganese 1n soil and cancer,
Marjanen (1969) correlated the amount of soluble manganese 1n cultivated
mineral soil 1n 199 parishes with the 5-year cancer Incidence rates from
1961-1965. He determined that cancer Incidence decreased with Increasing
content of manganese; there was a statistically significant correlation
coefficient of -0.66. The data excluded cities and were not age-adjusted.
Further work Is needed to assess the effect of confounding factors such as
age differences among parishes, social class and dietary habits, type of
cancer contributing to the association, and extent of consumption of local
foods.
Blood plasma levels of manganese were reported to be elevated 1n
patients with stage IV bronchogenlc carcinoma (T1mask1na et al., 1981). An
earlier study (Morgan, 1972) of autopsy samples of hepatic tissue from
patients who had died of bronchogenlc carcinoma, with and without chronic
0199P 7-7 4/28/83
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TABLE 7-3
10
10
-o
— J
1
ao
Dosage of
Mn Dust3
0 mg/rat
2.1 mg/ratb
0 mg/rat
0.5 mg/ratc
1 .0 mg/ratc
2.0 mg/ratc
4.0 mg/ratc
4.4 mg/ratd
4.4 mg/ratd
Induction of Sarcomas
Number of
2-yr Survivors
16/24
17/24
22/60
6/15
2/15
8/15
10/15
NR
NR
1n Rats by the Intramuscular Injection of Manganese Dust
No. of Rats with Injection Site
Sarcomas/Total Number of Rats Reference
0/24 Sunderman et al. ,
0/24
0/60 Sunderman et al. ,
0/15
0/15
0/15
0/15
0/20 Sunderman et al.,
0/20
1974
1976
1980
r«o
co
oo
aF1scher rats were given a single 1.m. Injection of 0.5 m8, of penicillin suspension containing the
manganese dust.
bMean particle diameter, 1.4 vm. Manganese dust was composed of 62% elemental Mn, 36% manganese
oxides (as Mn02), <0.1%N1, Cu, Cr, and Co, 2% Al.
cMean particle diameter 1.6 urn. Manganese dust was composed of 94% elemental Mn; 6% 02; <0.02% Al,
Co, Cu, and N1; 0.01% Cr.
dThe results of two 2-year experiments were reported 1n an abstract, but control data were not reported.
NR = Not reported
-------
bronchitis and emphysema, reported slightly elevated hepatic manganese con-
centrations 1n patients with emphysema and carcinoma (p = 0.05), but not 1n
patients with emphysema and bronchitis alone or lung carcinoma alone.
Malignant breast tissue concentrates contained significantly higher
amounts of copper, magnesium, zinc, and manganese than did noncancerous
breast tissue (Mulay et al., 1971). However, a subsequent study measured
trace metals 1n cancerous and noncancerous breast tissue and found only
magnesium and zinc levels to be elevated (Santol1qu1do et al., 1976). Man-
ganese was found to be elevated 1n osteogenlc sarcoma tissue when compared
to normal specimens (Leach, 1971; Jones et al., 1972).
The remainder of the studies pertaining to manganese levels 1n cancerous
tissue relate to manganese-superoxide dlsmutase. Superoxlde 1s an anlonlc
free radical and an active reducing agent. Superoxlde dlsmutases (SOD) con-
vert superoxide to H^O-, which 1n turn 1s converted to water by catalase
and peroxldase (Fee, 1980). Two types of SOD are found 1n eukaryotlc cells:
Zn/Cu SOD 1n the cytoplasm and Mn SOD within mitochondria (Sun et al., 1980;
Oberly and Buettner, 1979). Mn SOD 1s generally reduced or absent 1n tumor
mitochondria, Including mouse neuroblastoma cells (Oberly et al., 1978), rat
Morris hepatoma (B1ze and Oberly, 1979; B1ze et al., 1980), rat hepatoma
HC-252 (Sun et al., 1980), and human lymphoma lymphocytes (Issels and Leng-
felder, 1981). Other human tumors (Westman and Marklund, 1981) and chemi-
cally-Induced rat colon adenocardnoma (Loven et al., 1980), however, were
not found to have decreased levels of Mn SOD.
Diminished Mn SOD 1s correlated with Increased production of superoxide
radicals; manganese has been suggested as a dietary supplement 1n cancer
treatment, particularly for protection against the extra superoxide produced
by activated macrophages Involved 1n antHumor Immunity (McCarty, 1981).
0199P 7-9 4/28/83
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Reduced levels of Mn SOD have been hypothesized to prevent differentiation
of cancer cells due to Increased superoxlde, and addition of SOD to trans-
formed cells seems to overcome some of the blockage of cell differentiation
(Oberly et al., 1980).
7.3. SUMMARY
Prior to the adoption of the International Agency for Research on Cancer
(IARC) criteria, the U.S. EPA Carcinogen Assessment Group (U.S. EPA, 1979c)
judged manganese to be a possible human carcinogen based on the mutagenlc
properties and the positive responses 1n mice Injected 1.p. {DIPaolo, 1964)
and 1n rats (Furst, 1978). However, 1n the summary (U.S. EPA, 1979) 1t 1s
stated that the pathology was Incomplete and that there were no animal stud-
ies with long-term exposure by feeding or by Inhalation.
Therefore, using IARC criteria, the available evidence for manganese
cardnogenlcUy would be rated as Inadequate 1n animals (IARC, 1982). Since
no data are available for humans, manganese would be placed 1n IARC Group 3:
which states the chemical or group of chemicals cannot be classified as to
Us carc1nogen1c1ty for humans. More Information 1s needed before a conclu-
sion can be made about carc1nogen1c1ty of manganese or Us compounds.
0199P 7-10 5/06/83
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8. MUTAGENICITY AND TERATOGENICITY
8.1. MUTAGENICITY
8.1.1. Tests for Gene Mutations. Mutagenldty of manganese salts toward
bacteria was first described by Demerec and Hanson 1n 1951. A strain of E_.
coll dependent on streptomycin for Us growth was treated with MnCl 1n
suspension culture and then replated 1n the absence of the drug, to select
for mutations from streptomycin dependence to nondependence. The results
showed that the mutagenlc potency varied depending on the physiological
state of the organisms. Similar experiments with Salmonella also showed
manganese to be mutagenlc, although no details of methods or results are
described {Flessel, 1977).
M1yak1 et al. (1979) found that MnCl_ Increased the frequency of
8-azaguan1ne resistant Chinese hamster cells (due to a mutation at the
HGPRTase locus) from 2- to 5-fold.
8.1.2. Tests for Chromosomal Damage. MnCl- caused chromosomal aberra-
tions 1n 5% of C3H mouse mammary carcinoma cells when tested at a concentra-
tion of 10"3 M (Umeda and N1sh1mura, 1979). At concentrations >10"3 M,
potassium permanganate caused aberrations 1n up to 17% of cells (Including
breaks, exchanges and fragments). MnCl_ was too cytotoxlc to be tested at
the levels at which potassium permanganate caused chromosomal aberrations.
Oral administration of MnCl_ to male albino rats at a level of 50
vig/kg/day for 180 days did not Induce chromosomal damage 1n the bone
marrow or spermatogonlal cells (Dlkshlth and Chandra, 1978).
8.1.3. Tests for Other Genetic Damage. N1sh1oka (1975) reported a weakly
positive effect of several manganese compounds 1n the recombination (rec)
assay, which measures a difference 1n growth Inhibition between Bacillus
subtnis strains H17 (rec*, or recombination-efficient) and M45 (rec~,
0200P 8-1 05/06/83
-------
or recombination-deficient). MnCl2, Mn(N03)2, MnS04, and Mn(CH3COOH)2 were
weakly positive 1n this assay, while KMn04 was negative. More recent
results (Kanematsu et al., 1980; Kada et al., 1980) report negative effects
1n the rec assay for MnJNO,^, Mn(CH3COOH)2, and MnCl (highly
toxic). No explanation was advanced for these contradictory results, but
variations 1n culture conditions, medium composition or valence may be
responsible.
Orgel and Orgel (1965) showed that divalent manganese 1s also mutagenlc
to the bacterlophage T4. Treatment of T4-1nfected £. coll at concentrations
2
of 10 M Increased the proportion of rapid lysis (rll) mutants from
<0.04% to =1X.
Putrament et al. (1973) found that manganese Induced mutations 1n
Saccharomyces cereveslae. primarily Involving mltochondrlal genes. Although
manganese 1s mutagenlc toward yeast mltochondrlal DNA, 1t did not Induce
gene conversion or 1ntergen1c recombination (Baranowska et al., 1977).
MnCl2 reduced colony-forming ability 1n HeLa and V79 hamster cells;
this cytotoxldty was reversed when manganese was removed (Skreb et al.,
1980). Manganese has been found to bind to both phosphates and bases on
polynucleotldes (Kunkel and Loeb, 1979), but Its role 1n causing DNA damage
may Involve many factors.
It 1s well documented that manganese can reduce the fidelity of DNA syn-
thesis 1^ vitro (Nagamlne et al., 1978; Hlllebrand and Seattle, 1979; Loeb
et al., 1979; MUdvan et al., 1979; Kunkel and Loeb, 1979). Substitution of
Mn II for Mg II resulted 1n Increased m1s1ncorporat1on by £. coll DNA poly-
merase I, an Mg Il-actlvated enzyme.
Manganese was moderately effective 1n enhancing viral transformation of
Syrian hamster embryo cells (Casto et al., 1979). As was the case with §_._
0200P 8-2 05/06/83
-------
coll, medium composition can affect mutagenlcHy of manganese 1n CHO cells.
When CHO cells were treated 1n medium deficient 1n divalent cations, MnCl_
Increased the frequency of spontaneous mutations from 5x10 mutants/cell
to lOOxlO"6, and reduced cloning efficiency by 33% (Hs1e et al., 1979).
8.2. TERATOGENICITY
In animals, manganese deficiency during pregnancy causes a variety of
developmental defects related to decreased formation of chondroltln sulfate
and delayed otollth calcification. Resultant defects Included reduced coor-
dination, bone and growth deficiencies, reproductive difficulties, and CMS
changes (Oberleas and Caldwell, 1981; Hurley, 1981). The effect of manga-
nese excess has been studied by only a few Investigators.
In rodents, excess manganese during pregnancy affects behavioral param-
eters, as described 1n two recent abstracts. Hosh1sh1ma et al. (1978)
reported that geotaxls performance, but not Intelligence testing, was
Impaired 1n mice treated in utero with manganese. In another study, Massaro
et al. (1980) exposed female mice from days 0 through 18 of pregnancy with
3
MnOp dust (48.9£/.5 mg/m , continuous exposure). Litters from exposed
and nonexposed mothers were reduced to three pups of each sex, and the pups
were fostered equally among exposed and nonexposed mothers. Pup weight and
activity were not different whether or not they had been exposed in utero.
but as adults exposed pups were deficient 1n open-field, exploratory, and
rotarod (balance and coordination) performance. Normal offspring fostered
to exposed mothers also showed decreased rotarod performance, Indicating
that post-partum exposure can also have an adverse effect on behavioral
development. This 1s supported by the effect of manganese on learning 1n
the adult rat (Murthy et al., 1981), and by a study of the distribution of
54
Mn 1n fetal, young, and adult rats. Early neonates and 19-day fetuses
0200P 8-3 05/06/83
-------
were more susceptible to manganese than the older groups; manganese local-
ized to the liver and brain 1n the younger groups and they accumulated more
manganese per weight than the older groups {Kaur et al., 1980). No fetal
abnormalities were seen when 18-day embryos were exposed to 16 y.mol/200 g
maternal weight, but this 1s a late stage for detecting developmental
defects.
8.3. SUMMARY
Divalent manganese 1on has elicited mutagenlc effects 1n a wide variety
of m1crob1al systems, probably by substitution for magnesium 1on and Inter-
ference with DNA transcription (Flessel, 1977). Attempts to demonstrate
mutagenlc effects of manganese 1n mammalian systems have failed to show sig-
nificant activity.
Although data reported 1n abstracts suggest that excess manganese during
pregnancy affects behavioral parameters, there 1s Insufficient evidence to
define manganese as teratogenlc.
0200P 8-4 05/06/83
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9. EFFECTS OF CONCERN AND HEALTH HAZARD EVALUATION
9.1. EXISTING GUIDELINES, RECOMMENDATIONS AND STANDARDS
9.1.1. A1r. In the United States, the American Conference of Government-
3
al and Industrial Hyg1en1sts (ACGIH, 1980) has recommended 5 mg/m as both
the time-weighted average threshold limit value (TWA-TLV) and the short-term
exposure limit for manganese. This value 1s based on observations of
poisoning 1n humans at concentrations near or above the recommended TLV.
The National Institute for Occupational Safety and Health (NIOSH) has not
recommended an occupational criterion for exposure to airborne manganese,
and the Occupational Safety and Health Administration (OSHA) has not promul-
gated a standard for manganese exposure. Occupational standards 1n some
other countries, as summarized by the International Labour Office (ILO,
1980), are listed below:
Comment
celling value
celling value
Country
Belgium
Czechoslovakia
Japan
Poland
Roumanla
Switzerland
USSR
mg Mn/mJ
5
2
6
5
0.3
1
3
5
0.3
celling value
celling value
The World Health Organization (WHO, 1981) recommends a criterion of 0.3
3
mg/m for resplrable manganese 1n occupational exposures.
9.1.2. Water. No toxldty-based criteria or standards for manganese 1n
freshwater have been proposed. The WHO (1970), the U.S. PHS (1962), and the
U.S. EPA (1976) recommended a concentration of 0.05 mg/8, 1n water to
1805A 9-1 5/05/83
-------
prevent undesirable taste and discoloration. In the USSR, the recommended
maximum permissible concentration of KMnO. 1s 0.1 mg/fc (as Mn). The
recommendation Is Intended to prevent the discoloration of water by manga-
nese (Shlgan and VltvHskaya, 1971).
For marine waters, the U.S. EPA (1976) has recommended a criterion for
manganese of 0.1 mg/9. for the protection of consumers of marine mollusks.
Although the rationale for this criterion 1s not detailed, 1t 1s partially
based on the observation that manganese can bloaccumulate by "factors as
high as 12,000" 1n marine mollusks.
9.2. SUMMARY OF TOXICITY
Manganese 1s an essential element for humans and animals. The concen-
tration of manganese present In Individual tissues, particularly 1n the
blood, 1s controlled after 1ngest1on by homeostatlc mechanisms and remains
remarkably constant 1n spHe of rapid fluctuations 1n Intake (Cotzlas,
1958). The main routes of absorption are the gastrointestinal and respira-
tory tracts. Acute poisoning by manganese may occur 1n exceptional circum-
stances where large amounts of manganese compounds are Ingested or Inhaled.
Freshly formed manganese oxide fumes of resplrable particle size can cause
metal fume fever but are not believed to cause permanent damage (Plscator,
1976). The most pronounced toxic effects of manganese are a CNS syndrome
known as chronic manganese poisoning (manganlsm) and manganese pneumonltls.
The adverse effect on the CNS begins with a psychiatric disturbance
followed by a neurologic phase resembling Parkinson's disease. Manganlsm
has been well described 1n the literature with clinical details for case
clusters (Fllnn et al., 1940; Penalver, 1955; Rodler, 1955; Chandra et al..
1974). Cotzlas (1962) described three phases — a prodromal phase with
Insidious onset Including psychiatric disturbances, the extrapyramldal
1805A 9-2 5/04/83
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disease with symptoms of awkward speech and loss of skilled movement, and
typical manganlsm with severe rigidity, tremor, and Inappropriate emotional
reactions.
Manganlsm has been reported 1n workers 1n ore crushing and packing
mills, 1n the production of ferroalloys, 1n the use of manganese alloys 1n
the steel Industry and 1n the manufacture of dry cell batteries and welding
rods. Very high concentrations of manganese have been found 1n mines where
cases of manganlsm were reported. The manganese air concentration 1n the
3
Immediate vicinity of rock drilling 1n Moroccan mines was -450 mg/m 1n
3
one mine and -250 mg/m 1n another (Rodler, 1955). In two reports from
Chilean mines (Ansola et al., 1944a,b; Schuler et al., 1957) the air concen-
3 3
tratlons of manganese varied from 62.5-250 mg/m and from 0.5-46 mg/m ,
respectively.
In ferromanganese factories, neurological and psychic disturbances Indi-
cating manganese poisoning have been observed at manganese levels as low as
2-5 mg/m3 of air (Suzuki et al., 1973a,b).
While manganlsm and Its association with manganese has been well
described, a dose-response relationship 1n man cannot be evaluated because
duration of exposure 1s not well documented. Also, early signs of the
disease were sought 1n only a few studies (Sarlc et al., 1977; Tanaka and
Lleben, 1969), and none of the reported studies employed a standard cohort
design (e.g., there was no follow-up or comprehensive characterization of
the exposed populations).
A high Incidence of pneumonia and other respiratory ailments has been
reported 1n workers with occupational exposure to manganese (Baader, 1937;
Lloyd-Oavles, 1946; Rodler, 1955; Sarlc, 1978) and 1n Inhabitants living
around factories manufacturing ferromanganese or manganese alloys (Elstad,
1805A 9-3 5/09/83
-------
1939; Suzuki, 1970). The Increased Incidence of pulmonary disease found 1n
exposure to low concentrations of manganese 1s not necessarily directly
attributable to manganese Itself. Manganese exposure may Increase suscepti-
bility to pneumonia or other acute respiratory diseases by disturbing the
normal mechanism of lung clearance. Some Investigators have suggested that
long-term exposure to manganese may contribute to the development of chronic
lung disease (Sarlc and Luc1c-Pala1c, 1977), but there 1s Uttle data to
demonstrate this conclusively, particularly at ambient levels.
Effects on the cardiovascular system Include reports of decreased
systolic blood pressure 1n humans occupatlonally exposed via Inhalation
(Sarlc and Hrustlc, 1975). This symptom was also shown to occur experiment-
ally 1n orally exposed rats (Klmura et al., 1978). Reports about the
effects of manganese on human blood and hemoglobin show conflicting results
that have not been resolved by animal studies. The studies are difficult to
compare because of variations 1n exposure and 1n the severity of the effect.
There have been reports of Impotence 1n a majority of workers affected
by manganese (Chandra et al., 1974; Emara et al., 1971; Rodler, 1955;
Penalver, 1955). There 1s some experimental evidence of reproductive
effects 1n laboratory animals. Degenerative changes 1n the testes of rats
have been produced by excessive levels of manganese administered by multiple
1ntraper1toneal Injections (Chandra, 1971; Singh et al., 1974, 1975; Chandra
et al., 1975; Tandon et al., 1975; Shukla and Chandra, 1977) and by single
Intratracheal Injections In rabbits (Chandra et al., 1973a). Chronic
dietary exposure to manganese has caused decreased organ weight for the
preputlal gland, seminal vesicle and testls In mice (Gray and Laskey, 1980),
and decreased serum testosterone levels and reduced pregnancy percentage 1n
rats (Laskey et al., 1982).
1805A 9-4 5/05/83
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Manganese dlchlorlde Increased the Incidence of lymphosarcomas 1n DBA/1
mice following twice weekly subcutaneous or 1ntraper1toneal Injections for 6
months (OlPaolo, 1964), and elicited slightly elevated tumor Incidence 1n a
Strain A mouse lung tumor bloassay (Stoner et al., 1976). Single or repeat-
ed Intramuscular Injections of MnO or manganese powder did not result 1n
Increased Incidences of lymphosarcomas, leukemlas or local sarcomas 1n
either sex of F344 rats or female Swiss mice. However, repeated Intramuscu-
lar Injections of an organomanganese compound, MAA, elicited statistically
significant Increases 1n Injection site tumors 1n both sexes of F344 rats
(Furst, 1978). Oral administration of manganese powder for 12 months twice
monthly did not Induce lymphomas and/or leukemlas or flbromas In either sex
of F344 rats (Furst, 1978). Although the results of the studies with diva-
lent manganese are suggestive of carcinogenic activity, non-natural routes
of administration were employed.
Some reported animal studies Imply a carcinogenic potential for manga-
nese, but the data are Inadequate to support this conclusion (I.e., local
Injection site sarcomas 1n F344 rats, a marginal response 1n Strain A mice,
and Inadequate data 1n the experiment with DBA/1 mice). No ep1dem1olog1c
Information relating manganese exposure to cancer occurrence 1n humans has
been located. Using IARC criteria (IARC, 1980), the available evidence for
manganese cardnogenldty would be rated Inadequate for animals and "no data
available" for humans (Group 3). Consequently, the documented toxic effects
are of more practical concern.
9.3. SPECIAL GROUPS AT RISK
Several researchers have mentioned the marked differences 1n Individual
susceptibility to Inhaled manganese (Rodler, 1955; Penalver, 1955; Cotzlas,
1805A 9-5 5/09/83
-------
1958). They speculated that this may have been caused by alcoholism, syphi-
lis, carbon monoxide, lesions of the excretory system, or the physiological
or pathological condition of the respiratory tract. While 1t 1s reasonable
to assume that an Individual with an Impaired ability to clear Inhaled
manganese or to excrete absorbed manganese would be at Increased risk of
adverse effects, no studies exist to confirm this.
Experimental studies suggest that populations at greatest risk of
adverse effects due to manganese exposure are the very young and those with
Iron deficiency. The evidence for Increased absorption and retention of
manganese occurring 1n Iron deficiency was shown 1n an Inhalation study 1n
humans (Mena et al., 1969, 1974), dietary studies 1n humans (Thomson et al.,
1971), and 1ngest1on studies 1n experimental animals (Rehnberg et al., 1982;
Kostlal et al., 1980).
Ingestlon studies give useful Information on the effects of Inhalation
exposures because most Inhaled manganese 1s cleared to the gastrointestinal
tract. The early neonatal period may be critical for metal accumulation
because the very young also have an Increased Intestinal absorption and
retention of manganese. This has been demonstrated 1n preweanllng mice and
rats (Kostlal et al., 1978; Rehnberg et al., 1980) and 1n Infants (Mena et
al., 1974). High retention of manganese 1n the tissues, particularly the
liver and brain, 1s associated with the limited excretion of manganese 1n
the preweanllng rat (Miller et al., 1975).
Kostlal et al. (1978) report that oral toxldty measured by LD™
values 1s greater 1n very young (2 weeks) as well as old (54 weeks) rats,
but not as high as expected based on the rate of Intestinal absorption.
Although the neonate has not been shown to have Increased sensitivity to
metals, the early accumulation of manganese must be considered as an
additional risk factor.
1805A 9-6 5/05/83
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Another population at high risk 1s workers exposed to manganese at or
near the recommended TLV. Because neurological symptoms have been reported
3
at concentrations below this limit, the TLV of 5 mg/m has a low margin of
safety.
9.4. EFFECTS OF MAJOR CONCERN AND EXPOSURE/RESPONSE INFORMATION
9.4.1. Effects of Major Concern. The key health effects of manganese are
1n the CNS and the lungs. The effect on the CNS, manganlsm, 1s Irreversible
and severely Incapacitating although not directly associated with lethality.
3
The pulmonary effects reported at levels below 1 mg/m are for the most
part reversible but can limit function or Impose disability such as
Increased wheezing, bronchitis, or Increased susceptibility to respiratory
Illness. The lowest reported exposure levels associated with life threaten-
ing diseases such as pneumonia have been similar to ranges associated with
3
chronic manganese poisoning, e.g., 0.1-14 mg/m (Lloyd-Davles, 1946).
Several endpolnts suggested as effects from exposure to manganese are
nonspecific, Inconclusive or lack documentation In humans, such as degenera-
tive changes 1n the testes, or decreased blood pressure. Sexual dysfunction
has often been reported as an early effect of manganlsm at levels associated
with other effects on the CNS.
9.4.2. Exposure/Response Information. Tables 6-1 and 6-3 show that human
3
exposure to levels below 5 mg/m has been associated with adverse effects
to the CNS. These effects are either advanced manganlsm or a constellation
of signs Indicative of early stages of the disease (Suzuki et al., 1973a;
Chandra et al., 1981). There 1s some evidence suggesting that exposure to
3
levels below 1 mg/m 1s associated with nonspecific symptoms which are
common 1n early manganlsm and with abnormal neurological findings. However,
1n studies at these levels the findings reported could not be definitively
attributed to manganese exposure (Sarlc et al., 1977; Chandra et al., 1981).
1805A 9-7 5/06/83
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Studies of respiratory effects 1n humans (summarized 1n Table 6-8) show
pulmonary system adverse effects at levels below 1 mg/m . Schoolchildren
3
exposed to manganese emissions estimated at -3-11 vg/m from a ferro-
manganese plant developed an Increase 1n respiratory symptoms compared with
controls such as sore throat, wheezing and sputum on arising (Nogawa et al.,
1973). Sarlc and Luc1c-Pala1c (1977) reported Increased chronic bronchitis
3
1n workers exposed to 0.4-16 mg/m but the results at ambient levels
3
<1 mg/m (Sarlc et al., 1975) were Inconclusive because no exposure-
response relationship was seen and confounding factors were not controlled.
There are many pulmonary endpolnts that vary according to level of
exposure. Although exposure ranges are so broad that the exposure/response
relationship 1s sometimes masked, a continuum of effects has been observed
which qualitatively supports the pulmonary endpolnt. Pulmonary effects
reported and supported Include pneumonia (Elstad, 1939; Lloyd-Davles, 1946;
Wassermann and M1ha1l, 1961), chronic bronchitis {Lloyd-Davles, 1946; Sarlc
and Luc1c-Pala1c, 1977), radlographlc changes and flbrosls (Wassermann and
M1ha1l, 1961) and airways disability (Nogawa et al., 1973).
Animal studies also qualitatively support the association between
pulmonary effects and manganese exposure. Table 9-1 summarizes the animal
studies of the adverse effects of manganese Inhalation. Pathological
changes and decreased resistance to Infection occur 1n a variety of species
3
at levels above 0.7 mg/m . Inflammatory reactions and decreased resist-
ance to Infection have been observed 1n mice (Malgetter et al., 1976; Adklns
et al., 1980c). N1sh1yama et al. (1975) report pulmonary congestion and
Inflammatory changes 1n mice and monkeys after 5 months exposure to 3
3 3
mg/m and less severe changes at 0.7 mg/m . Suzuki et al. (1978) de-
scribe radlologlc changes after 10 months of exposure to 3 and 0.7 mg/m3.
1805A 9-8 5/09/83
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TABLE 9-1
Studies of Manganese Inhalation 1n Animals — Summary of Effect Levels
Species
Mouse
Guinea pig
Guinea pig
Mouse
Mouse
Mouse
Mouse
Monkey
Monkey
Mouse
Monkey
Monkey
Guinea pig
Mouse
Duration
1-3 months
6 months
7.5 months
15-21 days
29 days
39+20 days
14 days
5 months
10 months
14 days
5 months
10 months
1 day
1-4 days
Concentration
(mg/m3)
Ferromanganese
NR
2350
2350
Mn02
NR
NR
NR
0.7
0.7
0.7
3.0
3.0
3.0
22
109
Result*
NOEL
NOEL
unclear
PEL
NOEL
unclear
LOAEL
LOAEL
LOAEL
PEL
PEL
PEL
PEL
PEL
Reference
Heine, 1943
Heine, 1943
Heine, 1943
Lloyd-Davles,
1946
Jotten et al. ,
1939
Jotten et al. ,
1939
N1sh1yama et al. ,
1975
N1sh1yama et al. ,
1975
Suzuki et al . ,
1978
N1sh1yama et al. ,
1975
N1sh1yama et al. ,
1975
Suzuki et al. ,
1978
Bergstrom, 1977
Malgetter et al.,
1976
1805A
9-9
5/09/83
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TABLE 9-1 (cont.)
Species
Duration
Concentration
Result*
Reference
Monkey
Hamster
Mouse
Mouse
15 months
Rat, monkey 9 months
Rat, monkey 9 months
Rat 2 months
2 months
2 hours
2 hours
Mn304
0.10 NOEL
1.1 NOEL
0.11 NOEL
0.12 NOEL
engine exhaust
0.12 NOEL
0.89 NOEL
0.22-2.66 LOAEL
Coulston and
Griffin, 1977
UlMch, 1979c
Ulrlch, 1979c
Moore et al.,
1975
Moore et al.,
1975
Adklns et al.,
1980a
Adklns et al.,
1980c
*NOEL No-Observed-Effect Level: That exposure level at which there are no
statistically significant Increases 1n frequency or severity of
effects between the exposed population and Us appropriate control.
NOAEL No-Observed-Adverse-Effect Level: That exposure level at which
there are no statistically significant Increases 1n frequency or
severity of adverse effects between the exposed population and Its
'appropriate control. Effects are produced at this level, but they
are not considered to be adverse.
LOAEL Lowest-Observed-Adverse-Effect Level: The lowest exposure level 1n
a study or group of studies which produces statistically significant
Increases 1n frequency or severity of adverse effects between the
exposed population and Us appropriate control.
PEL Frank-Effect Level: That exposure level which produces unmistakable
adverse effects, ranging from reversible hlstopathologlcal damage to
Irreversible functional Impairment or mortality, at a statistically
significant Increase 1n frequency or severity between an exposed
population and Us appropriate control.
1805A
9-10
5/09/83
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Table 9-1 summarizes several studies which report no gross or microscopic
3
changes after exposure to ~0.1 mg/m Mn304.
Thus, the animal data qualitatively support a range of respiratory
effects associated with exposure to manganese. Human data qualitatively
describe such effects but have limited exposure/response Information because
exposure ranges are broad, cohorts are not followed for long time periods,
and duration of exposure 1s unreported or variable within a study popula-
tion. Therefore, the health effects assessment centers on the highest NOELs
or the LOEL 1n humans which are supported by human equivalent exposures
derived from animal data.
9.5. HEALTH HAZARD EVALUATION
9.5.1. Critical Effect and Effect Levels. The critical effect 1s that
adverse health effect which occurs at the lowest level of exposure. In
order to Identify the critical effect, the highest no-observed-effect-level
(NOEL) and the lowest-observed-effect-level (LOEL) for relevant toxic
effects are Identified and compared. Qualitative results and dose/response
data from experimental animals are compared with levels based on human
experience. Studies In humans report effects on the respiratory symptoms at
levels below 1 mg/m whereas studies of effects on the CNS below this
level are equivocal or negative. Two studies give exposure response Infor-
mation 1n humans for the critical effect. Nogawa et al. (1973) reported an
Increased prevalence of respiratory symptoms 1n schoolchildren exposed to
3
0.003-0.011 mg/m manganese emission from a ferromanganese plant. This 1s
the lowest-observed-adverse-effect level (LOAEL) 1n humans. Sarlc and
Luc1c-Pala1c (1977) report an Increased prevalence of chronic bronchitis 1n
3
workers exposed to 0.4-16 mg/m ; however, prevalence of chronic bronchitis
3
1n a group of workers exposed to 0.005-0.04 mg/m did not differ from
1805A 9-11 5/09/83
-------
controls. These results do not contradict the results of Nogawa because
1) children may be expected to be more sensitive than male workers, and
2) the latter study had less statistical power because fewer subjects were
Involved.
NOELs could be derived from several studies reported 1n laboratory
animals exposed to manganese oxides consisting largely of particles 1n the
alveolar fraction (<2 iim, see Section 3.6.4.1.). These studies are
summarized 1n Tables 6-10 and 9-1. Factors which compromise the use of
these studied for NOELs are described below.
Coulston and Griffin (1977) did not perform tests of lung function, did
not give details of the pathological examination and reported acarlasls and
associated pulmonary complications 1n a majority (8/12) of the animals
studied. Moore et al. (1975) reported no gross or microscopic abnormali-
ties; however, they observed the animals for only 8 hours/day and for only
56 days. Ulrlch et al. (1979a,b,c) exposed rats and squirrel monkeys to
three levels of manganese and a control for 9 months. This study also had
deficiencies which reduced confidence 1n the range of negative findings
reported. Due to the small group size of the monkeys (4 males and 4
females) and the large within group variability, 1t lacked sufficient
statistical power to detect any but the largest changes 1n the parameters
measured. The variability could have been reduced by using more appropriate
statistical analysis to control for within group variation. The description
of lung pathology was Inadequate. Negative results were reported at 1.15
3
mg/m ; however, Suzuki et al. (1978) reported pathologic changes 1n the
o
lungs of rhesus monkeys exposed to 700 iig/m of MnO? for 10 months.
1805A 9-12 5/09/83
-------
Based on these data, the next highest NOEL reported by Ulrlch et al.
3
(1979a,b,c) was 0.113 mg/m . However, the repeated reports of the absence
3
of gross and microscopic abnormalities at a similar level (0.1 mg/m )
suggest that this level may be close to a threshold.
These data do not exclude the possibility that more subtle toxic effects
3 3
on the lungs may occur at -0.1 mg/m . Effects do occur at 0.7 mg/m .
3
In order to compare the reported NOEL (0.1 mg/m ) and the LOAEL (0.7
3
mg/m ) to similar data 1n humans, 1t would be helpful to estimate a human
Intake equivalent to that of the experimental animals. The suggested
approach 1s provided 1n the Appendix.
1805A 9-13 5/05/83
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10. REFERENCES
Abernathy, R.F., M.J. Peterson and F.H. Gibson. 1969. Spectrochemlcal
analysis of coal ash for trace elements. Bur. Mines Report of Investiga-
tions 7281. U.S. Dept. Interior, Pittsburgh, PA. 30 p.
Abrams, E., J.W. Lasslter, W.J. Miller, M.W. Neathery and R.P. Gentry.
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1976a. Effect of dietary manganese as a factor affecting Mn absorption
1n rats. Nutr. Rep. Inter. 14(5): 561-565.
Abrams, E., J.W. Lasslter, W.3. Miller, M.W. Neathery, R.P. Gentry and R.D.
Scarth. 1976b. Absorption as a factor 1n manganese homeostasls. J. Anlm.
Sc1. 42(3): 630-636.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1958.
Committee on Recommended Analytical Methods: Determination of manganese 1n
air, perlodate oxidation method. In: Manual of Analytical Methods Recom-
mended for Sampling and Analysis of Atmospheric Contaminants. ACGIH, Cin-
cinnati, OH. Mn-1, Mn-4.
ACGIH (American Conference of Governmental and Industrial Hyglenlsts).
1980. Documentation of the Threshold Limit Values, Fourth ed. ACGIH, Cin-
cinnati, OH. p. 250-251.
Ad Hoc Working Group of Technical Committee - A1r Quality, International
Standards Organization. 1981. Recommendations on size definitions for
particle sampling. Am. Ind. Hyg. Assoc. J. 42: A64-A68.
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Adklns, B., Jr., G.H. Luglnbuhl and D.E. Gardner. 1980a. Acute exposure of
laboratory mice to manganese oxide. Am. Ind. Hyg. Assoc. J. 41: 494-500.
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APPENDIX
ESTIMATING HUMAN EQUIVALENT INTAKE LEVELS FROM ANIMAL STUDIES
TERMINOLOGY
The quantitative evaluation of potential health hazards 1s based upon
estimates of the threshold exposure level for the critical effect. The
threshold estimate 1s bracketed by the highest NOEL (see Table 9-1) and the
LOAEL. The values for the NOELs and LOAEL depend on which health effect 1s
considered. The estimate of the human threshold level 1s more uncertain 1f
animal data are used since there 1s presently limited Information on species
differences regarding toxic responses.
Human equivalent Intake rate (HEI) 1s defined here as the estimated
exposure level based on animal data which would cause the same severity of
health effect 1f continued over the same fraction of Hfespan as used 1n the
animal study. The conversion for manganese assumes that 1f the ratio
(exposure level)/(body surface area) 1s the same 1n humans as 1n the animal
study, then effects of the same severity will occur.
CRITICAL EFFECTS AND ESTIMATED EFFECT LEVELS
The lowest exposure level for humans associated with adverse effects 1s
3
a LOAEL of 3-11 y.g/m for respiratory effects 1n children reported by
Nogawa et al. (1973). Comparison among studies of respiratory effects In
laboratory animals (summarized 1n Table 9-1) shows that Ulrlch et al.
(1979a,b,c) and Suzuki et al. (1978) utilized the longest exposure periods
3
at exposure concentrations -100 v-g/m . Therefore, these studies were
selected for these calculations. The HEI 1s estimated from the data from
experimental animals by the following:
/ \
k2/3
HEI = CA x DE x Br x t
1806A A-l 5/06/83
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where C. = concentration 1n air 1n the animal study 1n ug/day
Or = fraction of day experimental animals were exposed
3
Br = volume of air breathed per day 1n m
W = body weight of the experimental animal 1n kg
a
This conversion 1s based on the following assumptions:
1. Agents that are 1n the form of partlculate matter are expected
to be absorbed and retained proportional to the breathing rate.
2. The fraction retained 1s approximately the same for all species.
3. The conversion from animals to humans based on exposure level
per body surface area more accurately reflects differences
among species than does a mg/kg body weight conversion (Rail,
1969). The surface area ratio 1s well approximated by the body
weight ratio to the 2/3 power (Calabrese, 1983).
The estimation of HEI 1s based on Intake by Inhalation of manganese 1n
excess of dietary Intake of this essential element because all studies used
here were so designed. Also, a sufficient oral Intake and strong homeostat-
1c control can be assumed so that excess exposure 1s appropriate. Inhala-
tion studies should be used since the critical effect 1s route specific.
The estimated HEI (1n mg/day) 1s converted to a human equivalent expo-
sure level (HEEL) by dividing by the average dally human respiratory rate of
3
20 m /day. All calculations are summarized 1n Table A-l.
In the studies considered here D equals 1. Therefore, for rhesus
monkeys 1n the study by Suzuki et al. (1978)
HEI = CA x Br x f—
V *a/
= 700 ug/m3 x 1.4 mVday x/70 kfl
\3.5 kg,
= 7293
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CD
O
TABLE A-l
Exposure Effect Information for Health Hazard Evaluation: Human Equivalent Exposure Levels Estimated from Animal Data
Species
Animal Intake Level Estimated Human Intake Level
Response Level Exposure
vg/day ixg/kg/day
ug/day ug/kg/day
Estimated Human
Equivalent Exposure
Level (HEEL)
Adjusted
HEEL*
Reference
1
CO
Rat
Squirrel monkey
Rhesus monkey
reported
reported
LOAEL
NOELb
NOELb
113
113
700
29
81
980
84
113
280
1022
1740
7293
15
25
104
51
87
365
5
8.7
36.5
UlMch et al.,
1979a,b.c
Ulrlch et al.,
1979a,b,c
Suzuki et al.,
1978
in
\
O
co
CO
aThe estimated HEEL 1s adjusted by dividing by an uncertainty factor of 10 to compensate for the heterogeneity In human populations and thereby protect
the sensitive Individual.
bThese NOELs are used to compare human and animal data despite some limitations which exist 1n the study. See text for further discussion.
-------
3
The HEEL obtained by dividing by the dally respiratory volume (20 m /day)
1s 365 ug/m - Note that this HEEL 1s based on a LOAEL and thus may be
above the human threshold level.
Similar calculations using data on rats from Ulrlch et al. (1979a,b,c)
(VJ = 0.35 kg, Br = 0.26 m3/day, and C. = 113 ug/m3) result In a
3 A
HEEL of 51 H9/m3. For the Ulrlch et al. (1979a,b,c) data on squirrel
monkeys (W3 = 0.72 kg, Br = 0.72 m3/day, and C. = 113 ug/m3) the
a A
HEEL 1s 87
These results, shown 1n Table A-l , can be compared with the data from
Nogawa et al. (1973) on children who had an estimated LOAEL of 3-11
3
ug/m . The data obtained from human data 1s, of course, crucial for
public health decision making. This level might be expected to be lower
than the animal level for the following reasons: 1) the studies on animals
have flaws resulting 1n uncertainty as to whether adverse effects are
missed; 2) certain endpolnts studied 1n humans cannot be ascertained as well
1n animal studies and are likely to be overlooked; and 3) children are a
sensitive group. A better comparison between animal and human data 1s
obtained by dividing the HEEL by 10 to compensate for the heterogeneity 1n
the human population and to better protect the sensitive Individual (Dourson
and Stara, 1983). The range of adjusted HEELs from the animal NOELs and the
o
LOAEL 1s 5-37 y.g/m , and supports the human LOAEL of 3-11
observed 1n a sensitive population.
..-, ,-,- ''-ay
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