EPA 600/8-83-013F
May 1984
Final Report
HEALTH ASSESSMENT
DOCUMENT FOR MANGANESE
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
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NOTICE
This document has been reviewed 1n accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade
names or commercial products does not constitute endorsement or recommenda-
tion for use.
11
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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 Is 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 In 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 In order to Identify the critical
effect and to place adverse health responses In perspective with observed
environmental levels. \
111
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TABLE OF CONTENTS
Page
1. .INTRODUCTION. T.-J
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 Vll
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 3-31
3.4.3. Relative Importance of Manganese Sources at
Several Locations as Determined by Mass Balance
and Enrichment Models 3-39
3.5. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES 3-49
3.5.1. Principal Cycling Pathways and Compartments . . . 3-49
3.5.2. Atmospheric Fate and Transport 3-51
3.5.3. Fate and Transport in Water and Soil 3-56
3.6. ENVIRONMENTAL LEVELS AND EXPOSURE . 3-60
3.6.1. Air 3-60
3.6.2. Water 3-76
3.6.3. Food 3-81
3.6.4. Human Exposure 3-81
1v
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Page
3.7.
SUMMARY OF GENERAL PROPERTIES AND BACKGROUND INFORMATION. 3-90
3.7.1. Chemical and Physical Properties 3-90
3.7.2. Sampling and Analysis 3-91
3.7.3. Production and Use J-«
374. Sources of Manganese in the Environment ...... s-vs
3.7.5. Environmental Fate and Transport Processes. . . . 3-95
3.7.6. Environmental Levels and Exposure 3-97
4. BIOLOGICAL ROLE AND PHARMACOKINETICS. . 4-1
4.1. BIOLOGICAL ROLE OF MANGANESE. 4-1
4.1.1. Biochemical Role. . J-l
4.1.2. Manganese Deficiency J-'
4.1.3. Manganese Requirements J-«
4.1.4. Summary • • • 4-2
4.2. COMPOUND DISPOSITION AND RELEVANT PHARMACOKINETICS. ... 4-3
4.2.1. Absorption • • • ' • f-3
4.2.2. Distribution and Normal Tissue Levels J-o
4.2.3. Excretion J-IO
4.2.4. Biological Half-time. *-«*
4.2.5. Homeostasis . . J-'jj
4.2.6. Summary *~*u
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 • ^D
5. TOXIC EFFECTS AFTER ACUTE EXPOSURE^ 5-1
5.1. ANIMAL STUDIES f-l
5.2. HUMAN STUDIES , J'J
5.3.' SUMMARY . " *-*
6. TOXIC EFFECTS AFTER CHRONIC EXPOSURE 6-1
6.1. INTRODUCTION 6-]
6.2. NEUROTOXIC EFFECTS - HUMAN STUDIES 6-4
6.2.1. Case Reports and Epidemiologic Studies 6-10
6.2.2. Pathology of Manganese Poisoning 6-22
6.2.3. Summary • b~"
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Page
6.3. NEUROTOXIC EFFECTS — ANIMAL STUDIES 6-24
6.3.1. Mechanism of Manganese Neurotox1c1ty 6-33
6.3.2. Altered Neurotransmitter Metabolism . . 6-34
6.3.3. Summary 6-45
6.4. LUNG EFFECTS 6_46
6.4.1. Human Studies 6-46
6.4.2. Animal Studies - 6-56
6.5. REPRODUCTIVE EFFECTS 6-68
6.5.1. Human Studies , . 6-68
6.5.2. Animal Studies. . 6-68
6.5.3. Summary 6-72
6.6. HEMATOLOGIC EFFECTS 6-73
6.6.1. Human Studies 6-73
6.6.2. Animal Studies 6-74
6.6.3. Summary 6-75
6.7. CARDIOVASCULAR SYSTEM EFFECTS 6-75
6.7.1. Human Studies 6-75
6.7.2. Animal Studies 6-76
6.7.3. Summary 6-76
6.8. BIOCHEMICAL EFFECTS 6-76
6.8.1. Human Studies 6-76
6.8.2. Animal Studies 6-78
6.8.3. Summary 6-78
6.9. DIGESTIVE SYSTEM EFFECTS 6-79
6.9.1. Gastrointestinal Tract Effects 6-79
6.9.2. Liver Effects * 6-79
6.9.3. Summary 6-81
7. CARCINOGENICITY 7-1
7.1. ANIMAL STUDIES 7-1
7.2. HUMAN STUDIES 7.7
7.3. SUMMARY 7_10
v1
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Paqe
8. MUTAGENICITY AND TERATOGENICITY 8-1
8.1. MUTAGENICITY 8-1
8.2. TERATOGENICITY 8-1
8.3. SUMMARY ..... 8-2
9. EFFECTS OF CONCERN AND HEALTH HAZARD EVALUATION 9-1
9.1. EXISTING GUIDELINES, RECOMMENDATIONS AND STANDARDS. ... 9-1
9.1.1. A1r 9-]
9.1.2. Water • 9-'
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 T^1
APPENDIX: ESTIMATING HUMAN EQUIVALENT INTAKE LEVELS FROM ANIMAL
STUDIES A-'
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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
Sllicomanganese 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
in 1968 3_32
3-11 Estimated Manganese Emissions from Controlled Submerged-Arc
Furnaces Producing Manganese Alloys 3-34
3-12 Manganese Concentrations of Coal, Fuel Oil, Crude Oil,
Gasoline, Fuel Additives and Motor Oil 3-36
3-13 Manganese Content 1n Coal Ash 3-37
3-14 Manganese Concentration in Fine (<2.0 ptn) and Coarse
(2.0-20 ym) Particle Fractions of Aerosols from Several
Sources in the Portland Aerosol Characterization Study. . . 3-41
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 . . . 3-43
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 3-44
3-17 Number of National Air Surveillance Network Stations within
Selected Annual Average Manganese Air Concentration
Intervals, 1957-1969 3-63
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LIST OF TABLES (cont.)
No. Title
3-18 National Air Surveillance Network Stations with Annual
Average Manganese A1r Concentrations Greater Than
Page
3-64
3-19
3-20
3-21
3-22
3-23
3-24
3-25
3-26
3-27
3-28
3-29
3-30
3-31
3-32
4-1
4-2
0 . 5 ug/md
Average Manganese Concentration 1n Ambient A1r and Total
Suspended Partlculates (TSP) In Urban and Nonurban NASN
Sites, 1966-1967
Urban NASN Sites, 1970-1982: National Cumulative Frequency
Distributions of Quarterly Values for Manganese Concentration
Nonurban NASN Sites, 1970-1982: National Cumulative Frequency
Distributions of Quarterly Values for Manganese Concentration
Manganese Concentrations in Air, Kanawha Valley Area,
West Virginia '
Ambient Air Sampling Data for Total Suspended Particulates
and Manganese (in Pg/m3) in the Marietta, OH-Parkersburg, WV
Vicinity, 1965-1966 and 1982-1983
Concentrations of Trace Metals in A1r Measured at Three
Locations in New York City
Selected Dichotomous Sampler Data on Manganese and Particle
Mass from 22 U.S. Cities in 1980
Concentration of Manganese in Various Lake and River Waters
Mean Concentrations of Dissolved Manganese by Drainage Basin
Dissolved and Suspended Manganese in Five U.S. Rivers . . .
Cumulative Frequency Distribution of Manganese Concentration
in Tap Waters Sampled in the HANES I Augmentation Survey of
Adults.
Estimates of Human Inhalation Exposure to Manganese in
Ambient Air
Dietary Intake of Manganese in the U.S
Intake of Manganese from Food by Children
Manganese in Human Tissues
Concentrations of Manganese in Liver, Kidney and Brain. . .
3C. C.
-66
3-67
3-68
3-»n
-/U
3-71
3-73
3-75
3-77
3-79
3-80
3-82
3-86
3-88
3-89
4-7
4-16
ix
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LIST OF TABLES (cent.)
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
6-12
6-13
6-14
Title
Acute LD50 Values for Manganese Compounds ....
Influence of Age on Manganese ToxIcHy 1n Rats: LDcn Values
8 Days after a Single Oral Administration of MnCl2. .
Psychological Disturbances in 15 Cases of Manganlsm ....
Neurological Symptoms in 15 Cases of Manganlsm. ....
Neurological Signs in 15 Cases of Manganism ....
Studies of Manganlsm in Humans and Exposure-Response
Relationship
Frequency of Abnormal Neurological Findings .
Ferroalloy Workers with Neurological Signs by Level
of Exposure to Manganese
Neurotoxic Effects of Manganese in Experimental Animals . .
Neurological Signs Induced by Manganese in 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,
Intraperitoneal 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 .
Paqe
5-2
5-3
6-6
6-7
6-9
5n
6-16
6 ?n
6-25
6-30
fi-in
6-CC
6-57
6-58
6-fiA
6-66
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LIST OF TABLES (cont.)
No.
7-1
7-2
7-3
9-1
A-l
Title
Pulmonary Tumors 1n Strain A Mice Treated with Manganese
Sulfate
Carcinogen1c1ty 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 Oust
Studies of Manganese Inhalation 1n Animals — Summary of
Exposure Effect Information for Health Hazard Evaluation:
Human Equivalent Exposure Levels Estimated from Animal Data
Page
7-2
7-4
7-8
9-9
A-4
x1
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LIST OF FIGURES
No.
3-1
3-2
6-1
6-2
6-3
6-4
Title
The Global Cycles of Manganese
Concentration Factors for Manganese in Hudson River ...
Principal Components and Connections in the Extrapyramidal
Motor System. . . . ,
Schematic Illustration Depicting Possible Sites of Damage
to the Nigral-Striatal System in Parkinsonism and
Manganism
Schematic Diagram Indicating the Distribution of the Main
Central Neuronal Pathways Containing Dopamine
Schematic Representation of a Dopamine Synapse Indicating
Possible Sites of Damage Produced by Manganese Exposure .
Page
3-50
3-61
6-2
6-3
6-11
6-37
xii
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The EPA Office of Health and Environmental Assessment (OHEA) 1s respon-
sible £or the preparation of this health assessment document. The OHEA
Environmental Criteria and Assessment Office (ECAO/CIn) had overall respon-
sibility for coordination and direction of the document, preparation and
production effort. Each chapter was originally drafted by the principal
authors as listed below. The document managers are identified by an
asterisk (*).
Principal Authors
Dr. Halka Bilinski
Institute for Medical Research
and Occupational of Health
Zagreb, Yugoslavia
Mr. Randall J.F. Bruins
Enviromental Criteria and'
Assessment Office
dncinnnati, Ohio
Or. Linda Erdreich*
Environmental Criteria and
Assessment Office
Cincinnati, Ohio
Ing. Hirka Fugas
Institute for Medical Research
and Occupational Health
Zagreb, 'Yugoslavia
Or. Dinko Kello
Institute for Medical Research
and Occupational Health
Zagreb, Yugoslavia
Dr. KMsta Kostial
Insitute for Medical Research
and Occupational Health
Zagreb, Yugoslavia
Dr. Marvin Legator
University of Texas
Medical Branch
Galveston, Texas
Chapters
3
1, 2, 3
5, 6, 9
4, 5, 6, 7
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Dr. Marco Sarlc 5,
Institute for Medical Research
and Occupational Health
Zagreb, Yugoslavia
Dr. Jerry F. Stara* 3
Environmental Criteria and
Assessment Office
Cincinnati, Ohio
Dr. Otto Weber 3
Institute for Medical Research
and Occupational Health
Zagreb, Yugoslavia
The OHEA Carcinogen Assessment Group (CAG) was responsible for reviewing
the sections on carcinogenicity. Participating members of the CAG are
listed below (principal reviewers for this document are designated by *).
Roy Albert, M.D. (Chairman)
Elizabeth L. Anderson, Ph.D.
Steven Bayard, Ph.D.*
David L. Bayliss, M.S.*
Margaret M.L. Chu, Ph.D.
Chao W. Chen, Ph.D.
Herman J. Gibb, M.S., M.P.H.
Bernard H. Haberman, D.V.M., M.S.*
Charalingayya B. Hiremath, Ph.D.
Robert E. McGaughy, Ph.D.
Dharm V. Singh, D.V.M., Ph.D.
Todd W. Thorslund, Sc.D.
xiv
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The following Individuals provided peer-review of this draft or earlier
drafts of this document:
U.S. Environmental Protection Agency
Dr. Jerry F. Stara (document manager)
ECAO-C1n
U.S. Environmental Protection Agency
Dr. Michael Dourson
ECAO-C1n
U.S. Environmental Protection Agency
v
Dr. Bernard Haberman
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, DC
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. William Pepelko
ECAO-C1n
U.S. Environmental Protection Agency
Dr. David Weil
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, NC
EPA Science Advisory Board
The substance of this document was Independently peer reviewed 1n a
public session of the Environmental Health Committee of the EPA Science
Advisory Board.
xv
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Consultants and/or Reviewers
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, HI
Dr. Laurence D. F.echter
School of Hygiene and Public Health
Johns Hopkins University
Baltimore, MD
Dr. D. Anthony Gray
Syracuse Research Corporation
Syracuse, NY
Dr. Paul Hammond
University of Cincinnati
Cincinnati, Ohio
Dr. Rolf Hartung
School of Public Health
University of Michigan
Ann Arbor, MI
Dr. T.J. Kneip
NYU Medical Center
Tuxedo, NY
Dr. James Lai
Burke Rehabilitation Center
Dementia Research
White Plains, NY
Mr. C.A. Hall
Ethyl Corporation
Ferndale, MI
Mr. Fred Moore
El kern Metals Company
Marietta, OH
xvi
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Dr. Mangus Plscator
School of Public Health
University of Pittsburgh
Pittsburgh, PA
Dr. Ivan Rabar
Institute for Medical Research
Zagreb, Yugoslavia
Dr. Samuel Shibko
Contaminants and Natl. Toxic. Evaluation Branch
Division of Toxicology, Food and Drug Administration
Washington, DC
Dr. Ellen Silbergeld
Environmental Defense Fund
Washington, DC
Dr. Helvyn Tochman
John Hopkins Hospital
Baltimore, HD
Dr. James Withey
Food Directorate, Bureau of Chemical Safety
Ottawa, Ontario
Special Acknowledgement: Technical Services and
Support Staff, ECAO-Cin
U.S. Environmental Protection Agency
xvii
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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 toxlclty from occupational exposure is 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 is based primarily on two
major issues, exposure and response. The first portion of the document is
devoted to manganese in the environment: physical and chemical properties,
the monitoring of manganese in various media, natural and human-made
sources, the transport and distribution of manganese within environmental
media, and the levels of exposure. The second part is devoted to biological
responses in laboratory animals and humans including metabolism, pharmaco-
kinetics, mechanisms of toxlcity, as well as toxicological effects of
manganese.
This assessment document is 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 in the environment.
1-1
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2. SUMMARY AND CONCLUSIONS
2.1. SUMMARY OF EXPOSURE
Manganese is a ubiquitous element 1n the earth's crust, 1n water and 1n
partlculate matter In 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 in acid solution, but are
readily oxidized in alkaline conditions. The heptavalent form 1s found only
in oxy-compounds.
Sampling of manganese in ambient air may be carried out by any of the
methods used for collecting atmospheric particulate matter. High-volume
samplers with glass fiber filters are widely used to measure total ambient
aerosol. If information on particle size 1s desired the dichotomous sampler
is often used, which separately collects fine (<2.5 ym) and coarse
(>2.5 vim) 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 in air usually are as low as 0.002
2-1
-------
Very little manganese 1s mined 1n this country; some 1s mined domestic-
ally as low-grade ores, but most 1s Imported. Ferromanganese and silico-
manganese are ferroalloys produced by the smelting of manganese ore 1n an
electric furnace. Manganese metal Is 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 is declining,
since demand has diminished recently and imports are increasing. The
remaining 5-6% of manganese demand is for a number of compounds which are
Important in the chemical industry and in battery manufacture.
Methylcyclopentadienyl manganese tricarbonyl (MMT) has been produced and
\
used in small quantities as a fuel additive since 1958. Major use as an
octane improver in unleaded gasoline (at 0.125 g Mn/gal) began in 1974, but
was discontinued in 1978 due to adverse effects on hydrocarbon emissions.
MMT continues to be used at -0.05 g Mn/gal in -20% of leaded gasoline.
Manganese is the 12th most abundant element and fifth most abundant
metal in the earth's crust. While manganese does not exist free in nature,
1t is a major constituent in at least 100 minerals and an accessory element
in more than 200 others. Its concentration in various crustal components
and soils ranges from near zero to 7000 vg/g; a mean soil content of 560
vg/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
2-2
-------
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 1n 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 1s 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 In 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
,f1ne 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 S02 transformation to
sulfurlc add, but the manganese concentration necessary for a significant
catalytic effect has been disputed.
s
2-3
-------
Atmospheric manganese 1s transported by air currents until dry or wet
deposition occurs. In New York CHy, 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 1s usually present as the divalent or tetra-
valent form. Divalent manganese,is soluble and relatively stable in neutral
or acidic conditions. Manganese tends to be mobile in oxygen-poor soils and
in 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,
microbial reduction can occur, causing re-release of divalent manganese to
the water column. Manganese is bioconcentrated (by a factor of 10 -104)
in lower organisms; however, the concentration factor decreases (10-102)
as trophic level increases. Thus blomagnlflcation of manganese does not
occur.
A rough assessment of trends in 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 yg/m in 1953-1957 to 0.073 pg/m3 in 1966-1967, and to
0.033 pg/m3 1n 1982. In 1953-1957, the percentage of urban stations
with an annual average of >0.3 yg/m3 was -10%. By 1969 these had
dropped to <4%, and since 1972 the number has been
2-4
-------
The highest manganese concentrations, with some observations exceeding
10 yg/m3, 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 ym) and coarse
(>2.5 ym) particles, but the manganese concentration 1n each fraction 1s
highly variable. On the average, <16% of manganese in aerosol mass is found
1n fine particles; however, it is estimated that in some situations the fine
fraction could contain as much as 50%.
Manganese concentrations 1n nonpolluted freshwaters are usually <20
yg/8,, but may exceed 1000 yg/8, where polluted. Concentrations 1n
groundwater typically are higher than in surface water. Concentrations
>1000 yg/a, are found 1n some drinking waters, but -95% of water
supplies contain manganese at <100 yg/a. A median concentration of 4
yg/9, for public supplies has been reported.
Total human exposure to manganese may be estimated from information on
levels in air, water and diet. Inhaled particles can be deposited either
extrathoradcally, 1n the tracheobronchial region, or in the alveoli. Time
required for particle clearance and probability of absorption Increases with
increasing depth of deposition in the respiratory tract. Deposition of
manganese in the alveoli can be calculated from the ambient concentration
and the fraction present in fine particles. Thoracic (tracheobronchial plus
alveolar) deposition is calculated from estimates of the manganese found in
particles <15 ym in size. Alveolar deposition of manganese at current
ambient levels is estimated as 0.072 yg/day as an average and 6.6 yg/day
under high exposure conditions. Estimates of total thoracic deposition are
2-5
-------
slightly higher; 0.26 pg/day (average) and 10.0 pg/day (high). Alveolar
and total thoracic deposition under the high exposure conditions (10
3
pg/m ) noted at certain locations 1n the 1960s were estimated to be 100
and 152 pg/day, respectively.
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 Is
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 Is 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 in humans are found in liver, kidney and endocrine
glands. Manganese has been shown to penetrate the blood-brain and placental
barriers. Animal data Indicate a higher manganese accumulation in suckling
animals, especially in the brain.
Manganese elimination from the body is accomplished mainly via feces.
Biliary excretion is predominant under normal conditions although excretion
via the pancreas . and intestinal wall are considered to be Important in
conditions of biliary obstruction or manganese overload. In humans and in
animals urinary excretion is low. The total body clearance of manganese 1n
humans can be described by a curve which is the sum of at least two exponen-
2-6
-------
tlal functions with half-times of 4 and 40 days, respectively. However, the
physiological significance of the estimated half-times cannot be obtained
from this data.
Manganese metabolism 1s rigorously controlled by homeostatic mechanisms.
The homeostatic 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 61 absorption depends not only on the amount ingested
and tissue levels of manganese, but also on manganese bioavailablllty and
interaction with other metals. The influence of tissue concentrations on
the excretory mechanism is still unknown.
It 1s generally accepted that under normal conditions 3-4% of orally
ingested manganese is absorbed in 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, it does lead to the hypothesis that iron-deficient individ-
uals may be more sensitive to manganese than the normal individual.
2.2.2. Tox1c1ty. The acute toxicity of manganese is greater for soluble
compounds and via the parenteral route. Acute poisoning by manganese in
humans is 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 manganism, resulting from occupational
exposures to manganese dusts and fumes is well documented. Earlier studies
report advanced cases of manganism 1n various miners, but more recent
2-7
-------
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 lowest-observed-effect level (LOEL). The full clinical
picture of chronic manganese 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 mg/m3 suggest 0.3 mg/m3 (300
3
vg/m ) as a LOEL. The data available for Identifying effect levels
3
below 0.3 mg/m 1s 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-
ity, resulting in no exposure-related effects on electromyograms or limb
tremor effects in monkeys after 9 months exposure to 11.6, 112.5 and 1152
3
yg/m Mn304.
Chronic treatment of rats with HnCl2 in the drinking water throughout
development is associated with selective regional alteration of synaptosomal
dopamine uptake but not of serotonin or noradrenallne uptake. The brain
regional manganese concentrations show dose-dependent increases and in
treated animals, the changes 1n synaptosomal dopamine uptake is associated
with decreased behavioral responses to amphetamine challenge. These
observations are consistent with the hypothesis that in chronic manganese
toxlcity the central dopaminergic system is disturbed, providing a mechanis-
tic explanation for the extrapyramidal disturbances seen in human manganlsm.
2-8
-------
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
5 mg Mn/m3. 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 yg/m )
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 levels estimated to correspond to 3-11 pg/m .
The study involved several hundred children, had a participation rate of
over 97% and documented monitored levels for settled manganese dust for
several years. It is plausible that exposure to manganese may increase
susceptibility to pulmonary disease by disturbing the normal mechanism of
lung clearance.
Inhalation studies of pulmonary effects in 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 MnO_ 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 is little data on toxicity after chronic exposure
3
to MnO? 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 Mn304 particle or
aerosols of respirable particle size, an appropriate form for health risk
2-9
-------
evaluation for airborne manganese. These studies have a variety of defi-
ciencies such as lack of description of pathological examination, small
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 in a majority of patients with chronic manganese
poisoning are common, however, no other supporting human data are available.
Existing animal data addressing reproductive failure in males describe
long-term dietary exposure to manganese. Results show that dietary levels
up to 1004 ppm as HnSO.-TH 0 and up to 3550 ppm as Mn»0 were
T1 C. «J *T
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 in
animals, none have been observed consistently. In some cases the implica-
tions for human health are uncertain.
There is some evidence of carcinogenic activity of manganese in labora-
tory animals 1n the literature, although problems exist with regard to the
value of these studies (I.e., local injection site sarcomas in F344 rats, a
marginal response in Strain A mice, and inadequate data in the experiment
with DBA/1 mice). There is no epidemiologic information relating manganese
exposure to cancer occurrence in humans.
Divalent manganese ion has elicited mutagenic effects 1n a wide variety
of mlcrobial systems, probably by substitution for magnesium ion and inter-
ference with DNA transcription. Attempts to demonstrate mutagenic effects
of manganese in mammalian systems have failed to show significant activity.
Two recent studies suggest that excess manganese during pregnancy affects
2-10
-------
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 in 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
is equivocal between 1 and 5 mg/m but suggest decreased prevalence.
3
Studies below 1 mg/m report some signs of the disease. There is 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
tests of lung function were reported in children exposed to an estimated
3
3-11 vg/m from emissions of a ferromanganese plant. In comparison,
3
studies of a smaller number of workers exposed to <40 yg/m resulted In
the conclusion that symptoms were generally unrelated to exposure to manga-
nese. There are no data describing the effects of manganese exposure 1n
asthmatics or other sensitive individuals.
Animal studies report increased susceptiblity to Infection and radio-
logical changes in 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.
The available evidence for manganese carcinogenic!ty in Jiumans would be
rated Group 3 overall using the International Agency for Research on Cancer
2-11
-------
(IARC) criteria, because of Inadequate data 1n animals and lack of any
available data 1n humans. Clearly, more Information 1s needed before a more
definitive conclusion can be made about the carc1nogen1c1ty of manganese and
Its compounds.
2-12
-------
3. GENERAL PROPERTIES AND BACKGROUND INFORMATION
3.1. PHYSICAL AND CHEMICAL PROPERTIES
Manganese 1s a ubiquitous element 1n the earth's crust, In water, and 1n
particulate 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., pyrolusite (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 In 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 1n 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+ and Mn7+. The Mn4* 1s significant
because of the important oxide, MnO-. The +2 compounds are stable in acid
solution but are readily oxidized in alkaline medium. The +7 valence is
found only in oxy-compounds (Reidies, 1981). Normal oxidation potentials of
manganese couples are given in Table 3-2.
3-1
-------
TABLE 3-1
Physical Properties of Manganese*
Property
Value
Atomic number
Atomic weight
Density
Melting point
Boiling point
Specific heat
Moh's hardness
Solubility
25
54.9380
7.43 at 2Q°C
1244°C
1S62°C
0.115 cal/g at 25.2°C
5.0
Soluble In dilute acids; reacts
slowly In hot or cold water.
*Source: Weast, 1980; Matricardl and Downing, 1981; Reidles, 1981
3-2
-------
TABLE 3-2
Normal Oxidation Potentials of Manganese Couples3
Oxidation
State
0,
+2,
+2,
+2,
+4.
+4,
+6,
0,
+2,
+2,
+4,
+4,
+6,
+2
+3
+4
+7
+6 .
+7
+7
+2
+3
+4
+6
+7
+7
Reaction
Add Solution
Mn ^ Mn2* + 2e
Mn2*^ Mn3* + e
Mn + 2H20 ^Mn02(py) + 4H* + 2e
Mn2* + 4H00 ^{MnO.)~ + 8H* + 5e
£. 4
2- +
Mn00 + 2H00^(MnO.) + 4H + 2e
c. C. *r
Mn00(py)b + 2H00^(MnO.)~ + 4H* + 3e
^ e. 4
(MnO.) "^ (MnO.)~ + e
4 4
Basic Solution
Mn + 2(OH)~^ Mn(OH)2 + 2e
Mn(OH)0 + (OH)~^ Mn(OH),, + e
C. O
b
Mn(OH)2 + 2(OH) ^ Mn02(py) + 2H20 + 2e
2-
Mn00 + 4(OH) ^ (MnO.) + 2H90 + 2e
d 4 c.
Mn02(py)b + 4(OH)~^ (Mn04)" + 2H20 + 3e
(Mn04)2- ^ (Mn04)- + e
E°
+1.18
-1.51
-1.23
-1.51
-2.26
-1.695
-0.564
+1.55
-0.1
+0.05
-0.60
-0.588
-0.564
aSource: Hay, 1967
b(py) Indicates pyroluslte made from decomposition of Mn(N03)2 on
which consistent values can be obtained.
3-3
-------
3.1.1. Manganese Compounds. Manganese forms numerous alloys with Iron
(ferromanganese, sHlcomanganese, 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{CQ)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 Is made by precipitation from manganese sulfate solu-
tions. It 1s used 1n ferrlte 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 Is used as a starting mater-
ial for other manganese compounds and 1n anhydrous form as a flux In 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 acid.
3.1.1.2.4. Manganous Acetate — Mn(CJ Q } »4H Q 1s 1n
£ v £ c. c.
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.
3-4
-------
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3-5
-------
3.1.1.2.5. Manganous Oxide — MnO is found 1n nature as manganoslte
and is manufactured by reducing higher oxides with carbon monoxide or coke
or by thermal decomposition of manganous carbonate. It is a good starting
material for preparing other manganous salts and has some use in ferrites,
in welding, and as a nutrient in agricultural fertilizers.
3.1.1.2.6. Manganous Phosphate — Mn (PO ) is made from car-
«J *r c.
bonate and phosphoric acid. It is used as an ingredient of proprietary
solutions for phosphatlng iron and steel.
3.1.1.2.7. Hanganous Sulfate — MnSO »H 0 can be made by treat-
Ing any manganese compound with sulfuric acid. It 1s also a co-product in
the manufacture of hydroquinone. In pure state 1t Is used as a reagent.
Its major use is as a nutrient in fertilizers and in animal feeds.
3.1.1.2.8. Manganese Soaps — Manganese(II) salts of fatty acids
(2-ethyl hexoate, linoleate, 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", hypophosphite,
nitrate, nitrite, perchlorate, sulflde, and sulfite.
3.1.1.3. MANGANESE (IV) COMPOUNDS --
3.1.1.3.1. Manganese Dioxide — MnO is the most important Mn(IV)
compound and the most important commercial compound of manganese. In nature
1t occurs as pyrolusite, the principal ore of manganese, as well as in
several other less common minerals. More than 90% of manganese dioxide 1s
used in the production of ferromanganese and other alloys and of manganese
metal. The rest is used for the production of dry cell batteries and chem-
icals, and as an oxidant 1n the manufacture of some dyes.
3-6
-------
Manganese dioxide 1s Insoluble In water. This property confers stabil-
ity, since the 1on Mn4* 1s unstable 1n solution. On heating, 1t forms
other oxides, ,Mn00 , Mn 0 and MnO. Hydrated forms are obtained by
2 o o 4
reduction of permanganates 1n basic solution. In acid solution 1t 1s an
oxidizing agent. The classic example 1s the oxidation of HC1 which has been
a convenient means of chlorine generation both In the laboratory and 1n the
Weldon process for manufacturing chlorine commercially (Hay, 1967).
Mn02 + 4HC1 -> Mn4+Cl4 + 2H2<3
Mn4*C14 -*
1/2C12
warm
Mn3+Cl3 -» Mn2+Cl2
1/2C1
Manganous sulfate and oxygen are produced 1n hot sulfurlc add In 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:
MnQ2 -i-
MnS0
2. Alternatively, 1t can occur stepwlse: ,
2Mn02 + 3S02 -
Mn2(S03)3 -
MnS03 + 1/202 -> MnS04
The end products of this series of reactions are MnS20& (manganese
dithionate) and MnS04 (Hay, 1967). Nitrogen dioxide also reacts similarly
with Mn02 to form manganous nitrate, Mn(N03)2 (Sullivan, 1969).
3-7
-------
3.1.1.4. MANGANESE (VII) COMPOUNDS --
3.1.1.4.1. Potassium Permanganate —KMnO. Is an Important Indus-
trial chemical as well as an analytical reagent (Reldies, 1981). Its use 1s
based on Its oxidizing ability. It is used in the organic chemical indus-
try, in the alkaline pickling process, and in cleaning preparatory for
plating. It is also used for water purification and odor abatement in
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 Is:
2KMnO 4- HO -* 2KOH * 2MnO + 3(0)
In neutral solution,
2KMn04 + MgS04 (buffer) + H20 -> K2S04 * Mg(OH)2 + 2Mn02 + 3(0.)
while 1n add solution it reacts as
2KMnO, + StLSO, -» ICSO, -i- 2MnSO, + 3H00 + 5(0)
4 2424 4 2
In organic reactions (MnO.)~ 1s a most versatile oxidant, 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 is potentially a more vigorous
oxidant than dlchrornate.
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 preconcentratton or a preseparatlon step.
3-8
-------
3.2.1. Sampling.
3.2.1.1. AIR — Virtually all of manganese present 1n air 1s Inor-
ganic, In 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,
f
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 in diameter
(Davies et al., 1951) and Impractical handling and transportation, the
impinger has been replaced by filtering media: 1) glass fiber filters,
which have a low resistance to air flow, have high efficiency for submicron
particles, and are hydrophoblc so that they can be weighed without trouble;
and 2) organic membrane filters, which are soluble in organic solvents and
strong adds. Electrostatic precipltators 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 in field use than filters,
and cannot be used in potentially explosive atmospheres.
3.2.1.1.2. Ambient Air -- 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 in 24 hours. Several
hundred samplers of this type are currently in use as part of the National
Air Surveillance Networks (NASN), and thousands are in use by state and
3-9
-------
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-
o
brane filters of 2.5 cm diameter, sampling 25-30 m over a week, have also
been used (WHO, 1976; Saric, 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 vsn in 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, dichotomous samplers are nojw most
widely used for this purpose. Samplers of this type separate fine and
coarse particles by use of a virtual impactor (Ozubay and Stevens, 1975).
The fine particle cut-off (05Q), at which 50% of larger-diameter particles
are excluded, ranges from 2-3.5 vim depending on the sampler used. A frac-
tloning inlet also 1s often used to determine the upper size limit for the
coarse fraction; 05Q is normally set at 10, 15 or 20 v.m (e.g., U.S. EPA,
1981a). Particles for metal analysis are typically collected on a teflon or
cellulose filter of ~1 vim pore size and -6-25 cm2 surface area
3-10
-------
(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 (=000°C), membrane or
cellulose filters may be used as well. Sampling Is usually performed 1so-
klnetlcally, and the filter holder 1s 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 1mp1ngers 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 condenser. Cascade Impactors are available
for collecting samples of particles by size from the stack (Pllat 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
A
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
3-11
-------
test cycle, were diluted 8 to 1 with 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 (Habibi, 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 in
bottles of glass or plastic (U.S. EPA, 1973; King, 1971). Preparation of
bottles to prevent contamination is discussed by Moody and Undstrom (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. Piscator 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 is 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 in the soil complex makes it desirable to
take paired samples.
3-12
-------
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 In 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, 197*6). 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 In 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 In 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.
3-13
-------
3.2.2. Sample Preparation. While sampling Is 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 1n 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 1n 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 1n 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, nonbolling 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, copredpHaton, 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
3-14
-------
selective, e.g., with thinoyltrifluoroacetone (Saric, 1978) or nonselectlve,
as with 8-hydroxyqu1nol1ne (Ajemian and Whitman, 1969; Kllnkhammer, 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 a!.,
1977) or Dovex Al (RHey and Taylor, 1968). Coprecipitation with dlethyl
dHhlocarbamate (Watanabe et al., 1972) or dibenzyldithlocarbamate (Under
et al., 1978) also has been applied for enrichment of samples as has
electrodepos1t1on (Wundt et al., 1979). Radio-chemical separation 1s most
often used before the analysis of Irradiated samples (Cotzias 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 colorlmetric (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). Colorlmetric methods are still used, especially in
water analysis, and are now coupled with an autoanalyzer (Crowther, 1978).
3-15
-------
The Introduction of atomic absorption spectrophotometry (AAS) In 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 flameless techniques using the carbon rod (Matousek and Stevens, 1971)
and graphite furnace (Slavln et al., 1972), made 1t possible to analyze
mlcrollter 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 in 1975-1976 was -0.0025 ixg/m3 (.U.S. EPA,
1979a).
X-ray fluorescence (XRF) is also used 1n multi-element analysis
(Gilfrich et al., 1973). Problems include particle size effect (Davison 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 ug/m3 in air are obtained (Dzubay and Stevens,
1975; Stevens et al., 1978).
3-16
-------
Neutron activation analysis (NAA) has been used for the determination of
manganese In various environmental media, mostly 1n multi-element analysis
(Robertson and Carpenter, 1974). NAA suffers from Interferences such as the
production of the same radioisotope by another element or one with a close
radiation peak, but most of these can be eliminated by optimizing irrida-
tion, decay, and counting times. The method is 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
if a greater sensitivity is required, a separation and preconcentration step
cannot be avoided for aqueous samples (Lee et al., 1977; Buono et a!., 1975;
Watanabe et al., 1972; Under et al., 1978).
Instrumental detection limits for manganese by several analytical tech-
niques are shown in 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 is difficult to compare
the sensitivities claimed by researchers using various methods since the
result may be expressed as absolute amount, concentration per mS, of final
solution, or per unit of measure of the medium from which the sample was
taken. i
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; Matricardi and Downing, 1981).
3-17
-------
TABLE 3-4
Relative Sensitivity of Some Important
Analytical Techniques for Manganese*
Analytical Method
Detection Limit
(ng)
Neutron activation analysis
Optical emission spectroscopy (DC arc)
Atomic absorption spectrophotometry
Spark source mass spectrometry
0.005
10
0.5
0.05
*Source: U.S. EPA, 1975
3-18
-------
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.
snicomanganese 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
3-19
-------
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 sulfide and air is added to remove colloidal sulfur,
colloidal metal sulfldes, and organic matter. The purified liquid is then
electrolyzed.
Manganese metal can also be produced via a fused-saTt electrolysis pro-
cess. The process is similar to the Hall method of producing aluminum. The
manganese ore is reduced to the manganese(II) level and charged to an elec-
trolytic cell containing molten calcium fluoride and Hme. The manganese is
formed in a molten state.
A number of compounds of managanese also are commercially produced.
Manganese oxide (MnO) is produced by reductive roasting of ores high 1n
managanese dioxide (MnO ). MnO is an Important precursor of several other
commercially-produced compounds, including electrolytic manganese dioxide, a
high-purity product formed by electrolysis of MnO. Potassium permanganate
is produced by a liquid-phase oxidation of managanese dioxide ore with
potassium hydroxide, followed by electrolysis (Reidies, 1981). United
States production capacities for several compounds are shown in Table 3-5.
Manganese supply-demand relationships for the yeSrs 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; sllicomanganese production
has also declined recently (Table 3-7).
3-20
-------
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- Mn02
ganese dioxide
High purity man- MnO
18,000
9,000
Dry-cell batteries;
ferrltes
High-quality ferrltes;
ganese oxide
60% manganese oxide MnO
Manganese sulfate MnS04
Manganese chloride
Potassium per- KMn04
manganate
36,000
68,000
3,000
14,000
Methylcyclopenta- CH3C5H4Mn(CO)3 500-1,000
dlenyl manganese
trlcarbonyl (MMT)
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 Reldles, 1981
3-21
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TABLE 3-7
Net United States Production
of Ferromanganese and S1l1comanganesea
Year
Ferromanganese
(103 short tons)
snicomanganese
(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)
bEst1mated gross production; exceeds net production (U.S. Bureau of Mines,
1983)
3-23
-------
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
(Reldles, 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 (Matrlcardl and Downing, 1981; Bacon,
1967). Its function 1s 3-fold: 1) 1t combines with sulfur, eliminating the
s
principal cause of hot-shortness; 2) 1t acts as a deoxfdlzer or cleanser in
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, MnSOJ, colorants in
brick and tile manufacture (various oxides, MnCl-), dry cell battery manu-
facture (electrolytic Mn02, MnCl2), chemical manufacture and processing
(KMn04, MnCOg, MnCl2) and fuel additives (MMT) (see Table 3-5).
MHT 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 In
3-24
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3-26
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fuel oil and 0.08-0.5 g Mn/gal 1n 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 the 12 months prior to Its ban In September, 1978 was
reported by Ethyl Corporation as -3750 tons/year (-940 tons Mn/year) (Hall,
1983b). 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 Mn/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 In =20% of leaded gasoline at levels of =0.05 g
Mn/gal, and 1s used 1n Canada 1n the majority of unleaded gasolines at
levels of up to 0.068 g Mn/gal (Hall, 1983a). Options for Us future use at
low levels 1n United States unleaded gasoline continue to be studied (Hall,
1983a).
3.4. SOURCES OF MANGANESE IN THE ENVIRONMENT
3.4.1. Crustal Materials and Soils. Manganese Is widely distributed 1n
the earth's crust. It 1s considered to be the 12th most abundant element
and fifth most abundant metal. Manganese 1s exceeded 1n abundance by alumi-
num, Iron, magnesium and tltantlum; 1t 1s more abundant than nickel, copper,
uranium, zinc, lead and vanadium. The concentration of manganese In various
components of the earth's crust ranges from near zero to 7000 pg/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)
3-27
-------
suggested the following distribution of manganese, expressed In yg/g, for
the major units of the earth's crust:
1. Igneous rock: ultrabaslc, 1620; basaltic, 1500; h1gh-calc1um
granitic, 540; low-calcium granitic, 390; and syenltlc, 850
2. Sedimentary rock: shales, 850; sandstones, essentially zero;
and carbonat'es, 1000
3. Deep-sea sediment: carbonate, 1000; and clay, 6700
Hodgson (1963) reported concentrations of manganese 1n yg/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). Manganese-containing
minerals Include anhydrous and hydrous oxides, carbonates, anhydrous and
hydrous silicates, sulfides, anhydrous and hydrous phosphates, arsenates,
tungstates, and borates. The most common manganese minerals and the
percentages of manganese contained therein are listed in Table 3-9.
Relatively little manganese is mined within the United States {Sittig,
1976). Manganese deposits are well-distributed through the southern Appa-
lachian and Piedmont regions, the Batesville district of Arkansas and many
of the western states. These deposits have been exhausted in 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 in the Cuyuna
Range of Minnesota, in the Artillery Mountains region of northwestern
Arizona, in the Batesville district of Arkansas, In Aroostok County in
Maine, and to a lesser extent in the Gaffney-Kings Mountain district of
North Carolina and South Carolina. Manganese ore (>35% Mn) is no longer
mined in the United States, but some manganlferous ore {5-35% Mn) is mined
1n Minnesota, New Mexico and South Carolina (DeHuff and Jones, 1980)
3-28
-------
TABLE 3-9
Manganese Content of Selected Minerals*
Mineral
Pyroluslte
Manganlte
Hausmannite
Rodochroslte
Rhodonite
Braunlte
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
3-29
-------
Researchers report various concentrations of manganese In different
types of soils. Swalne (1955) reported a range of 200-3000 yg/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 vg/g. Swaine and Mitchell (1960) studied representative Scottish
soil and reported a range for total manganese of 50-7000 pg/g 1n air-dried
soil. Shacklette et al. (1971) analyzed various soil samples in the United
States and reported a range of manganese content from <1-7000 pg/g, with
an arithmetic mean of 560 pg/g.
Crustal materials are entrained Into the atmosphere by a number of
natural and anthropogenic processes, and thus compose an Important fraction
of atmospheric particulate. 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 vm) (Dzubay, 1980). Since manganese is a typical
constituent of these dusts, some researchers have used this element as a
tracer to determine the degree of contributions from these sources In
ambient aerosol (Kleinman et al., 1980; Kneip et al., 1983).
Several other processes also result in 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 in
that much of the material is released in the form of fume or ash in the fine
particle range (<2.5 pm). 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 particulate in
ambient air will then be discussed in Section 3.4.3.
3-30
-------
3.4.2. Industrial and Combustion Processes. Manganese Is 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
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.). Oust
varying from 3-100 ym 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 In the
form of oxides. Silicates are a second major constituent. Particle size 1s
predominantly fine (<2 ym).
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
3-31
-------
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3-32
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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).
In addition, more recent measurements Indicate lower emission factors for
controlled submerged-arc facilities (Table 3-11). Ambient air measurements
1n 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%) 1s 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 (OeHuff, 1961-1980; DeHuff and Jones, 1981).
3.4.2.3. FOSSIL FUEL COMBUSTION -- 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
3-33
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additional source. The average and range for manganese concentration in
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.
Coal combustion was estimated to be the source of -11% of total manga-
nese emissions 1n 1968 (see Table 3-1.0). The emission factor assumed an
average manganese content of 26.4 yg/g 1n coal, and penetration to the
atmosphere of -16% (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 preclpltators (ESPs) showed manganese penetra-
tions of 0.07-0.13% for one plant, and 1.6% for another plant with partial
i
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 predpltator showed that manganese concentra-
tions were highest (1090-1180 yg/g) In particles of 0.2-1.5 ym, whereas
concentrations of 500-800 yg/g were found among particles of 3 to >140
vim (Smith et al., 1979). A similar trend but with lower concentrations
(150-470 yg/g, Increasing as particle size decreases) was found 1n air-
borne material not retained by a cyclonic predpltator 1n 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 yro
for the more-efficient and -8.2 ym for the less-efficient ESP (Ondov et
al., 1979).
3-35
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TABLE 3-13
Manganese Content In Coal Ash*
Type of Coal
Range of Content
(mg/g)
Pennsylvania Anthracite
Texas, Colorado, North
and South Dakota
West Virginia
Montana
Alabama
0.05-0.9
0.1 -10
0.12-1.8
3.3
0.4-0.5
*Source: Abernathy et al., 1969
3-37
-------
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.
P1ver (1974) reported that MMT production prior to Us use 1n unleaded
fuel was -500 tons/year, or -125 tons as manganese. Ethyl Corporation
reported that during peak use of MMT prior to the ban 1n 1978, consumption
was -3750 tons/year, or -940 tons as manganese (Hall, 1983b). 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), result-
Ing 1n an estimate of 140-280 tons of manganese emitted per year during the
peak of MMT use. The emitted manganese has been described as consisting
primarily of Mn^, 1n particles of 0.30-0.38 Pm mass median diameter
(Ethyl Corporation, 1972). However, the emission of water-soluble forms
from catalyst-equipped vehicles capable of producing H SO. cannot be
ruled out (Plerson et al., 1978). 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 in -20% of leaded gasoline (Hall, 1983) results in a
substantially lower emissions estimate than that given for 1977.
Estimates have been made of ambient air concentrations of manganese
which could result from specified levels of MMT usage. These estimates are
based on analogy to lead, for which both fuel concentrations and resulting
ambient concentrations are known. Accordingly, 100% usage of MMT at 0.125 g
Mn/gal would be estimated to result in ambient manganese concentrations
ranging from 0-0.25 vg/m , with a mean urban value of 0.05 pg/m3, in
addition to already existing concentrations (Ter Haar et al., 1975) (see
Section 3.6.1. for data on existing ambient manganese concentrations).
3-38
-------
Additional manganese concentrations of 0.16 pg/m as an average and up
3
to 0.52 pg/m near freeways would be estimated for Southern California
(H1dy et al., 1977). Usage levels lower than 0.125 g Mn/gal would result 1n
proportionally lower estimates for ambient air.
. Actual vehicle emissions of manganese were calculated by sampling air 1n
tunnels of the Pennsylvania turnpike during 1975-1977 (Plerson et al.,
1978). Calculations Include the total vehicle-generated aerosol, not simply
exhaust. Manganese content of fuel at uproad turnpike service plazas was
also monitored. Manganese emission rates for gasoline-powered vehicles were
0.03-0.05 mg Mn/km during 1975-1976 while MMT use was minimal (1-4 mg
Mn/gal). By 1977 MMT use was more frequent, giving an average for all
gasoline sampled of 16 mg Mn/gal, and the emission rate was 0.08 mg Mn/km.
However, manganese concentrations 1n the tunnel air, which averaged 0.11
o
yg/m , showed no trend over the period of study. The reason for this
lack of an overall Increase was that manganese emissions for dlesel trucks
were large (0.32-0.69 mg Mn/km) and overshadowed the change resulting from
MMT. Part of the manganese 1n dlesel emissions originated from road dust,
but the source of the remainder was unknown, as only traces of manganese
were present 1n the dlesel fuel (Plerson et al., 1978).
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 particulate 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
3-39
-------
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 ym) and fine particle fractions by a dlchotomous
sampler can result 1n better resolution of sources (Dzubay, 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 (17.3%), for ferromanganese furnace emis-
sions, to "0 mg/g", for leaded automobile exhaust. The elemental composi-
tions for several sources (soil, road dust, asphalt production, rock crusher
and coal fly ash) were so similar that they could not readily be disting-
uished; the manganese concentration of these aerosols varied only from 0.3-2
mg/g (Cooper and Watson, 1980).
Ozubay (1980) used six source terms for apportioning Regional A1r Pollu-
tion Study (RAPS) data from dlchotomous samplers in 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, argriculture, etc.), particulates from
quarrying or other manufacturing processes, and/or fly ash. The crustal-
limestone component Included suspended calcium-rich 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
3-40
-------
TABLE 3-14
•»
Manganese Concentration in Fine (<2.0 ym) and Coarse (2.0-20
Particle Fractions of Aerosols from Several Sources in 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
Sulfite 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
(mg/g)
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
3-41
-------
source aerosols were assigned a priori, based on data from various studies.
v
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
August and September, 1976 (Table 3-15). Dzubay et al. (1981) used similar
source terms In 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 manganes'e
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).
3-42
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3-45
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A direct comparison of the TTFA results with those of Dzubay (1980) for
St. Louis 1s not possible slncp 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 1n close proximity to Iron works and foundries, whereas site 112
(Table 3-16, part A) Is not. These differences are reflected 1n the absence
of a resolvable steel source at the latter site. However, the refinement of
sources by TTFA results In 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 S0» on coarse Mn-contalning 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 B) 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 a!.,
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 In 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-
• 3-46
-------
late (TSP) Increased from 420+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 usage 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 B2±2 to 54±2
vg/m3 was seen during this period. However, during the period
1979-1980, a decrease 1n the manganese coefficient to 670+160 seemed to
Indicate Increasing nonsoll contributions, and was accompanied by an
Increase 1n mean TSP to 66+2 vg/m3 (Knelp et al., 1983).
A simpler method for making Inferences about partlculate sources from
receptor data 1s 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 Is 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:
(Hn/Al) air
Crustal EF = a1r
crust
Values for elements arising exclusively from crustal material should be near
unity, although some variation would be expected due to natural variations
In soil (see Section 3.4.1.). As mentioned previously, crustal material
suspended by natural processes Is 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
sources, may be as high as 10 (Bernstein and Rahn, 1979; Lewis and
Maclas, 1980).
3-47
-------
Duce et al. (1974) reported a crustal EF of 2.6 for manganese over the
o
Atlantic Ocean north of 30 N. Bernstein and Rahn (1979) reported the
elemental composition of fine (<2.5 vm) 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.
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, HO (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 vm) ranged from 0.35-4.76
S
with an unweighted mean value of 1.9. For the fine fraction, values ranged
i>
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, H can be Inferred by this rough Illustration that manganese 1n coarse
aerosol fractions tended to be associated with aluminum 1n ratios found In
3-48
-------
crustal material. Lower relative concentrations of aluminum In fine frac-
tions Indicated a greater Influence of noncrustal manganese sources 1n fine
than 1n 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) (Ozubay, 1980). Therefore, Industrial processes
may be expected to have local Influence on manganese levels In the coarse
particle fraction, but this Influence 1s Hkely 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 In 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 1n 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
surface from about lOOxlO14 g/year pre-human to today's rate of about
3-49
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3-50
-------
225xl014 g/year. Because this Increase In stripping reflects an Increase
In 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 1s 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.
The mining of manganese ore has resulted In a net gain for the land
reservoir and a net loss from the sediment reservoir. There 1s 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 in 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 in the coarse particu-
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
is emitted primarily as Mn304 (Ethyl Corporation, 1972). Much of the
partlculate released from these processes is in the fine range (<2.5
3-51
-------
Fine particulate from fly ash usually 1s no more highly enriched 1n manga-
nese than are soils, but the fine particles arising from metallurgy and MHT
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 Hn/gal). About 0.1-0.5% of the manganese burned was
emitted 1n 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
were neglected, and <0.048 ng MMT/m3 (<0.012 ng Mn/m ) 1f photodegrada-
tlon were considered (Ter Haar et a!., 1975).
Coe et al. (1980) used gas chromatography-atomlc absorption spectrometry
to measure MMT levels 1n air 1n Canada, where MMT Is presently In use 1n
3
unleaded 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. ATMOSPHERIC REACTIONS — Except for the photodegradatlon of
MMT, very Uttle Information Is 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
4 25
3-52
-------
manganese nitrate [Mn(N03)2], respectively (Hay, 1967; Schroeder, 1970).
Various oxides of manganese (MnO, Mn_0 , MnO ), used as absorbants,
to £•
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.
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,
-2SO,
2SO_ + 0,
i t
It has been reported that under foggy conditions, an atmospheric manganese
concentration of 0.2 vg/m3 and a sulfur dioxide concentration of 1750
o 3
would result 1n a sulfurlc acid formation rate of 25 vg/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 v259 vg S02/m and 2 yg 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 MHT-conta1n1ng fuel on the disappearance of S02 1n
ambient air (Wright et al., 1973). In the absence of manganese, at a rela-
3
tlve humidity of 90-100% and an S02 concentration of 35 yig/m , the
rate constant for S02 disappearance was 14%/hr. This unusually high rate
was attributed primarily to 1mpact1on on the black polyethylene bag 1n which
the experiment was conducted. Addition of exhaust to give a manganese
concentration of 4 yg/m3, a level much higher than normally encountered
3-53
-------
1n ambient air (see Section 3.6.1.), did not noticeably affect this rate,
o
although manganese concentrations >30 yg/m did Increase the rate
constant. On the other hand, addition of 20 vg/m3 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
that addition of MHT to gasoline would have no measurable effect. This
conclusion with respect to manganese 1s weakened by the apparent magnitude
of the container effect, and because the control contained no exhaust,
rather than manganese-free exhaust.
H1dy et al. (1977), In an unpublished analysis of this topic prepared
for Ethyl Corporation, concluded that the manganese-Induced acceleration of
S02 oxidation was not truly catalytic, but occurred because the presence
of Hn enhanced the absorption of S02 by water droplets. In addition,
since Iron promotes S02 oxidation more efficiently than manganese, and 1s
present at much higher ambient concentrations, these authors concluded that
the effect of manganese on atmospheric sulfate formation 1s negligible and
would not be appreciably magnified by changes 1n MMT use.
3.5.2.3. DRY AND WET DEPOSITION — Atmospheric partlculate matter,
Including manganese, 1s transported by air currents until It 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 CHy. 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 (HMAD) = 0.56 vm].
3-54
-------
Manganese had the highest velocity (10.4 cm/sec), and a larger particle size
(MMAO = 1.3 ym). 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 participates to runoff, dry deposition resulted
1n an estimated manganese concentration In urban runoff of 39 ygA> 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-
2
ly was 120 ng/cm /month, stemming from a rainfall concentration of 19 vq-
Mn/8, (Volchok and Bogen, 1973). Thus, manganese deposited 1n dustfall was
more than twice that 1n rainfall.
Manganese deposition In precipitation at -30 stations throughout the
U.S. 1n September 1966-January 1967 was reported by Lazrus et al. (1970).
2
Amounts deposited ranged from undetectable (<10 ng/cm /month), for Mauna
Loa, Hawaii; Amarlllo, Texas; and Tampa, Florida to levels of 200-300
ng/cm2/month for Chicago, Illinois and Sadlt St. Marie, Michigan. An
<\
unusually high value of 540 ng/cm /month was observed In Caribou, Maine.
The latter city 1s located 1n Arlstook County, an area of low-grade manga-
2
nese ore deposits. The average value nationwide was -80 ng/cm /month,
and the average manganese concentration 1n precipitation was -12 yg/a
(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
1964-1965 study of air pollution 1n the Kanawha Valley, West Virginia
(NAPCA, 1970). In the two communities nearest a ferromanganese plant,
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.).
3-55
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3.5.3. Fate and Transport In Water and Soil.
3.5.3.1. CHEMICAL FORMS IN SOLUTION -- The aqueous chemistry of
manganese 1s complex, as manganese can be present In 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 maxl-
s*
mum concentration of soluble Mn + In many natural waters Is limited by the
solubility product of MnC03. With low alka!1n1t1es and reducing condi-
tions 1n freshwaters, solubility may be restricted by high sulflde concen-
trations.
The possible chelating Influence of natural organic compounds 1n natural
waters was studied on a hypothetical multimetal, multi-ligand system.
Calculations were' performed simultaneously by Morel and Morgan (1972) and
by Stumm and B1linsk1 (1972), and both concluded that a free manganese ion
may be present as a predominant species even if complex-forming organic
matter is present.
In water or soil of pH >8 or 9, the soluble divalent manganese ion is
chemically oxidized to the Insoluble tetravalent form. At pH <5.5, chemical
reduction of the tetravalent form takes place. However, the interconversion
of these forms which is commonly observed at Intermediate pH occurs only by
microbial 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
in acid-, 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 is precipitated, thus
3-56
-------
giving rise to stream sediments enriched with manganese. Mitchell (1971)
also showed that the mobilization of manganese was greatly enhanced In acid,
poorly drained podzollc soils and groundwaters. Josephson (1980) found that
manganese exists 1n a reduced state In groundwater and that H can be
readily leached from waste sites or from natural sources. High levels of
divalent manganese may also be found In add mine drainage (see Section
3.6.2.).
Various opinions exist regarding the dominant form of manganese 1n
seawater. According to SUlen (1961), the dominant form of manganese 1s
Mn(OH). or Mn(OH).. Moklevskaya (1961) and Spencer and Brewer (1971)
O '
found that In water of the Black Sea, the dominant form of manganese was the
divalent form. Fukal and Huynh-Ngoc (1968) found that divalent manganese
remained In that form 1n seawater for a' long period of time. According to
Breck (1974), the main species are Mn02 and/or Mn304- Ahrland (1975)
considered that dispersed Mn02(s) 1s predominant. Musanl-MarazovU and
Pucar (1977) concluded that 54Mn Introduced In divalent form Into seawater
behaves as a cation.
3.5.3.2. MICROBIAL TRANSFORMATION — Bacteria are Important agents in
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 mlcrobial tissue; oxidation of
manganese to a less available form; direct, enzymatic reduction of oxidized
manganese; or indirect transformation (especially reduction) through changes
in pH or E . Saxena and Howard (1977) also concluded that bacteria play a
major part in the modification, activation and detoxification of heavy
metals.
3-57
10/11/83
-------
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 microblal activity (I.e.,, 0? consumption or the
production of acidic metabolites) (Kuznetsov, 1970; Alexander, 1977). In
the first case the reduction 1s enzymatic; In the second H 1s nonenzymatlc.
Reduced manganese then diffuses upward In the sediment or Into the water
column. In Lake Pannus-Yarvi of the Karelian Isthmus (USSR), Iron- and
manganese-reducing bacteria are present 1n the upper 10 cm of the sediments.
Reduced manganese In the bottom waters of the profundal zone reaches 1.4
mg/fc, whereas the total manganese concentration 1n the rest of the lake Is
only 0.01 mg/9, {Kuznetsov, 1970).
Several types of bacteria have been found capable of oxidizing manga-
nese. 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 In their metabolic functioning"
(CulUmore and McCann, 1977). These have been assumed to be chemoauto-
trophs, utilizing energy from the reduction of manganese to carry out
synthetic processes (Kuznetsov, 1970), but others have questioned this
conclusion (Alexander, 1977; Konetzka, 1977). A second group consists of
heterotrophs possessing a slime capsule that can absorb divalent manganese.
Oxidation then occurs within the sheath, which becomes impregnated with the
hydroxide {Kuznetsov, 1970). Manganese-oxidizing ability has been shown to
occur 1n a wide variety of freshwater bacterial genera, comprising from
-------
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, In 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, mlcroblal
oxidation 1n the sediments can lead to the formation of manganese lake ores
(Kuznetsov, 1970).
Bacterial oxidation of Mn has also been Implicated in the formation
9
of manganese nodules on the ocean floor (Silver and Jasper, 1977). However,
this conclusion is far from certain, as some nodule-associated bacteria
catalyze manganese accretion via oxidation while others catalyze manganese
reduction (Ehrlich, 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 in wells In 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
poorly understood (Culllmore and McCann, 1977). Luthy (1964) stated that
0.05 mg Mn2+/9. is undesirable because of discoloration of the water, and
that measures for bacterial control should be taken at levels >0.15 mg
Mn /a. Control measures Include sterilization of equipment before
drilling of wells, and treatment of affected systems by chlorination, acidi-
fication, or other antibacterial agents (Culllmore and McCann, 1977).
In the soil, microorganisms play an important role in determining the
availability of manganese to plants. Several genera of bacteria and fungi
are capable of oxidizing soil manganese, many even under slightly acid
conditions. Numerically, the manganese oxidizers may constitute up to 5-15%
3-59
-------
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 nonenzymatic, as
1n water. The reduction proceeds more rapidly in poorly drained soils. In
such cases, manganese phytotoxicity may also occur (Alexander, 1977).
e
3.5.3.3. BIOCONCENTRATION — The tendency of a substance to be
concentrated in organisms will have an important effect on its ultimate
distribution in biological and nonbiological ecosystem compartments. Figure
3-2 shows an example of concentration factors for manganese in 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, b1omagn1fication or
increasing accumulation with trophic level evidently was not occurring.
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 in 17 cities. Some samples were analyzed individually and
others as quarterly composites. Twelve nonurban samples collected in
1955-1956 at Point Woronzof, Alaska, showed an average manganese concentra-
3 ?
tion of 0.01 v9/m , with a maximum of 0.02 yg/m (U.S. DHEW, 1958).
Over 100 suburban samples collected at nine different locations In the
United States in 1954-1956 averaged 0.06 yg/m3, with a maximum value of
3-60
-------
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FIGURE 3-2
Concentration Factors for Manganese 1n Hudson River
Aquatic Food Chain - June,1970
Source: Lentsch et a!., 1972
3-61
-------
x
0.50 vig/m In Kanawha County, West Virginia. Nearly 2000 urban samples
collected In 1953-1957 averaged 0.11 yg/m3, with a maximum value of 9.29
o
vg/m at Cincinnati, Ohio 1n 1955. Concentrations >3.0 vg/m3 were
found In Anchorage, Alaska 1n 1954-1955, probably after volcanic eruption;
1n Philadelphia, Pennsylvania 1n 1954; and In Chattanooga, Tennessee 1n
1955-1956.
• The National Air 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 pg/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
the percentage of sites with concentrations >0.100 pg/m3. Table 3-18
gives NASN sites for which average concentrations were >0.5 yg/m3.
Higher concentrations for shorter average times may be of considerable
significance In the evaluation of the potential biological effects of
airborne manganese. Several 24-hour values >10 pg/m3 were observed
during this time period (see Table 3-18).
A comparison of urban and nonurban NASN data for 1966-1967 was provided
by HcHullen et al. (1970). Urban samples showed an arithmetic mean manga-
nese concentration of 0.073 pg/m , while the mean for nonurban samples
decreased from 0.026 to 0.005 pg/m3 with Increasing remoteness of the
3-62
-------
TABLE 3-17
Number of National A1r Surveillance Network Stations within
Selected Annual Average Manganese A1r Concentration Intervals, 1957-1969*
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)
Number and Percent
by A1r Concentration
(percent shown In
of Stations
Interval, yg
parentheses)
0.100-0.199 0.200-0.299
29
(22.7)
12
(12.9)
14
(8.9)
8 ,
(6.3)
13
(9.2)
11
(7.6)
23
(11.0)
110
(11.0)
10
(7.8)
6
(6.5)
5
(3.2)
4
(3.1)
4
(2.8)
2
(1.4)
9
(4.3)
40
(4.0)
/ro3
>0.300
13
(TO. 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
3-63
-------
TABLE 3-18
National A1r Surveillance Network Stations with
Annual Average Manganese A1r Concentrations
Greater Than 0.5 vg/m3*
Year
1958
1959
1960 -
1961
1963
1964
1965
1966
1967
1968
1969
*Source:
NR = Not
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
Knoxville, TN
Johnstown, PA
Niagara Falls, NY
Johnstown, PA
Philadelphia, PA
NASN, 1957-1969
reported
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
3-64
Concentration,
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
vq/m3
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
-------
monitoring site from urban areas (Table 3-19). While this decrease of
manganese concentration primarily reflects a decrease In total suspended
partlculates, percent manganese In TSP mass also decreased with Increasing
remoteness (McMullen et'al., 1970).
An examination of NASN data for the early 1970s shows a further decline
In 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
sites declined from 0.040 vg/m3 1n 1965 to 0.016 pg/m3 1n 1974.
When urban values for the period 1970-1971 were compared to those for
1973-1974, a 50% decline was observed In 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 in 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 In the
metals Industry. Data examined for 16 nonurban sites were also said to
Indicate a dow'nward trend for manganese, but this conclusion was described
as tenuous (U.S. EPA, 1977a).
The frequency distributions of quarterly analytical values for manganese
at all urban and nonurban NASN sites for the years 1970-1982 are given in
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 in the
frequency distributions (Barrows, 1983). A rigorous trend analysis of these
3-65
-------
TABLE 3-19
Average Manganese Concentration 1n Ambient A1r and Total
Suspended Participates (TSP) In Urban and Nonurban NASN Sites, 1966-1967*
Stations
Type
Number
TSP
*Adapted from HcHullen et al., 1970
Mn
Mn/TSP
Urban
Nonurban
Proximate
Intermediate
Remote
Total nonurban
217
5
15
10
30
102
45
40
21
34.5
0.073
0.026
0.012
0.005
0.012«
0.07
0.06
0.03
0.02
0.03
3-66
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data Is not possible due to changes 1n sites and methodology. Decreases
over the period are Indicated, however, both In 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 In which ambient
manganese concentrations are given will be discussed. In 1964-1965, a study
was undertaken of air pollution In the Kanawha Valley, West Virginia (NAPCA,
1970). Average TSP levels for sites 1n the area ranged from 132-413
n 3
vg/m , compared to the national urban average of 100 -yg/m (Table
3-22). Yearly average suspended manganese concentrations were as high as
8.3 yg/m3, with quarterly composite samples ranging up to 11.0 and 13.0
yg/m3 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 In ambient manganese concentration
(see Table 3-22; U.S. EPA, 1979a).
A nearby region along the Ohio River between Marietta, Ohio and Parkers-
burg, West Virginia was studied during the period 1965-1966 (U.S. OHEW,
1967). A1r quality 1n this area was Influenced by a large plant producing
manganese metals and alloys. Sampling of ambient partlculate 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
were observed 1n 24-hour samples downwind of the plant. At one site, a
3-69
-------
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composite of samples collected by a directional sampler selective for wind
o
direction showed manganese levels 10 times higher for the 90 sector
3 °
toward the plant (4.1 pg/m ) than for the remaining 270 sector
3
(0.4 pg/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 In 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
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 In 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 In six
United States cities during 1970. Their data showed that, on an annual
average, 45-62% of ambient manganese was In particles of <2 ym diameter.
Bernstein and Rahn (1979) used a size-selective cyclone sampler to fraction-
ate New York City urban aerosol during 2 weeks of sampling in August, 1976.
3-72
-------
TABLE 3-24
Concentrations of Trace Metals 1n Air Measured at
Three Locations 1n New York CHy* (ng/m3)
Element
Cd
Cr
Cu
Fe
K
Mn
Na
Ni
Pb
V
Zn
TSP (yg/m3)
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
3-73
-------
In these samples, 64-68% of manganese was found In particles of <2.5 ym
diameter. Manganese was * blmodally distributed, with a peak 1n the
0.5-1.5 vm fraction, a nadir 1n the 1.5-2.5 vm fraction, and a second
peak In the 2.5-3.5 ym fraction. A single week of sampling with this
device 1n November, 1974, had shown only the latter (2.5-3.5 ym) peak
(Bernstein et al., 1976).
More recent data tend to Indicate that less of the ambient manganese 1s
found In 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 In the United States during 1980. The size classes were <2.5 ym
(fine) and 2.5-15 ym (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.
•
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 ym size-selective Inlet 1s less than the TSP measured by high-volume
samplers. The ratio DS-.TSP has been measured for samples where TSP Is >55
3
yg/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
3-74
-------
TABLE 3-25
Selected Dlchotomous Sampler Data on Manganese and Particle Mass
from 22 U.S. Cities In 1980a
Manganese
aSource: Davis et al., unpublished manuscript
bPart1cle size: fine, <2.5 vm; coarse, 2.5-15
cAr1thmet1c mean by city
Particle Mass
Parameter13
A1r concentration (vg/ro^)
Fine
Coarse
Total
Particle concentration (mg/g)
Fine
Coarse
Percent mass 1n fine fraction
Meanc
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
3-75
-------
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 In 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 is present In the fine fraction. However,
1t should be noted that of the 22 cities examined in this study, the city
(Akron, OH) with the highest manganese concentration (0.129 yg/m3) also
had the highest percentage In 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%.
3.6.2. Water. Natural concentrations of manganese 1n seawater are
reported to vary from 0.4-10 vg/s, (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
vg/8,". In surface freshwaters, background levels are frequently
exceeded due to human activities. Manganese concentration ranges In 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
3-76
-------
TABLE 3-26
Concentration of Manganese 1n Various Lake
and River Waters
Locality
Concentration
Range Ug/8,}
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
3-77
-------
Control Administration (FWPCA). Dissolved manganese was detected In 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 pg/g) of riverine sediments {Hem, 1970).
A comparison of suspended and dissolved manganese 1n Table 3-28 shows that,
1n river systems, the amount in suspension normally exceeds the amount in
solution. Exceptions to this pattern are the Allegheny and Monongahela
Rivers, which are characterized by add mine drainage (Kopp and Kroner,
1969).
Manganese levels In groundwaters frequently are much higher than 1n
surface waters because the more acid and reducing conditions which prevail
1n the sub-surface environment promote dissolution of manganese oxides.
Manganese concentrations as high as 9600 yg/i in add groundwater
(pH=4.0) and 1300 vg/g, in neutral groundwater (pH=7.0) have been
reported (H,em, 1970).
In a 1962 U.S. Geological Survey study of public water supplies of the
100 largest cities 1n the United States, Ourfor and Becker (1964) reported
manganese concentrations of up to 2500 yg/s, for treated water. Of these
water supplies, 97% contained concentrations below 100 Pg/8,. A U.S.
Public Health Service (U.S. PHS) community water survey In 1969 examined
2595 samples of tap water from 969 community water supplies (U.S. DHEW,
1970). The maximum concentration of manganese was 1320 pg/s,, but 91.9%
of samples and 91% of supplies did not exceed 50 Mg/ii.
As part of the first Health and Nutrition Examination Study (HANES I
Augmentation Survey of Adults), conducted in 1974-1975, tap water samples
from public and private water supplies of 35 urban and rural, randomly
3-78
-------
TABLE 3-27 '
Mean Concentrations of Dissolved Manganese by Drainage Basin*
Drainage Basin
Mn/a,
Northeast
North Atlantic
Southeast
Tennessee River
Ohio River
Lake Erie
Upper Mississippi
Western Great Lakes
Missouri River
Southwest-lower Mississippi
Colorado River
Western Gulf
Pacific Northwest
California
Great Basin
Alaska
3.5
2.7
2.8
3.7
232.0
138.0
9,8
2.3
13.8
9.0
12.0
10.0
2.8
2.8
7.8
18.0
*Source: Adapted from Kopp and Kroner, 1969
3-79
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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 In public water supplies
(Grea'thouse, 1983). Manganese concentration at the 95th percentile was 3
times higher 1n private (228 yg/ft) than In public supplies (78
yg/st). The median level for private supplies was below detection limits
while that for public supplies was 4 yg/2.; 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 (GuthMe, 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 yg/g. Manganese concentrations for
unpolished rice were given as 2.08 (United States), 32.5 (New Zealand) and
40 yg/g (Great Britain). Most non-cheese dairy products contained
<1 vg/g, but cheeses varied widely. Swiss cheese In the United States was
reported to contain 1.32 and 17.2 yg/g, respectively, by two different
authors. Most meat, poultry and fish contained manganese at <2 yg/g.
Most fresh fruits contained <2 yg/g, but bananas and canned fruits ranged
from this level to 19 and 10 yg/g, respectively. The manganese content of
various vegetables ranged from 0.14-12 yg/g. Most nuts contained from
7-35 yg/g, and certain spices (cloves, ginger, sage) contained >200
yg/g. Thus, 1t 1s obvious that wide differences In 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
3-81
-------
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
ND
NO
50
4
ND
Percentl
75
13
34
les (yq/8.
90
36
121
)
95
78
228
99
295
977
*Source: Unpublished EPA data (Greathouse, 1983)
ND = Less than detection limits (see text)
3-82
-------
made In 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 1s highly dependent upon
particle size. Particles of diameter >100 vm can be Inhaled, but few of
those larger than =15 pm 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 Is dependent on
type of breathing (I.e., oral or nasal), breathing flow rate, and particle
characteristics. Insoluble particles deposited In the tracheobronchlal
region normally are cleared within hours, whereas those deposited In the
alveolar region would be expected to remain for weeks, months or longer
(U.S. EPA, 1982b).
Particles of =10 vm 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 pm. Nearly all particles smaller than
2 urn. reach the alveoli, but many (=50-80%) remain suspended and are
3-83
-------
exhaled (U.S. EPA, 1982). However, some conventions conservatively assume
that none 1s exhaled; thus, >80% of particles smaller than 2 ym are
considered to be deposited 1n the alveoli, and for particles =4-10 ym,
<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 Is approximately excluded by, an upper
size cut-off, usually =05 ym. Thus, all aerosol sampled 1s assumed to
reach the thoracic region. The coarse aerosol from the dlchotomous sampler
Is generally taken to represent the tracheobronchlal fraction, and the fine
aerosol to be the alveolar fraction (Ozubay 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 is at
2-4 ym, 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 Is 100% deposit-
ed 1n 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 ym and some particles of up to 100
ym (Pace and Frank, 1983). Dlchotomous sampler data from around the
country Indicate that of the manganese sampled (particles 0-15 ym), an
average of -28% and a maximum of -66% 1s 1n the fine (<2.5 ym)
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
3-84
-------
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 (yg/day) = Ambient concentration (yg/m )
X Flne/DS X DS/TSP X 20 m3/day
' 3
Total thoracic deposition {yg/day) = Ambient concentration (yg/m )
X OS/TSP X 20 m3/day
where Fine/OS = Fine-fraction manganese/total dlchotomous-sampler manganese
and OS/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.
The most recent (1982) ambient air monitoring data for the urban,United
3
States show a median quarterly manganese level of 0.023 yg/m , and a
3
high quarterly value of 0.661 yg/m (see Table 3-20). Ambient levels
reaching ~10 yg/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 In ambient air.
Exposure estimates derived from these data are presented In Table 3-30.
Alveolar deposition of manganese at current ambient levels 1s estimated as
0.072 yg/day (average) and 6.6 yg/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 yg/day, respectively.
3-85
-------
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3-86
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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
In 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
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 Is much lower because of the low concentrations of manganese 1n 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
Is 4 vg/a. (see Table 3-29). Assuming daily adult consumption of 2 5,
of water, it 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 percentile
in private wells was 977 yg/S,, and therefore It should be recognized
3-87
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TABLE 3-31
Dietary Intake of Manganese In the U.S.
Group
Average Daily 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
Tlpton et al., 1969
U.S. FDA, 1978
3-88
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that 1n 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 s,/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 Is 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.
Therefore, for all practical purposes, 1ngest1on 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 meta.l forms numerous alloys
with Iron, aluminum and other metals (Matr1card1 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 acid solution, but
are readily oxidized 1n alkaline conditions. The heptavalent form 1s found
only 1n oxy-compounds (Re1d1es, 1981).
3-90
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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 in a 24-hour sampling
period. High-volume samplers may also be operated with filters composed of
organic membrane.
If Information on particle size is desired, other types of sampling
devices are used. Currently, the type most widely used is the dichotomous
sampler, which separately collects fine (<2.5 wm) and coarse (>2.5 ym)
particles. The upper size limit of coarse particles may be set at 10, 15 or
20 vim by a size-selective inlet. Particles are usually 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. Isokinetic 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.
3-91
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Sample preparation prior to analysis 1s necessary unless a non-destruc-
tive analytical technique Is used. Solid samples may be add digested, with
or without prior ashing of organic matter. Extraction of partlculate from
glass fiber filters Is done by son1f1cat1on In 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, Ion exchange or copredpltatlon.
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 detecion limits for any technique vary according to sampling method,
sample preparation and analytical method. Detection limits for manganese In
air are as low as 0.002 vg/m3 (Dzubay and Stevens, 1975; U.S. EPA,
1979a).
3.7.3. Production and Use. Very little manganese 1s mined In this
country; some Is mined domestically as low-grade ores, but most Is Imported.
Manganese alloys, manganese metal and many compounds of manganese are pro-
duced and used 1n the United States, however. Ferromanganese and slHco-
manganese are ferroalloys produced by the smelting of manganese ore In an
3-92
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electric furnace (MatMcardl 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 In 1982. Silico-
3 3
manganese production has decreased from 284x10 tons 1n 1968 to <75xlO
tons In,1982. Demand for these products has diminished recently and Imports
are Increasing (Jones, 1982; DeHuff and Jones, 1981; DeHuff, 1961-1980).
The remaining 5-6% of .manganese demand 1s for a number of compounds which
are Important 1n the chemical Industry And in 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 Mn02, 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 1n 1974, but
was discontinued 1n 1978 due to adverse effects on hydrocarbon emissions
(U.S. EPA, 1977b). MMT continues to be used at -0.05 g Mn/gal 1n -20%
of leaded gasoline (Hall, 1983).
3.7.4. Sources of Manganese 1n the Environment. Manganese is the 12th
most abundant element and fifth most abundant metal 1n the earth's crust.
While manganese does not exist free 1n nature, it 1s a major constituent In
3-93
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at least 100 minerals and an accessory element 1n more than 200 others
(Hewett, 1932). Its concentration 1n various crustal components and soils
ranges from near zero to 7000 yg/g; a mean soil content of 560 pg/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 vm) (Dzubay, 1980; Dzubay et al., 1981).
Manganese Is also released to the atmosphere by manufacturing processes.
Ferromanganese furnace emissions are composed mainly of fine partlculate
(<2.5 vm) with a high manganese content (15-25%). Ferroalloy manufacture
was the largest manganese emission source in 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 in manganese release. The manganese
content of coal 1s 5-80 Pg/g (U.S. EPA, 1975). Fly ash is about equal to
soil in manganese content (150-1200 jag/9), but contains particles finer in
size. This is an Important manganese source because of the volume of coal
burned each year. Combustion of residual oil is less important because of
its lower mangnese content. About 15-30% of manganese combusted in MMT-
containing 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 In St. Louis and Denver suggest that crustal
3-94
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sources are more Important In the coarse than In 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-,
turlng, the Influence of this process was seen In both the fine and coarse
fractions (Dzubay, 1980; Ozubay et al., 1981; Alpert and Hopke, 1981; Liu et
al., 1982).
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 Is 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 is often present in
fine particles with high concentrations of manganese as oxides (up to 250
mg/g). Organic manganese usually is not present In 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
3-95
-------
transformation to sulfurlc acid, 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 It 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 (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/cm /month (NAPCA, 1970).
In water or soil-, manganese Is 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, Interconverslon occurs only by mlcroblal mediation
(Alexander, 1977). -
Manganese tends to be mobile 1n oxygen-poor soils and In 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-
3-96
-------
tration factor is lower (10-102) as trophic level Increases, Indicating
that the element Is metabollcally regulated. Thus blomagnlfIcatlon of
manganese does not occur (Lentsch et al., 1972).
3.7.6. Environmental Levels and Exposure. Nationwide air sampling has
been conducted 1n some form since 1953 (U.S. DHEW, 1958). Analytical
methodology has Improved and monitoring stations have changed, complicating
any analysis of trends 1n manganese concentration. However, 1t Is evident
that manganese concentrations In ambient air have declined during the period
of record. The arithmetic mean manganese concentration of urban samples was
0.11 yg/m3 In 1953-1957 (U.S. DHEW, 1958), 0.073 vg/m3 1n 1966-1967
(McMullen et al., 1970), and decreased to 0.033 vg/m by 1982 (Barrows,
1983). In 1953-1957, the percentage of urban stations with an annual aver-
age of >0.3 v9/m3 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
10 vg/m3, were seen In 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 In 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 is associated with both fine (<2.5 ym) and coarse
3-97
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(>2.5 ym) particles (Bernstein and Rahn, 1979). The manganese concentra-
tion 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 in nonpolluted freshwaters are usually <20
yg/S,, but may exceed 1000 yg/s. where polluted. The amount of manga-
nese 1n suspension exceeds the amount in solution, except where acid mine
drainage 1s prevalent (Kopp and Kroner, 1969). Concentrations in ground-
water typically are higher than 1n 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 yg/a. are found in
some, notably private, water supplies, -95% of all supplies contain manga-
nese at <100 yg/a.. A median concentration of 4 yg/a. 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 In the alveoli. Time
required for particle clearance and probability of absorption Increases with
Increasing depth of deposition in the respiratory, tract (U.S. EPA, 1982).
Deposition of manganese in the alveoli can be calculated from the ambient
concentration and the fraction present in fine particles. Thoracic
(tracheobronchlal plus alveolar) deposition is calculated from estimates of
the manganese found 1n particles <15 ym 1n size. Alveolar deposition of
manganese at current ambient levels is estimated .as 0.072 yg/day as an
average and 6.6 yg/day under high exposure conditions. Estimates of total
thoracic deposition are slightly higher; 0.26 yg/day (average) and 10.0
yg/day (high). Alveolar and total thoracic deposition under the high
3-98
-------
3
exposure conditions (10 yg/m ) of the 1960s were estimated to be 100 and
152 vg/day, respectively.
Diet Is 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 ingestlon 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.
3-99
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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 It was demonstrated that manganese prevented a skeletal abnormality in
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 In 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 LUburn, 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-
4-1
-------
nese deficiency are those associated with skeletal abnormalities, Impaired
growth, ataxla of the newborn, and defects 1n Hpid 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
al., 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 daily 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 in
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 Theriault-Bell, 1974). Although the requirement of
manganese for development and growth has not been adequately studied,
Holtkamp and Hill (1950) concluded that 50 ppm manganese 1n 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 in humans. Manganese deficiency has been demonstrated
in mice, rats, rabbits and guinea pigs. The main manifestations of manga-
nese deficiency are those associated with skeletal abnormalities, impaired
4-2
-------
growth, ataxla of the newborn, and defects 1n llpld 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 (NAS,
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 Is considered to be an
additional route 1n occupatlonally exposed workers and 1n residents living
In 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 Is 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.
i
4.2.1.1.1. Human Studies — Mena et al. (1969) studied manganese
absorption 1n 11 healthy fasted human subjects by administering 100 y.C1 of
54MnCl2 with 200 y.g stable 55MnCl2 as a carrier. On the basis of
54
whole body counts performed dally for 2 weeks the absorption of Mn was
calculated to be ah 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 enterohepatic circulation was not taken Into
account but the authors considered this to be Insignificant.
4-3
-------
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.
This estimation was made on the basis of differences 1n biliary
54,
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 iimoles 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 Kostial 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) in
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 in other studies might
be due to administration of the isotope to fasted animals.
Little is known about mechanisms involved 1n manganese absorption. The
In. vitro experiments performed by Cikrt and Vostal (1969) show that manga-
nese absorption is likely to occur in the small as well as in the large
Intestine. However, whereas manganese is actively transported in the small
Intestine, there 1s only simple diffusion 1n large intestine. Miller et al.
(1972) found that in 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) is known to enter the
enterohepatlc circulation. Cikrt (1973) showed that manganese excreted in
the 'bile 1s in a form more easily absorbed than manganese dlchloride. He
4-4
-------
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 in general. Only
particles small enough (usually several tenths of y.m) to reach the alveo-
lar lining are likely to be absorbed directly into the blood. An unspeci-
fied fraction of the metal initially deposited in the lung is expected to be
removed by mucocilHary 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
aqueous solution of MnClp (7 normal controls and 10 exposed working
54
miners) or to a nebulized aqueous suspension of ^n?^3 ^ exposed
miners). The estimated mean particle size of the droplets delivered through
the nebulizer was 1 y.m. They found that about 40-70% (average 60%) of the
radioactivity Initially located in the lung was recovered in 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
4-5
-------
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 In pharmacoklnetlc studies after a single or repeated administration
of the radioactive tracer. Such data are almost always obtained 1n 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; Tlpton and Cook, 1963; Sumlno et al., 1975) are
presented In 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 1n liver and pancreas (~1 ixg Mn/g
wet weight or more). Kidney concentrations were between 0.6 and 0.9 ug/g.
Lowest concentrations were found 1n brain, heart, lung, Intestine and gonads
(usually between 0.2 and 0.3 v,g/g), with extremely low concentrations
(<0.10 ng/g) 1n muscles, bone, fat tissue and spleen.
4-6
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In spite of appreciable Individual variations of manganese concentra-
tions 1n the liver, there 1s Uttle variation from one part of the liver to
another (Perry et al., 1973). Normal brain concentrations 1n adults up to
0.6 y.g Hn/g wet weight were reported (Fischer and Welgert, 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 in 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 y.g Mn/g wet weight, with highest
values observed in 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 in biological fluids (blood and urine particularly) will be
discussed in Section 4.2.5.1. concerning their significance in relation to
exposure.
4.2.2.2. ANIMAL STUDIES — Distribution studies in 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 1n brain and bone.
When mice were exposed to MnO by Inhalation in concentrations of 5.6
3
and 8.9 mg/m and particle size of 3 vim for 2 hours daily for 8 and 15
days, respectively, the highest concentrations of manganese were found in
the kidney (10.8 and 8.4 mg/kg dry weight), liver (9.0 and 7.1 mg/kg),
pancreas (8.4 and 8.2 mg/kg) and" brain (5.9 mg/kg) (Mouri, 1973). After
Intraperitoneal administration of radioactive manganese to rats, the highest
concentrations were found In the suprarenal, pituitary, liver and kidney
4-8
-------
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 Cherian (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 HnCl «4H 0 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 mldbrain. In treated rats all brain regions showed an
Increase, the greatest being 1n the corpus strlatum 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 thalamlc 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.
Inv 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 (Haynard and Cotzlas, 1955).
Tissues rich 1n 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.
4-9
-------
From their data it Is apparent that bones, liver, kidneys and some endocrine
glands (pituitary 1n particular) carry higher manganese concentrations
(1.2-3.3 ug Hn/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 Is 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 1n urine 1n unexposed and exposed people
will be discussed 1n 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 v-g of manganese dichlorlde 1n rats 12% of the injected dose was
excreted Into the bile within 3 hours (Tichy et al., 1973) and 27% within 24
hours (Cikrt, 1972).
Adkins et al. (1980a) studied retention and subsequent clearance of
manganese after 2-hour inhalation exposure of Charles River CD-I mice to 1.8
4-10
-------
mg Mn/m as MngO^ aerosol, with average mass median diameter ~1.4
•jim. Seven data points were obtained In 24 hours, each for a group of six
mice. The exponential curve fit to the data Indicated that -47, 27 and
i
14% of the manganese remained 4, 6 and 24 hours after exposure, respectively.
Klaassen '(1974) estimated the biliary excretion of manganese In 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 v.g/m1n/kg was attained. This Indicates that a saturable
active transport mechanism may exist for manganese.
Although biliary excretion Is particularly Important 1n adjusting the
manganese body load, bile Is 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 in animals
show conclusively that manganese 1s also excreted through the Intestinal
wall (Bertlnchamps and Cotzias, 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 Heum (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
61 routes may Increase 1n the presence of biliary obstruction or with over-
loading of manganese (Bertlnchamps et al., 1966; PapavaslHou et al., 1966).
4-11
-------
Urinary excretion 1s low. Klaassen (1974) found that 1n rats 5 days
after Intravenous dosing 99% of administered manganese was eliminated 1n
feces and only 0.1% 1n urine. Biliary obstruction or overloading with
manganese did not Increase the urinary excretion (PapavaslHou et al.,
T966). 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 EOTA (ethylene diamlnetetra-
acetlc add) did urinary excretion become predominant for 24 hours, after
which time fecal elimination was resumed (Kosal and Boyle, 1956; Maynard and
Fink, 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.
Cotzias et al. (1968) studied the tissue clearance of manganese in 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 in the thigh 57, 39 and 48 days.
4-12
-------
4.2.4.2. ANIMAL STUDIES — BrHton and Cotzlas (1966) reported a two-
component whole body clearance rate for manganese In 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/a 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/fc. The half-time of manganese 1n 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 (Oastur 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 1n .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.
4-13
-------
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 In 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
different time Intervals after oral administration, the Mn concentration
was determined 1n various tissues. Four hours after administration all
tissues from rats fed the basal diet continued to have higher 54Mn concen-
tration than tissues of rats given higher unlabeled manganese 1n diet. The
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
levels of unlabeled dietary manganese accelerates Mn turnover after
\
absorption and tissue deposition. Suzuki (1974) reported an Intestinal
absorption of only 0.5-1.97% of Mn 1n mice prefed diets having levels of
Hn02 ranging from 20-2000 mg/kg. The retention of 54Mn observed 1n the
whole body was Inversely proportional to the dietary manganese level.
Absorbed manganese 1s 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 1n the feces and only traces appeared 1n
4-14
-------
urine. Subsequent experiments with rats at a lower level «(a 1 mg dose)
showed that 90% of the Intraperitoneally admlnstered dose appeared 1n the
feces within 3 days (Greenberg and Campbell, 1940).
IntraperUoneal 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 y.g/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 1ntraper1toneal administration of the same
high dose of manganese (10 mg MnCl»/kg bw) for a period of 4 months
resulted In Increased brain accumulation of manganese 1n rats. This manga-
nese treatment gave rise to significant Increases 1n 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 1n manganese levels 1n brain and
4-15
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4-16
-------
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 Mn as MnCl? In the drinking water for over 2 years.
Liver values were up 45%.
Klaassen (1974) demonstrated that manganese Is excreted Into the bile
against a concentration gradient. On the other hand, T1chy and Clkrt (1972)
suggested that manganese may be transferred from plasma Into the bile by
passive transfer followed by a nonenzymatlc complex formation In the bile.
However, In 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 In regu-
lating the body burden of manganese, this route of excretion 1s by no means
exclusive. This 1s because experiments 1n animals and humans conclusively
demonstrate that manganese Is also excreted through the Intestinal wall
(Bertlnchamps and Cotzlas, 1958; Kato, 1963; Papavas111ou et al., 1966;
Wassermann and M1ha11, 1964). For Instance, there 1s some Indication of
manganese excretion ttirough the rat Intestinal wall Into the duodenum, the
jejunum and, to a lesser extent, the terminal, 1leum (Bertlnchamps et al.,
1966; Clkrt, 1972). Both of these routes of excretion contribute signifi-
cantly toward the homeostasls of tissue contents of manganese. In addition,
manganese Is 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).
4-17
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4.2.5.1. LEVELS IN BIOLOGICAL FLUIDS AND BIOLOGICAL INDICATORS OF
EXPOSURE — Concentrations of the metal 1n 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 In 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.g/8-. but values up to 21
lig/8, have been reported (Horluchl et a!., 1967; Tlchy 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. HoMuchl 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 y.g/100 mil, and that manga-
nese concentration 1s much higher 1n the erythrocytes than 1n plasma or
serum (Cotzlas et al., 1966; Cotzlas and Papavaslliou, 1962; PapavaslHou
and Cotzlas, 1961; PapavaslHou et al., 1966; Muzzarelll 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 1n 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
4-18
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levels of manganese averaging 11-16 ixg/8- compared to a mean level of 10
V.g/8. 1n nonexposed persons. Variations 1n 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 (Horluchi et al., 1967) and several studies
Indicate that there 1s no difference 1n the concentration of manganese 1n
the blood of men and women (Horluchi 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
(Horluchi 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
4-19
-------
(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.,
T981).
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 Is absorbed from the
61 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 In spite of some rapid phases 1n manganese transport. The average
normal level of manganese 1n whole blood of humans 1s 7-12 y.g/i, while
the manganese levels 1n serum are normally distributed around a mean value
of 0.5-0.6 ng/a (Versleck and Cornells, 1980). The highest values of
manganese 1n humans are found 1n Hver, kidney and endocrine glands which do
v
not exceed 2 v.g/9 wet weight of tissue. Manganese penetrates the blood-
brain and placenta! 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).
4-20
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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 homeostatic mechanisms.
The homeostatic 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 In manganese
concentration. The GI absorption depends not only on the amount Ingested
and tissue levels of manganese, but also on manganese b1oava1lab1!1ty and
Interaction with other metals. The way tissue concentrations Influence the
excretory mechanism 1s stm unknown. B1le 1s the most Important route of
excretion.
4.3. SYNERGISTIC/ANTAGONISTIC FACTORS
The way In.which the body normally handles manganese is affected by the
age of the Individual and by the status of other metals In 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 in 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 in these patients showed that trie rate of
absorption was Increased 1n Iron-deficient patients and that this enhanced
absorption could be Inhibited by addition of Iron.
4-21
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Recent balance studies performed In 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 In 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. Wllgus and Patton (1939) reported that addi-
tion of ferric citrate to the diet of chickens accentuated the severity of
perosls. Matrone et al. (1959) found that excessive manganese 1n the diet
(2000 ppm) depressed hemoglobin formation In both rabbits (-88% of control
levels) and baby pigs (-50% of control levels). The minimal level of
manganese in the diet that Interfered with hemoglobin formation was esti-
mated to be 50 and 125 ppm, respectively.
The interaction of iron and manganese metabolism in rats was also
studied by Diez-Ewald et al. (1968). When iron absorption was increased in
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 In iron-deficient states and decreasing
manganese excretion in Iron loaded states.
Kostial et al. (1980) found that increasing the iron content of milk
decreased the whole body retention of orally administered Mn by a factor
of 10 in rats fed milk with or without 100 ppm iron additive. Thomson and
Valberg (1972) and Thomson et al. (1971) studied the interrelationship of
4-22
-------
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 a!., 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 Is 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 Welgert, 1977;
Casey and Robinson, 1978). The exception seems to be bone, where fetal
concentration 1s higher than in 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
4-23
-------
Welgert, 1977). Wlddowson et al.. (1972) reported that there was no consis-
tent change 1n the liver with age 1n 30 fetuses from 20 weeks of gestation
to full term but that generally manganese concentrations 1n full-term livers
t
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; Sumino 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 1n females than 1n males.
Several studies Indicate that manganese penetrates the placental barrier
and that manganese 1s more uniformly distributed In 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
than 1n adult animals.- Absorption of 54Mn 1n 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
4-24
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diet cause very high absorption (40%) of manganese In the Immature. The
addition of manganese to milk decreased the percentage of absorption of
54Mn In both suckling and adult rats, Indicating the existence of a
homeostatic 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 mitochondria! accumulation of elemental
manganese was vigorous. This suggested an initially avid accumulation of
manganese that was supplied In trace amounts in the mouse milk (54 ng/ma.).
The presence of high absorption coupled with the absence of excretion
resulted in a marked rise of tissue manganese In the neonates from an
exceedingly low to a very high level.
The tissue accumulation 1n the brain was particularly impressive as the
brain can be susceptible to both manganese poisoning and deficiency. Miller
and Cotzias (1977) noticed an absence of manganese excretion during the
first 18 days of life 1n neonatal rats and kittens. However, when laetatlng
mothers were given drinking water with concentrations of manganese ranging
from 40-40,000 mg/8,, the lactation barrier appeared to give adequate pro-
tection to the young. When the level exceeded 280 mg/il, newborn animals
initiated excretion before the 16th day of life. The neonates showed a
greater accumulation in the brain than their mothers, whereas the Increase
in liver concentrations was proportional to the concentrations found in the
liver of their mothers.
Silbergeld (1982) reports that older rats (24-32 months) had greater
striatal dopamine levels than younger rats (2-3 months) when manganese
acetate was added to the drinking water. Thus, the ageing brain is
suggested as an organ of special sensitivity.
4-25
-------
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 In the brain of 6-day-old sucklings as compared to
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. (1980) found that the tissue distribution of manganese oxide
1n preweanllng rats after oral exposure was: Hver > brain % kidney >
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 In rats
occurs during the preweanllng period. Cahlll 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).
4-26
-------
Manganese does penetrate the blood-brain barrier and the placenta!
barrier. Studies 1n animals Indicate a higher manganese concentration 1n
suckling animals, especially 1n the brain (Kostlal et al., 1978).
4-27
-------
-------
5. TOXIC EFFECTS AFTER ACUTE EXPOSURE
5.1. ANIMAL STUDIES
The average median lethal doses (LD ) 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 LD5Q 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 cationlc manganese forms are
more toxic than the anlonlc forms and that the bivalent cation 1s ~3 times
more toxic than a tMvalent 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 cationlc forms. Obviously, Insoluble
manganese oxide 1s 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 Us tox-
ldty. 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 In the
pharmacoklnetlcs and toxldty of heavy metals. The highest oral toxldty of
manganese was found 1n 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; LD5Q values were Increased by a factor
5-1
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TABLE 5-2
Influence of Age on Manganese Toxidty 1n Rats:
Values 8 Days after a Single Oral
Administration of MnCl2*
Average and Range of
Age in Weeks
2
3
6
18
54
MnCl
804 (
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850 (
619 (
2 • 4H20
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1655-2009)
1553-1887)
775-957)
564-702)
L050 (rog/kg) Values
Actual Mn Dose
223- (204-249)
516 (459-557)
475 (431-524)
236 (215-265)
' 171 (156-194)
*Source: Kostial et al., 1978
5-3
-------
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 toxicity due to a general
decrease in adaptive responsiveness, which is characteristic of the aging
process. It is difficult to evaluate the contribution of aging because the
animals were only about 1 year old. Increased toxicity in 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 is very rare. It may occur in exceptional
circumstances such as accidental or intentional ingestion of large amounts
of manganese compounds. Oagli et al. (1973) described a case where exten-
sive damage to the distal stomach, resulting 1n pylorlc stenosis, occurred 2
hours after Ingestion of potassium permanganate (10 tablets of 300 mg
each). Mahomedy et al. (1975) reported two cases of lethal methemoglobi-
nemia 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 in humans. Metal fume fever is 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 (Piscator, 1976).
5-4
-------
5.3. SUMMARY
The average ID-., 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.
5-5
-------
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6. TOXIC EFFECTS AFTER CHRONIC EXPOSURE
6.1. INTRODUCTION
Manganese "exposure can produce prominent psychological and neurological
disruptions. These manifestations of neurotoxicity are described below.
The neurologic signs and symptoms have received particularly close attention
because they resemble several other clinical disorders and, in particular,
Parkinsonism and dystonia. Collectively, these disorders have been de-
scribed as involving "extrapyramidal motor system dysfunction" because they
result in damage within the extrapyramidal motor system and especially 1n
the neostriatum, substantia nigra and, in the case of dystonia the thalamus
(Figure 6-1). As a consequence of such damage, a constellation of signs and
symptoms which disrupt the initiation, completion and smooth performance of
motor acts arises. These frequently include tremor, jerkiness of movement,
limb rigidity and postural disorders. While some controversy exists In the
scientific literature concerning whether manganism is a better model of
Parkinsonism or dystonia the principal value of such comparisons lies In the
formation of hypotheses concerning the target of manganese neurotoxicity
which can then be tested experimentally and which may ultimately assist in
determining the no-effect level in animal species.
Comparison of manganism and Parkinsonism has been important in one other
respect. Based upon similarities of symptoms, the principal therapy for
Parkinsonism, administration of the drug, levadopa (1-DOPA) has also been
applied to chronic manganese intoxication with some success.
Extensive laboratory research has been conducted to investigate the
neural circuit which is damaged in Parkinsonism and which is a presumed
target of manganese neurotoxicity. This circuit consists of nerves which
connect the substantia nigra and the neostriatum (Figure 6-2). These nerves
6-1
-------
NEOSTRIATUM
1) Caudate
2) Globus Pallidus
3) Putamen
CEREBELLUM
SUBSTANTIA
NIGRA
THALAMUS
Subthalamus
Reticular
Formation
Red Nucleus,
SPINAL CORD
and
MUSCLES
FIGURE 6-1
Principal Components and Connections 1n the Extrapyramldal Motor System
6-2
-------
NEOSTRIATUM
Dopamine Neuron
Substantia Nigra
FIGURE 6-2
Schematic Illustration Depicting Possible Sites of Damage to the
N1gral-Str1atal System 1n Park1nson1sm and Hanganlsm
Source: Adapted from Cooper et al., 1982
6-3
-------
contain the neurotransmitter, dopamlne, and have been shown to sustain
Injury 1n Park1nson1sm. In fact, 1-DOPA 1s the Immediate chemical precursor
of dopamlne and the simplest explanation of Us effectiveness 1n Parkinson-
ism 1s based on the notion of replacement of dopamlne available for neuro-
transmlsslon. As Indicated by both hlstopathologlc and neurochemlcal
studies conducted 1n animals 1t 1s unlikely that manganese produces the same
neurological damage as Parkinsonism. Rather, attention has been focused
upon nerve cells which are normally stimulated by the dopamine-containing
neurons that project to the neostriatum and upon nerve cells which mediate
the activity of the dopamlne-containing neurons. This section also
describes the different hypotheses which have been proposed to account for
the manifestations of manganese neurotoxiclty.
6.2. NEUROTOXIC EFFECTS - HUMAN STUDIES
The effect of manganese on the CNS is quite serious in the advanced form
known as manganism. According to Voss (1939) there were 152 cases of
manganism described in the literature prior to 1935. By 1943, Fairhall and
Neal (1943) found 353 cases of manganese poisoning. Subsequently, reports
of at least 200 additional cases of manganism have been published.
The signs and symptoms of chronic manganese poisoning have been de-
scribed in detail several times (Flinn et al., 1940; Ansola et al., 1944a,b;
Penalver, 1955; Rodier, 1955; Schuler et al., 1957; Chandra et al., 1974).
This poisoning can result from exposure to manganese aerosols after only a
few months, although it usually results from exposures of 2-3 years or
longer (Ansola et al., 1944b; Rodier, 1955). It has been suggested that
damage is reversible if the patient is removed from exposure at an early
stage. On the other hand, once profound neurologic signs and symptoms are
present they tend to persist and may even worsen several months after
6-4
-------
exposure has ceased (Barbeau et al., 1976). This finding 1s corroborated by
Cotzlas et al. (1968) who reported that the presence of elevated tissue
manganese concentrations was not necessary for the continued neurologic
manifestations of manganese poisoning.
Human manganese Intoxication produces signs and symptoms of central
i
nervous system toxicity which can be divided Into two broad stages, the
first dominated by psychological disturbances which subside 1f manganese
exposure 1s terminated and a second, predominantly neurological disturbance,
which occurs with continued manganese exposure and which 1s not reversible.
The disease begins Insidiously with anorexia, asthenia, and occasionally
psychotic behavior [the latter-most reported most frequently 1n studies of
manganese miners than those from other occupational categories (Table 6-1)].
Severe somnolence followed by Insomnia Is often found early 1n the disease.
Headache and leucopenla may further confuse the differential diagnosis
between manganlsm and viral encephalitis.
As manganese exposure continues, slurred speech, a mask-like face and
general clumsiness with loss of skilled movement are characteristic.
Indifference occurs, interrupted by spasmodic laughter or by crying spells
(Table 6-2).
A more specific description of the earlier stages of this disorder has
appeared in conjunction with a report of cases in 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 in the earliest
symptoms: somnolence, incoordination, speech disorder, gait difficulty, and
imbalance. Postural tremor and tremors at rest were seen in four of the six
cases. In no case was this tremor the only symptom and all four had slurred
speech, asthenia and somnolence.
6-5 -
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Fully developed manganlsm causes severe rigidity with the extremities
showing the "cogwheel" phenomenon 1n which passive movement of the limbs
results 1n resistance and jerky cog-like rather than smooth movement.
Tremors may occur Which become exaggerated by emotion, stress, fatigue or
trauma. Similarly, an autonomlc disturbance manifested by excessive saliva-
tion and sweating may become apparent (Table 6-3). These latter symptoms
are persistent.
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compared to Parkinson's disease, but certain differences should be noted.
Parkinson's patients show pronounced disturbances of motor behavior which
Include tremor observed at rest rather than during an Intentional motor act
as 1n manganlsm (Klawans et al., 1970). Parkinson's patients also exhibit
difficulty Initiating and stopping motor acts, expressionless face and hypo-
activity. While Park1nson1sm may be associated with psychological disturb-
ances such as depression and occasionally psychotic behavior, these are not
considered common manifestations of the disorder. Barbeau et al. (1976)
provide a revised description suggesting that chronic manganese poisoning is
a better model of another extrapyramldal disorder, dystonla, than of
Parkinson's disease. They point out that the tremor observed in some of the
patients with manganese poisoning is quite different from that seen in
Parkinson's disease. In their opinion it has much more of an attitudinal or
flapping quality. These authors note that some form of dystonla, defined as
a postural instability of complementary muscle groups, is an almost obliga-
tory feature of manganlsm. However, dystonla 1s an extremely broad diag-
nostic category and both its manifestations and hlstopathology show large
variability among patients.
6-8
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The clearest basis for distinguishing Parklnsonlsm and manganlsm Is on
hlstopathologlcal evidence. The classical findings In Parkinson's disease
are deplgmentatlon and loss of cells 1n the substantla nlgra, locus coerule-
us, and dorsal nucleus of the vagus with little damage to the strlatum or
pallidum (Figure -6-3). In chronic manganese poisoning there 1s no appre-
ciable destruction of the substantla nlgra; the lesions are f/)und mainly
within the strlatum and palUdum {see Figure 6-3).
However, on the basis of the similarity 1n clinical signs to Parkinson-
Ism, treatment with levadopa has been attempted In established manganlsm
with success 1n some cases (Mena et al., 1970; Rosenstock et al., 1971).
This finding adds credence to the belief that an essential aspect of manga-
nese neurotoxldty 1s disruption of function 1n dopamlne-contalnlng neurons.
6.2.1. Case Reports and Epidemiologlc Studies. Reports of cases of
manganlsm and the associated clinical descriptions have established that
exposure to manganese can cause chronic manganese poisoning 1n some individ-
uals. In order to establish levels of exposure at which effects do not
occur it is necessary to have data with clearly described levels of
exposures (Including specific compound and particle size). Additionally,
the number and selection of individuals exposed and studied should be
clearly defined. Although there has been a good deal of occupational
exposure to manganese, this type of dose/response data is not available.
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 v^hich 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
6-10
-------
Cerebral Cortex
Cerebellum
Neostriatum
1) caudate
2) putamen
3) globus pallidus
Substantia
nigra
FIGURE 6-3
Schematic diagram Indicating the distribution of the main central
neuronal pathways containing dopamlne. The stippled regions Indicate the
major nerve terminal areas. The cell groups 1n this figure are named
according to the nomenclature of Dahlstrom and Fuxe (1965).
Source: Adapted from Cooper et al., 1982
6-11
-------
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).
Hanganlsm has been described 1n workers 1n ore crushing and packing
mills, 1n ferroalloy production, 1n the use of manganese alloys 1n the steel
Industry, 1n the manufacture of dry cell batteries, and In welding rod manu-
facture. Exposure typically Involved dusts of manganese oxides generally
larger than 5 ym, or fumes produced through vaporization and subsequent
condensation with particle size of 0.1-1 ym, but Information on manganese
concentrations and the occurrence of other chemicals at working places was
usually limited. Few studies dealt with the particle size distribution of
manganese aerosols.
Most of the described cases of manganism occurred in manganese mines.
The reported poisonings were among Huelva miners 1n Spain (Dantin Gallego,
1935, 1944), Sinai miners (Nazif, 1936; Scander and Sallam, 1936), miners
from Giessen in Germany {BQttner and Lenz, 1937), Moroccan miners (Baader,
1939; Rodier and Rodier, 1949), Chilean miners (Ansola et al., 1944a,b),
Cuban miners (Garcia Avila and Penalver, 1953), Suceova miners in Rumania
(Wassermann et al., 1954), Mexican miners {Roldan, 1956), USSR miners
(Khazan et al., 1956; Khavtasi, 1958), Japanese miners (Suzuki et al.,
1960), and Indian miners (Balani et al., 1967).
Table 6-4 contains a summary of those studies with corresponding
exposure data and a description or response frequency for CNS involvement in
workers occupationally exposed to manganese by inhalation. These studies
are presented in chronological order. The earlier ones in particular have
several limitations due in part to the fact that they were designed to
obtain clinical information rather than incidence or prevalence rates. The
6-12
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developing exposure standards. Generally the exposure data covers a broad
range and does not Include particle size or chemical characterization. In
some cases exposures change over time (e.g., FUnn et al., 1941; Smyth et
al., 1973). The selection and composition of the exposed group may not be
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studies employs a standard cohort design. Duration of exposure Is sometimes
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subjected to statistical analysis. Percentages reported 1n the table
reflect prevalence of the pathological findings in the group as described.
While the use of this information for obtaining a dose-response association
is limited quantitatively, it does show evidence of effects in humans and
can be used to broadly estimate a range of LOELs.
Flinn 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 6-5 shows that these workers had some neuro-
logical findings which might be indicative of early manganism. The average
exposure for those affected was 5.3 years and for the exposed workers
unaffected was 2.4 years. No case of manganism was detected in nine workers
exposed to average manganese concentrations of 10-30 mg/m3 in two manga-
nese ore crushing mills (FUnn et al., 1940). The lowest average manganese
concentration at which the disease was found was 30 mg/m3. 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
r.
short to define 16-30 mg/m3 as a NOEL.
6-15
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6-16
-------
In 1955, Rodler reported 150 cases of manganlsm from three Moroccan
mines. Underground workers engaged in 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.
Concentrations of manganese were usually very high in the mines from which
cases of manganism were reported. The manganese concentration in the air in
the immediate vicinity of rock drilling in Moroccan mines was -450 mg/m3
in one mine and -250 mg/m3 in another. Analyses of the ores indicated
that toxicity was not strictly related to manganese content; most of the
cases of manganism 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-
tions of manganese in the air varied from 62.5-250 mg/m3 and from an aver-
age of 1.5-16 mg/m3, respectively. Schuler et al. (1957) observed that
the introduction of pneumatic drilling and the associated increase in dust
led to outbreaks of manganism. 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
in a factory manufacturing dry batteries. Average concentrations ranged
from 6.8-42.2 mg Mn/m3 in four areas. Eight workers (22%) exhibited symp-
toms of manganism. Concentrations at the main working areas of three of the
cases ranged from 6.2-7.2 mg/m3. Cases had been working .1-16 years prior
to diagnosis of chronic manganese poisoning.
After an industrial hygiene survey identified certain plants in Pennsyl-
vania as having manganese exposures above the threshold limit value (TLV) of
6-17
-------
5 mg/m3, Tanaka and Lieben (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
60J4 of chemical manufacturing plants. Neurological screening of 117 workers
from the factories where exposures >5 mg/m3 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-
sures <5 mg/m3 due to lack of standardized examination procedures, expla-
nation of selection patterns, details on industrial exposures, duration of
exposure, and the small, unrepresentative sample in 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 in a ferromanganese alloy pro-
cessing plant. They selected 71 employees for study who were exposed daily
in 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
0.12-13.3 mg/m3 for fumes and from 2.1-12.9 mg/m3 for manganese dust.
However, all cases were probably exposed to the high average dust concentra-
tions which had been recorded in previous years (30 mg/m3). The authors
reported a poor correlation between manganese exposure and manganese excre-
tion in the urine. This may not be surprising as manganese elimination
occurs primarily via biliary excretion. Fecal manganese content may have
provided a better correlate to manganese exposure. Five exposed individuals
and no controls had signs suggestive of early manganlsm. Three of these
cases had several classical signs such as masked fades, but the other two
6-18
-------
had only loss of associated arm movements bilaterally. The detailed expo-
sures by position were not explained on a case by case basis and therefore
could not be associated with each Individual. Exposure duration 1n the five
cases ranged from 8-26 years although 1t 1s not known when signs of manga-
nlsm first appeared.
Sarlc et al. (1977) compared 369 workers exposed to 0.3-20 mg Mn/m3 at
a ferroalloy plant to two other groups; 190 workers at an electrode plant
exposed to 0.002-0.03 mg/m3 (2-30 yg/m3) and 204 workers at an
aluminum rolling mill exposed to ambient levels <0.0001 mg/m3 (<0.10
yg/m3). 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, 1s not unique to
manganese, therefore all cases cannot be definitely attributed to exposure
to manganese. There was no apparent association of neurological symptoms
with smoking habit. The ferroalloy workers were further categorized Into
three groups by mean manganese concentrations at working places: <5
mg/m3, 9-11 mg/m3, and 16-20 mg/m3. In addition to manganese com-
pounds, carbon monoxide, carbon dioxide and coal dust were also present.
Table 6-6 summarizes neurological signs observed in these groups. These
data suggest that slight neurological disturbances may occur at exposures <5
mg/m3 and seem to be more prevalent at higher exposures.
Chandra et al. (1981) reported on three groups of 20 welders each
exposed to levels <3 mg/m3 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
6-19
-------
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6-20
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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/m3 with slightly
higher ranges 1n the workers' breathing zone (see Table 6-4). No data were
given on particle size, but It 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 In 25, 50 and 45% 1n these three groups respectively, where-
as none of the controls showed such effects. No details of the neurological
examination 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
were <2.3 mg/m3 for all workers in the factory, although maximum levels
were recorded up to 10 mg/m3. The medical officer of the factory reported
that he had observed neither acute nor chronic cases of manganese poisoning
among the workers. A list of subjective symptoms of manganism was prepared
for the medical officer who stated that no worker had reported such symp-
toms, but this list was not included in their report. This data cannot be
used to identify a NOEL because no clinical examinations were performed.
Other reports suggest that signs of manganism can be identified in individ-
uals not experiencing symptoms (e.g., Smyth et al., 1973).
Sabnls et al. (1966) relate in their report that manganese poisoning had
occurred in a nearby factory. High levels of 8.8 and 8.4 mg/m3 occurred
at operations here compared to 2.7 and 2.3 mg/m3 recorded in the ferro-
manganese alloy factory which had no reports of poisoning. Duration of
6-21
-------
exposure was not reported at either factory. The authors concluded that 6
mg/m3 (the standard 1n effect at that time) was unsafe and that dally
weighted exposures up to 2.3 mg/m3 were safe.
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.
6.2.2. Pathology of Manganese Poisoning. Pathologic findings observed at
autopsy have ranged from absence of morphologic changes, through specific
lesions of the neostriatum, to generalized pathology of both the central and
peripheral nervous systems (Casamajor, 1913; Ashizawa, 1927; Canavan et al.,
1934; Stadler, 1936; Trendtel, 1936; Voss, 1939, 1941; Flinn et al., 1941;
Ardid and Torrente, 1949; Parnitzke and Pfelffer, 1954; Bernheimer et al.,
1973; Barbeau et al., 1976). The most extensive degenerative changes have
been found 1n the neostriatum (caudate nucleus, putamen and pallidum) and
evidence indicates that the pallidum may be preferentially damaged.
6.2.3. Summary. An important effect of chronic exposure to manganese is
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 (in various miners), but more recent studies report cases showing
neurological symptoms and a few signs where the exposure was at much lower
concentrations. Whether this reflects different chemical form and particle
size of the Inhaled manganese, a straight dose-response effect or inconsis-
tencies in clinical examination is not clear.
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
6-22
-------
exposure levels below 5 mg/m3 (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.
Sarlc et al. (1977) report tremor at rest as the major effect on workers 1n
the electrode plant exposed to 2-30 yg/m3 (0.002-0.03 mg/m3) although
duration of exposure was not fully detailed. The prevalence of a few signs
1n workers exposed to 0.3-5 mg/m3 (Saric et al., 1977) and 0.4-2.6 mg/m3
(Chandra et al., 1981) suggest that the LOEL may range to as low as 0.3
mg/m3 (300 pg/m3). The data available for identifying effect levels
below this level is equivocal or inadequate. This is 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 manganism. There is no clear-cut
evidence of chronic manganese poisoning under 5 mg/m3.
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 respirable particles.
In order to obtain definitive dose response data, a cohort study is
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.
6-23
-------
6.3. NEUROTOXIC EFFECTS - ANIMAL STUDIES
The wide range of epidemlological studies Indicates that the clinical
manifestations, observed morphological lesions and biochemical changes
described 1n chronic manganese Intoxication closely resemble those that
occur in other extrapyramldal disorders, notably Parkinsonlsm. The exact
mechanism of biochemical changes is still debated, as is the role of
manganese 1n the extrapyramldal syndrome in exposed workers (Barbeau et al.,
1976; WHO, 1981). Such controversy regarding the neurological component of
chronic manganese intoxication in exposed workers prompted a wide range of
animal studies focused on the neurotoxic effects of this metal.
Host of the earlier neurologic studies in animals utilized the parenter-
al or respiratory route of administration. Table 6-7 summarizes some of the
more recent data on neurological effects. An in-depth analysis of all
available animal data suggests that 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 manga-
nese (Pentschew et al., 1963; Neff et al., 1969; Mustafa and Chandra, 1971;
Bonilla and Diez-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
(Chandra 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; Bonilla, 1978, 1980; Deskin et al., 1981a;
Chan et al., 1981; Lai et al., 1981b, 1983c). Furthermore, in recent
studies by the same group (Chandra et al., 1979b; Murthy et al., 1981) the
brain manganese levels are reportedly different from values in their other
studies (Chandra et al., 1979a; Chandra and Shukla, 1981).
6-24
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There 1s also concern about the appropriateness of certain animal
species in studying manganese toxldty. 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 SMvastava, 1970; Chandra et al., 1979a,b; Singh et al., 1974,
1975; Shukla and Chandra, 1976, 1977; SHaramayya et al., 1974). This lack
of effect seen 1n .the rat may not be specific to manganese toxlcity. In
attempting to develop animal models of Park1nson1sm and other extrapyramldal
dysfunctions, small laboratory animals have not been found to show similar
behavioral pathologies (e.g., tremor, aklnesla, gait disorders). As a
consequence of this, studies conducted 1n rodents have tended to rely on
what might be homologous behaviors. The accuracy with which such studies
model the disorder observed 1n primates 1s open to some question.
There may be additional reasons to favor primate over small laboratory
animal studies of manganese toxlcity. Manganese accumulation appears to be
relatively high 1n pigmented tissues. Since the primate, but not rodent
substantla nlgra shows pigmentation, there 1s some basis for predicting
species differences 1n accumulation and, consequently toxlcity, of manganese.
H1stopatholog1c studies of manganese toxidty 1n small animals have
found scattered neuronal degeneration 1n the cerebral and cerebellar cortex
(Chandra and Srlvastava, 1970; Chandra et al., 1979b; Shukla and Chandra,
1976), but have only occasionally observed changes 1n the neostrlatum
(Chandra, 1972). Consequently, with the exception of Intratracheally
exposed rabbits described below (Mustafa and Chandra, 1971, 1972; Chandra,
1972),. studies with small animals did not find the characteristic hlsto-
pathologlc features of the extrapyramldal disease of manganlsm which are
6-26
-------
prominent in exposed workers and which are presumed to be responsible for
the behavioral manifestations of manganese intoxication.
It 1s probable that the signs of extrapyramidal 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 in chronic manganese
poisoning appear in the rat after chronic manganese intoxication. They
found alteration of the sleep-wake cycle in rats exposed i.p. to 2.2 mg
Mn/kg bw daily for 8 months. Chronic manganese intoxication in this experi-
ment created an increase in 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 in cortical activity rather than to
lesions of the extrapyramidal system.
Experiments with rats indicate that a daily i.p. administration of 2-4
mg Mn/kg bw produces neuronal degeneration in 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 Srivastava, 1970; Shukla and
Chandra, 1976, 1977). These experiments also demonstrate that the maximum
number of degenerated neurons is present when the amount of manganese in the
brain is at maximum, thus indicating that the extent of damage to brain
cells is directly related to the amount of manganese present (Chandra and
Srivastava, 1970; Shukla and Chandra, 1977). Iron deficiency in the pres-
ence of treatment with manganese results in the highest levels of manganese
in rat brain tissue. Some other studies have shown that biochemical changes
(e.g., decreased activity of succlnic acid dehydrogenase, increased activity
of monoamine oxidase) may appear earlier than histological alteration of the
brain, I.e., even 30 days after the beginning of manganese exposure
6-27
-------
(SHaramayya et al., 1974; Shukla and Chandra, 1976, 1977; Chandra et al.,
1979a,b). However, from all these experiments performed on rats, H appears
that the threshold for the appearance of microscopic lesions and biochemical
changes occurs when the manganese 1n the brain reaches a level of -4-5
pg/g 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 norepine-
phrlne and dopamine, 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
conducted under inadequate experimental conditions (small numbers of animals
were exposed to large, widely spaced doses of manganese by non-natural
routes) (see Table 6-7). However, these exposures did consistently produce
extrapyramidal symptoms (excitability, intention tremors, rigidity in the
extremities) and/or histological lesions (damage to the putamen, caudate,
subthalamic nucleus, and pallidum) that were remarkably similar to those
described in cases of human manganism. Suzuki et al. (1975) administered
s.c. 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
6-28
-------
tissue concentrations in monkeys were proportional to cumulative dose (Table
6-8). Although the severity of symptoms was not dose-related, symptoms
appeared earlier when higher doses were administered.
In contrast to the experiments described above, Ulrich et al.
(1979a,b,c) observed no neurological or other pathological changes in groups
of 8 squirrel monkeys and 30 Sprague-Dawley rats exposed to Mn^ aero-
sol at 11.6, 112.5 or 1152 yg Mn/m3 24 hours/day (equivalent aerodynamic
diameters ~0.11 y). 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 limb tremor or electromyographic
activity were observed, although the techniques used to measure these
parameters were described as sensitive enough to demonstrate differences if
present. The authors report that there were no clinical signs of toxicity,
but no' details of the examination were presented. Histological examination
of brain tissue for CNS alterations was reported to reveal no degenerative
changes. These results indicate that large amounts of manganese may be
required to produce extrapyramidal effects, since manganese levels in the
blood of the monkeys exposed to the highest concentration were five times
higher than in the controls after 9 months of exposure. Brain manganese
levels were not reported.
Coulston and Griffin (1977) studied eight rhesus monkeys exposed contin-
uously to 100 yg/m3 of Mn 0 and observed daily for signs of toxic-
O *r
ity. Six monkeys served as unexposed controls. After 12 months the authors
report "no behavior or other visual manifestations of toxicity attributable
to exposure to manganese" with no further details of the clinical examina-
tion. Two other rhesus monkeys exposed to 5000 yg/m3 of Mn,^ for
23 weeks showed no signs of toxicity during the exposure period nor during a
6-29
-------
TABLE 6-8
Neurological Signs Induced by Manganese 1n Monkeys3
Single Dose
mg Mn (rag/kg)b 0
Time 1n Weeks and Cumulative Dose (mg Mn)
10
12
158 (39.5) 0
316 (79)
632 (158)
316
632
1264
632
1264
948
1264
1422
Tremor, excitability,
chorelform movement, con-
tracture of hand
1896 2528 2844
Tremor, excitability, chorelform
movement, contracture of hand
2528 3792 5056 5688
Tremor, excitability, chorelform movement
contracture of hand
aSource: Adapted from Suzuki et al., 1975
DDose per body weight not reported. Monkeys weighed 3.5-4.5 kg. Estimates
are based on 4.0 kg animal.
6-30
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10-month observation period. Examination of tissues showed no changes
attributable to manganese.
The chronic toxldty of orally-administered manganese has not been
adequately studied, but the available reports strongly suggest that 1t 1s
very difficult, If not Impossible, to produce the characteristic signs of
extrapyramldal neurological disease 1n small laboratory animals exposed via
drinking water or food. As discussed above, this may reflect fundamental
species differences 1n response to disruption of neostMatal function.
However, there 1s reason to expect that small laboratory animals may show
neurochemlcal or other behavioral evidence of toxlcity. Rats seem to be
unaffected by dietary Intakes as high as 2000 ppm (Wassermann and Wasser-
mann, 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 D1ez-Ewald (1974) exposed rats to 5000 ppm of manga-
nese 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. Hlstopathological observation of the
caudate nucleus revealed only moderate pyknosis of some neurons, and treated
animals showed significant decreases in brain concentrations of dopamlne and
homovanillic acid. Bonllla (1978a,b) found an increase in the concentration
of Y-aminobutyric add In the brains of rats that were exposed to 10,000
ppm MnCl in 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 husmanite, manganous manganic oxide
(Mn 0 ), the major residue produced- by heating MMT. The effect of
3 4
chronic manganese oxide ingestion in rats maintained on a normal iron diet
6-31
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(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).
Animals were exposed to four different levels of Mn 0 in their diet,
O T"
50, 400, 1100 and 3550 ppm manganese, corresponding to 2.25, 18, 50 and 160
mg Hn/kg bw, respectively. Animals treated with manganese and maintained on
a normal Iron diet or on a low Iron diet did not develop signs of extrapyra-
mldal 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 ppm manganese as Mn00,, corre-
o 4
spending to -140 mg/kg bw over a period of 2 months, reduces reactive
locomotor activity (RLA) 1n mice and retarded growth of the testes and sex
accessory glands. Whether the effects on activity and reproductive system
development are causally related is uncertain.
Biochemical changes 1n the brains of rats exposed to 4.4 mg Mn/kg bw in
their drinking water have been described (Singh et al., 1979), and similar
exposure to 0.28 mg Mn/kg bw reportedly produced neuronal degeneration in
the cerebral and cerebellar cortex of growing rats (Chandra and Shukla,
1978). Although dietary levels of manganese in the above studies were not
reported, it is unlikely that the described changes are attributable to man-
ganese exposure. It is important to note that the above doses are generally
below the dietary level of -20-30 mg Hn/kg bw that has been found to be
optimal for development and growth in rats (Holtkamp and Hill, 1950; Hill
and Holtkamp, 1954), and below the daily requirement for rats of 50 mg Mn/kg
of diet (3-6 mg Mn/kg/day bw) that was recently recommended by the WAS
(1978). Other recent studies relating biochemical changes in the brain to
administration of manganese are discussed in the following section.
6-32
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6.3.1. Mechanism of Manganese Neurotoxldty. 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
pharmacoklnetlcs, the homeostatic mechanisms as well as the deficiency -
sufficiency - toxlclty continuum of manganese; 2) the dose-effect relation-
ship 1n manganese encephalopathy has not been systematically or adequately
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 manga-
nese encephalopathy are Inadequate: the provision of complete data will
undoubtedly generate new Ideas and theories concerning the neurotoxlc mecha-
nisms underlying this syndrome (Sllbergeld, 1982). However, despite the
1
shortcomings just discussed, more recent studies employing animal models of
this disease have provided some Interesting and useful Information 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 relatively 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
6-33
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concepts, they can be grouped Into two broad categories: 1) those that
directly Implicate altered neurotransmitter metabolism, and 2) those that do
not directly involve dysfunctions of neurotransmitter systems, but also do
not preclude the latter as being secondary, indirect or side effects.
6.3.2. Altered Neurotransmitter Metabolism.
6.3.2.1. EARLY PHASE OF RESEARCH IMPLICATING DISTURBANCES OF THE
CENTRAL MONOAMINERGIC SYSTEMS — Early neuropathological and histological
findings reveal certain neuronal degenerative changes in the neostriatum,
the subthalamic nuclei and less frequently in other brain regions in chronic
manganese encephalopathy (Pentschew et al., 1963). From the more recent
mapping studies (Ungerstedt, 1971) of the central monoaminergic systems in
the mammalian CNS, it is apparent that some, if not most, of the neuronal
degenerative alterations in manganese encephalopathy occur in the anatomical
locations of these monoaminergic pathways (see Figure 6-3). Studies in
human manganism as well as in animal models of this disease indicate that
the levels of monoamines such as dopamine, noradrenaline and serotonin (and
some of their metabolites) in the neostriatum are decreased (Neff et al.,
1969; Mustafa and Chandra, 1971; Cotzias et al., 1971). Since these changes
1n the levels of monoamines also occur in Parkinsonism and since the
clinical signs and symptoms of chronic manganese encephalopathy show many
similarities with Parkinsonism, the hypothesis that the dysfunction of the
central monoaminergic systems (particularly the dopaminerglc system) was the
underlying pathophyslologlcal mechanism of chronic manganese encephalopathy
was first proposed (Cotzias et al., 1971). Consistent with this hypothesis
was the observation that treatment of patients with L-dopa, a classical
anti-Parkinsonlan drug, alleviates the symptoms of this disease (Mena et
al., 1970).
6-34
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6.3.2.2. RECENT STUDIES THAT SUPPORT THE HYPOTHESIS THAT THE CENTRAL
DOPAMINERGIC SYSTEM IS DISTURBED IN CHRONIC MANGANESE TOXICITY — Since the
central dopamlnergic system plays a key role in the normal functions of the
basal ganglia, and dysfunctions of the basal ganglia are clearly discernible
in chronic manganese encephalopathy, the proposal that a major, if not the
major, neurotoxic effect of manganese involves disturbances of the central
dopaminergic system appears most reasonable. Furthermore, the observations
that in the human brain the manganese concentrations in the basal ganglia
are higher than those in other regions (Curzon, 1975) and that in manganese-
poisoned animals this brain region accumulates more manganese than other
regions (Lai et al., 1981b, 1983a,c; Scheuhammer and Cherian, 1981; Chan et
al., 1983) are consistent with this hypothesis. However, contrary data
which do not provide evidence of greatest manganese accumulation in neostri-
atal structures has also been reported (Austissier et al., 1982; Kontur and
Fechter, 1983). Despite the concensus that the central dopaminergic system
is disturbed in experimental manganese neurointoxication, the precise
details of the temporal, qualitative as well as the quantitative aspects of
the disturbances are still controversial.
Recent studies which suggest a relationship between experimental
manganese intoxication and some aspect of dopaminergic neurochemistry are
reviewed below. These studies are organized in terms of different processes
necessary for neurotransmission, namely: 1) synthesis of dopamine and sus-
ceptibility of the.rate-limiting synthesizing enzyme, tyrosine hydroxylase;
2) release of dopamine into the synaptic cleft and its subsequent inactiva-
tion by re-uptake into the nerve terminal; 3) metabolism of the neurotrans-
mitter to inactive products via such enzymes as monoamine oxidase; 4) bind-
ing to receptors with consequent biological activity such as changes in ion
6-35
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channels and Increased adenylate cyclase activity. Processes are presented
schematically 1n Figure 6-4.
6.3.2.2.1. Manganese and Synthesis of Dopamlne — Since tyroslne
hydroxylase (TOH) catalyses the rate-limiting step 1n brain catecholamlne
biosynthesis, the changes 1n brain dopamlne (DA) concentrations 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 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"1". In young male rats
chronically treated with MnCl2«4H20 (1 mg/mfc in the drinking water)
strlatal dopamlne level is Initially Increased and, upon more chronic treat-
ment with this manganese salt, is decreased (Chandra and Shukla, 1981). In
adult male rats chronically treated with MnCl (10 mg/mft 1n the drinking
water) TOH activities in neostrlatum, midbrain, hypothalamus and hippo-
campus, but not 1n frontal cortex and cerebellum, are Increased in the first
few months of treatment (Bonilla, 1980). However, upon more chronic treat-
ment with HnCl2, TOH activities are decreased in the neostriatum but its
activities 1n the other brain regions are essentially the same as values in
control animals (Bonilla, 1980). Thus in manganese-treated rats the changes
in brain TOH activities closely parallel the fluctuations of brain dopamlne
levels (Bonllla, 1980; Chandra and Shukla, 1981). However, manganese admin- '
istratlon by oral gavage in the form of MnCl -4H 0 at doses of 1, 10
and 20 pg Hn/g bw/day in rat pups during postnatal development for 24 days
gives rise to dose-dependent decreases in TOH activities, dopamine levels
and dopamlne turnover in the hypothalamus (Deskln et al., 1981a). Further-
more, the dose-dependent changes (decreases at the lowest dose but increases
6-36
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TYROSIN'f .
FIGURE 6-4
Schematic representation of a dopamlne synapse Indicating possible sites
of damage produced by manganese exposure: 1) synthesis of dopa by tyroslne
hydroxylase, 2) release of dopa and Us 1nact1vat1on by reuptake,
3) dopamlne metabolism to Inactive products, 4) dopamlne bind to post
synaptlc receptor sites.
Source: Adapted from Cooper et a!., 1982
6-37
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at the higher doses) 1n tyroslne hydroxylase activities closely parallel the
•
dose-related changes 1n dopamlne levels 1n the strlatum of these manganese-
treated rat pups (Deskln et a!., 1981a). Employing a different route of
administration of manganese (1 mg HnCl -4H 0 per 100 g/day 1.p.)»
Aut1ss1er et al. (1982) also found decreases in strlatal dopamlne and
dopamlne turnover 1n rats 4 months after such treatment.
6.3.2.2.2. Manganese and Dopamlne Release and Re-uptake — 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 ma of
drinking water) throughout brain development leads to transient, age-
dependent but definite decreases 1n dopamlne uptake by synaptosomes, nerve
endings containing neurotransmitter storage sites 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
administration of MnCl -4H 0 (1 mg/ma, of drinking water) throughout
development gives rise to Increased accumulation of this metal 1n all the
brain regions studied, with the exception of the cerebral cortex (Lai et
al., 1981b), and that the in vitro inhibitory effects of manganese on dopa-
mlne uptake by synaptosomes vary depending on the brain region from which
the synaptosomes are isolated (Lai et al., 1981c). However, the ijv 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/ms, of drinking water) leads to increased (rather
than decreased) synaptosomal dopamlne uptake measured ex-vivo (Leung et al.,
1982b). In comparison with its effects on synaptosomal dopamlne uptake, the
effects of manganese on dopamine release have not been extensively studied,
6-38
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although a recent study by Daniels et al. (1981) reveals that dopamlne
release by the rat striatal slice preparation 1s stimulated by 5 pM Mn *.
6.3.2.2.3. Manganese and Dopamlne Metabolism — Another mechanism by
which manganese can Influence the steady-state dopamlne levels 1n the brain
1s through Its actions on dopamlne metabolism (breakdown). A key enzyme
Involved 1n this process 1s monoamlne oxldase (MAO). In earlier studies by
Chandra and co-workers (SUaramayya et al., 1974; Chandra and Shukla, 1978),
Increased brain activities of MAO 1n manganese-treated rats were reported.
More recently, Chandra and Shukla (1981) found that the striatal MAO activi-
ties are only Increased during the Initial phase of chronic manganese treat-
ment. Others have reported that brain MAO activities 1n manganese-treated
rats show both Increases and decreases (Oeskln et al., 1981a) or remain
unchanged (Klmura et al., 1978; Autissier et al., 1982). However, 1t 1s
Important to point out that, since MAO 1n brain and other tissues exists 1n
multiple forms (La1 et al., 1980), none of the studies so far discussed
(SUaramayya et al., 1974; Chandra and Shukla, 1978, 1981; Klmura et al.,
1978; Deskln et al., 1981a; Autissier et al., 1982) set out to address the
effects of manganese on the heterogeneity of MAO. The studies of La1 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 chronically treated with
MnCl «4H 0 (1 mg/mi of drinking water) throughout development until
adulthood, only type A MAO activity in the cerebellum 1s slightly decreased
(Leung et al., 1981). In these treated rats, type A MAO activities 1n all
the other brain regions, type B MAO activities in all the brain regions as
6-39
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well as the type A to type B MAO activity ratios 1n all the brain regions
remain unchanged. Furthermore, the development of type A and type B MAO
activities 1n the whole brain of rats treated with MnCl -4H 0 (either
1 or 10 mg/mS, 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 1n 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 during development,
Hfespan treatment of rats with MnCl »4H 0 (1 mg/mS, 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 exam-
ple, consider the age-related decreases 1n type A MAO and dopamlne-oxldlzing
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; Sllbergeld, 1982).
6.3.2.2.4. Manganese and Effects at the Receptor — In human ampheta-
mine 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 pathophysiology of chronic human manganism. Since chronic
manganese encephalopathy commences with a phase of psychotic behavior
6-40
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("locura manganlca" or "manganese madness") (Cotzias et al., 1971; Barbeau
et al., 1976) resembling that of schizophrenia and amphetamine psychosis,
and alterations of the central dopamlnerglc receptor functions have been
Implicated 1n the pathophyslology of the latter two syndromes, 1t Is reason-
able to hypothesize that one of the neurotoxlc mechanisms of manganese may
be Its effect on these receptors. Several groups of researchers have specu-
lated and proposed that some of the transient neurochemlcal changes during
the Initial stages of chronic and very long-term manganese neurolntoxlcatlon
1n animals could be viewed as pathophyslologlcal parallels to the Initial
manifestation of psychotic behavior in human manganism (Bonilla, 1980;
Chandra and Shukla, 1981; Lai et al., 1983b,c). There is some evidence that
manganese exerts definite effects on the dopamine receptors. The binding of
agonist and antagonist to dopamine receptors is potently enhanced by manga-
nous ions (Usdin et al., 1980). Intraperltoneal administration of MnCl
(10 or 15 mg/kg bw/day) to rats for 15 days results in increased binding of
the dopamine antagonist spiroperidol to striatal membranes (Seth et al.,
1981). Moreover, manganese also stimulates brain adenylate cyclase activity
In. vitro (Walton and Baldessarini, 1976). Recently Bonilla (1983) found
that striatal adenylate cyclase activity is markedly decreased in rats
exposed to 2.5, 5 and 10 mg Mn (as MnCl ) per ma. of drinking water for 8
months. In addition, the cyclase activity in the treated animals does not
respond to stimulation by dopamine (Bonilla, 1983). In rats chronically
treated with MnCl «4H 0 (10 mg/rnl of drinking water) throughout
development, the increases in open-field behavior elicited with i.p. amphet-
amine 'administration (1 mg/kg bw) are far less marked (Leung et al., 1982b).
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6.3.2.3. IMPLICATIONS OF THE ALTERED METABOLISM OF OTHER NEUROTRANS-
MITTERS IN MECHANISMS OF MANGANESE NEUROTOXICITY —As noted 1n the Intro-
duction to this chapter and represented 1n Figure 6-2, dopamlne neurons make
synaptlc contact with neurons located 1n the neostMatum which contain other
neurotransmitters. Some of these neurons are capable of affecting activity
1n the dopam1ne-conta1n1ng cells through a process of feedback Inhibition.
Thus 1t 1s quite possible that toxic damage to these non-dopamlnerglc cells
could 1n fact have the secondary consequence of altering function In the
dopamlne neurons. Two nerve types Identified 1n the neostrlatum which could
serve such a role are those containing the neurotransmitiers gamma amlno
butyric add (GABA) and those containing acetylchollne. The evidence that
manganese may affect these cells is reviewed below.
6.3.2.3.1. GABAergic Systems -- In rats treated with MnCl2 (10
mg/mS, of drinking water) for 2 months, the caudate gamma amino butyric
acid (GABA) level 1s increased markedly although the activities of glutamic
acid decarboxylase (GAD), the rate-limiting enzyme responsible for GABA
synthesis, and GABA-transaminase, the enzyme which metabolizes GABA, remain
unchanged (Bonllla, 1978a). Employing a developmental rat model of chronic
manganese encephalopathy (1 mg MnCl »4H 0 per ma of drinking water
throughout development), Lai et al. (1981a) demonstrated that chronic
manganese toxicity does not alter the brain regional activities of GAD:
these results confirm those obtained by Bonilla (1978a,b) in the rat
caudate. Short-term 1.p. treatment with Mn (15 mg MnCl2/kg bw/day for 15
days) gives rise to a small decrease 1n cerebellar GABA binding (Seth et
al., 1981).
6.3.2.3.2. Cholinergic System — Since the pathophysiology of
manganese encephalopathy and that of Parkinsonism show certain similarities
6-42
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(Cotzias et al., 1971) and the cholinergic system may be Implicated 1n the
pathogenesls of Parkinsonism (Erickson, 1978), several systematic studies
have been initiated to investigate the possibility that the neurotoxic
effects of manganese also involve the cholinergic mechanism (Lai et al.,
1981a, 1982a,c; Bonilla and Martinez, 1981). In adult rats chronically
treated with MnCl «4H 0 (1 mg/ms, of drinking water) throughout
development, the activities of ChAT, the enzyme that catalyses the synthesis
of acetylcholine, decrease slightly in cerebellum and midbrain whereas the
activities of this enzyme in the other brain regions as well as the activi-
ties of AChE, the enzyme that catalyses the metabolism of aeetylcholine,
remain unaltered in all the brain regions studied (Lai et al., 1981a).
However, in rats treated similarly (Lai et al., 1982a, 1983b), choline
uptake by hypothalamic 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 in the brain regional
development of AChE activities (Lai et al., 1982c). Bonilla and Martinez
(1981) studied the activities of ChAT and AChE in different brain regions in
adult rats treated with 10 mg MnCl2 per ma of drinking water for 1-8
months and found virtually no changes in the activities of these enzymes.
The results of Bonilla and Matinez (1981) and those of Glanutsos and Murray
(1982) are compatible with those of Lai et al. (1981a, 1982c).
6.3.2.3.3. Other Neurotransmltter Systems — Although the lack of
systematic studies precludes any critical and accurate assessment of the
possible roles of other neurotransmitters in the pathogenesls and pathophys-
iology of the neurotoxic effects of manganese, there is some indication that
6-43
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the noradrenerglc system may also be Implicated (Chandra et al., 1979c;
Chandra and Shukla, 1981; Aut1ss1er et al., 1982).
6.3.2.4. MECHANISMS THAT DO NOT DIRECTLY IMPLICATE NEUROTRANS-
MITTERS -- 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.
6.3.2.4.1. Free-rad1cal-med1ated Neuronal Degeneration — This mecha-
nism 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
generation of free radicals (e.g., superoxlde anlon, hydrogen peroxide and
hydroxyl radicals) giving rise to degenerative changes (Donaldson, 1981;
Donaldson et al., 1981, 1982).
6.3.2.4.2. Autoxldatlon of Amines to Qulnones Enhanced by Manganese —
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).
6.3.2.4.3. 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) in their normal capacity (Lai et al., 1983d)
or antagonize other metals (e.g., manganese is a potent Ca antagonist).
6-44
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Under both of these conditions, altered metabolic or cellular regulation may
be the predicted result.(La1, 1983; Laiet al., 1983d,e).
6.3.3. 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
pg/m3 Mn«0 . Unfortunately, this study did not Include biochemical
0 *
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
neunotoxlc 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 in brain levels of monoamlnes,
t
particularly dopamine: More recent studies Indicate that chronic treatment
of rats with MnCl 1n the drinking water throughout development is asso-
ciated with selective regional alteration of synaptosomal dopamine uptake
but not of serotonin or noradrenaline uptake (Lai et al., 1982b). In the
latter studies, the brain regional manganese concentrations show dose-depen-
dent increases (Chan et al., 1981, 1983) and 1n animals treated with the
higher manganese dose, the changes in synaptosomal dopamine uptake is asso-
ciated with decreased behavioral responses to amphetamine challenge (Leung
et al., 1982a). All these observations are consistent with the notion that
1n chronic manganese toxicity the central dopaminerglc system is disturbed.
6-45
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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.
6.4. LUNG EFFECTS
6.4.1. 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), Dantln Gallego (1935), and ViglVanl (1937), Baader (1937)
concluded that pneumonia should be regarded as an occupational disease among
%
manganese workers.
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,
compared 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
6-46
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symptoms of bronchitis and Irritation of the nasopharynx. Manganese concen-
trations 1n air, calculated from the MnO~ content of dust, were between
0.1 and 13.7 mg/m3. Approximately 80% of the particles were <0.2 y 1n
size and nearly all particles were <1 p.
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 it 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
Incidence 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.
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 In
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.
6-47
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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
(Gotten 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
similar and the chest symptoms to be caused primarily by the manganese in
the slag.
Wassermann and Hihall (1961) studied manganese miners, coal miners and
forest workers, all working in 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
of the dust were 28-840 mg/m3, and the concentration of manganese ranged
from 2-200 mg Hn/m3 depending on workplace. Particles contained 12-30%
manganese and the range of particles <5 v was 34-81%. Silicon dioxide was
also present. Measurements showed manganese concentrations of 55 and 78
mg/m3 in 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
pulmonary fibrosls and the presence of nodules. Evidence of manganism was
reported 1n 19 workers (2%). Definitive evidence of flbrotic or other
specific lung changes has rarely been reported with occupational exposure to
manganese aerosols because radiological examinations were not performed.
6-48
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F1brot1c changes observed by Buttner and Lenz (1937) were almost certainly
due to the 20% silica present 1n dust from the Glessen pyrolusite (MnOp)
mines. Manganocon1os1s was confirmed or suspected In 21% of all of the
miners and the percentage Increased with age and duration of work In 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 Ludc-Palaic (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
level of manganese exposure was reported as 0.4-16.35 mg/m3 for workers 1n
the production of ferroalloys, 5-40 yg/m3 for workers 1n the electrode
plant and 0.05-0.007 vg/m3 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 symptoms of phlegm
and wheezing was compared 1n smokers and nonsmokers In the group of ferro-
alloy workers and 1n the control groups. Chronic bronchitis was defined as
bringing up phlegm 1n- the morning and during the day and/or night for at
least three winter months 1n the last 2 years or longer. Table 6-9 shows
that chronic bronchitis was highest 1n smokers 1n the high exposure group.
The percentage of chronic bronchitis associated with the objective finding
of reduced forced vital capacity was 5% (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 respiratory symptoms
among smokers did not show an exposure-response association among the group.
6-49
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TABLE 6-9
Prevalence of Chronic Bronchitis 1n Groups of Workers
According to Smoking Statusa»b
Manganese
Alloy
Production
Exposure to
Manganese
Smokers
Non-smokers
Total0
(0.4-16,4
Number
46/143
14/169
64/369
mg/m3 )
%
32.2
8.3
17.3
Aluminum
Electrode plant
(5-40
Number
14/69
11/102
28/190
yg/m3 )
%
20.3
10.8
14.7
Rolling Mill
(0.05-0.07
Number
17/94
4/81
25/204
yg/m3 )
%
18.1
2.0
12.3
aAdapted from Sarlc and Luc1c-Pala1c, 1977
Statistical analysis 1n original publication 1s multiple t-tests. This
was considered Inappropriate and Is therefore not presented.
cThe denominators do not total 369 because data for 57 past smokers are
not Included.
6-50
-------
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 synergism between airborne manganese and smoking
habit in the occurrence of respiratory symptoms. However, the results do
not support synergism because there is no consistent increase in symptoms
among the group. Further, percentages appear to be additive, but data is
not sufficient to support this.
Several reports suggest an influence of manganese on the rate of pneu-
v
monia and other respiratory ailments among inhabitants living in 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
manganese ore smelting works in 1923. Data about manganese concentration in
air from Sauda are not reliable because only one measurement was made. The
report indicates that manganese was contained in visible clouds of brown
smoke polluting the atmosphere and the dry matter in the smoke was found to
contain silica. From 1924-1935, lobar pneumonia accounted for 3.65% of all
deaths in all of Norway and 32.3% of all deaths in Sauda, although the dis-
ease had been infrequent in 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 50% 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 pneumococci in Sauda did not differ from the rest of Norway.
6-51
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Nogawa et al. (1973) studied subjective symptoms and ventHatory 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. These authors cite exposure measures made by the Ishlkawa Prefectural
Research Institute (White Paper, 1971). Manganese dustfall measured monthly
for 3 years averaged 200 kg/kmVmonth (20,000 ng/cmVmonth) In the
vicinity of the plant compared to 20-fold lower levels measured at four
other points elsewhere 1n town. In July, 1970, when the survey by Nogawa et
al. took place, the manganese concentration 1n the dust fall was -100
kg/kmVmonth. Levels over 200 kg/km2/month did not occur In 1970 until
December. Amounts of dustfall and sulfur oxide concentrations plotted over
the same time period showed almost no difference between areas within the
vicinity of the plant and other areas. Other heavy metals were present but
only manganese and iron were high compared to other cities. This dustfall
level 1s indicative of an ambient air concentration of about 3-11 ng/m3,
based on similar measurements taken in the vicinity of a U.S. ferromanganese
plant (see Table 3-22) where settled manganese dust was related to quarterly
measures of airborne manganese. Atmospheric concentration of manganese
100 m from the plant measured by a high volume air sampler was reported as
4.04 pg/m3. The author cites a previous report of a 5-day average of
6.7 yg/m3 at a point 300 m from the plant.
Data on subjective symptoms and medical history of the student and
family were obtained in July by 1970 by the British Medical Research Council
questionnaire for which the response rate was over 98% in each school. Of
the 30 Items the following were reported to have higher prevalence in
students from the school near the factory: presence of sputum in winter on
arising, presence of sputum 1n summer, wheezing, clogged nose, frequent
6-52
-------
colds, and all six Hems referring to symptoms of the throat. These were
reported to be statistically significant at p<0.05 but the test used was not
specified. The authors addressed several Issues which could affect relia-
bility of results. Since ventilation function was related to stature, they
compared the stature of students 1n the two schools and found no difference
sufficient to bias results. They noted that the exposure values at the two
schools could distinguish among the two groups because students at the
polluted school lived within 1500 m of the plant whereas students from the
control school lived at least 5 km from the plant. Furthermore, data on
schoolchildren are far less likely to be biased by smoking habit and occupa-
tional 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 97% 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
polluted area Improved after manganese exhaust diminished.
In a study on the effect of air polluted with manganese 1n the vicinity
of a plant smelting pig Iron and ferromanganese, Dokuchaev and Skvortsova
(1962) examined clinical histories of 1200 children up to 16 years of age.
6-53
-------
Manganese concentrations 1n air within a distance <1 km from the plant
fluctuated from 0.002-0.262 mg/m3. Residents within 0.5 km of the plant
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% of nasal mucosa smears from 700 children. Roentgenologlcal
examinations showed pulmonary changes In 75% of the children, many of tuber-
culous etiology or other residuals of past disease. However, 1t 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 contam-
inated by a ferromanganese plant. Table 6-10 shows the 3-year cumulative
Incidence of acute bronchitis (and peribronchitls) in 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 in the population of the town did not vary by pollu-
tion zone, nor did it show the expected difference between summer and winter
periods. Because the concentrations of manganese in the ambient air were
higher in summer than in winter, the question was raised whether vthe expect-
ed difference was masked by respiratory disease associated with observed
seasonal variations in the level of manganese. Incidence rates were pre-
sented 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 in the town (Saric, 1983). The
authors also stressed the fact that in this study some other potentially
relevant factors may not have been sufficiently controlled. :
6-54
-------
TABLE 6-10
Cumulative Incidence of Acute Respiratory Diseases During
the 3-Year Period*
Mn Concentration
(vg/m3)
i
Acute bronchitis
and peribronchltis
Winter
Summer
Pneumonia
Winter
Summer
0.27-0.44
I (N=8690)
Number
474
296
47
39
*
5.5
3.4
0.5
0.4
0.18-0.25
II (N=17105)
Number
1125
698
84
93
0.
Ill
05-0.07
(N=5296)
% Number %
6.6
4.1
0.5
0.5
2261
141
17
19
4.3
2.7
0.3
0.4
*Adapted from Sarlc et al., 1975
6-55
-------
6.4.1.1. 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-
pational exposure, 5 mg Mn/m3, 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 6-11 summarizes those studies which report levels of exposure to
manganese. The study 1n schoolchildren (Nogawa et al., 1973) was suffi-
ciently well documented to support an association between the Increased
respiratory symptoms 1n children and exposure to the dusts containing
manganese from the emissions of the ferromanganese plant estimated by EPA to
correspond to exposure levels of 3-11 yg/m3. It 1s plausible that
exposure to manganese may Increase susceptibility to pulmonary disease by
disturbing the normal mechanism of lung clearance. Uncertainties regarding
manganese as an etlologlcal factor 1n the development of pulmonary diseases
(I.e., pneumonia) among workers prompted the animal studies described 1n the
next section.
6.4.2. Animal Studies. Studies with animals (Table 6-12) 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.
6-56
-------
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6-59
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Hlstologlcal examination of lung tissue from animals exposed to manganese by
Inhalation Indicates that slight to Intense leukocyte Infiltration charac-
terizes the acute pulmonary responses (Jotten et al., 1939; Lloyd-Davies,
1946; Halgetter 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 in the lungs (e.g., bronchopneumonla or pneumo-
nitls, chronic inflammatory effects such as fibrosis); instead, it 1s likely
that susceptibility to infection is increased. Table 6-12 shows the pulmo-
nary effects of exposure to manganese with and without simultaneous exposure
to bacteria. Since the pulmonary reaction after exposure to manganese is
more pronounced in lungs challenged with bacteria {Jotten et al., 1939;
Heine, 1943; Lloyd-Davies, 1946; Zaidi et al., 1973; Maigetter et al., 1976;
Bergstrom, 1977), and because sufficient evidence indicates that exposure to
manganese has a depressive effect on the number and phagocytic 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
6-61
-------
some immunological 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 In Table
6-12 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 bio-
chemical 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
(Zaidl 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-Oavies and Harding,
1949; Levina and Robacevskaja, 1955), and even after 5 mg MnClp (Lloyd-
Davies and Harding, 1949). However, it 1s reasonable to conclude that the
usually rapid lung clearance of Inhaled manganese (Maigetter et al., 1976;
Bergstrom, 1977) is ineffective in the Intratracheal inoculation, so that an
amount of 5 mg manganese is sufficient to induce local lesions in 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 in
the lungs of guinea pigs exposed to 2350 mg/m3 ferromanganese dust 8
hours/day for up to 200 days. Further, in experiments on rats exposed to
150 mg MnO An3 for up to 15 months, no signs of pneumonia were observed.
6-62
-------
Table 6-13 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.
aerosol are supportive of the pulmonary toxlcity of manganese (Adklns et
al., 1980a,b,c). Charles River CD-I mice (4-8/group) were exposed for 2
hours to Hn 0 aerosol 1n concentrations ranging from 0-2.9 mg Mn/m3.
O *r
Dry/wet ratios of tissue weight were examined as an index of edema and the
fe
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.
Exposure of groups of 22-195 mice for 2 hours to 897 yg Mn/m3 signifi-
cantly reduced the total number of mlcrocytic pulmonary cells (p<0.01,
t-test), but did not affect the differential cell count (macrophages, PMNs,
lymphocytes). Reduction 1n phagocytic capability was not statistically
significant (Adklns et al., 1980b).
Adkins et al. 1980c also exposed 20-80 mice/group to Hn 0
O *r
(0.22-2.65 mg/m3) and subsequently to airborne Streptococcus pyoqenes.
Animals exposed to manganese showed higher mortality rates than Infected
%
control animals (at 0.38 mg Mn/m3 a 1.5% mortality increase was within 95%
confidence limits). These results support the concept that a primary
inflammatory reaction to manganese can occur In the respiratory tract after
exposure to manganese, causing a decrease 1n the resistance to respiratory
Infections.
Ulrich et al. (1979a,b,c) exposed Sprague-Dawley rats (30/group) and
squirrel monkeys (8/group) to Mn 0 aerosol at concentrations of 11.6,
«J T"
112.5 and 1152 yg Mn/m3 for 24 hours/day, 7 days/week for 9 months.
6-63
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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 after neurologic, hlstopathologlc, organ
weight, pulmonary function or hematologlc observations. The Investigators
evaluated pulmonary physiology data for the 4 exposure groups of monkeys
each at 5 points 1n time but the report presents only the mean percent of
pre-exposure values 1n groups of 4 after 9 months of exposure (Table 6-14).
Few statistically significant differences were found using the Mann-Whitney
U test. Mean value showed Increased airway resistance 1n some of the
exposed groups and standard error of the mean showed wide 1ntra-group varia-
bility. The authors conclude that, there were no time-related effects or
trends attributable to manganese exposure. However, it is not clear which
two groups were compared statistically, which is particulararly confusing
since there are four groups 1n the experiment. Data over time is not pre-
sented, regression methods are not used, and numbers of animals tested are
too small to detect lung damage unless 1t is quite severe. Furthermore, a
9-month exposure period even at 24 hours would not qualify as a chronic
study in the monkey and thus might be inadequate for the development of
detectable lung damage at these exposure levels.
The authors state that lungs were free of inflammatory and/or degenera-
tive changes. The microscopic examination is not described. Thus this
study as reported does not present sufficient evidence for lack of adverse
pulmonary effects because of small sample size within group variability,
insufficient exposure duration and inadequate statistical analysis. It does
support a lack of gross toxic effects at this level. Serum biochemical
evaluations showed some evidence of hypophosphatemia in the male rats
6-65
-------
TABLE 6-14
Pulmonary Physiology Data for Male
and Female Monkeys After Nine Months of Exposure3
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 vg
III 11.25 vg
IV 1152 vg
I
II
III
IV
I
II
III
IV
I
II
III
IV
I
II
III
IV
I
II
III
IV
Mean +_ SEMb
134+31
88 + 9
175 + 32
157 ±32
,90 + 4
141 + 33C
98 + 16
94 + 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 i 14
115 + 15
104 + 14
185 + 36
100 i 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.
CD = 0.028
6-66
-------
exposed to 1152 vg Mn/m3, but the toxicologic significance of this
finding 1s uncertain. The amount of manganese present in the diets of the
animals was not stated.
Coulston and Griffin .(1977) exposed seven rhesus monkeys to 100 yg
Mn/m3 as partlculate Mn 0 due to combustion of MMT for 6, 12 or 15
O *f
months. The conclusion states that there were no abnormalities on gross or
microscopic examinations. However, no objective measures of pulmonary
function were reported. Peribronchlolitis and pneumonltis was reported 1n
association with infection to mites (acariasis) in 6 of 7 exposed monkeys,
and a statistically significant increase 1n manganese 1n the lungs was
B
reported in 2 controls.
Moore et al. (1975) studied chfonic exposure to automobile emissions
from the combustion of gasoline with MMT additive. The average concentra-
tion was 117 yg Mn/m3 over 56 days, 8 hours/day. No gross or micro-
scopic changes were seen in lungs of exposed animals. [For a review of the
toxicology of MMT see Stara et al. (1973).]
6.4.2.1. SUMMARY — Information from earlier studies on the pulmonary
toxidty of manganese is Incomplete and sometimes contradictory, particular-
ly in respect to the exposure-response relationship. Some pathomorphologl-
cal changes in the lung tissue of experimental animals were observed after
intratracheal inoculation of 10 mg MnO or after 5 mg MnCl (Lloyd-
Davies and Harding, 1949).
Inhalation studies represent much better experimental models for study-
Ing pulmonary effects. Experimental evidence Indicate that acute respira-
tory effects appear when the level of exposure exceeds 20 mg/m3 of MnO
(Bergstrom, 1977; Maigetter et al., 1976). Although studies of toxlcity
6-67
-------
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 Mn 0 particle or aerosols of resplrable
«J T1
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
mg/m3, and Adklns et al. (1980c) report Increased mortality from Infection
1n mice at ~0.4 mg/m3.
Table 6-13 shows the two studies 1n which the lowest levels of exposure
to manganese occurred (UlMch et al., 1979a,b,c; Coulston and Griffin,
1977). These report no effect due to the exposure, but the latter, In par-
ticular, had deficiencies which reduce confidence 1n. the negative results.
The existence of three negative studies 1n this range supports a lack of
gross toxic effect at this level.
6.5. REPRODUCTIVE EFFECTS
6.5.1. Human Studies. Impaired sexual behavior 1n workers showing symp-
toms of manganlsm has often been reported. Diminished libido 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) re-
ported Impotence 1n ~80% of his patients, although- this symptom can be pre-
ceded by a short phase of sexual stimulation. Emara et al. (1971) reported
one case of hypersexualHy which was not followed by diminished libido.
6.5.2. Animal Studies. Influence of manganese exposure on sexual behav-
ior 1n experimental animals has not been reported 1n the literature.
However, studies have been done on hlstologlcal, biochemical and/or morpho-
logical changes. Chandra (1971) reported that i.p. administered MnCl (8
mg/kg bw dally) 1n rats caused no hlstologlcal changes 1n seminiferous
6-68
-------
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-
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 (-10%) 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
and LDH), and add phbsphatase (AP), and an Increase 1n manganese concentra-
tion 1n the testes. The authors explained their histologlcal findings as
manganese-Induced Inhibition of enzymes involved in energy metabolism of the
cells. Simultaneous administration of zinc had a beneficial effect, but
various chelating agents failed to improve morphological changes.
In another experiment in rats, Shukla and Chandra (1977) administered
MnCl2-4H20 i.p. (15 mg/kg bw daily) for 15, 30 or 45 days. An in-
crease 1n manganese concentration in brain, liver and testes was accompanied
by a decrease in nonprotein sulfhydryls, and a reduction in activity of
glucose-6-phosphate dehydrogenase and glutathione reductase. This was
explained by possible reduction of cystelne content of the tissues due to
formation of manganese-cysteine complex and its excretion from the body.
Oral administration of MnCl «4H 0 (50 yg/kg 'bw daily) to rats for
180 days did not induce chromosomal damage in the bone marrow or spermato-
gonial cells (Dikshith and Chandra, 1978). In this experiment, however, the
6-69
-------
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 vm) resulted 1n marked destruction and calcification of
the seminiferous tubules at 8 months after exposure (Chandra et al., 1973a).
There was extensive desquamation and cytolysis of various elements of the
epithelium with markedly degenerated spermatocytes and spermatids. Females
kept with experimental males did not become pregnant, but no details on the
reproductive performance testing procedure were given. Similar to results
observed in rat experiments, the activities of some enzymes were signifi-
cantly reduced (ATPase, SDH and AP). Seth et al. (1973) using the same
experimental design in rabbits, showed that degenerative changes in -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 histochemical effects of
manganese on testicular enzymes occur prior to morphological changes, Imam
and Chandra (1975) administered MnCl «4H 0 i.v. to rabbits (3.5 mg/kg
bw daily) for up to 30 days. Manganese inhibited SDH activity in seminifer-
ous tubules 5 days after the beginning of exposure, when morphological
alterations were not apparent. They demonstrated that manganese affects the
r-
germinal function of testicular tissue without disturbing steroidogenesis,
and reached the same conclusion on manganese-induced disturbances in energy
metabolism as in rat experiments.
Jarvinen and Ahlstrom (1975) exposed female rats to manganese in diet
from weaning for 8 weeks and during pregnancy. MnSO «7H 0 was the
4 2
dietary additive and final manganese concentrations in the diet were 4, 24,
6-70
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54, 154, 504 and 1004 mg Mn/kg. Exposed animals had normal reproductive
performance. No gross malformations or bone structure anomalies were
observed in 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 Hvers of their dams, but no
Increase 1n liver manganese was found 1n 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 MnCl2 as an agent producing early fetal deaths and preimplanta-
tion losses within control limits. In a similar study using dominant lethal
test procedures Jorgenson et al. (1978) administered HnSO to male rats by
single or multiple gavages at three dosage levels (levels not mentioned),
and concluded that HnSO was not mutagenic to the rat.
Gray and Laskey (1980) investigated the reproductive development associ-
ated with chronic dietary exposure to manganese. Male mice (CD-I) were ex-
posed to 1050 ppm Mn as Mn^ in a casein diet from day 15 of lactation
to 90 days of age. Wet weights of preputial 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 in 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 Mn30. (average particle size 1.02 pm) to a normal
6-71
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(240 yg Fe/g; 50 vg Hn/g) and an Iron-deficient (20 vg Fe/g; 50 pg
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,
measured 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 size, number of ovulations, resorptlons and prelmplanta-
tlon deaths, as well as fetal weights) were within control values 1n all
manganese-treated groups.
6.5.3. Summary. Except for reports of Impotence 1n patients with chronic
manganese poisoning, human data are largely lacking.
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 studies.
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.-THJ) and up to 3550 ppm (Laskey et al., 1982) as Hn304 were
almost without effect on reproductive performance. However, some observa-
tions 1n all these studies need to be verified using well-defined reproduc-
tive testing protocols.
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6.6. HEMATOLOGIC EFFECTS
6.6.1. 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.
Kesic and Hausler (1954) reviewed these data and suggested that many authors
had not considered the variability 1n normal Individuals.
Kesic and Hausler (1954) reported hematological data comparing 52 ex-
posed miners without symptoms of poisoning to 60 sawmill workers of similar
age and social conditions. The miners had higher mean levels of erythro-
cytes, 4.5xlO~6 compared to 4.3xlO~6. Mean hemoglobin levels were
higher in miners, 15.03 compared to 14.19 g, and mean monocyte levels were
lower (6.4 vs. 7.8%).
In a study on Industrial manganese poisoning, Flinn et al. (1941) found
a low white cell count in 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,
leucopenia became more pronounced with the progress of the disease.
Chandra et al. (1974) reported lower erythrocyte counts (RBCs) and lower
hemoglobin concentrations in 12 cases diagnosed as manganese poisoning
compared 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 Rodier
(1955). The RBC levels ranged from 3.5-4.8xlO~6/mm3, and controls from
5.0-5.6xlO~6/mm3. Hemoglobin levels for cases and controls were 11-14.5
g/100 mil and 15-17 g/100 ma, respectively. Total white blood cell
counts ranged from 7000-11,000/mm3 in both groups with a normal percentage
of white cell forms.
6-73
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Paternl (1954) claimed that small doses of manganese had a stimulatory
effect on erythropolesls. From other findings encountered in chronic
manganese 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 in
the number of polymorphonuclear cells. Details and a comparison group are
lacking.
6.6.2. Animal Studies. Animal studies have confirmed some of the
observed hematologlcal effects 1n humans. For example, Baxter et al. (1965)
found that hematocrlt and mean corpuscular volume were significantly
Increased 1n rats receiving 150 mg Mn/kg bw s.c.,. while serum calcium and
Iron were markedly depressed. Blood volume was unchanged; serum magnesium,
chloride, and phosphorus showed significant Increases. Similar findings
were reported by Dol (1959), who exposed rabbits to MnO 1n specially
designed Inhalation chambers. Both erythrocyte count and hemoglobin content
tended to Increase. The leukocyte count changed more extensively with a
relative Increase of lymphocytes. Hatrone 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 manganese 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 Mn304 at 50 ppm (normal dietary level), 400, 1100
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
"
6-74
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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 microcytic
anemia related to manganese dose.
6.6.3. Summary. Reports of hematological effects are conflicting, but
increased hemoglobin values and erythrocyte counts have been associated with
human (Kesic 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 microcystic anemia (Carter et al., 1980).
6.7. CARDIOVASCULAR SYSTEM EFFECTS
6.7.1. Human Studies. Saric and Hrustic (19:75) measured blood pressure
in three groups of workers aged 20-59 to observe the effect of exposure to
airborne manganese. The diastolic and systolic blood pressure of 367
exposed workers from a ferromanganese plant were compared to 189 workers in
electrode production within the same plant not directly exposed to manga-
;
nese, and 203 workers in 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
alloy varied from 0.39-20.44 mg/m3. At sites for electrode production,
the concentrations varied from 0.002-0.30 mg/m3.
Workers in 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 in each of four
10-year age groups and in all workers excluding hypertensives. The lowest
mean diastolic pressure was in workers in the light metal plant, followed by
the manganese alloy plant workers and then those from the electrode plant.
6-75
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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 in 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. Saric (1978) suggests that the differences found
1n the behavior of systolic and diastolic blood pressure in those occupa-
tionally exposed to manganese may indicate an action of manganese ions on
the myocardium.
6.7.2. Animal Studies. In rats, Kimura et al. (1978) found that dietary
exposure to 564 ppm manganese produced a significant increase in the level
of blood serotonin and a decrease in blood pressure. The researchers
attributed the final marked decrease of blood pressure to the elevated
concentration of serotonin in the blood, probably released from different
»
tissues.
6.7.3. Summary. Manganese exposure has elicited decreases in systolic
blood pressure in humans (Saric and Hrustic, 1975) and in animals (Kimura et
al., 1978). This latter finding was attributed to the elevated concentra-
tion of serotonin 1n the blood.
6.8. BIOCHEMICAL EFFECTS
6.8.1. Human Studies. Rodier (1955) reported diminished excretion of
17-ketosteroids 1n 81% of the patients with chronic manganese poisoning and
an increase in basal metabolism in 57% of the cases with manganism. These
conclusions are reported with no supporting data.
6-76
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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 glutathione, 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 In 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, B-l1poprote1ns and total Upoprotelns, as well as Increased
Incidences of hypertension and atherosclerosis 1n the exposed group.
However, there 1s no stratification or other control for confounding varia-
bles such as smoking or obesity. The Information available from table head-
Ings 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 glutathione levels.
Hemoglobin 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
6-77
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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 detect manganese poisoning in the early
stages.
6.8.2. Animal Studies. Intratracheal administration of 400 mg MnOp/kg
bw to rats caused' a significant decrease in the levels of serum alkaline
phosphatase and inorganic phosphate, and an increase 1n calcium (Chandra et
a!., 1973b). Similar observations were reported by Jonderko (1965).
Rabbits injected intramuscularly with 3.5 mg Mn/kg bw showed a distinct
increase of serum calcium and a decrease of inorganic phosphorus. However,
the mechanism of hypercalcaemia and hypophosphataemia in manganese toxicity
was not clear because no gross or microscopic abnormalities were observed in
parathyroids and bones of exposed rats (Chandra et al., 1973b).
Chandra and Imam (1975) studied the effect of i.v. administered 2.5 mg
MnCl /kg bw on the rabbit adrenal cortex. An increase in the cholesterol
content and marked degenerative changes in the zona glomeruloza and zona
fasciculata 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.
6.8.3. Summary. Effects of manganese exposure on the biochemical param-
eters include an increase in serum calcium, adenosine deamlnase, cholester-
ol, total liplds and S-lipoproteins in workers occupationally exposed to
manganese (Jonderko et al., 1974). A diminished excretion of 17-ketoster-
oids has been reported in patients with chronic manganese poisoning. Animal
experiments demonstrate a decrease in the levels of serum alkaline phospha-
tase and inorganic phosphate, and an increase in calcium 1n manganese toxic-
ity (Chandra et al., 1973b).
6-78
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6.9. DIGESTIVE SYSTEM EFFECTS
6.9.1. Gastrointestinal Tract Effects. The paucity of data and the
controversy regarding the doses used 1n the available studies cause great
difficulty 1n assessing toxic effects of manganese on the GI tract. For
example, Chandra and Imam (1973) described significant histochemical and
histologlcal alterations in 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 daily requirements, Everson et al. (1959) reported a diet
to be adequate with the presence of 40 ppm manganese. Further, Shrader and
f
Everson (1968) reported that manganese supplementation (125 ppm for 2
months) completely reversed the reduced glucose utilization caused by
congenital manganese deficiency.
6.9.2. Liver Effects. The liver plays a significant role 1n manganese
metabolism, and the biliary route is very important for the removal of man-
ganese from the body. Over 99% of an i.v. dose excreted by the rat appeared
in the feces (Klaassen, 1974). However, manganese has produced intrahepatic
cholestasis in rats, with large doses causing both functional and morpho-
logical alterations (Witzleben et al., 1968; WitzTeben, 1972). An i.v. dose
of 55-60 mg/kg bw manganese caused necrosis in rat liver and other ultra-
structural alterations resembling some of those seen in human cholestasis
Induced by drugs (Witzleben, 1969). When manganese overload was followed by
infusion of billrubin, the lesions were even more severe (Witzleben, 1971,
197.2), depending upon the dose of billrubin (Boyce and Witzleben, 1973).
Klaassen (1974) reported that no alteration in the bile flow was
observed 1n rats even at the relatively high 1.v. dose of 10 mg Mn/kg bw.
6-79
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However, when b1!1rub1n was administered Immediately after manganese Injec-
tion, 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 bH1rub1n may form a chelate
with manganese which precipitates and obstructs the biliary tree.
De Lamirande and Plaa (1978, 1979a,b) showed 1n a series of experiments
on rats that both manganese and bH1rub1n are essential for the induction of
cholestasis. Small noncholestatic doses of each resulted in cholestasis
when given together, but the order and time of injection were critical.
These observations suggest that the manganese-billrubin Interaction might
depend on the presence of short-lived intermediate compounds during the
process of manganese biliary excretion.
In an attempt to study the ultrastructural changes in the liver using
doses known to be nontoxic, 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 reticulum, a
proliferated smooth endoplasmic reticulum, prominent Golgl apparatuses and
the occurrence of multiple rough endoplasmlc cisternae, which may be inter-
preted as an adaptation process to increased exposure to MnCl .
Various biochemical or hlstological changes in the liver were reported
in 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 hlstopathological alterations in 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)
6-80
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did not manifest abnormalities 1n the liver, and the Hver monoamlne oxldase
activity remained the same as 1n the control group of animals (Klmura et
al.t 1978).
Parenteral administration of manganese sulfate In a dose of 6 mg Mn/kg
bw did not significantly affect the enzyme activity In the liver of exposed
rats, 1n spite of a significant accumulation of this metal 1n the Hver
(Singh et al., 1974, 1975). Only the activity of sucdnlc dehydrogenase and
lactate dehydrogenase decreased to a considerable extent. .Some pathomorpho-
loglcal alterations were observed In 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.
Microscopic examination of the liver 1n 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 Injected s.c. 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.
6.9.3. 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 1.v. dose was excreted
6-81
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by the rat in the feces. Manganese has been described as an agent that
produces Intrahepatlc cholestasis, large doses causing both functional and
morphological alterations. An 1.v. dose of manganese at a concentration of
55-60 mg/kg bw of the rat caused necrosis 1n the Hver and other ultrastruc-
tural alterations resembling some of those seen 1n human cholestasis induced
by drugs (WHzleben, 1969). Microscopic examination of the liver 1n monkeys
exposed parenterally to relatively high doses of manganese showed only mild
changes, for example, hemosiderosis of the Kupffer cells.
6-82
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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 in that certain specific criteria should be met before a com-
pound 1s considered positive (Shimkln and Stoner, 1975):
1. A significant Increase in 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,
it can be concluded that the results of this experiment are suggestive of
carcinogenic activity.
7-1
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DIPaolo (1964) Injected DBA/1 mice subcutaneously or 1ntraper1toneally
with 0.1 mi of a 1% 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 in controls was 24% (16/66).
Tumors appeared earlier in the treated groups than in the control group, but
statistically significant differences in the number of other tumors (e.g.,
mammary adenocardnomas, leukemias, Injection site tumors) did not occur.
The results of this study were published in abstract form, and additional
details regarding experimental design or results were not given. Therefore,
a thorough evaluation of the results is not possible.
Furst (1978) evaluated the carcinogenicity of manganese powder and
MnO_ in F344 rats and Swiss mice, and manganese (II) acetylacetonate (MAA)
in F344 rats. The test materials were suspended in trioctanoin, and admin-
istered intramuscularly (i.m.) or by gavage as follows. Groups of 25 rats
of each sex were administered 10 mg manganese (i.m.) per month for 9 months,
10 mg Mn02 (i.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 i.m. injection, but
the frequencies of injection 1n these experiments were not stated. Complete
necropsies were performed on all animals and obvious growths, suspicious
ti.ssues, lungs and livers were examined histologlcally. The duration of the
experiments were not specifically stated, but were implied to be 2 years in
the rat experiments. As summarized in Table 7-2, no difference in tumor
incidence was noted between treated and control animals with respect to
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manganese powder and Mn02. In contrast, a statistically significant
number of flbrosarcomas (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
HAA 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].
IntrapeMtoneal 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 mft, of penicillin suspensions containing manganese dust
7-6
-------
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 NUSp-lnduced tumor 1genes1s. Subsequent wojk 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
i
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 in
patients with stage IV bronchogenic carcinoma (Timaskina et al., 1981). An
earlier study (Morgan, 1972) of autopsy samples of hepatic tissue from
patients who had died of bronchogenic carcinoma, with and without chronic
7-7
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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 a!., 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-superoxlde dlsmutase. Superoxlde 1s an anlonlc
free radical and an active reducing agent. Superoxlde dlsmutases (SOD) con-
vert superoxide to H^Op, which 1n turn 1s converted to water by catalase
and peroxidase (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 Is 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 antltumor Immunity (McCarty, 1981).
7-9
-------
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.t 1980).
7.3. SUMMARY
Repeated subcutaneous or 1ntraper1toneal (1.p.) Injections of manganese
dlchlorlde Induced increased incidences of lymphosarcomas in DBA/1 mice, and
manganous sulfate (i.p.) elicited suggestive results in a strain A mouse
lung tumor bioassay. Intramuscular injections of MnO_ or manganese powder
did not induce a statistically significant increased incidence of lympho-
sarcomas, leukemias or local sarcomas in either sex of F344 rats or female
Swiss mice, and oral administration of manganese powder for 12 months did
not product lymphomas, leukemias or fibromas in either sex of F344 rat.
Intramuscular injection of manganese acetylacetonate resulted in a statis-
tically significant Increased incidence of Injection site fibrosarcomas in
both sexes of F344 rats. Although the results of the studies with divalent
manganese were probably suggestive of carcinogenic activity, it should be
emphasized that non-natural routes of administration were employed.
There is some evidence of carcinogenic activity of manganese in labora-
tory animals in the literature, although problems exist with regard to the
value of these studies (I.e., local injection site sarcomas in F344 rats, a
marginal response in strain A mice, and Inadequate data 1n the experiment
with DBA/1 mice). There is no ep1dem1olog1c information relating manganese
exposure to cancer occurrence 1n humans.
7-10
-------
In conclusion, the available evidence for manganese cardnogenldty In
humans would be rated Group 3 overall using the International Agency for
Research on Cancer (IARC) criteria, because of Inadequate data In animals
and lack of any available data 1n humans. Clearly, more Information 1s
needed before a more definitive conclusion can be made about the cardno-
genldty of manganese and Us compounds.
7-11
-------
-------
8. MUTAGENICITY AND TERATOGENICITY
8.1. MUTAGENICITY
A preliminary review of the currently available mutagenlcVty data has
been performed. The data are both Insufficient and Inadequate at this time
to reach a conclusion about the mutagenlc potential of manganese.
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 CNS
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 j£ utero with manganese. In another study, Massaro
et al. (1980) exposed female mice from days 0 through 18 of pregnancy with
3
HnOp dust (48.9+7.5 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 In 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 (Hurthy et al., 1981), and by a study of the distribution of
8-1
-------
54
Mn 1n fetal, young, and adult rats. Early neonates and 19-day fetuses
were more susceptible to manganese than the older groups; manganese local-
ized to the liver and brain in 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 jjmol/200 g
maternal weight, but this is a late stage for detecting developmental
defects.
8.3. SUMMARY
^
Although data reported in abstracts suggest that excess manganese during
pregnancy affects behavioral parameters, there is insufficient evidence to
define manganese as being teratogenic.
8-2
-------
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
ma 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 x
mg/m for resplrable manganese 1n occupational exposures.
9.1.2. Water. No tox1c1ty-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/fc 1n water to
9-1
-------
prevent undesirable taste and discoloration. In the USSR, the recommended
maximum permissible concentration of KMnO. is 0:1 mg/8, (as Mn). The
recommendation is Intended to prevent the discoloration of water by manga-
nese (Shigan and VHvltskaya, 1971).
For marine waters, the U.S. EPA (1976) has recommended a criterion for
manganese of 0.1 mg/8. for the protection of consumers of marine mollusks.
Although the rationale for this criterion is not detailed, it is partially
based on the observation that manganese can bioaccumulate by "factors as
high as 12,000" 1n marine mollusks.
9.2. SUMMARY OF TOXICITY
Manganese is an essential element for humans and animals. The concen-
tration of manganese present in individual tissues, particularly in the
blood, is controlled after 1ngest1on by homeostatic mechanisms and remains
remarkably constant 1n spite of rapid fluctuations in intake (Cotzias,
1958). The main routes of absorption are the gastrointestinal and respira-
tory tracts. Acute poisoning by manganese may occur in exceptional circum-
stances where large amounts of manganese compounds are ingested or inhaled.
Freshly formed manganese oxide fumes of respirable particle size can cause
metal fume fever but are not believed to cause permanent damage (Piscator,
1976). The most pronounced toxic effects of manganese are a CNS syndrome
known as chronic manganese poisoning (manganism) and manganese pneumonltls.
The adverse effect on the CNS begins with a psychiatric disturbance
followed by a neurologic phase resembling Parkinson's disease. Manganism
has -been well described In the literature with clinical details for case
clusters (FUnn et al., 1940; Penalver, 1955; Rodier, 1955; Chandra et a!.,
1974). Cotzias (1962) described three phases — a prodromal phase with
Insidious onset Including psychiatric disturbances, the extrapyramldal
9-2
-------
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 In the
3
Immediate vicinity of rock drilling 1n Moroccan mines was -450 mg/m 1n
one mine and -250 mg/m3 1n another (Rodler, 1955). In two reports from
Chilean mines (Ansola et a!., 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 Us 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;
P "
Lloyd-Davles, 1946; Rodler, 1955; Sarlc, 1978) and 1n Inhabitants living
around factories manufacturing ferromanganese or manganese alloys (Elstad,
9-3
-------
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 in humans occupationally exposed via Inhalation
(Sarlc and Hrustic, 1975). This symptom was also shown to occur experiment-
ally 1n orally exposed rats (Klmura et a*l., 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 in the severity of the effect.
There have been reports of Impotence in a majority of workers affected
by manganese (Chandra et al., 1974; Emara et a!., 1971; Rodier, 1955;
* v
Penalver, 1955). There 1s some experimental evidence of reproductive
effects in laboratory animals. Degenerative changes 1n the testes of rats
have been produced by excessive levels of manganese administered by multiple
Intraperitoneal 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 testis in mice (Gray and Laskey, 1980),
%
and decreased serum testosterone levels and reduced pregnancy percentage 1n
rats (Laskey et al., 1982).
9-4
-------
Manganese dlchloMde Increased the Incidence of lymphosarcomas 1n DBA/1
mice following twice weekly subcutaneous or 1ntraper1toneal Injections for 6
months (DIPaolo, 1964), and elicited slightly elevated tumor Incidence 1n a
Strain A mouse lung tumor bloassay (Stoner et al., 1976). Single of 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, HAA, 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 1n 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 wVth 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 carc1nogen1c1ty 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,
9-5
-------
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 (Hena 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). H1.gh 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 LD5Q
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.
9-6
-------
Another population at high risk 1s workers exposed to manganese at or
i
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 MAOOR 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, Is 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
chronic manganese poisoning, 0.3 and up for brain effects.
Several endpolnts suggested as effects from exposure to manganese are
nonspecific, Inconclusive or lack documentation In humans, such as degenera-
tive changes In 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
levels below 1 mg/m3 1s associated with nonspecific symptoms which are
common in 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).
: •
9-7
-------
Studies of respiratory effects 1n humans (summarized 1n Table 6-8) show
3
pulmonary system adverse effects at levels below 1 mg/m . Schoolchildren
' o
exposed to manganese emissions estimated at ~3-ll vig/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 a,t 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-Oavles, 1946;
Wassermann and Hlhall, 1961), chronic bronchitis (Lloyd-Oavles, 1946; Sarlc
and Luc1c-Pala1c, 1977), radlographlc changes and flbrosls (Wassermann and
Hlhall, 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). Nlshlyama 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.
9-8
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9-10
-------
Table 9-1 summarizes several studies which report no gross or microscopic
3
changes after exposure to ~0.1 mg/m Mn^O..
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 is unreported or variable within a study popula-
tion.
The mechanisms for toxic effects other than carclnogenicity are consis-
tent with the concept of a threshold. The conventional approach toward
determining the threshold for noncarclnogenlc toxlclty 1s to bracket 1t by
Identifying the highest level at which no adverse effects are observed
(NOEL) and the lowest level at which adverse effects are observed (LOAEL).
Therefore, the health effects assessment for manganese, considering the data
available, focuses on the highest NOELs In humans or on the LOAEL as avail-
able. These data can be supported by animal data by estimating human equiv-
alent exposures from animal exposure/effect levels.
9.5. HEALTH HAZARD EVALUATION
9.5.1. Critical Effect and Effect Levels. The critical effect is 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-adverse-effect-level (LOAEL) 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 symp-
3
tarns 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
9-11
-------
Information In humans for the critical effect. Nogawa et al. (1973) report-
ed an Increased prevalence of respiratory symptoms 1n schoolchildren exposed
3
to 0.003-0.011 mg/m manganese emission from a ferromanganese plant. This
Is the LOAEL In humans. Saric and Luclc-Palalc (1977) report an Increased
3
prevalence of chronic bronchitis In workers exposed to 0.4-16 mg/m ;
however, prevalence of chronic bronchitis In a group of workers exposed to
3
0.005-0.04 mg/m did not differ from controls. These results do not
contradict the results of Nogawa because 1) children may be expected to be
e
more sensitive than male workers, and 2) the latter study had less statisti-
cal power because fewer subjects were involved.
NOELs could be derived from several studies reported in laboratory
animals exposed to manganese oxides consisting largely of particles In the
alveolar fraction (<2 ym, 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 acarlasis and
associated pulmonary complications In 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. Ulrich et al. (1979a,b,c) exposed rats and squirrel monkeys to
three levels of manganese and a control for 9 months. Pulmonary function
tests were performed only on the monkeys. 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
9-12
-------
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 mg/m3; however, Suzuki
et al. (1978) reported pathologic changes 1n the lungs of rhesus monkeys
3
exposed to 700 wg/m of Mn02 for 10 months. Based on these data, the
next highest NOEL reported by Ulrlch et al. (1979a,b,c) was 0.113 mg/m3.
However, the repeated reports of the absence of gross and microscopic
3
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 1
on the lungs may occur at ~0.1 mg/m . Effects do occur at 0.7 mg/m .
In order to compare the reported NOEL (0.1 mg/m3) and the LOAEL (0.7
3
mg/m ) to similar data 1n humans, It would be helpful to estimate a human
Intake equivalent to that of the experimental animals. The suggested
approach 1s provided 1n the Appendix.
9-13
-------
-------
10. REFERENCES
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Adklns, B., Jr., 6.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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Ahrland, D.S. 1975. Metal complexes present 1n seawater. In.: The Nature
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Alpert, O.J. and P.K. Hopke. 1981. A determination of the sources of
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Amdur, Mo., L.C. Morris and G.F. Heuser. 1945. The need for manganese 1n
bone development 1n the rat. Proc. Soc. Exp. B1ol. Hed. 59: 254-255.
Anke, M. and H.3. Schneider. 1974. Trace element concentrations 1n human
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* •
legal reparations. Rev. Med. Chile. 72: 311-322.
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JO-3
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10-77
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APPENDIX
ESTIMATING HUMAN EQUIVALENT INTAKE LEVELS FROM ANIMAL STUDIES
TERMINOLOGY AND APPROACH
The quantitative evaluation of potential health hazards for noncarclno-
genlc toxicants Is based upon estimates of the threshold exposure level for
the critical effect. Exposure levels for each study are evaluated as
follows.:
NOEL
NOAEL
No-Observed-Effect Level: That exposure level at which there are no
statistically significant Increases In frequency or severity of
effects between the exposed population and Us appropriate control.
No-Observed-Adverse-Effect Level: That exposure level at which
there are no statistically significant Increases In frequency or
severity of adverse effects between the exposed population and Us
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 In frequency or severity of adverse effects between the
exposed population and Its 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 Its appropriate control.
The threshold estimate 1s bracketed by the highest NOEL 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 based on data
for animals rather than for humans since there Is presently limited Informa-
tion on species differences regarding toxic responses. Nevertheless, given
limited dose-response data for humans It Is necessary to extrapolate from
the animal data.
»
Human equivalent Intake rate (HEI) Is defined here as the exposure level
estimated from animal data which would cause the same health effect 1n
humans If continued over the same fraction of llfespan as used In the animal
A-l
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study. The conversion for manganese assumes that 1f the ratio (exposure
level)/(body surface area) Is the same 1n humans as In 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 Is
3
an estimated LOAEL of 3-11 jig/m (based on emissions from a ferromanga-
nese plant) for respiratory effects In children reported by Nogawa et al.
(1973). Comparison among studies of respiratory effects In laboratory
animals (summarized In Table 9-1) shows that Ulrlch et al. (1979a,b,c) and
Suzuki et al. (1978) utilized the longest exposure periods at exposure
3
concentrations ~100 yg/m . Although there are shortcomings 1n each
study (see Section 9.5.) the repeated observations suggest that this level
may be close to the threshold. Therefore, these studies were selected for
these risk assessment calculations. The HEI Is estimated from the data from
'experimental animals by the following:
/70 kc\2/3
HEI = CA x DE x Br x ' •
where C = concentration 1n air In the animal study In
A
Dr = fraction of day experimental animals were exposed
3
Br = volume of air breathed per day 1n m
W = body weight of the experimental animal In kg
d
This conversion Is based on the following assumptions:
1. Agents that are In 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 Is well approximated by the body
weight ratio to the 2/3 power (Calabrese, 1983).
A-2
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The estimation of HEI 1s based on Intake by Inhalation of manganese Vn
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 Is route specific.
The estimated HEI (In mg/day) Is 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 In Table A-l.
In the studies considered here D equals 1. Therefore, for rhesus
monkeys 1n the study by Suzuki et al. (1978)
v2/3
HEI = CA x Br x
700
x 1.4 m3/day x
3.5 kg
7293 yg/day.
The HEEL obtained by dividing by the dally respiratory volume (20 m /day)
3
Is 365 yg/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)
3 3
(Wa = 0.35 kg, Br = 0.26 m /day, and CA = 113 vg/m ) result 1n a
HEEL of 51 ng/m3. For the Ulrlch et al. (1979a,b,c) data on squirrel
3 3
monkeys (W, = 0.72 kg, Br = 0.72 m /day, and CA = 113 yg/m ) the
a n
HEEL 1s 87 vg/m3.
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
vg/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
A-3
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CO
N
CO
C =>
CO 1/1
e o •
E
^.
ra
I— CsJ
r— C\J
i— i— O
o
IU
D)
O
. o
.£=
3
o.
VI
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have flaws resulting 1n uncertainty as to whether adverse effects are
missed; 2) certain endpolnts studied In humans cannot be ascertained as well
In 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
n 3
LOAEL Is 5-37 vg/m , and supports the human LOAEL of 3-11
observed In a sensitive population.
A-5
* U.S. GOVERNMENT PRINTING OFFICE: 1984 - 759-102/10644
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