DRAFT
 

TOXICOLOGICAL PROFILE FOR
 

MANGANESE
 


 


 


 


 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

September 2008 
 

 

MANGANESE ii 

DISCLAIMER
 

The use of company or product name(s) is for identification only and does not imply endorsement by the 

Agency for Toxic Substances and Disease Registry. 

This information is distributed solely for the purpose of pre dissemination public comment under 

applicable information quality guidelines. It has not been formally disseminated by the Agency for Toxic 

Substances and Disease Registry. It does not represent and should not be construed to represent any 

agency determination or policy. 

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MANGANESE iii 

UPDATE STATEMENT
 

A Toxicological Profile for Manganese was released in 2000. This present edition supersedes any 

previously released draft or final profile. 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch
 

1600 Clifton Road NE
 

Mailstop F-32
 

Atlanta, Georgia 30333
 

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MANGANESE iv 

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MANGANESE v 

FOREWORD 

This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic 

Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary. 

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

information for the hazardous substance described therein. Each peer-reviewed profile identifies and 

reviews the key literature that describes a hazardous substance’s toxicologic properties. Other pertinent 

literature is also presented, but is described in less detail than the key studies. The profile is not intended 

to be an exhaustive document; however, more comprehensive sources of specialty information are 

referenced. 

The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile 

begins with a public health statement that describes, in nontechnical language, a substance’s relevant 

toxicological properties. Following the public health statement is information concerning levels of 

significant human exposure and, where known, significant health effects. The adequacy of information to 

determine a substance’s health effects is described in a health effects summary. Data needs that are of 

significance to protection of public health are identified by ATSDR and EPA. 

Each profile includes the following: 

(A) The examination, summary, and interpretation of available toxicologic information and 

epidemiologic evaluations on a hazardous substance to ascertain the levels of significant human 

exposure for the substance and the associated acute, subacute, and chronic health effects; 

(B) A determination of whether adequate information on the health effects of each substance 

is available or in the process of development to determine levels of exposure that present a 

significant risk to human health of acute, subacute, and chronic health effects; and 

(C) Where appropriate, identification of toxicologic testing needed to identify the types or 

levels of exposure that may present significant risk of adverse health effects in humans. 

The principal audiences for the toxicological profiles are health professionals at the Federal, State, and 

local levels; interested private sector organizations and groups; and members of the public. We plan to 

revise these documents in response to public comments and as additional data become available. 

Therefore, we encourage comments that will make the toxicological profile series of the greatest use. 

Comments should be sent to: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine
 

1600 Clifton Road NE
 

Mail Stop F-32
 

Atlanta, Georgia 30333
 

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MANGANESE vi 

Background Information 

The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization 

Act (SARA) of 1986 (Public Law 99 499) which amended the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed ATSDR to 

prepare toxicological profiles for hazardous substances most commonly found at facilities on the 

CERCLA National Priorities List and that pose the most significant potential threat to human health, as 

determined by ATSDR and the EPA. The availability of the revised priority list of 275 hazardous 

substances was announced in the Federal Register on December 7, 2005 (70 FR 72840). For prior 

versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866); 

October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17,1990 (55 FR 42067); 

October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); February 28, 1994 (59 FR 9486); 

April 29, 1996 (61 FR 18744); November 17, 1997 (62 FR 61332); October 21, 1999(64 FR 56792); 

October 25, 2001 (66 FR 54014) and November 7, 2003 (68 FR 63098). Section 104(i)(3) of CERCLA, 

as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on 

the list. 

This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been 

peer-reviewed. Staff of the Centers for Disease Control and Prevention and other Federal scientists have 

also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel 

and was made available for public review. Final responsibility for the contents and views expressed in 

this toxicological profile resides with ATSDR. 

Howard Frumkin M.D., Dr.P.H. Julie Louise Gerberding, M.D., M.P.H. 

Director Administrator 

National Center for Environmental Health/ Agency for Toxic Substances and 

Agency for Toxic Substances and Disease Registry 

Disease Registry 

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MANGANESE vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children?
 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)?
 

Section 3.7 Children’s Susceptibility
 

Section 6.6 Exposures of Children
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or Fax: (770) 488-4178 

1-888-232-6348 (TTY) 

E-mail: cdcinfo@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 

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MANGANESE viii 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

Other Agencies and Organizations 

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, 

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 

• Phone: 800-35-NIOSH. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212. 

Referrals 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk 

Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 

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MANGANESE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Malcolm Williams, DVM, Ph.D. 

G. Daniel Todd, Ph.D.
 

Nickolette Roney, M.P.H.
 

Jewell Crawford, M.D.
 

Charleton Coles, Ph.D.
 

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA
 

Peter R. McClure, Ph.D., DABT
 

Joan D. Garey, Ph.D.
 

Mario Citra, Ph.D.
 

Syracuse Research Corporation, North Syracuse, NY
 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1.	 Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2.	 Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3.	 Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

4.	 Green Border Review. Green Border review assures the consistency with ATSDR policy. 

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MANGANESE x 

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MANGANESE xi 

PEER REVIEW
 

A peer review panel was assembled for manganese. The panel consisted of the following members: 

1.	 David Dorman, D.V.M., Ph.D., Associate Dean for Research and Graduate Studies, College of 

Veterinary Medicine, Professor of Toxicology, Department of Molecular Biomedical Sciences, 

North Carolina State University, Raleigh, North Carolina 27606, 

2.	 Donald Smith, Ph.D., Professor of Environmental Toxicology, University of California, Santa 

Cruz, California 95064, and 

3.	 Wei Zheng, Ph.D., Director of Graduate Studies, School of Health Sciences, Purdue University, 

West Lafayette, Indiana 47907. 

These experts collectively have knowledge of manganese's physical and chemical properties, 

toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and 

quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer 

review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, 

and Liability Act, as amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 

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MANGANESE xii 

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MANGANESE xiii 

CONTENTS
 

DISCLAIMER ..............................................................................................................................................ii
 

UPDATE STATEMENT .............................................................................................................................iii
 

FOREWORD ................................................................................................................................................v
 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS....................................................................vii
 

CONTRIBUTORS.......................................................................................................................................ix
 

PEER REVIEW ...........................................................................................................................................xi
 

CONTENTS...............................................................................................................................................xiii
 

LIST OF FIGURES ..................................................................................................................................xvii
 

LIST OF TABLES.....................................................................................................................................xix
 

1. PUBLIC HEALTH STATEMENT..........................................................................................................1
 

1.1 WHAT IS MANGANESE?.........................................................................................................2
 

1.2 WHAT HAPPENS TO MANGANESE WHEN IT ENTERS THE ENVIRONMENT?............3
 

1.3 HOW MIGHT I BE EXPOSED TO MANGANESE? ................................................................3
 

1.4 HOW CAN MANGANESE ENTER AND LEAVE MY BODY? .............................................4
 

1.5 HOW CAN MANGANESE AFFECT MY HEALTH? ..............................................................5
 

1.6 HOW CAN MANGANESE AFFECT CHILDREN? .................................................................6
 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO MANGANESE? .............7
 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
 

EXPOSED TO MANGANESE? .................................................................................................8
 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH?.................................................................................................8
 

1.10 WHERE CAN I GET MORE INFORMATION? .......................................................................9
 

2. RELEVANCE TO PUBLIC HEALTH .................................................................................................11
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO MANGANESE IN THE
 

UNITED STATES.....................................................................................................................11
 

2.2 SUMMARY OF HEALTH EFFECTS......................................................................................14
 

2.3 MINIMAL RISK LEVELS (MRLs) .........................................................................................19
 

3. HEALTH EFFECTS..............................................................................................................................37
 

3.1 INTRODUCTION.....................................................................................................................37
 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................39
 

3.2.1 Inhalation Exposure ..............................................................................................................40
 

3.2.1.1 Death ............................................................................................................................58
 

3.2.1.2 Systemic Effects...........................................................................................................59
 

3.2.1.3 Immunological and Lymphoreticular Effects...............................................................65
 

3.2.1.4 Neurological Effects.....................................................................................................65
 

3.2.1.5 Reproductive Effects....................................................................................................88
 

3.2.1.6 Developmental Effects .................................................................................................91
 

3.2.1.7 Cancer...........................................................................................................................91
 

3.2.2 Oral Exposure........................................................................................................................92
 

3.2.2.1 Death ............................................................................................................................92
 

3.2.2.2 Systemic Effects.........................................................................................................133
 

3.2.2.3 Immunological and Lymphoreticular Effects.............................................................142
 

3.2.2.4 Neurological Effects...................................................................................................143
 

3.2.2.5 Reproductive Effects..................................................................................................165
 

3.2.2.6 Developmental Effects ...............................................................................................170
 

3.2.2.7 Cancer.........................................................................................................................179
 

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MANGANESE xiv 

3.2.3 Dermal Exposure.................................................................................................................180
 

3.2.3.1 Death ..........................................................................................................................180
 

3.2.3.2 Systemic Effects.........................................................................................................180
 

3.2.3.3 Immunological and Lymphoreticular Effects.............................................................182
 

3.2.3.4 Neurological Effects...................................................................................................182
 

3.2.3.5 Reproductive Effects..................................................................................................183
 

3.2.3.6 Developmental Effects ...............................................................................................183
 

3.2.3.7 Cancer.........................................................................................................................183
 

3.2.4 Diagnostic Uses...................................................................................................................183
 

3.2.4.1 Death...............................................................................................................................184
 

3.2.4.2 Systemic Effects .............................................................................................................185
 

3.2.4.3 Immunological and Lymphoreticular Effects.................................................................189
 

3.2.4.4 Neurological Effects.......................................................................................................189
 

3.2.4.5 Reproductive Effects.......................................................................................................191
 

3.2.4.6 Developmental Effects....................................................................................................192
 

3.3 GENOTOXICITY ...................................................................................................................194
 

3.4 TOXICOKINETICS................................................................................................................199
 

3.4.1 Absorption...........................................................................................................................200
 

3.4.1.1 Inhalation Exposure....................................................................................................200
 

3.4.1.2 Oral Exposure.............................................................................................................203
 

3.4.1.3 Dermal Exposure........................................................................................................207
 

3.4.2 Distribution .........................................................................................................................207
 

3.4.2.1 Inhalation Exposure....................................................................................................210
 

3.4.2.2 Oral Exposure.............................................................................................................220
 

3.4.2.3 Dermal Exposure........................................................................................................223
 

3.4.2.4 Other Routes of Exposure ..........................................................................................223
 

3.4.3 Metabolism..........................................................................................................................229
 

3.4.4 Elimination and Excretion...................................................................................................231
 

3.4.4.1 Inhalation Exposure....................................................................................................233
 

3.4.4.2 Oral Exposure.............................................................................................................235
 

3.4.4.3 Dermal Exposure........................................................................................................236
 

3.4.4.4 Other Routes of Exposure ..........................................................................................236
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models...........237
 

3.5 MECHANISMS OF ACTION ................................................................................................257
 

3.5.1 Pharmacokinetic Mechanisms.............................................................................................257
 

3.5.2 Mechanisms of Toxicity......................................................................................................260
 

3.5.3 Animal-to-Human Extrapolations.......................................................................................267
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ........................269
 

3.7 CHILDREN’S SUSCEPTIBILITY.........................................................................................271
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................282
 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Manganese ....................................283
 

3.8.2 Biomarkers Used to Characterize Effects Caused by Manganese.......................................288
 

3.9 INTERACTIONS WITH OTHER CHEMICALS ..................................................................290
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE.............................................292
 

3.11 METHODS FOR REDUCING TOXIC EFFECTS.................................................................297
 

3.11.1 Reducing Peak Absorption Following Exposure ................................................................297
 

3.11.2 Reducing Body Burden.......................................................................................................298
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects..............................................300
 

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3.12 ADEQUACY OF THE DATABASE......................................................................................301
 

3.12.1 Existing Information on Health Effects of Manganese.......................................................301
 

3.12.2 Identification of Data Needs ...............................................................................................302
 

3.12.3 Ongoing Studies..................................................................................................................320
 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................323
 

4.1 CHEMICAL IDENTITY.........................................................................................................323
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................323
 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................331
 

5.1 PRODUCTION .......................................................................................................................331
 

5.2 IMPORT/EXPORT .................................................................................................................337
 

5.3 USE..........................................................................................................................................337
 

5.4 DISPOSAL..............................................................................................................................339
 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................341
 

6.1 OVERVIEW............................................................................................................................341
 

6.2 RELEASES TO THE ENVIRONMENT................................................................................343
 

6.2.1 Air .......................................................................................................................................348
 

6.2.2 Water...................................................................................................................................350
 

6.2.3 Soil ......................................................................................................................................351
 

6.3 ENVIRONMENTAL FATE....................................................................................................351
 

6.3.1 Transport and Partitioning...................................................................................................351
 

6.3.2 Transformation and Degradation ........................................................................................354
 

6.3.2.1 Air...............................................................................................................................354
 

6.3.2.2 Water ..........................................................................................................................354
 

6.3.2.3 Sediment and Soil.......................................................................................................355
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT...............................355
 

6.4.1 Air .......................................................................................................................................355
 

6.4.2 Water...................................................................................................................................358
 

6.4.3 Sediment and Soil ...............................................................................................................361
 

6.4.4 Other Environmental Media................................................................................................362
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .....................................364
 

6.6 EXPOSURES OF CHILDREN...............................................................................................368
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ...........................................372
 

6.8 ADEQUACY OF THE DATABASE......................................................................................375
 

6.8.1 Identification of Data Needs ...............................................................................................375
 

6.8.2 Ongoing Studies..................................................................................................................379
 

7. ANALYTICAL METHODS................................................................................................................381
 

7.1 BIOLOGICAL MATERIALS.................................................................................................382
 

7.2 ENVIRONMENTAL SAMPLES............................................................................................384
 

7.3 ADEQUACY OF THE DATABASE......................................................................................388
 

7.3.1 Identification of Data Needs ...............................................................................................389
 

7.3.2 Ongoing Studies..................................................................................................................390
 

8. REGULATIONS, ADVISORIES, AND GUIDELINES.....................................................................391
 

9. REFERENCES ....................................................................................................................................397
 

10. GLOSSARY ......................................................................................................................................485
 

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MANGANESE xvi 

APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1
 

B. USER’S GUIDE.................................................................................................................................. B-1
 

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS...................................................................... C-1
 

D. INDEX ................................................................................................................................................D-1
 

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MANGANESE xvii 

LIST OF FIGURES
 

3-1. Levels of Significant Exposure to Inorganic Manganese – Inhalation............................................... 55
 

3-2. Levels of Significant Exposure to Inorganic Manganese – Oral ...................................................... 123
 

3-3. Levels of Significant Exposure to Organic Manganese-MMT – Oral.............................................. 130
 

3-4. Metabolism of MnDPDP..................................................................................................................232
 

3-5. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a
 

Hypothetical Chemical Substance....................................................................................................239
 

3-6. Qualitative PBPK Model for Manganese .........................................................................................241
 

3-7. Schematic Structures of Nong et al. (2008) PBPK Models A and B for Manganese in CD Rats....243
 

3-8. Schematic of Models for Nasopharyngeal and Lung Deposition of Manganese and Transport
 

to Blood in the Nong et al. (2008) PBPK Models A and B for Manganese in CD Rats..................244
 

3-9. Schematic of the Leavens et al. (2007) Model to Describe Olfactory and Blood Delivery of 

Manganese to the Left Side of the Brain Isilateral to the Olfactory Mucosa (OM) in the Left 

Nasal Cavity.....................................................................................................................................252
 

3-10. Existing Information on Health Effects of Inorganic Manganese ..................................................303
 

6-1. Frequency of NPL Sites with Manganese Contamination................................................................342
 

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MANGANESE xix 

LIST OF TABLES
 

2-1. Adequate Intake (AI) for Manganese .................................................................................................13
 

3-1. Levels of Significant Exposure to Inorganic Manganese – Inhalation............................................... 41
 

3-2. Levels of Significant Exposure to Inorganic Manganese – Oral ........................................................ 93
 

3-3. Levels of Significant Exposure to Organic Manganese-MMT – Oral.............................................. 128
 

3-4. Scores on Intelligence Tests.............................................................................................................149
 

3-5. Genotoxicity of Manganese In Vitro ................................................................................................195
 

3-6. Genotoxicity of Manganese In Vivo .................................................................................................198
 

3-7. Manganese Levels in Human and Animal Tissues...........................................................................208
 

3-8. Manganese Levels in Human Serum/Plasma....................................................................................211
 

3-9. Terminal Mean (±Standard Error on the Mean) Tissue Manganese Concentrations (μg Manganese/g 

Tissue Wet Weight) in Maternal CD Rats Exposed to Aerosols of Manganese Sulfate 6 Hours/Day, 

7 Days/Week Starting 28 Days Prior to Breeding Through Postnatal Day 18.................................215
 

3-10. Mean (±Standard Error on the Mean) Tissue Manganese Concentrations (μg Manganese/g Tissue
 

Wet Weight) in Young Male Rhesus Monkeys Exposed to Aerosols of Manganese Sulfate
 

(1.5 mg Manganese/m3

) 6 Hours/Day, 5 Days/Week for Up to 65 Days ......................................216
 

3-11. Manganese Concentrations in Brain Tissues of Lactating CD Rats and Offspring Exposed to
 

Aerosols of Manganese Sulfate......................................................................................................219
 

3-12. Manganese Levels in Rat Tissue After Oral Exposure...................................................................221
 

3-13. Levels of Manganese in Exposed and Non-Exposed Workers.......................................................234
 

3-14. Parameter Values in the Teeguarden et al. (2007c) PBPK Model for Manganese in CD Rats 

(Nong et al. 2008) Model A...........................................................................................................245
 

3-15. Refined Parameter Values in Nong et al. (2008) Model A.............................................................249
 

3-16. Parameter Values in Nong et al. (2008) Model B...........................................................................251
 

3-17. Parameter Values for Manganese Chloride in the Leavens et al. (2007) PBPK Model for
 

Olfactory Transport of Manganese in Rats....................................................................................253
 

3-18. Parameter Values for Manganese Phosphate in the Leavens et al. (2007) PBPK Model for
 

Olfactory Transport of Manganese in Rats....................................................................................254
 

3-19. Parameter Values for Describing Blood Concentrations in the Leavens et al. (2007) PBPK
 

Model for Olfactory Transport of Manganese in Rats...................................................................256
 

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MANGANESE xx 

3-20. Ongoing Studies on Manganese .....................................................................................................321
 

4-1. Chemical Identity of Manganese and Compounds...........................................................................324
 

4-2. Physical and Chemical Properties of Manganese and Compounds..................................................327
 

5-1. Facilities that Produce, Process, or Use Manganese.........................................................................332
 

5-2. Facilities that Produce, Process, or Use Manganese Compounds ....................................................334
 

5-3. Manganese Import/Export Data for 2003–2007 ...............................................................................338
 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Manganese .................344
 

6-2. Releases to the Environment from Facilities that Produce, Process, or Use Manganese 

Compounds ......................................................................................................................................346
 

6-3. Average Levels of Manganese in Ambient Air................................................................................356
 

6-4. Levels of PM2.5 and PM10 in Indoor and Outdoor Air in Toronto, Canada and Indianapolis, 

Indiana..............................................................................................................................................359
 

6-5. Manganese Detections and Concentrations in Surface Water and Groundwater in the United 

States ................................................................................................................................................360
 

6-6. Mean Concentrations of Manganese for FDA’s Total Diet Study Market Baskets 1991 

through 1997 ....................................................................................................................................363
 

6-7. Summary of Typical Human Exposure to Manganese .....................................................................365
 

6-8. Levels of PM2.5 in Personal Air Samples Collected in Toronto, Canada and Indianapolis,
 

Indiana..............................................................................................................................................369
 

7-1. Analytical Methods for Determining Manganese in Biological Materials.......................................383
 

7-2. Analytical Methods for Determining Manganese in Environmental Samples .................................385
 

8-1. Regulations, Advisories, and Guidelines Applicable to Manganese ................................................393
 

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MANGANESE 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about manganese and the effects of exposure to it. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the 

nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term 

federal clean-up activities. Manganese has been found in at least 869 of the 1,699 current or former NPL 

sites. Although the total number of NPL sites evaluated for this substance is not known, the possibility 

exists that the number of sites at which manganese is found may increase in the future as more sites are 

evaluated. This information is important because these sites may be sources of exposure and exposure to 

this substance may harm you. 

When a substance is released either from a large area, such as an industrial plant, or from a container, 

such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You 

can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, 

eating, or drinking the substance, or by skin contact. 

If you are exposed to manganese, many factors will determine whether you will be harmed. These factors 

include the dose (how much), the duration (how long), and how you come in contact with it. You must 

also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, and 

state of health. 

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MANGANESE 2 

1. PUBLIC HEALTH STATEMENT 

1.1 WHAT IS MANGANESE? 

Description Manganese is a naturally occurring substance found in many 

types of rocks and soil. Pure manganese is a silver-colored 

metal; however, it does not occur in the environment as a pure 

metal. Rather, it occurs combined with other substances such 

as oxygen, sulfur, and chlorine. Manganese is a trace element 

and is necessary for good health. 

Uses 

• Manufacturing 

• Consumer products 

Manganese is used principally in steel production to improve 

hardness, stiffness, and strength. It is used in carbon steel, 

stainless steel, high-temperature steel, and tool steel, along 

with cast iron and superalloys. 

Manganese occurs naturally in most foods and may be added 

to food or made available in nutritional supplements. 

Manganese is also used in a wide variety of other products, 

including: 

• fireworks 

• dry-cell batteries 

• fertilizer 

• paints 

• a medical imaging agent 

• cosmetics 

It may also be used as an additive in gasoline to improve the 

octane rating of the gas. 

Small amounts of manganese are used in a pharmaceutical 

product called mangafodipir trisodium (MnDPDP) to improve 

lesion detection in magnetic resonance imaging of body organs. 

Chapters 4, 5, and 6 have more information on the properties and uses of manganese and how it behaves 

in the environment. 

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MANGANESE 3 

1. PUBLIC HEALTH STATEMENT 

1.2 WHAT HAPPENS TO MANGANESE WHEN IT ENTERS THE ENVIRONMENT? 

Sources Manganese is a normal constituent of air, soil, water, and food. 

Additional manganese can be found in air, soil, and water after 

release from the manufacture, use, and disposal of manganesebased products. 

Breakdown As with other elements, manganese cannot break down in the 

environment. It can only change its form or become attached or 

separated from particles. The chemical state of manganese 

and the type of soil determine how fast it moves through the soil 

and how much is retained in the soil. In water, most of the 

manganese tends to attach to particles in the water or settle into 

the sediment. 

The manganese-containing gasoline additive may degrade in 

the environment quickly when exposed to sunlight, releasing 

manganese. 

For more information on manganese in the environment, see Chapter 6. 

1.3 HOW MIGHT I BE EXPOSED TO MANGANESE? 

Food – primary The primary way you can be exposed to manganese is by eating food 

source of exposure or manganese-containing nutritional supplements. Vegetarians who 

consume foods rich in manganese such as grains, beans and nuts, as 

well as heavy tea drinkers, may have a higher intake of manganese 

than the average person. 

Workplace air Certain occupations like welding or working in a factory where steel is 

made may increase your chances of being exposed to high levels of 

manganese. 

Water and soil Because manganese is a natural component of the environment, you 

are always exposed to low levels of it in water, air, soil, and food. 

Manganese is routinely contained in groundwater, drinking water and 

soil at low levels. Drinking water containing manganese or swimming 

or bathing in water containing manganese may expose you to low 

levels of this chemical. 

Air Air also contains low levels of manganese, and breathing air may 

expose you to it. Releases of manganese into the air occur from: 

• industries using or manufacturing products containing manganese 

• mining activities 

• automobile exhaust 

See Chapter 6 for more information on how you might be exposed to manganese or its compounds. 

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MANGANESE 4 

1. PUBLIC HEALTH STATEMENT 

1.4 HOW CAN MANGANESE ENTER AND LEAVE MY BODY? 

Enter your body 

• Inhalation When you breathe air containing manganese, a small amount of the 

manganese will enter your body through your lungs and the remainder 

can become trapped in your lungs. Some of the manganese in your 

lungs can also be trapped in mucus which you may cough up and 

swallow into your stomach. 

• Ingestion Manganese in food or water may enter your body through the digestive 

tract to meet your body’s needs for normal functioning. 

Only very small amounts of manganese can enter your skin when you 

• Dermal contact come into contact with liquids containing manganese. 

Leave your body Once in your body, manganese-containing chemicals can break down 

into other chemicals. However, manganese is an element that cannot 

be broken down. Most manganese will leave your body in feces within 

a few days. 

For more information on how manganese enters and leaves the body, see Chapter 3. 

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MANGANESE 5 

1. PUBLIC HEALTH STATEMENT 

1.5 HOW CAN MANGANESE AFFECT MY HEALTH? 

This section looks at studies concerning potential health effects in human and animal studies. 

General population Manganese is an essential nutrient, and eating a small amount of it 

each day is important to stay healthy. 

Workers The most common health problems in workers exposed to high levels 

• Inhalation of manganese involve the nervous system. These health effects 

include behavioral changes and other nervous system effects, which 

include movements that may become slow and clumsy. This 

combination of symptoms when sufficiently severe is referred to as 

“manganism.” Other less severe nervous system effects such as 

slowed hand movements have been observed in some workers 

exposed to lower concentrations in the work place. 

The inhalation of a large quantity of dust or fumes containing 

manganese may cause irritation of the lungs which could lead to 

pneumonia. 

Loss of sex drive and sperm damage has also been observed in men 

exposed to high levels of manganese in workplace air. 

The manganese concentrations that cause effects such as slowed hand 

movements in some workers are approximately twenty thousand times 

higher than the concentrations normally found in the environment. 

Manganism has been found in some workers exposed to manganese 

concentrations about a million times higher than normal air 

concentrations of manganese. 

Laboratory animals 

• Inhalation 

Respiratory effects, similar to those observed in workers, have been 

observed in laboratory monkeys exposed to high levels of manganese. 

Laboratory animals 

• Oral 

Manganese has been shown to cross the blood-brain barrier and a 

limited amount of manganese is also able to cross the placenta during 

pregnancy, enabling it to reach a developing fetus. 

Nervous system disturbances have been observed in animals after very 

high oral doses of manganese, including changes in behavior. 

Sperm damage and adverse changes in male reproductive 

performance were observed in laboratory animals fed high levels of 

manganese. Impairments in fertility were observed in female rodents 

provided with oral manganese before they became pregnant. 

Illnesses involving the kidneys and urinary tract have been observed in 

laboratory rats fed very high levels of manganese. These illnesses 

included inflammation of the kidneys and kidney stone formation. 

Cancer The EPA concluded that existing scientific information cannot 

determine whether or not excess manganese can cause cancer. 

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MANGANESE 6 

1. PUBLIC HEALTH STATEMENT 

Further information on the health effects of manganese in humans and animals can be found in 

Chapters 2 and 3. 

1.6 HOW CAN MANGANESE AFFECT CHILDREN? 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 

Effects in children Studies in children have suggested that extremely high levels of 

manganese exposure may produce undesirable effects on brain 

development, including changes in behavior and decreases in the 

ability to learn and remember. In some cases, these same manganese 

exposure levels have been suspected of causing severe symptoms of 

manganism disease (including difficulty with speech and walking). We 

do not know for certain that these changes were caused by manganese 

alone. We do not know if these changes are temporary or permanent. 

We do not know whether children are more sensitive than adults to the 

effects of manganese, but there is some indication from experiments in 

laboratory animals that they may be. 

Birth defects Studies of manganese workers have not found increases in birth 

defects or low birth weight in their children. 

No birth defects were observed in animals exposed to manganese 

In one human study where people were exposed to very high levels of 

manganese from drinking water, infants less than 1 year of age died at 

an unusually high rate. It is not clear, however, whether these deaths 

were attributable to the manganese level of the drinking water. The 

manganese toxicity may have involved exposures to the infant that 

occurred both before (through the mother) and after they were born. 

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MANGANESE 7 

1. PUBLIC HEALTH STATEMENT 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO MANGANESE? 

Avoid inhalation of High levels of airborne manganese are observed in certain 

manganese at work occupational settings such as steel factories or welding areas. You 

should take precautions to prevent inhalation of manganese by 

wearing an appropriate mask to limit the amount of manganese you 

breathe. 

Avoid wearing Workers exposed to high levels of airborne manganese in certain 

manganese dust- occupational settings may accumulate manganese dust on their work 

contaminated work clothes. Manganese-contaminated work clothing should be removed 

clothing in your home before getting into your car or entering your home to help reduce the 

or car exposure hazard for yourself and your family. 

Avoid inhalation of If you weld objects around your home, do so in a well-ventilated area 

welding fumes at and use an appropriate mask to decrease your risk of inhaling 

home manganese-containing fumes. Children should be kept away from 

welding fumes. 

Diet Children are not likely to be exposed to harmful amounts of 

manganese in the diet. However, higher-than-usual amounts of 

manganese may be absorbed if their diet is low in iron. It is important 

to provide your child with a well-balanced diet. 

Water While tap and bottled water generally contain safe levels of 

manganese, well water may sometimes be contaminated with 

sufficiently high levels of manganese to create a potential health 

hazard. If drinking water is obtained from a well water source, it may 

be wise to have the water checked for manganese to ensure the level 

is below the current guideline level established by the EPA. 

Smoking Manganese is a minor constituent of tobacco smoke. Avoiding 

tobacco smoke may reduce your family’s exposure to manganese. 

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MANGANESE	 8 

1. PUBLIC HEALTH STATEMENT 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 

MANGANESE? 

Detecting exposure Several tests are available to measure manganese in blood, urine, 

hair, or feces. Because manganese is normally present in our body, 

some is always found in tissues or fluids. 

Normal ranges of manganese levels are about 4–15 μg/L in blood, 1– 

8 μg/L in urine, and 0.4–0.85 μg/L in serum (the fluid portion of the 

blood). 

Measuring exposure Because excess manganese is usually removed from the body within 

a few days, past exposures are difficult to measure with common 

laboratory tests. 

A medical test known as magnetic resonance imaging, or MRI, can 

detect the presence of increased amounts of manganese in the brain. 

However, this type of test is qualitative, and has not been shown to 

reliably reflect or predict toxicologically meaningful exposures. 

Information about tests for detecting manganese in the body is given in Chapters 3 and 7. 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. Regulations 

can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the 

Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic 

substances. Recommendations provide valuable guidelines to protect public health, but cannot be 

enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National 

Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop 

recommendations for toxic substances. 

Regulations and recommendations can be expressed as “not-to-exceed” levels, that is, levels of a toxic 

substance in air, water, soil, or food that do not exceed a critical value that is usually based on levels that 

affect animals; they are then adjusted to levels that will help protect humans. Sometimes these not-toexceed levels differ among federal organizations because they used different exposure times (an 8-hour 

workday or a 24-hour day), different animal studies, or other factors. 

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MANGANESE 9 

1. PUBLIC HEALTH STATEMENT 

Recommendations and regulations are also updated periodically as more information becomes available. 

For the most current information, check with the federal agency or organization that provides it. Some 

regulations and recommendations for manganese include the following: 

Drinking water The EPA has established that exposure to manganese in drinking water at 

concentrations of 1 mg/L for 1 or 10 days is not expected to cause any 

adverse effects in a child. 

The EPA has established that lifetime exposure to 0.3 mg/L manganese is 

not expected to cause any adverse effects. 

Bottled water The FDA has established that the manganese concentration in bottled 

drinking water should not exceed 0.05 mg/L. 

Workplace air OSHA set a legal limit of 5 mg/m3 manganese in air averaged over an 

8-hour work day. 

For more information on regulations and advisories, see Chapter 8. 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These clinics 

specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous 

substances. 

Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You may 

request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information and technical 

assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at cdcinfo@cdc.gov, or by writing 

to: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine
 

1600 Clifton Road NE
 

Mailstop F-32
 

Atlanta, GA 30333
 

Fax: 1-770-488-4178
 

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MANGANESE 10 

1. PUBLIC HEALTH STATEMENT 

Organizations for-profit may request copies of final Toxicological Profiles from the following: 

National Technical Information Service (NTIS) 

5285 Port Royal Road 

Springfield, VA 22161 

Phone: 1-800-553-6847 or 1-703-605-6000 

Web site: http://www.ntis.gov/ 

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MANGANESE 11 

2. RELEVANCE TO PUBLIC HEALTH
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO MANGANESE IN THE 

UNITED STATES 

Manganese is a naturally occurring element and an essential nutrient. Comprising approximately 0.1% of 

the earth’s crust, it is the twelfth most abundant element and the fifth most abundant metal. Manganese 

does not exist in nature as an elemental form, but is found mainly as oxides, carbonates, and silicates in 

over 100 minerals with pyrolusite (manganese dioxide) as the most common naturally-occurring form. 

As an essential nutrient, several enzyme systems have been reported to interact with or depend on 

manganese for their catalytic or regulatory function. As such, manganese is required for the formation of 

healthy cartilage and bone and the urea cycle; it aids in the maintenance of mitochondria and the 

production of glucose. It also plays a key role in wound-healing. 

Manganese exists in both inorganic and organic forms. An essential ingredient in steel, inorganic 

manganese is also used in the production of dry-cell batteries, glass and fireworks, in chemical 

manufacturing, in the leather and textile industries and as a fertilizer. The inorganic pigment known as 

manganese violet (manganese ammonium pyrophosphate complex) has nearly ubiquitous use in 

cosmetics and is also found in certain paints. Organic forms of manganese are used as fungicides, fuel-oil 

additives, smoke inhibitors, an anti-knock additive in gasoline, and a medical imaging agent. 

The erosion of crustal rocks to create soil results in average manganese soil concentrations in the United 

States of 40–900 mg/kg. Its presence in soil results in vegetable and animal foods reliably containing 

varying amounts of the mineral. As an essential nutrient, manganese is added to certain foods and 

nutritional supplements. Vegetarians often have diets richer in manganese than those who select 

omnivorous diets. 

The most important source of manganese in the atmosphere results from the air erosion of dusts or soils. 

The mean concentration of manganese in ambient air in the United States is 0.02 μg/m3

; however, 

ambient levels near industrial sources can range from 0.22 to 0.3 μg/m3

. Manganese is released into 

waterways mainly through the erosion of rocks and soils, mining activities, and industrial waste, or by the 

leaching of manganese from anthropogenic materials discarded in landfills or soil, such as dry-cell 

batteries. Surface waters in the United States contain a median manganese level of 16 μg/L, with 

99th percentile concentrations of 400–800 μg/L. Groundwater in the United States contains median 

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MANGANESE 12 

2. RELEVANCE TO PUBLIC HEALTH 

manganese levels of 5 to 150 μg/L, with the 99th percentile at 2,900 or 5,600 μg/L in rural or urban areas, 

respectively. 

The general population is exposed to manganese through consumption of food and water, inhalation of 

air, and dermal contact with air, water, soil, and consumer products that contain manganese. The primary 

source of manganese intake is through diet. The Food and Nutrition Board (FNB) of the Institute of 

Medicine (IOM) has set adequate intake (AI) levels for manganese for humans. These levels are 

presented in Table 2-1. 

The inhalation of air contaminated with particulate matter containing manganese is the primary source of 

excess manganese exposure for the general population in the United States. Populations living in close 

proximity to mining activities and industries using manganese may be exposed by inhalation to high 

levels of manganese in dust. Workers in these industries are especially vulnerable to exposure to 

manganese dust. Manganese concentrations in soil may be elevated when the soil is in close proximity to 

a mining source or industry using manganese and may therefore pose a risk of excess exposure to children 

who ingest contaminated soil. Manganese is ubiquitous in drinking water in the United States. Although 

certain water sources in the United States are contaminated with excess manganese, there is little risk of 

excessive exposure to manganese through ingestion of fish or shellfish emanating from contaminated 

waters, unless the manganese levels in the fish are extremely high and/or the fish are eaten as subsistence. 

Although many forms of manganese are water-soluble, there is little evidence that dermal contact with 

manganese results in significant absorption through the skin. Thus, dermal contact with manganese is not 

generally viewed as an important source of exposure to the population at large. 

Excess exposure to manganese may be revealed by tests to detect heightened levels in body fluids as well 

as in hair samples. Normal ranges of manganese levels in body fluids are 4–15 μg/L in blood, 1–8 μg/L 

in urine, and 0.4–0.85 μg/L in serum. Excess manganese in the body characteristically accumulates in the 

brain region known as the basal ganglia. This accumulation can be revealed by magnetic resonance 

imaging (MRI) as a distinctive symmetrical high-signal lesion in the globus pallidus region of the basal 

ganglia on T1- but not T2-weighted MRI. 

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MANGANESE 13 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-1. Adequate Intake (AI) for Manganese 

Life stage Age Males (mg/day) Females (mg/day) 

Infants 0–6 Months 0.003 0.003 

Infants 7–12 Months 0.6 0.6 

Children 1–3 Years 1.2 1.2 

Children 4–8 Years 1.5 1.5 

Children 9–13 Years 1.9 1.6 

Adolescents 14–18 Years 2.2 1.6 

Adults 19 Years and older 2.3 1.8 

Pregnancy All ages — 2.0 

Lactation All ages — 2.6 

Source: FNB/IOM 2001 

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MANGANESE 14 

2. RELEVANCE TO PUBLIC HEALTH 

2.2 SUMMARY OF HEALTH EFFECTS 

Although low levels of manganese intake are necessary for human health, exposure to high manganese 

levels are toxic. Reports of adverse effects resulting from manganese exposure in humans are associated 

primarily with inhalation in occupational settings. Inhaled manganese is often transported directly to the 

brain before it is metabolized by the liver. The symptoms of manganese toxicity may appear slowly over 

months and years. Manganese toxicity can result in a permanent neurological disorder known as 

manganism with symptoms that include tremors, difficulty walking, and facial muscle spasms. These 

symptoms are often preceded by other lesser symptoms, including irritability, aggressiveness, and 

hallucinations. Some studies suggest that manganese inhalation can also result in adverse cognitive 

effects, including difficulty with concentration and memory problems. Although the workplace is the 

most common source of excess inhalation of manganese, frequent inhalation of fumes from welding 

activities in the home can produce a risk of excess manganese exposure leading to neurological 

symptoms. Environmental exposures to airborne manganese have been associated with similar preclinical 

neurological effects and mood effects as are seen in occupational studies. Acute or intermediate exposure 

to excess manganese also affects the respiratory system. Inhalation exposure to high concentrations of 

manganese dusts (specifically manganese dioxide [MnO2] and manganese tetroxide [Mn3O4]) can cause 

an inflammatory response in the lung, which, over time, can result in impaired lung function. Lung 

toxicity is manifested as an increased susceptibility to infections such as bronchitis and can result in 

manganic pneumonia. Pneumonia has also been observed following acute inhalation exposures to 

particulates containing other metals. Thus, this effect might be characteristic of inhalable particulate 

matter and might not depend solely on the manganese content of the particle. 

Many reports indicate that oral exposure to manganese, especially from contaminated water sources, can 

produce significant health effects. These effects have been most prominently observed in children and are 

similar to those observed from inhalation exposure. An actual threshold level at which manganese 

exposure produces neurological effects in humans has not been established. However, children 

consuming the same concentration of manganese in water as adults are ultimately exposed to a higher 

mg/kg-body weight ratio of manganese than adults (as a consequence of the lower body weight of 

children as well as their higher daily consumption volume and greater retention of manganese). Children 

are also potentially more sensitive to manganese toxicity than adults. A study conducted in infant 

monkeys suggests that soy-based infant formula, which contains a naturally higher concentration of 

manganese than human or cow’s milk, may produce mild effects on neurological development, although 

such effects have not been documented in humans. While many of the studies reporting oral effects of 

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MANGANESE 15 

2. RELEVANCE TO PUBLIC HEALTH 

excess manganese have limitations that preclude firm conclusions about the potential for adverse effects, 

these studies collectively suggest that ingestion of water and/or foodstuffs containing increased 

concentrations of manganese may result in adverse neurological effects. 

There is indirect evidence that reproductive outcomes might be affected (decreased libido, impotence, and 

sexual dysfunction have been observed in manganese-exposed men). The available studies on the effect 

that manganese has on fertility (as measured by birthrate) is inconclusive. Two studies in men 

occupationally exposed to manganese show adverse effects on reproductive parameters: one found 

increased sexual dysfunction and the other found reduced sperm quality, but neither measured birthrate in 

wives of affected workers. Impaired sexual function in men may be one of the earliest clinical 

manifestations of manganese toxicity, but no dose-response information is currently available, so it is not 

possible to define a threshold for this effect. There is a lack of information regarding effects in women 

since most data are derived from studies of male workers. Developmental data in humans exposed to 

manganese by inhalation are limited and consist mostly of reports of adverse pulmonary effects from 

inhaling airborne manganese dust and adverse neurological effects in offspring following ingestion 

exposure. Animal studies indicate that manganese is a developmental toxin when administered orally and 

intravenously, but inhalation data concerning these effects are scarce and not definitive. Some studies in 

children suggest that routine exposures to high levels of manganese from contaminated drinking water 

may ultimately impair intellectual performance and behavior. 

The few available inhalation and oral studies in humans and animals indicate that inorganic manganese 

exposure does not cause significant injury to the heart, stomach, blood, muscle, bone, liver, kidney, skin, 

or eyes. However, if manganese is in the (VII) oxidation state (as in potassium permanganate), then 

ingestion may lead to severe corrosion at the point of contact. Studies in pigs have revealed a potential 

for adverse coronary effects from excess manganese exposure. 

There is no evidence that manganese causes cancer in humans. Although no firm conclusions can be 

drawn from the mixed results in animal studies, there are little data to suggest that inorganic manganese is 

carcinogenic. The EPA has provided manganese with a weight-of-evidence classification D—not 

classifiable as to human carcinogenicity. 

It should be noted that individuals with cirrhosis of the liver, as well as children with a congenital venous 

anomaly known as a portosystemic shunt, may be at heightened risk of health deficits from exposure to 

dietary and environmental sources of manganese. Manganese is ordinarily eliminated from the body 

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MANGANESE 16 

2. RELEVANCE TO PUBLIC HEALTH 

through bile, but cirrhosis and portosystemic shunts impair the normal functioning of the liver and thus 

limit the ability of the body to excrete manganese, which then can accumulate in the blood and, 

eventually, the brain. 

A more detailed discussion of the critical targets of manganese toxicity (i.e., the nervous system, 

respiratory system, reproductive system, and development), follows. 

Neurological Effects. There is clear evidence from studies of humans exposed to manganese dusts in 

mines and factories that inhalation of high levels of manganese can lead to a series of serious and 

ultimately disabling neurological effects in humans. This disease, termed manganism, typically begins 

with feelings of weakness and lethargy. As the disease progresses, a number of other neurological signs 

may become manifest. Although not all individuals develop identical signs, the most common are a slow 

and clumsy gait, speech disturbances, a masklike face, and tremors. The neurological symptoms may 

improve when exposure ceases; however, in most cases, the symptoms are found to persist for many years 

post-exposure. In addition, a syndrome of psychological disturbances (hallucination, psychosis) 

frequently emerges, although such symptoms are sometimes absent. As the disease progresses, patients 

develop severe muscle tension and rigidity and may be completely and permanently disabled. Workplace 

inhalation exposure levels producing overt symptoms of manganism have been on the order of 2–22 mg 

manganese/m3

. Subclinical neurological effects have been observed in several occupational studies. 

These effects include decreased performance on neurobehavioral tests; significantly poorer eye-hand 

coordination, hand steadiness, and reaction time; poorer postural stability; and lower levels of cognitive 

flexibility. Manganese air concentrations producing these effects in chronically exposed workers range 

from about 0.07 to 0.97 mg manganese/m3

. In addition, a study on environmental manganese sources 

indicated that both men and women were adversely affected by non-occupational exposure to manganese 

as evidenced by performance on neurobehavioral tests and increased neuropsychiatric disturbances. In 

these studies, a blood manganese level-age interaction was observed, with the poorest performance 

occurring among those older than 50 years who had the highest blood manganese levels. While 

manganese neurotoxicity has clinical similarities to Parkinson’s disease, it can be clinically distinguished 

from Parkinson’s. Manganism patients present a hypokinesia and tremor that is different from 

Parkinson’s patients. In addition, manganism patients sometimes have psychiatric disturbances early in 

the disease, a propensity to fall backward when pushed, less frequent resting tremor, more frequent 

dystonia, a “cock-walk”, and a failure to respond to dopaminomimetics. 

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MANGANESE 17 

2. RELEVANCE TO PUBLIC HEALTH 

While there is limited evidence that oral exposure to manganese leads to neurological effects similar to 

those reported for inhalation exposure, an accumulating body of evidence suggests that when children are 

exposed to excess levels of manganese in drinking water (≥0.2 mg/L), subtle learning and behavioral 

deficits may follow (see developmental effects below). Other studies have revealed cases of apparent 

manganism in both children and adults where exposures to high levels of manganese in drinking water 

were implicated as the probable cause. The symptoms in these cases are similar to those of individuals 

inhaling high levels of the mineral. 

Respiratory Effects. Inhalation exposure to manganese dusts often leads to an inflammatory 

response in the lungs of both humans and animals. This generally leads to an increased incidence of 

cough and bronchitis and can lead to mild-to-moderate injury of lung tissue along with minor decreases in 

lung function. In addition, susceptibility to infectious lung disease may be increased, leading to increased 

pneumonitis and pneumonia in some manganese-exposed worker populations. These effects have been 

reported primarily in workers exposed to fairly high concentrations of manganese dusts in the workplace, 

although there are some data that indicate that, in populations living and attending school near 

ferromanganese factories, there was an increased prevalence of respiratory effects. The risk of lung 

injury in people exposed to the levels of manganese typically found in the general environment is 

expected to be quite low. However, exposure to manganese-containing dusts from factories, mining 

operations, automobile exhaust, or other sources may be of concern. It should be noted that these effects 

on the lung are not unique to manganese-containing dusts but are produced by a variety of inhalable 

particulate matter. On this basis, it seems most appropriate to evaluate the risk of inflammatory effects on 

the lung in terms of total suspended particulate matter (TSP) or particulate matter <10 μm in diameter 

(PM10), as well as the concentration of manganese in the air. Studies involving controlled inhalation 

exposures in humans or animals to methylcyclopentadienyl manganese tricarbonyl (MMT), a gasoline 

additive that improves combustion efficiency, are not available because the compound breaks down 

readily in light to form inorganic manganese compounds. Rats exposed to high concentrations of car 

exhaust containing oxidation products from MMT-containing fuel exhibited labored breathing. 

Reproductive Effects. Impotence and loss of libido are common symptoms in male workers 

afflicted with clinically identifiable signs of manganism. These symptoms could lead to reduced 

reproductive success in men. Impaired fertility (measured as a decreased number of children/married 

couple) has been observed in male workers exposed for 1–19 years to manganese dust (0.97 mg/m3

) at 

levels that did not produce frank manganism. This suggests that impaired sexual function in men may be 

one of the earliest clinical manifestations of manganese toxicity, but no dose-response information is 

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MANGANESE 18 

2. RELEVANCE TO PUBLIC HEALTH 

available; therefore, it is not possible to define a threshold for this effect. Evidence obtained in laboratory 

mammals indicates that exposure to high levels of manganese may adversely effect sperm quality, 

produce decreased testicular weights, and impair development of the male reproductive tract. 

No direct effect of manganese toxicity has been observed on fertility in women. Although many studies 

in laboratory mammals have attempted to detect effects of manganese on female fertility, only one study 

demonstrated the possibility that excess manganese exposure outside of pregnancy may impair future 

fertility (decreased number of offspring). 

Developmental Effects. There is evidence to suggest that children exposed to high levels of 

manganese in drinking water may develop a variety of adverse developmental effects, particularly 

relevant to their behaviors and ability to learn and remember. Some studies suggest that children exposed 

to particularly high levels of manganese over a long period of time (months or years) will eventually 

develop one or more symptoms, including diminished memory, attention deficit, aggressiveness, and/or 

hyperactivity. However, it is not clear from any of these studies whether other factors, perhaps 

environmental or genetic, are responsible for these changes in the presence of manganese, or whether 

manganese along can produce these effects. 

A potentially serious developmental effect of manganese was suggested by the results of a study where 

high infant mortality in a Bangladesh community was reported in conjunction with the presence of a local 

drinking water supply containing high levels of manganese (concentration up to 8.31 mg/L). Infants 

exposed to levels of manganese equal to or greater than those recommended by the World Health 

Organization (WHO) were at the highest risk of mortality prior to 1 year of age. The nature of this 

epidemiological study, with nutritional deficits in the population anticipated but not documented, prevents 

a determination that manganese alone was responsible for the high rate of infant mortality. 

Developmental studies involving the use of laboratory animals have detected subtle changes in growth; 

(e.g., diminished body weight, in animals provided with relatively high doses of manganese). These 

changes have been observed both when the animals were exposed while in utero or postpartum when the 

animals have already been born. 

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MANGANESE 19 

2. RELEVANCE TO PUBLIC HEALTH 

2.3 MINIMAL RISK LEVELS (MRLs) 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for manganese. An 

MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an 

appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are 

derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive 

health effect(s) for a specific duration within a given route of exposure. MRLs are based on 

noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for 

acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate 

methodology does not exist to develop MRLs for dermal exposure. 

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), 

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional 

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an 

example, acute inhalation MRLs may not be protective for health effects that are delayed in development 

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic 

bronchitis. As these kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

A User’s Guide has been provided at the end of this profile (see Appendix B). This guide should aid in 

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

Inhalation MRLs for Inorganic Manganese 

Acute and Intermediate Inhalation Exposure. MRL values were not derived for acute- or intermediateduration inhalation exposures to manganese. The available data on the toxicity of inhaled manganese 

were considered inadequate for derivation of acute- or intermediate-duration inhalation MRLs. Data are 

lacking on whether exposure to inhaled manganese across these durations has any significant adverse 

effects on numerous end points including reports on developmental and reproductive effects. 

Reports of human exposure at acute and intermediate durations (i.e., 15–364 days) indicate adverse 

respiratory and neurological effects, but these reports consist of anecdotal case studies and lack 

quantitative exposure values. 

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MANGANESE 20 

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A few animal studies for these durations also evaluated respiratory effects in rodents and monkeys and 

reported no-observed-adverse-effect levels (NOAELs). Inhalation of particulate manganese compounds 

such as manganese dioxide or manganese tetroxide leads to an inflammatory response in the lungs of 

animals, although inhalation of MnCl2 did not cause lung inflammation in rabbits (Camner et al. 1985). 

Several acute- and intermediate-duration studies in animals report various signs of lung inflammation 

following periods ranging from 1 day to 10 months at manganese concentrations ranging from 0.7 to 

69 mg/m3 (Bergstrom 1977; Camner et al. 1985; Shiotsuka 1984; Suzuki et al. 1978; Ulrich et al. 1979a, 

1979b). Bergstrom (1977) and Ulrich et al. (1979a, 1979b) determined NOAELs, which are reported in 

the levels of significant exposure (LSE) table and figure. Increased susceptibility to lung infection by 

bacterial pathogens following inhalation of manganese dusts has been noted in acute animal studies 

(Maigetter et al. 1976). Conversely, Lloyd Davies (1946) reported no increase in the susceptibility of 

manganese-treated mice to pneumococci or streptococci. 

More recently, reversible inflammation (pleocellular inflammatory infiltrates and fibrinonecrotic debris) 

in the nasal respiratory epithelium (but not the olfactory epithelium) was observed in young adult male 

Crl:CD(SD)BR rats following 13 weeks of inhalation exposure to 0.5 mg manganese/m3 as manganese 

sulfate, but not in rats exposed to 0.1 mg manganese/m3 as manganese sulfate or manganese phosphate 

(hureaulite) (Dorman et al. 2004b). The lesions were not apparent in groups of rats assessed 45 days after 

the end of exposure, indicating their transient nature. In studies with young male rhesus monkeys 

exposed to 0, 0.06, 0.3, or 1.5 mg manganese/m3 as manganese sulfate 6 hours/day, 5 days/week for 

65 days, no nasal histological effects were found in exposed monkeys, but the high exposure level 

induced lesions in the lower respiratory tract (mild subacute bronchiolitus, alveolar duct inflammation, 

and proliferation of bronchus-associated lymphoid tissue) (Dorman et al. 2005b). The lower airway 

lesions from intermediate-duration exposure appear to have been transient, because they were not found 

in monkeys assessed 45 days after the end of exposure (Dorman et al. 2005b). These findings in rats and 

monkeys are consistent with the understanding that inflammation of respiratory tissues from high-level 

exposure to inhaled manganese particulates is likely a consequence of the inhaled particulate matter. 

Bredow et al. (2007) reported that nose-only inhalation exposure to 2 mg manganese/m3 as manganese 

chloride aerosols 6 hours/day for 5 consecutive days did not cause lung lesions in female GVB/N mice, 

but induced a 2-fold increase in pulmonary levels of mRNA for vascular endothelial growth factor 

(VGEF), a regulator of proliferation, migration, and formation of new capillaries. Elevated levels of 

VGEF have been associated with respiratory diseases, but current understanding is inadequate to 

understand if this pulmonary gene expression response to manganese is adverse or benign. 

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MANGANESE 21 

2. RELEVANCE TO PUBLIC HEALTH 

There are limited evaluations of neurological end points in animals following intermediate-duration 

inhalation exposure to manganese. Neurological effects comparable to those observed in humans have 

been reported in monkeys exposed to manganese by parenteral routes (intravenous) for intermediate 

duration (Newland and Weiss 1992), but no reports of the application of sensitive neurobehavioral test 

batteries to animals following acute or intermediate-duration inhalation exposure to inorganic manganese 

were located. 

In monkeys exposed to manganese oxide aerosol concentrations as high as 1.1 mg manganese/m3 

24 hours/day for 9 months, no exposure-related effects on limb tremor or electromyograms were 

observed, even though blood manganese levels were 5-fold higher in exposed compared with control 

monkeys (Ulrich et al. 1979a, 1979b, 1979c). No gross signs of neurological impairment were observed 

in rats exposed by the same protocol to manganese oxide aerosol concentrations as high as 1.1 mg 

manganese/m3 (Ulrich et al. 1979a, 1979b, 1979c). 

More recent studies of monkeys exposed to concentrations up to 0, 0.06, 0.3, or 1.5 mg manganese/m3 as 

manganese sulfate 6 hours/day for 65 days reported: (1) no obvious signs of gross toxicity in the exposed 

monkeys; (2) about 2-fold higher manganese concentrations in most brain regions at 1.5 mg 

manganese/m3

, except for the globus pallidus which showed manganese concentrations 6-fold greater 

than control concentrations; and (3) a spectrum of exposure-related changes in biochemical markers of 

neurotoxicity in various regions of the exposed monkeys, compared with control monkeys (Dorman et al. 

2006a, 2006b; Erikson et al. 2007). No published accounts of the application of sensitive neurobehavioral 

test batteries to these animals are available and there are no studies in monkeys reporting NOAELs and 

lowest-observed-adverse-effect level (LOAELs) for neurological effects following chronic-duration 

exposure. 

Increased locomotor activity has been observed in Sprague-Dawley rats exposed for 90 days (6 hours/day, 

5 days/week) to a manganese phosphate/manganese sulfate mixture at concentrations ≥0.03 mg 

manganese/m3 (Salehi et al. 2003) and to manganese sulfate at concentrations ≥0.009 mgmanganese/m3 

(Tapin et al. 2006), but this effect was not observed with exposure to hureaulite (manganese phosphate) at 

aerosol concentrations as high as 1 mg manganese/m3 (Normandin et al. 2002). Significant neuronal cell 

loss in the globus pallidus and caudate putamen was also observed in Sprague-Dawley rats exposed for 

90 day (6 hours/day, 5 days/week) to the manganese phosphate/manganese sulfate mixture at an aerosol 

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MANGANESE 22 

2. RELEVANCE TO PUBLIC HEALTH 

concentration of 3 mg manganese/m3; these changes, however, were not accompanied with signs of 

tremor as assessed with electromyographic techniques (Salehi et al. 2006). 

MRL values for acute or intermediate durations based on animal studies were not derived, because an 

MRL based on animal data would be lower than the proposed chronic-duration inhalation MRL that is 

based on effects observed in humans. It is uncertain if this is due to species differences in susceptibility 

to the neurotoxic properties of inhaled manganese or to the testing of humans with sensitive 

neurobehavioral tests that have not been applied to animals following inhalation exposures to manganese. 

•	 An MRL of 0.0003 mg manganese/m3 (manganese in respirable dust; 0.3 μg manganese/m3

) has 

been derived for chronic inhalation exposure (365 days or more) to manganese. 

The study chosen to derive the MRL is from an investigation of an occupational cohort involving 92 male 

workers in a dry alkaline battery plant (Roels et al. 1992). They and the 101 age- and area-matched 

controls (with no industrial exposure to manganese) were observed for performance on a battery of 

neurobehavioral tests. Manganese workers were exposed for an average (geometric mean) of 5.3 years 

(range: 0.2–17.7 years) to a respirable dust concentration of 215 μg manganese/m3 and a total dust 

concentration of 948 μg manganese/m3

. Manganese concentrations were measured with personal 

samplers, with respirable dust being <5 microns in diameter. The authors noted that plant exposure 

conditions had not changed considerably in the last 15 years, suggesting that past exposures were 

consistent with those measured at the time of the study. Performance in measured neurobehavioral tests, 

especially on measures of simple reaction time, eye-hand coordination, and hand steadiness, was 

significantly worse in manganese-exposed workers than in the comparison group. 

Manganese-exposed workers performed significantly worse than the controls on the neurobehavioral 

tests, with particular differences in simple reaction time, eye-hand coordination, and hand steadiness. 

Dr. Harry Roels provided the data on the manganese-exposed group evaluated in this study. These data 

included individual exposure levels and whether the individual had an abnormal performance in the 

neurobehavioral tests (scores below the 5th percentile score of the control group). Percent precision score 

in the eye-hand coordination test was the most sensitive end point among the end points showing 

statistically significantly elevated incidences of abnormal scores and was selected as the basis of the 

MRL. Average exposure concentration for each worker was calculated by dividing the individual lifetime 

integrated respirable concentration (LIRD; calculated by Dr. Roels from occupational histories and 

measurements of workplace air manganese concentrations) by the individual’s total number of years 

working in the factory. Individuals were grouped into eight exposed groups and the control group, and 

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MANGANESE 23 

2. RELEVANCE TO PUBLIC HEALTH 

the average of the range in each group was used in benchmark modeling of the incidence data for number 

of workers with abnormal percent precision eye-hand coordination scores (see Table A-1 in Appendix A). 

Available dichotomous models in the EPA Benchmark Dose Software (version 1.4.1c) were fit to the 

incidence data for abnormal eye-hand coordination scores in workers exposed to respirable manganese 

(Roels et al. 1992, Table A-1). Results from the modeling are shown in Table A-2 in Appendix A. Based 

on the chi-square and Akaike Information Criterion (AIC) measures of fit, all of the models provided 

adequate and comparable fits to the data (the quantal linear and Weibull models had the same parameter 

values). The model with the lowest AIC, the logistic model, was selected as the best fitting model, and 

the BMCL10 from the logistic model, 142 μg respirable manganese/m3

, was selected as the point of 

departure for the chronic inhalation MRL. An alternative approach to selecting a point of departure 

(averaging BMCL10 values across all models in Table A-2) arrived at a similar point of departure of 

105 μg respirable manganese/m3

, which would yield an identical MRL value. 

The MRL of 0.3 μg manganese/m3 was derived by adjusting the point of departure to a continuous 

exposure basis (142 x 5/7 x 8/24) and dividing by an uncertainty factor of 100: 

•	 10 for uncertainty about human variability including possibly enhanced susceptibility of the 

elderly, infants, and children; individuals with chronic liver disease or diminished hepatobiliary 

function; and females and individuals with iron deficiency; and 

•	 10 for limitations/uncertainties in the database including the lack of epidemiological data for 

humans chronically exposed to soluble forms of manganese and the concern that the general 

population may be exposed to more soluble forms of manganese than most of the manganeseexposed workers in the principal and supporting studies and the uncertainty that a factor of 10 for 

human variability will provide enough protection for manganese effects on brain development in 

children. In addition, data on developmental toxicity for this route and duration of exposure are 

lacking. There is limited information on reproductive effects in females (one study in rat dams) 

and reported effects on male reproductive organs have not been clearly associated with decreased 

reproductive function. Though it is clear that the neurological system is the target organ for 

effects from chronic-duration inhalation exposure to manganese, data are lacking to fully 

characterize the potential risk for all organ systems from chronic inhalation exposure. 

Neurological effects from repeated inhalation exposure to manganese are well recognized as effects of 

high concern based on case reports and epidemiological studies of groups of occupationally exposed 

people and results from animal inhalation studies. A number of epidemiological studies have used 

batteries of neurobehavioral tests of neuromotor, cognition, and mood states to study the psychological or 

neurological effects of exposure to low levels of manganese in the workplace (Bast-Pettersen et al. 2004; 

Beuter et al. 1999; Blond and Netterstrom 2007; Blond et al. 2007; Bouchard et al. 2003, 2005, 2007a, 

2007b; Chia et al. 1993a, 1995; Crump and Rousseau 1999; Deschamps et al. 2001; Gibbs et al. 1999; 

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MANGANESE 24 

2. RELEVANCE TO PUBLIC HEALTH 

Iregren 1990; Lucchini et al. 1995, 1999; Mergler et al. 1994; Myers et al. 2003a, 2003b; Roels et al. 

1987a, 1992, 1999; Wennberg et al. 1991) or in environmental media close to manganese-emitting 

industries (Lucchini et al. 2007; Mergler et al. 1999; Rodríguez-Agudelo et al. 2006). Some of these 

studies have found statistically significant differences between exposed and non-exposed groups or 

significant associations between exposure indices and neurological effects (Bast-Pettersen et al. 2004; 

Chia et al. 1993a; Iregren 1990; Lucchini et al. 1995, 1999; Mergler et al. 1994; Roels et al. 1987a, 1992; 

Wennberg et al. 1991), whereas others have not found significant associations (Deschamps et al. 2001; 

Gibbs et al. 1999; Myers et al. 2003a, 2003b; Young et al. 2005). Table A-3 in Appendix A summarizes 

results from these studies. The neurological effects associated with prolonged low-level manganese 

exposure generally have been subtle changes including deficits in tests of neuromotor or cognitive 

functions and altered mood states; they have been referred to by various authors as preclinical or 

subclinical neurological effects. Manganese air concentrations associated with these effects in 

chronically exposed workers range from about 0.07 to 1.59 mg manganese/m3 (manganese in total or 

inhalable dust measurements; values for manganese in respirable dust are noted in parentheses in 

Table A-3). Comparison of the effect levels in these studies provides support for selection of the Roels et 

al. (1992) as the basis of the MRL; the advantage of the Roels et al. (1992) study is that individual worker 

data were available to support a benchmark dose analysis. 

Several benchmark analyses of results from other epidemiological data for neurobehavioral deficits in 

manganese-exposed workers provide support for the MRL. 

Dr. Anders Iregren provided ATSDR with individual worker data on total dust manganese exposure and 

performance on neurobehavioral tests for the occupational cohort that participated in his study (Iregren 

1990; Wennberg et al. 1991). A benchmark analysis was also performed with these data (Clewell and 

Crump 1999) and the BMCL10 value derived from this evaluation was 0.071 mg manganese/m3 based 

upon the reported observation that the respirable fraction ranged upwards to 80% of the total dust 

measured. This BMCL10 value is similar to that estimated for the Roels et al. (1992) study (0.105 mg 

manganese/m3

), thus giving support to the value obtained for the current MRL study. 

Clewell et al. (2003) conducted benchmark analyses on data from three neuromotor tests in the Roels et 

al. (1992) study (visual reaction time, eye-hand coordination, and hand steadiness) and from five 

neuromotor tests in the Gibbs et al. (1999) study (hole 6 of the hand steadiness test, percent precision of 

the eye-hand coordination test, reaction time in the complex reaction test, RMS amplitude in the steady 

test, and tap time). Exposure measures in these analyses were recent measures of manganese 

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MANGANESE 25 

2. RELEVANCE TO PUBLIC HEALTH 

concentrations in respirable dust. BMCL10 values were 0.257, 0.099, and 0.202 mg manganese/m3, 

respectively, for the visual reaction time, eye-hand coordination, and hand steadiness data from the Roels 

et al. (1992) study. BMCL10 values from the analyses of outcomes from the Gibbs et al. (1999) study 

ranged from 0.09 to 0.27 mg manganese/m3 (averaging the BMCLs within end points across different 

benchmark dose models applied to the data). Clewell et al. (2003) did not have individual worker data 

from the Iregren (1990) or Mergler et al. (1994) studies, but, based on some assumptions about exposures 

(e.g., all exposed workers were exposed to average concentrations for the facilities and respirable 

manganese concentrations were calculated for the Iregren workers based on an assumption that 50% of 

total dust manganese was respirable), they calculated BMCL10 values for six end points from the Mergler 

et al. (1994) study and the simple reaction time end point in the Iregren (1990) study. BMCL10 values 

ranged from 0.1 to 0.3 mg manganese/m3 from the Mergler et al. (1994) study end points to 0.1 mg 

manganese/m3 for the reaction time end point in the Iregren (1990) study. 

Health Canada (2008) recently prepared a draft document in which benchmark dose analyses were 

conducted on data for neurobehavioral end points from the study of manganese alloy workers by Lucchini 

et al. (1999). Using the average manganese concentrations in respirable dust over the 5-year period 

before testing as the dose metric, dose-response data for six tests of fine motor control, two aspects of 

memory tests, and one test of mental arithmetic were fit to linear models, which were used to calculate 

BMCL05 values ranging from about 0.019 to 0.0588 mg manganese/m3

. After adjustment to convert from 

occupational exposure (5 days/week, 8 hours/24 hours) to continuous exposure, adjusted BMCL05 values 

were divided by a total uncertainty factor of 100 to arrive at prospective reference concentrations. The 

uncertainty factor was comprised of a factor of 10 to account for interindividual variability in response to 

manganese to protect possibly enhanced susceptibility of the elderly, infants and children, individuals 

with asymptomatic pre-parkinsonism, individuals with chronic liver disease or parenteral nutrition, and 

females and individuals with iron deficiency and a second factor of 10 to account for limitations/ 

uncertainties in the database including: (1) the general population may be exposed to more soluble forms 

of manganese than most of the manganese-exposed workers; (2) the lack of extensive studies of the effect 

of prenatal exposure to manganese; and (3) the potential effects that manganese exposure early in life may 

have on health outcomes later in life. The prospective reference concentrations ranged from about 0.05 to 

0.08 μg manganese/m3

. 

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MANGANESE 26 

2. RELEVANCE TO PUBLIC HEALTH 

Oral MRLs for Inorganic Manganese 

Overview. No oral MRLs were derived for acute-, intermediate-, or chronic-duration oral exposure to 

manganese, even though the limited human data and extensive animal data clearly identify 

neurobehavioral changes as the most sensitive effect from intermediate- and chronic-duration oral 

exposure to excess inorganic manganese. However, inconsistencies in the dose-response relationship 

information across studies evaluating different neurological end points under different experimental 

conditions in different species, as well as a lack of information concerning all intakes of manganese (e.g., 

dietary intakes plus administered doses), make it difficult to derive intermediate- or chronic-duration 

MRLs using standard MRL derivation methodology from the animal studies. New reports of 

neurobehavioral effects in children associated with elevated concentrations of manganese in drinking 

water were evaluated as the possible basis of an oral MRL for intermediate and/or chronic durations of 

exposure. However, the data were assessed to be unsuitable for MRL derivation due to uncertainties 

about other possible confounding exposures to neurotoxic agents in the drinking water or via food, and 

the lack of information about dietary intakes of manganese by the children. An interim guidance value of 

0.16 mg manganese/kg/day, based on the Tolerable Upper Intake Level for 70 kg adults of 11 mg 

manganese/day (established by the U.S. Food and Nutrition Board/Institute of Medicine [FNB/IOM 

2001]) is recommended to be used for ATSDR public health assessments of oral exposure to inorganic 

forms of manganese. 

Acute Oral Exposure. Quantitative data are not available to derive acute-duration oral MRLs. The only 

new acute-duration study reported that a single dose of 50 mg manganese chloride/kg (13.9 mg 

manganese/kg) to a group of 10 white rats caused worsened acquisition of an avoidance reaction in 

response to unconditioned and condition stimuli, increased latent period of a conditioned reflex activity, 

and increased numbers of errors and time taken to navigate a maze (compared with controls), beginning 

on day 5 after dose administration and lasting until day 10–15 (Shukakidze et al. 2003). Although 

neurobehavioral impairment from acute oral exposure to manganese is plausible based on results from 

studies of manganese-exposed workers and repeatedly exposed animals, there are no corroborating data 

from other acute-duration studies to confirm this finding of impaired neurobehavior following a single 

oral dose of 13.9 mg manganese/kg. 

Other acute-duration oral studies found only decreased liver and body weight and decreased leukocyte 

and neutrophil counts in rats at dietary doses of 1,300 mg manganese/kg/day and no effects in mice at 

dietary doses up to 2,600 (males) or 3,900 (females) mg manganese/kg/day after 14 days of exposure to 

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MANGANESE 27 

2. RELEVANCE TO PUBLIC HEALTH 

manganese sulfate in the diet (NTP 1993). No signs of developmental or maternal toxicity were observed 

in a standard developmental toxicity study of pregnant rats given daily gavage doses of 2,200 mg 

manganese/kg/day as manganese chloride on gestation days 6–17 (Grant et al. 1997a). With 

intermediate-duration, no exposure-related effects on fetal body weight or skeletal development or 

anomalies were found in pregnant rabbits exposed to 33 mg manganese/kg/day on gestation days 6–20, 

but some evidence for delayed fetal skeletal development was found in pregnant Sprague-Dawley rats 

exposed to the same dose of manganese chloride on gestation days 0–21 (Szakmáry et al. 1995). 

Intermediate Oral Exposure. With intermediate-duration oral exposure, effects on neurobehavior are 

expected to be the most sensitive effects from excessive manganese, particularly during early 

developmental periods, based on findings for subtle neurobehavioral effects in epidemiological studies on 

manganese-exposed workers (see Section 3.1), higher brain manganese levels and altered brain dopamine 

levels in neonatal rats, compared with adult rats, due to immaturity of the blood-brain barrier and the lack 

of biliary excretion in preweanling rats (Aschner et al. 2005; Dorman et al. 2000, 2005a; Kontur and 

Fechter 1985, 1988), and results from studies of the effects of intermediate-duration oral exposure on 

systemic toxicity end points and neurobehavioral, neurochemical, and neurodevelopmental end points in 

adult and young laboratory animals (Calibresi et al. 2001; Reichel et al. 2006; Tran et al. 2002a, 2002b). 

The discussion that follows provides evidence that, while systemic effects of manganese are not typically 

the most sensitive end point of action, some evidence exists to support adverse cardiovascular effects of 

manganese at relatively low dose levels, followed by a review of the large number of studies that most 

consistently support neurobehavior effects as the most sensitive effects from excessive oral manganese 

exposure. 

In standard toxicity studies of intermediate-duration oral exposure to inorganic manganese, marginal 

evidence for systemic toxicity was found in rats at doses ≥33 mg manganese/kg/day (increased neutrophil 

count and decreased liver weight in males; decreased body weights at higher doses) and in mice at the 

highest administered dose of 1,950 mg manganese/kg/day (decreased hemoglobin, mild hyperplasia of 

forestomach, decreased liver and body weight) (NTP 1993). Corroborative evidence comes from reports 

of decreased red blood cell counts and body weight in mice following 100 days of dietary exposure to one 

of several forms of inorganic manganese (manganese acetate, carbonate, oxide, or chloride) at a dose 

level of 284 mg manganese/kg/day (Komura and Sakamoto 1991). 

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However, other animal studies indicate that excessive oral intake of manganese may present a 

cardiovascular hazard. Under magnesium deficiency conditions (4.1 mmol Mg/kg diet), swine fed 

moderately elevated levels of manganese (about 500 mg manganese/kg diet) died suddenly within 

5 weeks and showed necrosis and mineralization of the heart (Miller et al. 2000). This finding was 

supported with subsequent findings of myocardial necrosis and mitochondrial swelling in magnesiumdeficient pigs fed a diet high in manganese (500 mg manganese/kg diet) for 8 weeks (Miller et al. 2004) 

and of depressed heart muscle mitochondrial O2 consumption and decreased red blood cells in rats 

consuming a high manganese diet (250 mg manganese/kg diet) under marginal magnesium dietary 

conditions; the manganese-induced effects on hematological end points in rats were absent when adequate 

dietary magnesium was provided (Miller et al. 2006). In another study involving rats supplied with 

adequate and excessive Mn in the diet (10–15 and 45–50 mg manganese/kg diet), aortas from rats with 

excessive dietary manganese showed less expression and sulfation of heparin sulfate glycosaminoglycans, 

compared with the adequate condition (Kalea et al. 2006). The results from these studies suggest that 

excessive intermediate-duration oral intake of manganese may present a cardiovascular hazard, especially 

under magnesium-deficient dietary conditions, but their use as the basis of an intermediate-duration oral 

MRL for inorganic manganese is limited due to the lack of reported information to accurately calculate 

daily intakes. Myocardial lesions were not found in rats or mice provided manganese sulfate in the diet 

for 2 years at dose levels up to 232 or 731 mg manganese/kg/day, respectively (NTP 1993). 

Numerous studies support the sensitivity of neurobehavioral end points to intermediate-duration oral 

doses of manganese. In humans and nonhuman primates exposed orally for intermediate durations, 

neurobehavioral end points have been examined in healthy adult female subjects given low (0.01 mg 

manganese/kg/day) or high (0.3 mg manganese/kg/day) manganese diets for 8 weeks (Finley et al. 2003) 

and in infant monkeys fed either a commercial cow’s milk formula (17.5 mg manganese/kg/day), a 

commercial soy formula (107.5 mg manganese/kg/day), or a soy formula with added magnesium chloride 

(328 mg manganese/kg/day) for 4 months with monkeys tested through 18 months of age (Golub et al. 

2005). No differences between the low and high dietary-intake states were found in the adult females on 

scores for hand-steadiness and self-reported traits such as assertiveness and anger (Finley et al. 2003). 

Monkeys provided the highest manganese dose level showed no marked differences from the cow’s milk 

controls in gross motor maturation, growth, cerebrospinal fluid levels of dopamine or serotonin 

metabolites, or performance on tests of cognitive end points, but showed decreased activity during sleep 

at 4 months and decreased play activity between 1 and 1.5 months. These results suggest that daily 

intakes of 328 mg manganese/kg/day (but not 107.5 mg manganese/kg/day) during neonatal periods may 

cause subtle neurobehavioral changes in primates. 

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MANGANESE 29 

2. RELEVANCE TO PUBLIC HEALTH 

In neurobehavioral assessments of rodents orally exposed to inorganic manganese for intermediate 

durations during neonatal periods, subtle neurobehavioral effects have been observed at supplemental 

dose levels as low as about 10–20 mg manganese/kg/day (Brenneman et al. 1999; Dorman et al. 2000; 

Kristensson et al. 1986; Pappas et al. 1997; Reichel et al. 2006; Tran et al. 2002a, 2002b). Although there 

are some inconsistencies in the results obtained in these studies (e.g., Brenneman et al. [1999] found 

increased motor activity with exposure to 22 mg manganese/kg/day after exposure on postnatal days 1– 

49, but Dorman et al. [2000] found no effects of the same dose level on motor activity after exposure on 

postnatal days 1–21), the weight of evidence suggests that subtle neurobehavioral effects can occur in rats 

with intermediate-duration neonatal exposures at doses ≥10–20 mg manganese/kg/day. 

Findings for histopathological changes in the rat brain following intermediate-duration oral exposure to 

inorganic manganese during neonatal periods are less consistent than the findings for subtle 

neurobehavioral effects. Chandra and Shukla (1978) reported neuronal degeneration in cortical and 

cerebellar sections from the brains of young rats orally exposed to 0.3 mg manganese/kg/day as 

manganese chloride between postnatal days 21 and 51. In contrast, Kristensson et al. (1986) reported no 

adverse histological changes in cerebellum or hippocampus in rats exposed to a much higher dose level of 

manganese chloride (150 mg manganese/kg/day) between postnatal days 3 and 44. Pappas et al. (1997) 

reported a decreased cortical thickness in the offspring of rat dams exposed to 120 or 650 mg 

manganese/kg/day from gestation day 1 through postnatal day 30, but found no immunohistological 

evidence for increased glial fibrillary acidic protein in the cortex, caudate, or hippocampus. Dorman et al. 

(2000) reported that no adverse histological changes were found in sections of the following brain regions 

in Sprague-Dawley rats exposed to 11 or 22 mg manganese/kg/day on postnatal days 1–21: olfactory 

bulbs, cerebral cortex, hippocampus, basal ganglia, thalamus, hypothalamus, midbrain, and cerebellum. 

The weight of evidence from these studies indicates that subtle neurobehavioral effects in neonatally 

exposed rats are not consistently associated with histological changes in the brain. 

Neurobehavioral effects have also been observed in adult rats orally exposed to inorganic manganese for 

intermediate durations. In several studies, doses inducing these effects were higher than those inducing 

subtle neurobehavioral effects after neonatal exposure (Calabresi et al. 2001; Centonze et al. 2001; 

Torrente et al. 2005), but in two other studies, neurobehavioral effects were observed at doses as low as 

5.6 mg manganese/kg/day (Shukakidze et al. 2003) and 6.5 mg manganese/kg/day (Vezér et al. 2005, 

2007). Increased open field activity, increased interest in a novel object, and increased signs of fear were 

observed in adult male Wistar rats exposed to drinking water containing 20 mg manganese chloride/L for 

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MANGANESE 30 

2. RELEVANCE TO PUBLIC HEALTH 

10 weeks (estimated doses of 1,310 mg manganese/kg/day), but no effects on radial maze performance, 

numbers of neuronal cells or levels of glial fibrillary acidic protein in striatum, or intrinsic 

electrophysiological membrane properties of striatal neurons with the exception of a manganese-induced 

increase in the frequency and amplitude of spontaneous excitatory postsynaptic potentials (Calabresi et al. 

2001; Centonze et al. 2001). In an earlier study of adult male Wistar rats exposed to 20 mg manganese 

chloride/L for 13 weeks, no neuronal loss or gliosis was evident in the globus pallidus by either 

histological or immunohistochemical examination (Spadoni et al. 2000). Decreased open field activity 

and impaired spatial learning were observed in restraint stressed adult male Sprague-Dawley rats exposed 

to 153 mg manganese/kg/day (but not 76 mg manganese/kg/day) as manganese chloride in drinking water 

for 19 weeks (Torrente et al. 2005). No changes in motor activity or performance in a passive avoidance 

test were observed in adult male Sprague-Dawley rats exposed to 11 or 22 mg manganese/kg/day for 

21 days; these doses induced increased pulse-elicited acoustic startle response with neonatal exposure, but 

exposure during adulthood did not (Dorman et al. 2000). The lowest intermediate-duration daily dose 

associated with neurobehavioral effects in adult rats is 5.6 mg manganese/kg/day for severely impaired 

cognitive performance in a maze test following a 30-day exposure of white rats to manganese chloride in 

the diet (strain not otherwise indicated) (Shukakidze et al. 2003). In another study, decreased open-field 

locomotor activity and acoustic startle response and impaired performance in maze learning (a test of 

spatial memory) were observed in male adult Wistar rats exposed to gavage doses of 6.5 or 25.9 mg 

manganese/kg/day for 10 weeks, compared with controls (Vezér et al. 2005, 2007). Decreased acoustic 

startle response and impaired spatial memory were still evident in exposed rats, compared with controls, 

after 5–7 weeks without exposure (Vezér et al. 2005, 2007). 

Several types of reproductive effects have been reported for manganese. A study by Hafeman et al. 

(2007) reported a high mortality rate among infants <1 year of age in a Bangladesh community where 

manganese levels in drinking water were high, but the actual association between the manganese levels in 

drinking water and infant mortality is difficult to make with certainty. The average level of manganese 

intake was calculated to be 0.26 mg manganese/kg/day. Other reproductive effects reported for 

manganese in intermediate-duration animal studies include 25% decreased pregnancy rate in Long-Evans 

rats (males and females) exposed to manganese oxide in the diet at 180 mg manganese/kg/day (but not 

55 mg manganese/kg/day) for 100–224 days (Laskey et al. 1982), increased incidence of testicular 

degeneration in male Sprague-Dawley rats exposed to manganese acetate at gavage doses of 137 (but not 

69) mg manganese/kg/day for 63 days (Ponnapakkam et al. 2003c), and delayed growth of testes and sex 

accessory glands in CD-1 mice exposed to manganese oxide in the diet at 205 mg manganese/kg/day 

(Gray and Laskey 1980). In Swiss mice exposed for 12 weeks to manganese chloride in drinking water, 

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MANGANESE 31 

2. RELEVANCE TO PUBLIC HEALTH 

impaired fertility was observed in males at 309 mg manganese/kg/day (but not a 154 mg manganese/ 

kg/day) and in females at 277 mg manganese/kg/day (Elbetieha et al. 2001). Decreased sperm motility 

and sperm counts were observed in CD-1 mice exposed to 4.8 or 9.6 mg manganese/kg/day as manganese 

acetate, but no effects on the ability of exposed males to impregnate unexposed female mice were found 

at these doses (Ponnapakkam et al. 2003a). The results from the intermediate-duration animal studies 

suggest that oral exposure to manganese may produce adverse effects on reproduction, but at much higher 

doses than those inducing subtle neurobehavioral effects in adult or neonatal rats. 

In summary, results from animal studies identify subtle neurobehavioral effects as the critical effect in 

rodents from intermediate-duration oral exposure to inorganic manganese. Potential points of departure 

for an intermediate-duration oral MRL include LOAEL values of 5.6 mg manganese/kg/day for severely 

impaired cognitive performance in a maze test following 30-day dietary exposure of adult white rats 

(Shukakidze et al. 2003); 6.5 mg manganese/kg/day for decreased open-field locomotor activity and 

acoustic startle response and impaired performance in maze learning (a test of spatial memory) in male 

adult Wistar rats exposed for 10 weeks by gavage (Vezér et al. 2005, 2007); and 11 mg manganese/ 

kg/day for increased pulse-initiated acoustic startle response in Sprague-Dawley rats exposed (orally by 

pipette) on postnatal days 1–21 (Dorman et al. 2000). In contrast, hand steadiness or self-reported scales 

for assertiveness or anger were not different in adult female subjects following 8 weeks of exposure to 

dietary doses of 0.01 or 0.3 mg manganese/kg/day (Finley et al. 2003). In young monkeys, decreased 

activity during sleep at 4 months and decreased play activity between 1 and 1.5 months were observed 

following daily intakes of 328 mg manganese/kg/day (but not 107.5 mg manganese/kg/day), but no 

effects on gross motor maturation or performance in cognitive tests were observed at either dose level 

compared with controls (Golub et al. 2005). 

The effects noted in the rat study by Shukakidze et al. (2003) are much more severe than effects noted in 

adult rats at reportedly higher dose levels of 1,310 mg manganese/kg/day (Calabresi et al. 2001; Centonze 

et al. 2001) or 153 mg manganese/kg/day (Torrente et al. 2005) or in adult rats at comparable reported 

doses of 6.5 mg manganese/kg/day (Vezér et al. 2005, 2007). Shukakidze et al. (2003) reported that the 

exposed rats “showed increased aggresivity, frequently fell from the platform in the maze, and were 

unable to perform the maze test.” Because the reporting of the experimental conditions in the Shukakidze 

et al. (2003) study is sparse and the severity of effects is so unusual, the results are considered to be 

outlying results that are not consistent with the rest of the database and not appropriate as the basis of an 

MRL. 

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MANGANESE 32 

2. RELEVANCE TO PUBLIC HEALTH 

If the LOAEL of 6.5 mg manganese/kg/day for decreased open-field locomotor activity and acoustic 

startle response and impaired performance in maze learning in male adult Wistar rats exposed for 

10 weeks by gavage (Vezér et al. 2005, 2007) was used as the point of departure for the intermediateduration oral MRL, a value of 0.007 mg manganese/kg/day would be derived if an uncertainty factor of 

1,000 were used (10 for use of a LOAEL, 10 for extrapolating across species, and 10 for human 

variability). However, this rodent-based value of 0.007 mg manganese/kg/day would be about 4-fold 

below the FNB/IOM (2001) recommended AI of 1.8 and 2.3 mg manganese/day for women and men, 

respectively (approximately 0.03 mg manganese/kg/day) and about 23-fold below the FNB/IOM (2001) 

recommended Tolerable Upper Intake Level (UL) of 11 mg/day for adults ≥19 years of age 

(approximately 0.16 mg manganese/kg/day). Part of the apparent discrepancy between this prospective 

MRL and the recommended dietary intakes is that the MRL is based only on manganese intakes above the 

normal dietary intakes. Unfortunately, the dietary intakes of manganese by the rats in the Vezér et al. 

study (2005, 2007) cannot be estimated from the information provided in the published report. 

Alternatively, using the monkey NOAEL of 107 mg manganese/kg/day for decreased activity during 

sleep at 4 months and decreased play activity between 1 and 1.5 months in formula-fed infant monkeys 

provided soy-based formula from birth to 4 months of age (Golub et al. 2005), a value of 1 mg 

manganese/kg/day would be derived if an uncertainty factor of 100 were used (10 for extrapolating across 

species and 10 for human variability). The monkey-based value would be about 6-fold higher than the 

FNB/IOM (2001) UL of 11 mg manganese/day for adults (0.16 mg manganese/kg/day assuming a 70-kg 

body weight). The formulas fed to the infant monkeys in this study are expected to have been the 

principal source of manganese. 

For children and adolescents, FNB/IOM (2001) scaled the adult UL values according to reference body 

weights for children and adolescents, noting that there were no reports of manganese toxicity in children 

and adolescents and that it was not possible to establish UL values for infants (0–12 months). 

Based on several surveys, FNB/IOM (2001) reported that average intakes of adults with typical “Westerntype” and vegetarian diets ranged from 0.7 to 10.9 mg/day (0.01–0.156 mg manganese/kg/day, assuming 

a 70-kg body weight). WHO (2004b) recently calculated an estimated daily intake of about 0.0003 mg 

manganese/kg/day for 70-kg subjects drinking 2 L of water per day at a concentration of 0.010 mg 

manganese/L, the median of a survey of manganese in drinking water. 

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MANGANESE 33 

2. RELEVANCE TO PUBLIC HEALTH 

Chronic Oral Exposure. Data on the effects of manganese following chronic oral exposure are less 

extensive than intermediate-duration data, but these reports do suggest that neurological effects similar to 

those seen after intermediate-duration exposure may be anticipated following chronic oral exposure to 

excess manganese. In the reports of neurological effects in humans following chronic oral exposure, 

there is either uncertainty regarding the exposure level (He et al. 1994; Zhang et al. 1995) or uncertainty 

that the effects observed were solely attributable to manganese (Bouchard et al. 2007c; Holzgraefe et al. 

1986; Kawamura et al. 1941; Kilburn 1987; Kondakis et al. 1989; Wasserman et al. 2006; Wright et al. 

2006). However, there is no clear understanding of the threshold for manganese deficiency/sufficiency or 

toxicity. Males consuming 0.35 and 0.11 mg manganese/day exhibited symptoms of manganese 

deficiency (Doisy 1973; Friedman et al. 1987, respectively). But Davis and Greger (1992) did not report 

any deficiency symptoms among female subjects, 20% of whom consumed <1 mg manganese/day and 

Finley et al. (2003) did not observe signs of manganese deficiency or toxicity in adult females with 

dietary intakes of 0.8 or 20 mg manganese/day for 8 weeks. Authors of a case study suspected abuse of 

vitamin and mineral preparations to be the source for excess manganese and neurological symptoms 

observed in their patient (Banta and Markesbery 1977). 

Four reports of manganese neurotoxicity in children have been published recently including: (1) severe 

manganism-like neurotoxic symptoms (inability to stand independently, tendency to fall backward, and 

development of a “cock-like” walk) in a previously healthy 6-year-old female that were associated with 

elevated drinking water concentrations of manganese (1.7–2.4 mg manganese/L), pica, a diet high in 

manganese-rich foods, and elevated levels of plasma manganese (Sahni et al. 2007); (2) inattentiveness 

and lack of focus in the classroom and low-percentile performance in tests of memory in a 10-year-old 

male with no history of learning problems associated with elevated manganese in drinking water (1.21 mg 

manganese/L) (Woolf et al. 2002); (3) a statistically significant relationship for decreasing intelligence 

scores with increasing manganese levels in drinking water in a cross-sectional epidemiological study of 

142 10-year-old children in Bangladesh (Wasserman et al. 2006); and (4) a statistically significant 

relationship between increased levels of oppositional behaviors and hyperactivity and increased levels of 

manganese in drinking water in an epidemiological study of 46 children (ages 6–15 years) in Quebec, 

Canada (Bouchard et al. 2007c). Although these recent reports cannot causally link the observed 

neurotoxic effects to excessive manganese intakes, they provide added weight to the evidence for the 

neurotoxic potential of excessive manganese in children. 

As shown in the chronic exposure section of the oral LSE table and figure in Chapter 3, estimated daily 

intakes from drinking water were calculated as 0.103 mg manganese/kg/day for the 6-year-old female 

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MANGANESE 34 

2. RELEVANCE TO PUBLIC HEALTH 

(Sahni et al. 2007), 0.06 mg manganese/kg/day for the 10-year-old male (Woolf et al. 2002), 0.11 mg 

manganese/kg/day based on the mean manganese drinking water concentration for the fourth quartile 

group of Bangladesh 10-year-old children (1.923 mg manganese/L), reference daily water intakes 

(1.3 L/day) and average body weights (22.4 kg) (Wasserman et al. 2006), and 0.02 mg manganese/kg/day 

for the high-manganese intake children in Quebec (0.5 mg manganese/L), reference daily water intakes 

(1.3 L/day) and reference body weights (37.2 kg) (Bouchard et al. 2007c). 

To derive an oral MRL for intermediate and chronic durations, an average of the drinking water LOAELs 

for neurobehavioral effects in the two case reports (Sahni et al. 2007; Woolf et al. 2002), the crosssectional study of 10-year-olds in Bangladesh (Wasserman et al. 2006), and the study of children in 

Quebec (Bouchard et al. 2007c) could potentially serve as a point of departure for the MRL. However, 

the following uncertainties associated with these studies of children preclude their use as the basis for an 

intermediate- or chronic-duration MRL: (1) whether or not the observed effects were solely due to excess 

manganese alone or could have been influenced by other drinking water or dietary components; (2) the 

lack of information about manganese levels in food and air; and (3) the small sample sizes. 

Interim Guidance Value for Oral Exposure to Inorganic Manganese. As discussed in the preceding 

sections, no oral MRLs were derived for acute-, intermediate-, or chronic-duration exposure to inorganic 

manganese, but it is recommended that an interim guidance value of 0.16 mg manganese/kg/day be used 

for ATSDR public health assessments. The interim guidance value is based on the Tolerable Upper 

Intake Level for adults of 11 mg manganese/day established by the U.S. Food and Nutrition 

Board/Institute of Medicine (FNB/IOM 2001) based on a NOAEL for Western diets (0.16 mg 

manganese/kg/day assuming an adult body weight of 70 kg). The interim guidance value is well above 

the FNB/IOM Adequate Intake (AI) value for manganese for men and women of 2.3 and 1.8 mg 

manganese/day, respectively (for 70-kg individuals, this would result in exposures of 0.033 and 0.026 mg 

manganese/kg/day, respectively). The interim guidance value is necessary because of the prevalence of 

manganese at hazardous waste sites and the fact that manganese is an essential nutrient. It is 

recommended that this value be used until more information on actual intake levels across environmental 

media can be obtained. 

MRLs for MMT 

Inhalation and oral MRL values for acute, intermediate, or chronic exposures to MMT have not been 

derived. There are currently insufficient data regarding the systemic toxicity and carcinogenicity of this 

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MANGANESE 35 

2. RELEVANCE TO PUBLIC HEALTH 

compound via inhalation or oral exposures and no reliable data concerning current environmental or 

occupational exposures with appropriate dose-response information. 

MRLs for Mangafodipir 

MRL values for mangafodipir are not believed to be warranted. This compound is used in a clinical 

environment, is administered intravenously only, and is restricted to a very limited population. Thus, it is 

believed unlikely that this compound would be found at hazardous waste sites or other environmental 

settings. 

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MANGANESE 37 

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3.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of manganese. It 

contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

Manganese is a naturally occurring element found in rock, soil, water, and food. In humans and animals, 

manganese is an essential nutrient that plays a role in bone mineralization, protein and energy 

metabolism, metabolic regulation, cellular protection from damaging free radical species, and formation 

of glycosaminoglycans (Wedler 1994). Manganese acts as both a constituent of metalloenzymes and an 

enzyme activator. Enzymes that contain manganese include arginase, pyruvate carboxylase, and 

manganese-superoxide dismutase (MnSOD) (Keen and Zidenberg-Cher 1990; NRC 1989; Wedler 1994). 

Manganese, in its activating capacity, can bind either to a substrate (such as adenosine triphosphate, 

ATP), or to a protein directly, thereby causing conformational changes (Keen and Zidenberg-Cher 1990). 

Manganese has been shown to activate numerous enzymes involved with either a catalytic or regulatory 

function (e.g., transferases, decarboxylases, hydrolases) (Wedler 1994). The nutritional role of 

manganese is discussed in Section 3.4. Although manganese is an essential nutrient, exposure to high 

levels via inhalation or ingestion may cause some adverse health effects. 

It has been suggested that these adverse health effects, especially neurologic effects, are occurring on a 

“continuum of ...dysfunction” that is dose-related (Mergler et al. 1999). In other words, mild or unnoticeable effects may be caused by low, but physiologically excessive, amounts of manganese, and these 

effects appear to increase in severity as the exposure level or duration of exposure increases. Case reports 

and occupational studies address this continuum of nervous system dysfunction and help to characterize 

the apparent dose-response relationship. It is clear that chronic exposure to manganese at very high levels 

results in permanent neurological damage, as is seen in former manganese miners and smelters. Chronic 

exposure to much lower levels of manganese (as with occupational exposures) has been linked to deficits 

in the ability to perform rapid hand movements and some loss of coordination and balance, along with an 

increase in reporting mild symptoms such as forgetfulness, anxiety, or insomnia. 

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MANGANESE 38 

3. HEALTH EFFECTS 

Chemical Forms of Concern. Manganese can exist in both inorganic and organic forms. This 

profile will discuss key manganese compounds in both forms, with inorganic compounds discussed first. 

The inorganic forms include manganese chloride (MnCl2), manganese sulfate (MnSO4), manganese 

acetate (MnOAc), manganese phosphate (MnPO4), manganese dioxide (MnO2), manganese tetroxide 

(Mn3O4), and manganese carbonate (MnCO3). Emphasis has been placed on the health effects of 

compounds containing inorganic manganese in the Mn(II), Mn(III), or Mn(IV) oxidation states, since 

these are the forms most often encountered in the environment and the workplace. There is evidence in 

animals and humans that adverse neurological effects can result from exposure to different manganese 

compounds; much of this information on toxicity differences between species of manganese is from 

reports and experiments of acute exposures to very high doses. Results from animal studies indicate that 

the solubility of inorganic manganese compounds can influence the bioavailability of manganese and 

subsequent delivery of manganese to critical toxicity targets such as the brain; however, the influence of 

manganese oxidation state on manganese toxicity is not currently well understood. Manganese in the 

form of permanganate produces toxic effects primarily through its oxidizing capacity. However, because 

of its tendency to oxidize organic material, the permanganate ion is not stable in the environment; thus, 

the probability of exposure to this species around waste sites is considered very low. For this reason, data 

on exposures to permanganate are only briefly discussed. 

The organic compounds that will be discussed are methylcyclopentadienyl manganese tricarbonyl (MMT) 

and mangafodipir. The latter is a chelate of Mn(II) and an organic ligand, dipyridoxyl diphosphate 

(MnDPDP; Mn(II) N,N’-dipyridoxylethylenediamine-N,N’-diacetate 5,5'bis(phosphate)). These 

compounds were chosen for this profile because their toxicity is expected to be mediated by excess 

exposure to elemental manganese. Organic fungicides containing manganese, such as maneb, were not 

chosen for discussion in this profile, because their critical toxic effects are expected to be mediated by the 

organic moities of their chemical structure, not by excessive elemental manganese. 

MMT is a fuel additive developed in the 1950s to increase the octane level of gasoline and thus improve 

the antiknock properties of the fuel (Davis 1998; Lynam et al. 1999). Additional information on the 

chemical, physical, and environmental properties of MMT is included in Chapter 4. Exposure to MMT is 

expected to be primarily through inhalation or oral pathways, although occupational exposure for gasoline 

attendants or mechanics may be more significant via dermal absorption. Engines using MMT-containing 

gasoline and equipped with catalytic converters primarily emit manganese in inorganic phosphate and 

sulfate forms and smaller amounts of manganese dioxides can be detected (Mölders et al. 2001; Ressler et 

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MANGANESE 39 

3. HEALTH EFFECTS 

al. 2000; Zayed et al. 1999a, 1999b). These findings and observations that MMT is very unstable in light 

and degrades quickly in air (Garrison et al. 1995) suggest that human exposure to manganese from the use 

of MMT in gasoline is most likely to occur in inorganic forms as a result of the combustion of MMT, 

with the exception of people occupationally exposed to uncombusted gasoline containing MMT. 

However, despite this evidence, there are some reports that MMT levels in the environment increase with 

traffic density (Garrison et al. 1995; Zayed et al. 1999a, 1999b); therefore, inhalation and/or ingestion 

exposures to the parent compound are possible. Exposure and resultant toxicity from MMT’s inorganic 

combustion products are covered under the inorganic subsections, while toxicity attributable to MMT is 

covered under the organic subsections. 

Mangafodipir is a contrast agent for magnetic resonance imaging (MRI) used primarily (after intravenous 

administration) to detect and characterize neoplastic liver lesions; it has also been found to aid in the 

identification of kidney and pancreatic tumors (Federle et al. 2000; Grant et al. 1997a, 1997b; Ni et al. 

1997). The compound is only used in the diagnosis of organ-specific cancers and is found exclusively in 

a clinical setting. Mangafodipir is injected intravenously; therefore, inhalation, oral, and dermal pathways 

of exposure are not a concern. Because exposure to this compound is pathway-specific and the exposure 

population is inherently limited, toxicity arising from exposure to mangafodipir will be discussed in a 

separate subsection to Section 3.2.4, Diagnostic Uses. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

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MANGANESE 40 

3. HEALTH EFFECTS 

considerable amount of judgment may be required in establishing whether an end point should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL and that, in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between 

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 

considered to be important because it helps the users of the profiles to identify levels of exposure at which 

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not 

the effects vary with dose and/or duration and place into perspective the possible significance of these 

effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user's perspective. Public health officials and others concerned with 

appropriate actions to take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no 

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans 

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. 

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in 

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

3.2.1 Inhalation Exposure 

Inorganic manganese compounds are not volatile, but they can exist in the air as aerosols or suspended 

particulate matter. Table 3-1 and Figure 3-1 summarize the available quantitative information on the 

health effects that have been observed in humans and animals following inhalation exposure to various 

inorganic manganese compounds. All exposure levels are expressed as milligrams of manganese per 

cubic meter (mg manganese/m3

). 

Many of the studies, especially those dealing with occupational exposures, make the distinction between 

respirable and total manganese dust. Respirable dust is usually defined by a particular dust particle size 

that varies from study to study. It is typically defined as those particles ≤5 microns; these smaller dust 

particles can enter the lower areas of the lungs, including the bronchioles and the alveoli. These particles 

can be absorbed by the lung and will enter the bloodstream immediately, thus avoiding clearance by the 

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32

43

138

20

2.8

1100

2

16

14

25

69

1116

0.71

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation 

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) 

ACUTE EXPOSURE Systemic 

1 Rat 

(SpragueDawley) 

10 d 6 hr/d 

System 

Resp 

NOAEL 

(mg/m3) 

Less Serious 

(mg/m3) 

Serious 

(mg/m3) 

43 (pneumonitis and 

increased lung weight) 

Hemato 138 

2 Mouse 

(CD-1) 

2 hr Resp 2.8 F 

3 Mouse 

(FVB/N) 

5 d 6 h/d Resp 2 F 

4 Gn Pig 

(NS) 

Immuno/ Lymphoret 

5 Mouse 

(CD-1) 

1 hr 24 hr/d 1-4 d 3 hr/d 

Resp 14 

69 M (increased susceptibility 

to pneumonia) 

Neurological 

6 Rat 

(SpragueDawley) 

Gd 9-10 or pnd 37-47 or Gd 9-10 and pnd 37-47 

0.71 (decreased APP, COX-2, 

nNOS, GFAP, TGF-beta mRNA in the brain) 

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Reference Chemical Form 

Shiotsuka 1984 MnO2 

Adkins et al. 1980b Mn3O4 

Bredow et al. 2007 (MnCl2) Bergstrom 1977 MnO2 Maigetter et al. 1976 MnO2 HaMai et al. 2006 (MnSO4) 
1117

0.71

1105

0.3

1.5

1106

1.50.3

1.5

0.3

1.5

1.51.51.51.5

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ 

Duration/ 

Frequency 

(Route) 

Gd 9-10 or pnd 37-47 or Gd 9-10 and pnd 37-47 

System 

Resp 0.3 M Resp 1.5 M 

Cardio 0.3 M Hemato 0.3 M Hepatic 1.5 M Renal 1.5 M Endocr 1.5 M Bd Wt 1.5 M 

NOAEL 

(mg/m3) 

LOAEL 

a 

Key to Species 

Figure (Strain) 

Developmental 

7 Rat 

(SpragueDawley) 

Less Serious Serious 

(mg/m3) (mg/m3) 

0.71 (decreased APP, COX-2, 

nNOS, and GFAP mRNA) 

1.5 M (increased incidence of

subacutebronchiolitis/alveolar ductinflammation)

1.5 M (17% decrease in relative

heart weight 90 dayspost-exposure)

1.5 M (decreased total bilirubin

concentrations)

Reference Chemical Form 

HaMai et al. 2006 (MnSO4) Dorman et al. 2005b (MnSO4) Dorman et al. 2006a (MnSO4) 

INTERMEDIATE EXPOSURESystemic 

8 Monkey 

(Rhesus) 

9 Monkey 

90 d 6 h/d 5 d/wk 90 d 6 h/d 5 d/wk 
33

0.7

35

1.1

1102

0.1

0.5

1104

0.1

1109

0.11

1119

0.03

0.3

1134

0.9

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

***DRAFT FOR PUBLIC COMMENT***

a 

Key to 

Figure 

10 11 12 13 14 15 16 

Species 

(Strain) 

Monkey (Rhesus) Monkey (NS) Rat (CD) Rat (CD) Rat (SpragueDawley) Rat (SpragueDawley) Rat (SpragueDawley) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

10 mo 22 hr/d 9 mo (continuous) 13 wk 6 h/d 5 d/wk 13 wk 6 h/d 5 d/wk 12 wk 6 h/d 5 d/wk 90 d 5 d/wk 6 hr/d 90 d 5 d/wk 6 h/d 

LOAEL 

Less Serious 

(mg/m3) 

0.7 F (mild inflammation) 0.5 M (transient inflammatory 

changes in the nasal respiratory epithelium) 

0.11 M (12% decreased body 

weight) 

0.3 M (10% decreased body 

weight) 

Serious 

(mg/m3) 

Reference Chemical Form 

Suzuki et al. 1978 MnO2 Ulrich et al. 1979a Mn3O4 Dorman et al. 2004b (MnSO4) Dorman et al. 2004b MnPO4 El-Rahman 2004 hureaulite Salehi et al. 2003 manganese phosphate/mixture Tapin et al. 2006 manganese sulfate dihy

System 

Resp Resp Resp Resp Bd Wt Bd Wt Bd Wt 

NOAEL 

(mg/m3) 

1.1 0.1 M 0.1 M 

0.03 M 

0.9 M 
37

1.11.11.1

22

3.9

605

0.167

1107

1.5

1111

0.06

34

1.1

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/m3) Less Serious (mg/m3) 

LOAEL 

Serious 

(mg/m3) 

Reference Chemical Form 

9 mo (continuous) Resp 

Hemato Hepatic 

1.1 1.1 1.1 

Ulrich et al. 1979b Mn3O4 

4 wk 5 d/wk 6 hr/d 

Resp 3.9 M Camner et al. 1985 

MnCl2 

5 d/wk 

5, 9, or 13 wk (IC) 

Hemato 0.167 (decrease in total blood 

proteins (p<= 0.05) at 13 weeks of exposure that persisted 2 weeks after exposure ended) 

Sierra et al. 1998 Mn3O4 

90 d 6 h/d 5 d/wk 

1.5 M Dorman et al. 2006a 

(MnSO4) 

90 d 6 h/d 5 d/wk 

0.06 M (altered levels of GS, 

GLT-1 mRNA, GLAST, TH mRNA, GLT-1 mRNA, GLAST mRNA, and TH mRNA in the brain) 

Erikson et al. 2007 (MnSO4) 

9 mo (continuous) 1.1 Ulrich et al. 1979a Mn3O4 

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a 

Key to Species 

Figure (Strain) 

17 Rat 

(NS) 

18 Rabbit 

(NS) 

19 Pigeon 

Neurological 

20 Monkey 21 Monkey 

(Rhesus) 

22 Monkey 

(NS) 
1101

0.5

1103

0.1

1110

0.11

1.1

1112

0.05

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/m3) Less Serious (mg/m3) 

LOAEL 

Serious 

(mg/m3) 

Reference Chemical Form 

13 wk 6 h/d 5 d/wk 

0.5 M Dorman et al. 2004b 

(MnSO4) 

13 wk 6 h/d 5 d/wk 

0.1 M Dorman et al. 2004b 

MnPO4 

12 wk 6 h/d 5 d/wk 

0.11 M (increased free amino 

acid contents; focal glial cell proliferation; astrocytic nodules) 

1.1 M (neuronal degeneration) El-Rahman 2004 

MnPO4 

Gd 0-19, pnd 1-18 6 h/d 7 d/wk 

0.05 (decreased brain GS 

mRNA, MT mRNA and GHS levels in F1 females and decreased brain MT mRNA and GSH levels F1 males) 

Erikson et al. 2005 (MnSO4) 

***DRAFT FOR PUBLIC COMMENT***

a 

Key to Species 

Figure (Strain) 

23 Rat 

(CD) 

24 Rat 

(CD) 

25 Rat 

(SpragueDawley) 

26 Rat 

(CD) 
1115

0.05

1120

1

1118

0.03

1121

3

1122

0.009

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/m3) Less Serious (mg/m3) 

LOAEL 

Serious 

(mg/m3) 

Reference Chemical Form 

Gd 0-19, pnd 1-18 6 h/d 5 d/wk 

0.05 (decreased brain GS and 

TH protein and mRNA, MT, and GSH and increased GSSG levels in F1 rats) 

Erikson et al. 2006 (MnSO4) 

90 d 5 d/wk 6 h/d 

1 M Normandin et al. 2002 

hureaulite 

90 d 5 d/wk 6 hr/d 

0.03 M (increased locomotor 

activity) 

Salehi et al. 2003 manganese phosphate/mixture 

90 d 5 d/wk 6 h/d 

3 M (significant neuronal cell 

loss in the globus pallidus and caudate putamen) 

Salehi et al. 2006 manganese phosphate/mixture 

90 d 5 d/wk 6 h/d 

0.009 M (increased locomotor 

activity) 

Tapin et al. 2006 manganese sulfate dihy

***DRAFT FOR PUBLIC COMMENT***

a 

Key to Species 

Figure (Strain) 

27 Rat 

(CD) 

28 Rat 

(SpragueDawley) 

29 Rat 

(SpragueDawley) 

30 Rat 

(SpragueDawley) 

31 Rat 

(SpragueDawley) 
36

1.1

26

61

29

72

1108

1.5

27

61

1113

0.05

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/m3) Less Serious (mg/m3) 

LOAEL 

Serious 

(mg/m3) 

Reference Chemical Form 

9 mo (continuous) 1.1 Ulrich et al. 1979b Mn3O4 

18 wk 5 d/wk 7 hr/d 

61 F (decreased maternal pup 

retrieval latency) 

Lown et al. 1984 MnO2 

16-32 wk 5 d/wk 7 hr/d 

72 M (increased open-field 

behavior) 

Morganti et al. 1985 MnO2 

90 d 6 h/d 5 d/wk 

1.5 M Dorman et al. 2006a 

(MnSO4) 

18 wk 5 d/wk 7 hr/d 

61 F Lown et al. 1984 

MnO2 

Gd 0-19, pnd 1-18 6 h/d 7 d/wk 

0.05 (decreased brain GS 

mRNA, MT mRNA and GHS levels in F1 females and decreased brain MT mRNA and GSH levels F1 males) 

Erikson et al. 2005 (MnSO4) 

***DRAFT FOR PUBLIC COMMENT***

a 

Key to Species 

Figure (Strain) 

32 Rat 

(NS) 

33 Mouse 

(Swiss ICR) 

34 Mouse 

(Swiss ICR) 

Reproductive 

35 Monkey 

(Rhesus) 

36 Mouse 

(Swiss ICR) 

Developmental 

37 Rat 

(CD) 
1114

0.05

1125

90

2

3.6

7

0.97

0.97

1038

0.180.18

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) System 

Exposure/ 

Duration/ 

Frequency 

(Route) NOAEL (mg/m3) 

LOAEL 

Less Serious 

(mg/m3) 

Serious 

(mg/m3) 

Reference Chemical Form 

38 Rat 

(CD) 

Gd 0-19, pnd 1-18 6 h/d 5 d/wk 

Erikson et al. 2006 (MnSO4) 

0.05 (decreased brain GS and 

TH protein and mRNA, MT, and GHS and increased GSSG levels in F1 rats) 

CHRONIC EXPOSURE Systemic 

39 Resp Human 7.5 yr (average duration in Mn 

mine) (occup) 

90 M (increased respiratory Boojar and Goodarzi 20

symptoms and prevalence of subjects with impaired pulmonary function) 

40 Resp Human NS (occup) Lloyd Davies 1946 MnO2 3.6 M (pneumonia) 

41 Resp Human 1-19 yr (occup) Roels et al. 1987a Mn salts and oxides 0.97 M (cough, decreased lung function) 

Hemato 0.97 M 

42 Resp Human 5.3 yr (occup) 

Endocr 

0.18 0.18 

Roels et al. 1992 MnO2 

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167

0.1

1124

0.07

1123

0.07

1127

0.23

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/m3) Less Serious (mg/m3) 

LOAEL 

Serious 

(mg/m3) 

Reference Chemical Form 

43 Monkey 

(Rhesus) 

Neurological 

44 Human 

66 wk 24 yr (median employment in steel plant) (occup) 

Hemato 0.1 

0.07 M (longitudinal analysis 

showed impaired ability to perform fast pronation/supination of the hands and fast finger tapping compared with controls) 

EPA 1977 Mn3O4 Blond and Netterstrom 2

45 Human 24 yr (median 

employment in steel plant) 

0.07 M Blond et al. 2007 

46 Human 19.3 yr 

(average employment in Mn alloy plant) (occup) 

0.23 M (increased Mn 

impairment with age in 1/9 neuromotor tests, 3/12 cognitive tests, and 1 or 4 sensory tests) 

Bouchard et al. 2005 

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1128

0.23

1129

0.23

355

1.59

138

22

1131

2.05

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/m3) Less Serious (mg/m3) 

LOAEL 

Serious 

(mg/m3) 

Reference Chemical Form 

47 Human 15.7 yr 

(average employment) (occup) 

0.23 M (significantly higher 

scores for 2 [depression, anxiety] of 9 neuropsychiatric symptoms) 

Bouchard et al. 2007a 

48 Human 15.3 yr 

(average employment) (Occup) 

0.23 M (impaired performance 

on 1/5 neuromotor tests and enhanced score for 1 [confusion-bewilderment] of 6 mood states) 

Bouchard et al. 2007b 

49 Human 1.1-15.7 yr 

(occup) 1.59 M (postural sway with eyes closed) Chia et al. 1995 MnO2 

50 Human NS 

(occup) 22 M (bradykinesia, mask-like face) Cook et al. 1974 NS 

51 Human 19.87 yr; mean 

(SD±9) employment in enamels production (occup) 

2.05 Deschamps et al. 2001 

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700

0.051

178

0.14

403

0.149

701

0.0967

304

0.032

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/m3) Less Serious (mg/m3) 

LOAEL 

Serious 

(mg/m3) 

Reference Chemical Form 

52 Human 12.7 yr 

(mean) (occup) 

0.051 Gibbs et al. 1999 

NS 

53 Human 1-35 yr 

(2.6 median) (occup) 

0.14 M (decreased reaction time, 

finger tapping) 

Iregren 1990 MnO2 

54 Human 1-28 yr 0.149 M (decreased 

neurobehavioral performance finger tapping, symbol digit, digit span, additions) 

Lucchini et al. 1995 (primarily MnO2) (MnOx oxides) 

55 Human 11.5 yr 

(mean) (occup) 

0.0967 M (decreased performance 

on neurobehavioral exams) 

Lucchini et al. 1999 MnO2, Mn3O4 

56 Human 16.7 yr (mean) 

(occup) 0.032 M (decreased motor function) Mergler et al. 1994 NS 

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1132

0.21

1133

0.85

6

0.97

266

0.179

9

2.6

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/m3) Less Serious (mg/m3) 

LOAEL 

Serious 

(mg/m3) 

Reference Chemical Form 

57 Human 10.8 yr (mean 

employment in Mn mines) (occup) 

0.21 Myers et al. 2003a 

58 Human 18.2 yr; mean 

(SD 7.6) employment in a Mn smelter (occup) 

0.85 Myers et al. 2003b 

59 Human 1-19 yr 

(occup) 0.97 M (altered reaction time, short-term memory, 

decreased hand steadiness) 

Roels et al. 1987a Mn salts and oxides 

60 Human 5.3 yr 

(occup) 

b

0.179 (impaired visual time, 

eye-hand coordination, and hand steadiness) 

Roels et al. 1992 MnO2 

61 Human NS 

(occup) 2.6 M (tremor, decreased reflexes) Saric et al. 1977 NS 

***DRAFT FOR PUBLIC COMMENT***
10

6

12

5

13

3.5

21

30

166

0.1

4

0.97

428

2.82

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL 

Duration/ 

Frequency 

(Route) System NOAEL (mg/m3) Less Serious (mg/m3) Serious (mg/m3) 

1-9 yr (occup) 6 M (psychomotor disturbances, weakness, 

pain) 

NS (occup) 5 M (weakness, ataxia, pain) 1 yr (occup) 3.5 M (weakness, anorexia, ataxia) 2 yr 5 d/wk 6 hr/d 

30 F (altered DOPA levels) 

66 wk 0.1 1-19 yr (occup) 0.97 M (decreased fertility in males as assessed by 

number of observed vs expected children) 

at least 1 yr (occup) 2.82 M (abnormal sperm) 

Reference Chemical Form 

Schuler et al. 1957 MnO2 Tanaka and Lieben 196NS Whitlock et al. 1966 NS Bird et al. 1984 MnO2 EPA 1977 Mn3O4 Lauwerys et al. 1985 Mn salts and oxides Wu et al. 1996 (MnO2) 

a 

Key to 

Figure 

62 63 64 65 66 

Species 

(Strain) 

Human Human Human Monkey (Rhesus) Monkey (Rhesus) 

Reproductive 

67 Human 68 Human 
429

44.4

Table 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/m3) (mg/m3) (mg/m3) Chemical Form 

69 Human at least 1 yr 44.4 M (abnormal sperm) Wu et al. 1996 (occup) (Mn fumes) 

***DRAFT FOR PUBLIC COMMENT***

All doses expressed as mg manganese/m3. a The number corresponds to entries in Figure 3-1. b The chronic-duration inhalation minimal risk level (MRL) of 0.0003 mg manganese/m3 was derived by using a benchmark dose analysis BMDL10 (surrogate NOAmanganese/m3 for performance deficits in several neurobehavioral tests. This value was adjusted using the following uncertainty and modifying factors: 10 for humfor intermittent exposure (5 days/week), 8/24 for intermittent exposure (8 hours/day), and 10 for potential differences in toxicity due to the different forms of manganlimitations in the database. APP = amyloid precursor protein; Bd Wt = body weight; Cardio = cardiovascular; COX = cyclooxygenase; d = day(s); DOPA = dihydroxyphenylalanine; Endocr = en

Female; Gd = gestational day; GFAP = glial fibrillary acidic protein; GLAST = glutamate/aspartate transporter; GLT-1= glutamate transporter-1; Gn pig = guinea pigsynthetase; GSH = reduced glutathione; GSSG = oxidized glutathione; Hemato = hematological; hr = hour(s); Immuno/Lymphoret = immunological/lymphoreticular; lowest-observed-adverse-effect level; M = male; mo = month(s); mRNA = messenger ribonucleic acid; MT = metallothionein; nNOS = neuronal nitric oxide synthaseno-observed-adverse-effect level; NS = not specified; occup = occupational; pnd = post-natal day; Resp = respiratory; TGF-beta = transforming growth factor beta; hydroxylase; wk = week(s); yr = year(s) 
Respiratory 

Hematological Immuno/Lymphor Neurological Developmental 

MANGANESE

3. HEALTH EFFECTS

55

***DRAFT FOR PUBLIC COMMENT***

Figure 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation 

Acute (≤14 days) 

Systemic 

mg/m3 

1000 

1r
	

100
	

5m 

1r 

4g
	

10
	

2m 

3m 

1 

6r 7r 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Respiratory 

Cardiovascular Hematological Hepatic Renal Endocrine Body Weight Neurological Reproductive Developmental 

MANGANESE

3. HEALTH EFFECTS

56

***DRAFT FOR PUBLIC COMMENT***

Figure 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (Continued)

Intermediate (15-364 days) 

Systemic 

mg/m3

100
	

34m 33m 36m 

10 

18h 

30r 

8k 9k 9k 9k 9k 9k 9k 9k 20k 35k 

11k 17r 17r 17r 22k 25r 32r 1 28r 16r 

10k 

12r 23r 

8k 9k 9k 15r 

19j 

14r 25r 0.1 12r 13r 24r 

21k 26r 27r 37r 38r 

15r 29r 

0.01 31r 

0.001 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Level 
Respiratory 

Hematological Endocrine Neurological Reproductive 

MANGANESE

3. HEALTH EFFECTS

57

***DRAFT FOR PUBLIC COMMENT***

Figure 3-1 Levels of Significant Exposure to Inorganic Manganese - Inhalation (Continued)

Chronic (≥365 days) 

Systemic 

mg/m3

100
	 39
	

69
	

65k 

50
	

10
	

62
	 63
	

40
	 64
	 61 68

51
	 49
	

1
	 41
	 41
	 59
	 67 58
	

46
	 47
	 48
	 57 42
	 42
	 60

53
	 54

0.1 43k 55
	 66k

44
	 45
	 52
	

56
	

0.01 

0.001 

0.0001 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 
 

 

 

 

 

 

 

 

 

 

 

 

MANGANESE 58 

3. HEALTH EFFECTS 

liver. Total dust represents larger particles that cannot travel as deeply into the lungs as respirable dust, 

and will largely be coughed up and swallowed. Although many of the recent occupational studies have 

provided information on the size of the respirable particles that are associated with the exposure levels 

documented, some of the occupational studies and historical studies in miners only measure total dust. 

The profile provides, where possible, the different exposure levels in terms of respirable and total dust, 

but does not make a further distinction between particle sizes of the respirable dust. 

3.2.1.1 Death 

No conclusive studies have been located that show inhalation exposure of humans to manganese resulting 

in death. Hobbesland et al. (1997a) investigated nonmalignant respiratory diseases as a cause of death in 

male ferromanganese and silicomanganese workers. The authors found a slight excess in the numbers of 

deaths caused by pneumonia for manganese furnace workers, but could not discount other work-related 

exposures as potential causes of the pneumonia. 

In analyses performed several years ago, MMT in gasoline was found to combust primarily to manganese 

tetroxide, but in the low levels currently used in gasolines, it is primarily combusted to manganese 

phosphate and manganese sulfate (Lynam et al. 1999). Therefore, inhalation exposures to exhaust from 

gasoline containing MMT will be discussed with inorganic manganese exposures. No deaths were 

observed in male outbred albino rats and male golden hamsters exposed to the exhaust (either irradiated 

or non-irradiated) from automobiles that were fueled with MMT-containing gasoline (Moore et al. 1975). 

No other studies were located regarding death in humans or animals after inhalation exposure to inorganic 

manganese. 

MMT has been used in very few inhalation studies due to the photolability of the compound; its short 

half-life in air makes it a very difficult compound to administer to laboratory animals in exposure 

chambers or nose-cones. Hinderer (1979) evaluated the toxicity of various unspecified MMT 

concentrations administered to 10 male Sprague-Dawley rats per exposure group during 1- and 4-hour 

exposure periods. The inhalation LD50 was determined to be 62 mg manganese/m3 (247 mg 

MMT/m3

*55 mg manganese/218.1 mg MMT=62 mg manganese/m3) for a 1-hour exposure and 19 mg 

manganese/m3 for a 4-hour exposure. No mention was made in the report of steps taken to prevent MMT 

photodegradation during the experiment. 

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MANGANESE 59 

3. HEALTH EFFECTS 

3.2.1.2 Systemic Effects 

The highest NOAEL values and all LOAEL values from each reliable study for (systemic effects in each 

species and duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

Respiratory Effects. In humans, inhalation of particulate manganese compounds such as manganese 

dioxide or manganese tetroxide can lead to an inflammatory response in the lung. This is characterized 

by an infiltration of macrophages and leukocytes, which phagocytize the deposited manganese particles 

(Lloyd Davies 1946). Damage to lung tissue is usually not extensive, but may include local areas of 

edema (Lloyd Davies 1946). Symptoms and signs of lung irritation and injury may include cough, 

bronchitis, pneumonitis, and minor reductions in lung function (Abdel-Hamid et al. 1990; AkbarKhanzadeh 1993; Boojar and Goodarzi 2002; Lloyd Davies 1946; Roels et al. 1987a); occasionally, 

pneumonia may result (Lloyd Davies 1946). These effects have been noted mainly in people exposed to 

manganese dust under occupational conditions, although there is some evidence that respiratory effects 

may also occur in residential populations near ferromanganese factories (Kagamimori et al. 1973; 

Nogawa et al. 1973; WHO 1987). The frequency of effects has been shown to decrease in at least one 

population when concentrations of total manganese in falling dust declined (Kagamimori et al. 1973). It 

is likely that the inflammatory response begins shortly after exposure and continues for the duration of the 

exposure. 

It is important to note that an inflammatory response of this type is not unique to manganese-containing 

particles, but is characteristic of nearly all inhalable particulate matter (EPA 1985d). This suggests that it 

is not the manganese per se that causes the response, but more likely the particulate matter itself. 

An increased prevalence of pneumonia has also been noted in some studies of workers with chronic 

occupational exposure to manganese dust (Lloyd Davies 1946) and in residents near a ferromanganese 

factory (WHO 1987). It seems likely that this increased susceptibility to pneumonia is mainly secondary 

to the lung irritation and inflammation caused by inhaled particulate matter, as discussed above. 

Inhalation of particulate manganese compounds such as manganese dioxide or manganese tetroxide also 

leads to an inflammatory response in the lungs of animals, although inhalation of manganese chloride did 

not cause lung inflammation in rabbits (Camner et al. 1985). Several acute- and intermediate-duration 

studies in animals report various signs of lung inflammation following periods ranging from 1 day to 

10 months at manganese concentrations ranging from 0.7 to 69 mg/m3 (Bergstrom 1977; Camner et al. 

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MANGANESE 60 

3. HEALTH EFFECTS 

1985; Shiotsuka 1984; Suzuki et al. 1978; Ulrich et al. 1979a, 1979b). Bergstrom (1977) and Ulrich et al. 

(1979a, 1979b) determined NOAELs, which are reported in Table 3-1. Increased susceptibility to lung 

infection by bacterial pathogens following inhalation of manganese dusts has been noted in acute animal 

studies (Maigetter et al. 1976). Conversely, Lloyd Davies (1946) reported no increase in the 

susceptibility of manganese-treated mice to pneumococci or streptococci. Bredow et al. (2007) reported 

that nose-only inhalation exposure to 2 mg manganese/m3 as manganese chloride aerosols 6 hours/day for 

5 consecutive days did not cause lung lesions in female GVB/N mice, but induced a 2-fold increase in 

pulmonary levels of mRNA for vascular endothelial growth factor (VGEF), a regulator of proliferation, 

migration, and formation of new capillaries. Elevated levels of VGEF have been associated with 

respiratory diseases, but current understanding is inadequate to know if this pulmonary gene expression 

response to manganese is adverse or benign. 

Moore et al. (1975) exposed male golden hamsters and outbred albino rats to automobile exhaust from a 

car that burned MMT-containing fuel. The animals were exposed to non-irradiated exhaust or irradiated 

exhaust; the irradiation served to convert hydrocarbon gases and vapors to particulate form. Controls for 

each species were exposed to clean air. The animals were exposed for 8 hours/day for 56 consecutive 

days. While the hamsters were fed a diet containing an adequate amount of manganese for normal 

development, the rats were divided into two groups: one group was fed a manganese-sufficient diet 

(42.2 μg manganese/g diet) and the other group was fed a manganese-deficient diet (5 μg manganese/g 

diet). After the exposure, the authors observed a thickening of the cuboidal epithelium at the level of the 

terminal bronchiole in the golden hamsters. The lesion was not classified as severe and only affected one 

to two sites per lung section. Further, the lesions did not increase with length of exposure to the exhaust 

products (from 1 to 9 weeks). The incidence of lesions in the lung was 21% after exposure to irradiated 

exhaust, 14% after exposure to non-irradiated exhaust, and 6% after exposure to clean air. 

More recently, reversible inflammation (pleocellular inflammatory infiltrates and fibrinonecrotic debris) 

in the nasal respiratory epithelium (but not the olfactory epithelium) was observed in young adult male 

Crl:CD(SD)BR rats following 13 weeks of inhalation exposure to 0.5 mg manganese/m3 as manganese 

sulfate, but not in rats exposed to 0.1 mg manganese/m3 as manganese sulfate or manganese phosphate 

(hureaulite) (Dorman et al. 2004b). The lesions were not apparent in groups of rats assessed 45 days after 

the end of exposure, indicating their transient nature. In studies with young male Rhesus monkeys 

exposed to 0, 0.06, 0.3, or 1.5 mg manganese/m3 as manganese sulfate 6 hours/day, 5 days/week for 

65 days, no nasal histological effects were found in exposed monkeys, but the high exposure level 

induced lesions in the lower respiratory tract (mild subacute bronchiolitus, alveolar duct inflammation, 

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and proliferation of bronchus-associated lymphoid tissue) (Dorman et al. 2005b). The lower airway 

lesions from intermediate-duration exposure appear to have been transient, because they were not found 

in monkeys assessed 45 days after the end of exposure (Dorman et al. 2005b). These findings in rats and 

monkeys are consistent with the understanding that inflammation of respiratory tissues from high-level 

exposure to inhaled manganese particulates is likely a consequence of the inhaled particulate matter. 

No studies were located concerning respiratory effects in humans following inhalation exposure to MMT. 

Male rats exposed to high concentrations of MMT (exposure doses not reported) via inhalation exhibited 

labored breathing during and after 1- and 4-hour exposures (Hinderer 1979). Gross necropsy or 

histopathological analyses on these animals were not performed. 

Cardiovascular Effects. Three studies reported adverse cardiovascular effects after occupational 

exposure to manganese. Saric and Hrustic (1975) observed a lower mean systolic blood pressure in male 

workers at a ferromanganese plant. Manganese concentrations in the plant ranged from 0.4 to 20 mg/m3

, 

but specific data on exposure levels were lacking. More recently, Jiang et al. (1996a) studied the potential 

cardiotoxicity of manganese dioxide exposure in 656 workers (547 males, 109 females) involved in 

manganese milling, smeltering, and sintering. The authors took 181 samples of airborne manganese (not 

specified if respirable or total dust), with a geometric mean of 0.13 mg/m3

. The workers, whose work 

tenure ranged from 0 to 35 years, had a greater incidence of low diastolic blood pressure. The incidence 

of this effect was highest in young workers with the lowest tenure in the plant. There was no increase of 

abnormal electrocardiograms between workers and their matched controls. The authors surmised that 

manganese’s ability to lower the diastolic blood pressure weakens with age as the elasticity of the blood 

vessels deteriorates. 

Hobbesland et al. (1997b) reported a significantly increased incidence in sudden death mortality for 

workers in ferromanganese/silicomanganese plants during their employment period (standardized 

mortality ratio [SMR]=2.47). The sudden deaths included cardiac deaths and other natural causes. More 

specifically, among furnace workers, who are more likely to be exposed to manganese fumes and dusts 

than non-furnace workers, the mortality during active-person time was statistically significantly elevated 

(38.7%) compared to non-furnace workers (23.3%; p<0.001). However, the authors caution that the 

association of increased death and manganese exposure is speculative and the increase in sudden death 

could also be caused by common furnace work conditions (heat, stress, noise, carbon monoxide, etc.). 

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No studies on cardiovascular effects from inhalation exposure to MMT in humans or animals were 

located. 

Gastrointestinal Effects. There are no reports of gastrointestinal effects following inhalation 

exposure to inorganic manganese in humans or animals. 

There are no reports concerning the gastrointestinal effects following inhalation exposure to MMT in 

humans or animals. 

Hematological Effects. Examination of blood from persons chronically exposed to high levels of 

manganese in the workplace has typically not revealed any significant hematological effects (Mena et al. 

1967; Roels et al. 1987a; Smyth et al. 1973; Whitlock et al. 1966). The effect of manganese exposure on 

erythrocyte superoxide dismutase activity remains inconsistent; some investigators observed increased 

activity among male manganese smelters (Yiin et al. 1996), while others reported decreased activity in 

male welders (Li et al. 2004). However, an increased plasma malondialdehyde level is consistent 

between manganese-exposed smelters (Yiin et al. 1996) and welders (Li et al. 2004). Malondialdehyde is 

a product of lipid peroxidation; lipid peroxidation is believed to be a mechanism for cell toxicity. The 

authors observed that plasma malondialdehyde and manganese levels were strongly correlated in exposed 

workers and interpreted this response to be an indicator of manganese toxicity via lipid peroxidation. 

No studies on hematological effects from inhalation exposure to MMT in humans or animals were 

located. 

Hepatic Effects. Even though the liver actively transports manganese from blood to bile (see 

Section 3.4.4), there is no information to indicate that the liver is adversely affected by manganese; 

however, there are few specific studies on this subject. In a study by Mena et al. (1967), workers 

chronically exposed to manganese dust in the workplace exhibited no abnormalities in serum levels of 

alkaline phosphatase. Of 13 patients who were hospitalized with chronic manganese poisoning, 1 had a 

20% sulfobromophthalein (SBP) retention and 1 had a 12% SBP retention, although histological 

examination of a liver biopsy from the latter revealed no abnormal tissue (Mena et al. 1967). No 

significance was ascribed to the elevated SBP retention. 

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Rats exposed to manganese tetroxide dusts for 9 months exhibited no adverse effects or histopathological 

lesions; however, slight increases in liver weights were noted (Ulrich et al. 1979b). These data, although 

limited, indicate that the liver is not significantly injured by manganese. 

No studies on hepatic effects from inhalation exposure to MMT in humans or animals were located. 

Musculoskeletal Effects. No studies were located concerning musculoskeletal effects from 

inhalation exposure to inorganic manganese. 

No studies were located concerning musculoskeletal effects from inhalation exposure to MMT in humans 

or animals. 

Renal Effects. The kidney is not generally considered to be a target for manganese, but specific 

studies are rare. No abnormalities in urine chemistry were detected in workers chronically exposed to 

manganese dusts in the workplace (Mena et al. 1967), but other more sensitive tests of renal function 

were not performed. 

No studies were located regarding renal effects in animals after inhalation exposure to inorganic 

manganese. 

No studies on renal effects from inhalation exposure to MMT in humans or animals were located. 

Endocrine Effects. Few studies have measured endocrine effects in humans exposed to inorganic 

manganese. Two studies measured hormonal levels after exposure to manganese. The first study 

(Alessio et al. 1989) involved chronic exposure of foundry workers to manganese for approximately 

10 years. The exposure levels were reported as 0.04–1.1 mg manganese/m3 (particulate matter) and 0.05– 

0.9 mg/m3 as fumes. These levels overlap the current American Congress of Governmental Industrial 

Hygiene (ACGIH) threshold limit value-time weighted average (TLV-TWA) of 0.2 mg/m3 for particulate, 

but are less than the limit of 1 mg/m3 for manganese fumes. The study reported both elevated prolactin 

levels and elevated cortisol levels; however, no changes in the levels of follicle stimulating hormone 

(FSH) and luteinizing hormone (LH) were noted. 

Smargiassi and Mutti (1999) reported effects in a group of workers from a ferroalloy plant who were 

exposed occupationally to elevated levels of airborne manganese. Serum prolactin levels in these workers 

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were evaluated in a 1992 study and again in a 1997 study. Serum prolactin levels, which were 

significantly elevated in the earlier analysis, had also increased significantly over the earlier measurement 

(p<0.001). This difference was especially noticeable in those with abnormally high prolactin levels. 

During the five year period between studies, exposure levels were consistent and were not reduced; 

therefore, it is unclear whether prolactin levels reflect current or cumulative exposure. 

Other elements of endocrine function (reproductive function, etc.) are discussed elsewhere in the text. 

No studies were located regarding endocrine effects in animals after inhalation exposure to inorganic 

manganese. 

No studies on endocrine effects from inhalation exposure to MMT in humans or animals were located. 

Dermal Effects. No studies have been located concerning dermal effects in humans or animals 

following inhalation exposure to inorganic or organic manganese. 

Ocular Effects. No studies have been located concerning ocular effects in humans or animals 

following inhalation exposure to inorganic manganese. 

There are no studies reporting ocular effects following inhalation exposure of humans to MMT. One- and 

4-hour exposures to doses of MMT used in lethality studies resulted in conjunctivitis in rats (Hinderer 

1979). 

Body Weight Effects. No studies were located regarding body weight effects in humans following 

exposures to inorganic manganese. 

No studies were located regarding body weight effects in humans following inhalation exposure to MMT. 

Hinderer (1979) observed a decrease in weight gain in Sprague-Dawley rats during the first 7 days 

following a 1- or 4-hour exposure to unspecified MMT concentrations in an acute toxicity test. The rats 

resumed their normal weight gain by 14 days post-exposure. 

Metabolic Effects. No studies were located concerning metabolic effects from inhalation of inorganic 

manganese in humans or animals. 

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No studies were located concerning metabolic effects following inhalation exposure to MMT in humans 

or animals. 

3.2.1.3 Immunological and Lymphoreticular Effects 

One study on immunological effects in humans following inhalation to inorganic manganese was located. 

Male welders exposed to manganese (0.29–0.64 mg/m3 for an unspecified duration), vibration, and noise 

exhibited suppression of the T and B lymphocytes characterized by reductions in serum immunoglobin G 

(IgG) and total E-rosette-forming cells (Boshnakova et al. 1989). However, the welders in this study 

were exposed to numerous other compounds, including cobalt, carbon dioxide, and nitric oxide. 

Therefore, it is impossible to determine whether exposure to manganese caused the effects. It is not 

known whether any of these changes are associated with significant impairment of immune system 

function. No studies were located on lymphoreticular effects in humans exposed to manganese by the 

inhalation route. 

No studies were located on immunological or lymphoreticular effects in animals exposed to inorganic 

manganese by the inhalation route. 

As noted above, inhalation exposure to particulate manganese compounds can lead to an inflammatory 

response in the lung (i.e., pneumonitis), and this is accompanied by increased numbers of macrophages 

and leukocytes in the lung (Bergstrom 1977; Lloyd Davies 1946; Shiotsuka 1984; Suzuki et al. 1978). 

However, this is an expected adaptive response of the immune system to inhaled particulates, and these 

data do not indicate that the immune system is injured. Conflicting data are reported concerning 

increased susceptibility to bacterial infection after exposure to airborne manganese. Lloyd Davies (1946) 

indicated that manganese exposure did not increase the susceptibility of mice to bacterial infection, 

whereas Maigetter et al. (1976) reported that exposure to aerosolized manganese dioxide altered the 

resistance of mice to bacterial and viral pneumonias. 

No studies on immunological or lymphoreticular effects from inhalation exposure to MMT in humans or 

animals were located. 

3.2.1.4 Neurological Effects 

Neurological effects from repeated inhalation exposure to manganese are well recognized as effects of 

high concern based on case reports and epidemiological studies of groups of occupationally exposed 

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people and results from animal inhalation studies. The highest NOAEL values and all LOAEL values 

from each reliable study for neurological effects in each species and duration category are recorded in 

Table 3-1 and plotted in Figure 3-1. 

Manganism from High Level Occupational Exposure to Inorganic Manganese. There is conclusive 

evidence from studies in humans that inhalation exposure to high levels of manganese compounds 

(usually manganese dioxide, but also compounds with Mn(II) and Mn(III)) can lead to a disabling 

syndrome of neurological effects referred to as ‘manganism’. Manganism is a progressive condition that 

usually begins with relatively mild symptoms, but evolves to include dull affect, altered gait, fine tremor, 

and sometimes psychiatric disturbances. Some of these symptoms also occur with Parkinson’s disease, 

which has resulted in the use of terms such as “Parkinsonism-like disease” and “manganese-induced 

Parkinsonism” to describe those symptoms observed with manganese poisoning. Despite the similarities, 

significant differences between Parkinsonism and manganism do exist (Barbeau 1984; Calne et al. 1994; 

Chu et al. 1995). Barbeau (1984) reported that the hypokinesia and tremor present in patients suffering 

from manganism differed from those seen in Parkinson’s disease. Calne et al. (1994) noted other 

characteristics that distinguish manganism from Parkinson’s disease: psychiatric disturbances early in the 

disease (in some cases), a “cock-walk,” a propensity to fall backward when displaced, less frequent 

resting tremor, more frequent dystonia, and failure to respond to dopaminomimetics (at least in the late 

stages of the disease). 

Manganism and Parkinson’s disease also differ pathologically. In humans and animals with chronic 

manganese poisoning, lesions are more diffuse, found mainly in the pallidum, caudate nucleus, the 

putamen, and even the cortex with no effects on the substantia nigra and no Lewy bodies (Pal et al. 1999; 

Perl and Olanow 2007). In people with Parkinson’s disease, lesions are found in the substantia nigra and 

other pigmented areas of the brain (Barbeau 1984). Moreover, Lewy bodies are usually not found in 

substantia nigra in manganism cases, but are almost always found in cases of Parkinson’s disease (Calne 

et al. 1994; Perl and Olanow 2007). Manganese appears to affect pathways that are post-synaptic to the 

nigrostriatal system, most likely the globus pallidus (Chu et al. 1995). MRI of the brain reveals 

accumulation of manganese in cases of manganism, but few or no changes in people with Parkinson’s 

disease; fluorodopa positron emission tomography (PET) scans are normal in cases of manganism, but 

abnormal in people with Parkinson’s disease (Calne et al. 1994). Other studies suggest that manganese 

produces a syndrome described as parkinsonism, distinct from Parkinson’s Disease or manganism 

(Lucchini et al. 2007, Racette et al. 2005). It is likely that the terms Parkinson-like-disease and 

manganese-induced-Parkinsonism will continue to be used by those less knowledgeable about the 

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significant differences between the two. Nonetheless, comparison with Parkinson’s disease and the use of 

these terms may help health providers and health surveillance workers recognize the effects of manganese 

poisoning when encountering it for the first time. 

Typically, the clinical effects of high-level inhalation exposure to manganese do not become apparent 

until exposure has occurred for several years, but some individuals may begin to show signs after as few 

as 1–3 months of exposure (Rodier 1955). The first signs of the disorder are usually subjective, often 

involving generalized feelings of weakness, heaviness or stiffness of the legs, anorexia, muscle pain, 

nervousness, irritability, and headache (Mena et al. 1967; Nelson et al. 1993; Rodier 1955; Tanaka and 

Lieben 1969; Whitlock et al. 1966). These signs are frequently accompanied by apathy and dullness 

along with impotence and loss of libido (Abdel-Hamid et al. 1990; Emara et al. 1971; Mena et al. 1967; 

Nelson et al. 1993; Rodier 1955; Schuler et al. 1957). Early clinical symptoms of the disease include a 

slow or halting speech without tone or inflection, a dull and emotionless facial expression, and slow and 

clumsy movement of the limbs (Mena et al. 1967; Nelson et al. 1993; Rodier 1955; Schuler et al. 1957; 

Shuqin et al. 1992; Smyth et al. 1973; Tanaka and Lieben 1969). In a study by Wolters et al. (1989), 

6-fluorodopa (6-FD) and 18F-2-fluoro-2-deoxyglucose (FDG) PET were used to investigate the 

neurochemistry of four patients with "early manganism." FDG PET demonstrated decreased cortical 

glucose metabolism. No anomalies were noted in the 6-FD scans. This led the authors to suggest that, in 

early manganism, damage may occur in pathways that are postsynaptic to the nigrostriatal system, and 

most likely involve striatal or pallidal neurons. 

As the disease progresses, walking becomes difficult and a characteristic staggering gait develops. 

Muscles become hypertonic, and voluntary movements are accompanied by tremor (Mena et al. 1967; 

Rodier 1955; Saric et al. 1977a; Schuler et al. 1957; Smyth et al. 1973). Few data are available regarding 

the reversibility of these effects. They are thought to be largely irreversible, but some evidence indicates 

that recovery may occur when exposure ceases (Smyth et al. 1973). Manganism has been documented in 

welders and in workers exposed to high levels of manganese dust or fumes in mines or foundries. 

Extreme examples of psychomotor excitement have been observed in manganese miners and, to a lesser 

extent, in industrial workers (Chu et al. 1995; Mena et al. 1967; Nelson et al. 1993). The behavior, 

known as “manganese madness” (Mena 1979) includes nervousness, irritability, aggression, and 

destructiveness, with bizarre compulsive acts such as uncontrollable spasmodic laughter or crying, 

impulses to sing or dance, or aimless running (Emara et al. 1971; Mena et al. 1967; Rodier 1955; Schuler 

et al. 1957). Patients are aware of their irregular actions, but appear incapable of controlling the behavior. 

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The reports of frank manganism (Rodier 1955; Schuler et al. 1957; Smyth et al. 1973) observed in 

manganese miners clearly indicate that the onset of manganism results from chronic exposure to high 

concentrations of the metal. Documented cases indicate that the most important route of exposure is 

inhalation of manganese dusts or fumes, while other pathways such as ingestion of the metal from 

mucociliary transport of larger particles and hand-to-mouth activity, may contribute a smaller amount. 

Based on the data provided by Rodier (1955) and Schuler et al. (1957), it appears that the frequency of 

manganism cases increased with prolonged exposure, suggesting that the seriousness of the symptoms 

presented increases with cumulative exposure. For example, Rodier (1955) reports that the highest 

percentage of manganism cases (28, or 24.4%) occurred in miners with 1–2 years experience. Only six 

cases of manganism (5.2%) were reported in males with 1–3 months exposure, and 68% of the cases 

reported occurred after exposures >1–2 years in length. Rodier did not present statistics on the number of 

men in the mine who were employed for comparable durations who did not suffer from manganism. 

Schuler et al. (1957) studied fewer manganism cases, but showed that the number of men with 

manganism increased with time spent mining, with the average time delay before onset of the disease 

being 8 years, 2 months. In fact, the minimum duration of exposure to the metal was 9 months before 

signs of manganism became recognizable, and the maximum exposure was 16 years. However, Schuler 

et al. (1957) point out that their study was not intended to “suggest incidence rates” and of the 83 miners 

selected for examination of potential manganism, only 9 were chosen as actually suffering from 

manganese poisoning. As with the Rodier (1955) study, the Schuler et al. (1957) study did not discuss the 

exposure duration or symptomatology of those men not displaying “frank manganism;” therefore, these 

collective data, although suggestive of a cumulative effect of manganism neurotoxicity, must be 

interpreted with caution. 

Huang et al. (1998) documented the progression of clinical symptoms of manganism in five surviving 

workers (from an original six) chronically exposed to manganese in a ferroalloy plant. These men were 

exposed from 3 to 13 years and were examined 9–10 years after manganese exposure had ceased. 

Neurologic examination revealed a continuing deterioration of health exhibited in gait disturbance, speed 

of foot tapping, rigidity, and writing. The men had high concentrations of manganese in blood, urine, 

scalp, and pubic hair at the time of the original neurologic evaluation. Follow-up analyses revealed a 

drastic drop in manganese concentrations in these fluids and tissues (e.g., 101.9 μg/g manganese in blood 

from patient 1 in 1987; 8.6 μg/g manganese in blood in 1995). Further, T1-weighted MRI analysis did 

not reveal any high-signal intensity areas. These data support the progression and permanence of clinical 

effects from excess manganese exposure, even when tissue levels of the metal had returned to normal. 

Further, it shows that this neurotoxicity can continue in the absence of continuing manganese exposure 

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and that a spectrum of responses to excess manganese exposure can be seen depending upon dose, 

duration of exposure, and timing of the observation. While some subclinical manifestations of manganese 

neurotoxicity will resolve, once neuropathology has occurred (in the form of loss of dopaminergic 

neurons), then reversal becomes more limited and is restricted to functional compensation. 

As shown in Table 3-1 and Figure 3-1, cases of frank manganism have been associated with workplace 

exposure levels ranging from about 2 to 22 mg manganese/m3 (Cook et al. 1974; Rodier 1955; Saric et al. 

1977; Schuler et al. 1957; Tanaka and Lieben 1969; Whitlock et al. 1966). For example, Tanaka and 

Lieben (1969) reported that no cases of frank manganism were diagnosed in 38 workers from 

Pennsylvania industrial plants in which estimated air concentrations were below 5 mg manganese/m3

, 

whereas 7 cases were diagnosed in 117 workers from plants with air concentrations exceeding 5 mg/m3

. 

Whitlock et al. (1966) reported on two cases of frank manganism in workers who were exposed to 

estimated air concentrations ranging from 2.3 to 4.7 mg manganese/m3

. 

Neurological Assessments of Workers Exposed to Low Levels of Inorganic Manganese. Studies 

estimating the impact of low-level exposure to manganese on neurological health have employed a 

number of sensitive tests designed to detect signs of neuropsychological and neuromotor deficits in the 

absence of overt symptoms (Iregren 1990, 1994, 1999). These analyses allow the comparison of discrete 

performance values that are associated with either biological levels of manganese or approximations of 

exposure levels. Thus, they allow for the comparison of one exposure group to another without the 

subjective description of neurological symptoms that were prevalent in the studies with miners and others 

with frank manganism. A number of epidemiological studies have used these techniques to study the 

psychological or neurological effects of exposure to low levels of manganese in the workplace (BastPettersen et al. 2004; Beuter et al. 1999; Blond and Netterstrom 2007; Blond et al. 2007; Bouchard et al. 

2003, 2005, 2007a, 2007b; Chia et al. 1993a, 1995; Crump and Rousseau 1999; Deschamps et al. 2001; 

Gibbs et al. 1999, Iregren 1990; Lucchini et al. 1995, 1999; Mergler et al. 1994; Myers et al. 2003a, 

2003b; Roels et al. 1987a, 1992, 1999; Wennberg et al. 1991) or in environmental media close to 

manganese-emitting industries (Lucchini et al. 2007; Mergler et al. 1999; Rodríguez-Agudelo et al. 2006). 

Some of these studies have found statistically significant differences between exposed and non-exposed 

groups or significant associations between exposure indices and neurological effects (Bast-Pettersen et al. 

2004; Chia et al. 1993a; Iregren 1990; Lucchini et al. 1995, 1999; Mergler et al. 1994; Roels et al. 1987a, 

1992; Wennberg et al. 1991), whereas others have not found significant associations (Deschamps et al. 

2001; Gibbs et al. 1999, Myers et al. 2003a, 2003b; Young et al. 2005). The neurological effects 

associated with prolonged low-level manganese exposure generally have been subtle changes, including 

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deficits in tests of neuromotor or cognitive functions and altered mood states; they have been referred to 

by various authors as preclinical or subclinical neurological effects. As shown in Table 3-1 and 

Figure 3-1, manganese air concentrations associated with these effects in chronically exposed workers 

range from about 0.07 to 0.97 mg manganese/m3 (manganese in total or inhalable dust measurements). 

For several of these work environments, values of concentrations of manganese in respirable dust 

(generally particulate diameters <10 μm) represented <20–80% of the total dust values. 

In a cross-sectional epidemiological study of 141 male workers in a manganese dioxide and salt 

producing plant, Roels et al. (1987a) detected preclinical neurological effects (alterations in simple 

reaction time, audioverbal short-term memory capacity, and hand tremor) in workers exposed to 0.97 mg 

manganese (median concentration in total dust)/m3 as manganese dioxide, manganese tetroxide, 

manganese sulfate, manganese carbonate, and manganese nitrite for a group average of 7.1 years. End 

points in exposed workers were compared with end points in a matched control group of 104 non-exposed 

male workers from a nearby chemical plant. The prevalences of subjective symptoms were similar in 

exposed and control workers, except for the elevation of nonspecific symptoms (such as fatigue, tinnitus, 

trembling of fingers, and increased irritability) in the exposed workers. Statistically significant mean 

deficits were found in exposed workers (compared with controls) in tests of simple reaction time (visual), 

audioverbal short-term memory capacity, eye-hand coordination, and hand steadiness. The prevalence of 

abnormal values in the neurological tests were not statistically significantly correlated with manganese 

levels in blood or urine or duration of employment, with the exception that blood levels of manganese 

were correlated with prevalence of abnormal responses in tests of eye-hand coordination and hand 

steadiness. 

Iregren (1990) used neurobehavioral tests (simple reaction time, digit span, finger tapping, verbal ability, 

hand dexterity, and finger dexterity tests from the Swedish Performance Evaluation System, SPES) to 

study adverse effects in 30 male workers from two different manganese foundries exposed to an estimated 

median concentration of 0.14 mg manganese (in total dust)/m3 as manganese dioxide for 1–35 years 

(mean, 9.9 years). The exposed workers had below-average scores on a number of the tests, such as 

reaction time and finger tapping, when compared to matched controls with no occupational manganese 

exposure. 

Roels et al. (1992) provided similar results to these earlier reports. Workers in a dry alkaline battery 

factory exhibited impaired visual reaction time, hand-eye coordination, and hand steadiness when 

exposed to concentrations of manganese dioxide in total dust ranging from 0.046 to 10.840 mg 

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manganese/m3 and in respirable dust from 0.021 to 1.32 mg manganese/m3 (exposure ranged from 0.2 to 

17.7 years). A lifetime integrated exposure (LIE) for both total manganese dust and respirable manganese 

was estimated for each of the exposed workers (LIE=∑((Cjob 1 x T1) + (Cjob 2 x T2) + ... (Cjob n x Tn)), 

where C is concentration, T is years of exposure, and LIE is expressed as mg manganese/m3 times year). 

Based on the analysis of data by a logistic regression model, it was suggested that there was an increased 

risk (odds ratio [OR]=6.43, 95% confidence interval [CI]=0.97–42.7) of decreased hand steadiness at a 

lifetime integrated exposure level of 3.575 mg/m3

*year for total dust or 0.730 mg/m3*year for respirable 

dust. It should be noted that the LIE at which an increased risk of abnormal neurological function occurs 

is based on exposures in an occupational setting. Therefore, periods of exposures would be followed by 

periods that would be relatively free of manganese inhalation. Presumably, during these “rest” periods 

the homeostatic mechanism would excrete excess manganese to maintain the manganese concentration 

within physiologic limits. Further, the LIE for deleterious neural effects may be biased in favor of a 

higher concentration due to the “healthy worker effect” (i.e., the most susceptible individuals are not 

incorporated into the study). 

Crump and Rousseau (1999) performed a follow-up study of 213 men occupationally exposed to 

manganese, 114 of whom were subjects in the Roels et al. (1987a, 1987b) studies. Exposure data were 

unavailable during the 11 years of study (1985–1996) during which blood and urine samples were taken 

and neurological tests (short-term memory, eye-hand coordination, and hand steadiness) were 

administered as in the Roels studies. Yearly blood and urine manganese levels remained fairly consistent 

throughout the study period, and were comparable to the levels reported in the previous studies. The 

authors suggest that the consistency of these data on manganese levels indicates that the airborne 

manganese concentrations to which the subjects were exposed during the study period were likely 

comparable to those at the time of the Roels studies. The average age and exposure duration of the 

subjects increased from 36 and 7 years, respectively, in 1985, to 41 and 14 years, respectively, in 1996. 

Variations in year-to-year test results were observed that were not attributable to age of the subject or 

exposure to manganese. The authors observed decreases in errors in the short-term memory test (number 

of repeated words and number of errors). During 1987, 1988, and 1989, the average number of words 

remembered on the memory test was lower than in any other year. However, there was a progressive 

improvement in percent precision and percent imprecision on the eye-hand coordination test during 1985– 

1988 (after 1991, the design of the test was modified and percent imprecision was lower in that year and 

all subsequent testing years). The authors suggest several reasons for the inter-year variability in test 

results (Crump and Rousseau 1999), including variations in test conditions, different groups of workers 

being tested in different years, the mood of the workers following a plant restructuring, and increased 

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caution on the part of the subjects when answering test questions. When data analysis was controlled for 

year of testing, older workers performed significantly worse than younger workers on total words recalled 

in the memory test, and on percent precision and percent sureness in the eye-hand coordination test. 

Further, blood and urine manganese levels were not significantly associated with performance on memory 

or eye-hand coordination tests, but blood manganese was negatively associated with performance on the 

hand steadiness test (p<0.05). Age was not a factor in hand steadiness when the year of test was 

controlled for in the analysis. Crump and Rousseau (1999) investigated whether individual test scores 

worsened with time by studying the group of 114 men from the original Roels et al. (1987a, 1987b) 

studies and a subset of 44 long-term employees who had been given both memory and hand steadiness 

tests on two occasions, 8 years apart. These analyses revealed decreases in performance over time for a 

particular hole in the hand steadiness test and improvements in repetitions and errors on the memory test, 

both of which were statistically significant. The authors suggest that the improvements in the memory 

test were likely the result of increased caution on the part of the subject. The changes in performance 

over time could not be attributed solely to manganese exposure because it was impossible to control for 

age and year of testing in all of the analyses. The authors noted the lack of an age-matched control group 

with which to compare test results and the absence of data caused by workers ending their terms of 

employment. Some have questioned whether inter-year variability in test results, potentially caused by 

different test administrators over time, would affect interpretation of the findings. While this may 

contribute to the changes in performance over time seen in the Crump and Rousseau (1999) study, this 

factor will potentially impact any study of this type. The lack of a control group precludes the 

determination of a reliable NOAEL or LOAEL based on the results of this study. 

A study by Mergler et al. (1994) also supports the work of Iregren and Roels. This epidemiologic study 

included 115 (95% of the total) male workers from a ferromanganese and silicomanganese alloy factory 

who were matched to other workers from the region with no history of exposure. The groups were 

matched on the following variables: age, sex, educational level, smoking, and number of children. These 

workers were exposed to both manganese dioxide dusts and manganese fumes. Environmental levels of 

manganese in total dust were measured at 0.014–11.48 mg/m3 (median, 0.151 mg/m3

; arithmetic mean, 

1.186 mg/m3

, geometric mean, 0.225 mg/m3), while manganese levels in respirable dust were 0.001– 

1.273 mg/m3 (median, 0.032 mg/m3

; arithmetic mean, 0.122 mg/m3; geometric mean, 0.035 mg/m3), and 

mean duration of exposure was 16.7 years. The exposed workers had significantly greater blood 

manganese levels, but urinary manganese did not differ between groups. Manganese workers showed 

decreased performance on tests of motor function (including those from the SPES) as compared to 

matched control workers with no manganese exposure. Using test results obtained from performance of 

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the groups on the Luria-Nebraska Neuropsychological Battery and other tests, the authors reported that 

manganese-exposed workers performed more poorly than controls on tests of motor function, particularly 

on tests that required alternating and/or rapid hand movements and hand steadiness. The exposed workers 

also differed significantly from the controls in cognitive flexibility and emotional state. They also 

exhibited significantly greater levels of tension, anger, fatigue, and confusion. Further, these workers had 

a significantly lower olfactory threshold than controls; this is the first study to report this effect following 

inhalation exposure to manganese. Several follow-up studies of the workers from this manganese alloy 

plant are described later in this section (Bouchard et al. 2005, 2007a, 2007b). 

Similar effects to those observed in the Mergler et al. (1994) study were observed by Chia et al. (1993a). 

Workers in a manganese ore milling plant exposed to 1.59 mg manganese (mean concentration in total 

dust)/m3 exhibited decreased scores in several neurobehavioral function tests including finger tapping, 

digit symbol, and pursuit aiming. Further, the workers exhibited an increased tendency for postural sway 

when walking with their eyes closed (Chia et al. 1995). 

An epidemiologic study (Lucchini et al. 1995) also supports findings of these studies concerning the 

preclinical neurological effects of manganese exposure. This study, which evaluated performance on 

neuromotor tests (seven tests from the SPES, including simple reaction time, finger tapping, digit span, 

additions, symbol digit, shapes comparison, and vocabulary) involved 58 male workers from a ferroalloy 

plant. The workers had been exposed for 1–28 years (mean, 13; standard deviation [SD], 7) to geometric 

mean airborne concentrations of manganese, as manganese dioxide, in total dust as high as 0.070– 

1.59 mg/m3 (geometric means in different areas). These concentrations had decreased in the last 10 years 

to a range of 0.027–0.270 mg manganese (in total dust)/m3

. At the time of the study, the exposed workers 

were undergoing a forced cessation from work of 1–48 days. Blood and urine manganese levels were 

analyzed. A cumulative exposure index (CEI) was calculated for each subject by multiplying the average 

annual airborne manganese concentration in respirable dust characteristic of each job by the number of 

years for which this activity was performed. Significant correlations were found between the log value of 

blood manganese concentrations in exposed workers and the tests of additions, digit span, finger tapping, 

and symbol digit (log values for the last two tests); between the log value of urinary manganese levels and 

the performance on the additions test; and between the log value of the CEI and the log value of the 

symbol digit score. Further, a significant correlation on an individual basis was found between external 

exposure, represented by CEI, and blood and urine manganese levels. These results are unique in that 

they are the first to suggest that blood and urine manganese concentrations are indicative of exposure on 

an individual basis. As suggested by Lucchini et al. (1995), the correlations may be observable in this 

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study, when they have not existed in past studies (Roels et al. 1987a, 1992), because the workers were 

assessed at a time when they were not currently being exposed to manganese. In support of this 

possibility, the correlation coefficients between the urine and manganese levels and the CEI increased 

with time elapsed since the last exposure to airborne manganese (Lucchini et al. 1995). 

Roels et al. (1999) performed an 8-year prospective study with 92 subjects exposed to manganese dioxide 

at a dry-alkaline battery plant (Roels et al. 1992) to determine if poor performance on tests measuring 

visual reaction time, eye-hand coordination, and hand steadiness could be improved if occupational 

manganese exposure were decreased. The workers were divided into “low” (n=23), “medium” (n=55), 

and “high” (n=14) exposure groups depending on location within the plant and job responsibility. At the 

end of the 1987 study, technical and hygienic improvements had been implemented within the plant to 

decrease atmospheric manganese concentrations. Yearly geometric mean values for airborne total 

manganese dust (MnT) in the “low,” “medium,” and “high” exposure areas decreased in the following 

manner, respectively: ~0.310–~0.160; ~0.900–~0.250; and ~3–~1.2 mg/m3

. The cohort decreased from 

92 subjects in 1987 to 34 subjects in 1995 due to turnover, retirement, or dismissal, but no worker left due 

to neurological signs or symptoms. A separate group of workers was selected who had prior manganese 

exposure (ranging from 1.3 to 15.2 years). These subjects had left the manganese processing area of the 

plant prior to the end of 1992, and therefore, their exposure to manganese had ceased at that time; these 

workers were still employed in other areas of the plant. The control group consisted of 37 workers 

employed at the same polymer factory that had provided the control population in the previous study 

(Roels et al. 1992). This group, with an average age of 38.5 (range, 32–51 years) allowed for the analysis 

of age as a confounder. Exposure data (respirable manganese and total manganese dust, MnT) were taken 

with personal air samplers. Time-trend analysis of air sampler data revealed a significant decrease in total 

manganese from 1987 to 1995, with a more pronounced decline from 1992 forward. From 1987 to 1990, 

the authors observed that the precision of the hand-forearm movement (PN1) in the eye-hand coordination 

test for the whole cohort worsened, but then got progressively better. Hand steadiness and visual simple 

reaction time variables were inconsistent over time, and time-trends were not observed. When the cohort 

was divided into exposure groups, and analyzed for performance on the eye-hand coordination test, it was 

revealed that in general, the performance on the PN1 aspect of the test improved from 1987 to 1995, 

especially after 1991. The performance of the “low-dose” group was comparable to that of the control 

group in 1987 (Roels et al. 1992) and to that of the control group in 1997. The performance of the 

“medium-dose” group was intermediate between the “low-dose” and “high-dose” group. The only 

significant differences in performance were in the “high-dose” group as compared to the “low-dose” 

group during the years 1988–1990 (test scores of 49–51 for the high-dose group and 63–65 for the “low­

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dose” group). However, it was noted that performance on the eye-hand coordination test for the 

“medium” and “high-dose” groups was considerably poorer than the controls. 

Significant differences were noted in variables in the hand steadiness test between the exposure groups 

during 1987–1992 (data not reported), when manganese concentrations were at their highest. However, 

no readily identified temporal changes in performance among the groups on this test was found, nor with 

the visual reaction time test. When the authors performed separate time-trend analysis on MnT levels and 

PN1 (eye-hand coordination test) values, a significant time effect was present for each variable. An 

analysis of covariance was performed for each exposure group (low, medium, and high) in which log 

MnT was considered as covariate in order to adjust for estimation of PN1 variations as log MnT changed 

over time. The resultant data suggested that a reduction in log MnT was associated with an improvement 

in PN1 for each group. The authors also found that when time was also considered with log MnT as an 

interaction term, it did not influence PN1 variations over the years and the effect of time on PN1 values 

disappeared when log MnT was maintained as an ordinary covariate. The authors interpreted this to mean 

that performance on the eye-hand coordination tests were only related, and inversely so, to the exposure 

to manganese. In other words, when manganese exposure was increased, test performance decreased and 

vice versa (Roels et al. 1999). However, in the high-exposure group, the performance increased from 

71 to 83% of that of the control group, and leveled off at this point, despite decreased manganese 

exposure occurring from 1991/1992 with most dramatic improvements occurring in 1994. The authors 

suggest that this leveling off of performance by the high-exposure group may be indicative of a 

permanent effect of manganese on eye-hand coordination. The authors tested PN1 values in exposed 

subjects 3 years following a cessation of exposure. They found that in 20/24, the PN1 values were below 

the mean PN1 values of the control group, but 16 of these individuals showed an improvement in 1996 

(percent improvement unspecified). The remaining four subjects (three “low-exposure” and one 

“medium-exposure” subjects) had PN1 values that exceeded the mean value of the control group. 

However, these data indicate that although there was improvement in performance on the coordination 

test, the vast majority of the exposed group still could not perform to the level of an unexposed worker 

3 years after manganese exposure ceased. In addition, the exposed workers who did perform as well or 

better than the control subjects were among the least exposed workers while at the plant. As discussed 

previously, performance of the “low-exposure” group on eye-hand coordination tests during 1992–1995 

was comparable to that of the control groups from 1987 and 1997, indicating that manganese exposure of 

these individuals during that time did not severely impact their ability to perform this neurobehavioral 

test. Comparable performance on the tests by the same control group in 1987 and 10 years later, in 1997, 

indicates that age was not a confounder in this study. None of the variables except visual reaction time 

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was significantly correlated with age, and the existing correlation in the visual reaction time test only 

represented a 3% difference (Roels et al. 1999). 

Lucchini et al. (1999) also investigated differences in neurobehavioral test performance over time as 

exposure to manganese (manganese dioxide and manganese tetroxide) decreased. The study group 

consisted of 61 men who worked in different areas of a ferroalloy plant. The plant was divided into three 

exposure areas with total manganese dust (geometric mean) values decreasing from 1981 to 1995: “highexposure” values decreased from 1.6 to 0.165 mg/m3

; “medium-exposure” values decreased from 

0.151 to 0.067 mg/m3

; and “low-exposure” values decreased from 0.57 to 0.012 mg/m3. The authors 

estimated that the annual average manganese concentration in the “medium-exposure” group was 

0.0967 mg manganese in total dust/m3

. Respirable dust constituted 40–60% of the total dust value. 

Control subjects consisted of 87 maintenance and auxiliary workers from a nearby hospital who had not 

been exposed to neurotoxins. The study and control groups were well matched except for years of 

education and the percentage of subjects working night shifts. The study groups answered a questionnaire 

concerning neuropsychological and Parkinsonian symptoms and underwent testing to determine the effect 

of manganese on neuromotor performance. Four tests were from the SPES (addition, digit span, finger 

tapping, symbol digit) and five timed tasks were from the Luria Nebraska Neuropsychological Battery 

(open-closed dominant hand--Luria 1, open-closed non-dominant hand—Luria 2, alternative open-closed 

hands—Luria 3, thumb-fingers touch dominant hand—Luria 4, and thumb-fingers touch non-dominant 

hand—Luria 5). Individual scores were taken from these subtests, and the sum of the Luria tests was 

taken (Luria sum). Postural tremor was also measured, as was visual reaction time and coordination 

ability via the hand pronation/supination test. Manganese levels in blood and urine, as well as blood lead 

levels were analyzed prior to each neurobehavioral test. Manganese levels in both blood and urine were 

significantly elevated in exposed workers compared to controls (p<0.0001). Blood lead levels were also 

significantly higher in the ferroalloy workers (p=0.0002). The authors noted that the study groups did not 

report as many complaints as those reported in the Mergler et al. (1994) study. 

After correcting for age, education, alcohol, smoke, coffee, shift work, and blood lead levels, an analysis 

of test results indicated that performance of the exposed workers was significantly different than that of 

controls on all tests except for Luria 5 and Luria sum (Lucchini et al. 1999). A comparison of SPES test 

results from workers tested in 1990 or 1991 and those from this study did not indicate any difference in 

paired t-test values; this indicates that performance did not improve over time or with decreasing 

exposure to manganese. CEI values were calculated (in the same manner as in Lucchini et al. [1995]) for 

each exposure group and performance on the neurobehavioral tests was analyzed for correlation to these 

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values and to manganese levels in body fluids. Significant differences were found between those with 

low CEI values of <0.5 mg/m3

*years, mid CEI values of 0.5–1.8 mg/m3*years, and high CEI values of 

>1.8 mg/m3

*years and performance on the following tests: symbol digit, finger tapping, dominant and 

non-dominant hand, and digit span. A positive correlation was observed between the log CEI value and 

these tests, indicating that performance decreased as exposure increased. No correlations were found 

between CEI values and manganese levels in blood and urine; these results differ from the correlation 

between CEI and manganese levels in fluids from the previous study (Lucchini et al. 1995). Lucchini et 

al. (1995) estimated a manganese dose (total dust) that would represent the annual airborne manganese 

concentration indicative of neurobehavioral deficit in this study by dividing the geometric mean CEI of 

the mid-exposure subgroup, 1.1 mg/m3

*years, by the geometric mean value of years of exposure for this 

same subgroup, 11.51, yielding a value of 0.096 mg/m3

. A comparable respirable dust value would be 

0.038 mg/m3 (0.096*0.40). 

Gibbs et al. (1999) studied a population of workers in a U.S. plant that produces electrolytic manganese 

metal. These 75 workers and a well-matched group of control workers with no manganese exposure were 

administered a computerized questionnaire concerning neurological health issues (including mood, 

memory, fatigue, and other issues) and were analyzed for performance on several neurobehavioral tests 

including hand steadiness (Movemap steady, Movemap square, and tremor meter), eye-hand coordination 

(orthokinisimeter), and rapidity of motion (four-choice reaction time and finger tapping). The Movemap 

test is a relatively recent test that has not undergone widespread use, and it has not been validated by other 

researchers. Further, although technically sophisticated, the test has not been observed to discriminate 

between exposure groups any better than simpler current methods (Iregren 1999). Airborne levels of total 

and respirable manganese were obtained using personal samplers and were not available for years prior to 

1997. Using the arithmetic mean of samples collected in 12 different job categories, exposure was 

estimated for the years prior to 1997. Cumulative exposure values for each worker were estimated for the 

30-day and 12-month exposure periods just prior to neurobehavioral testing. Multiple regressions of the 

test scores were performed using age and each of the following manganese exposure variables 

individually as explanatory variables: duration of exposure; 30-day cumulative exposure; 1-year 

cumulative exposure; and cumulative occupational exposure to either respirable or total manganese. Shift 

work was also used as a variable in conjunction with age and cumulative 30-day exposure to respirable or 

total manganese. The authors threw out outlying data points if they were >3 times the SD of the residual 

after a model fit. Exposures to respirable and total dust were highly correlated (r2

, 0.62–0.75), as were 

cumulative exposures over the previous 30 days and the previous year (r2

, 0.72–0.82); however, lifetime 

integrated exposure was not correlated with either 30-day or 12-month exposure values. The average 

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exposure value for manganese-exposed workers was estimated at 0.066±0.059 mg/m3 (median, 

0.051 mg/m3

) for respirable dust, and 0.18±0.21 mg/m3 for total dust. 

Responses to the questionnaire and performance on the neurobehavioral tests did not differ significantly 

between exposed and control groups (Gibbs et al. 1999). Cumulative years of exposure had an effect on 

tapping speed—speed increased with increased exposure, but only when outliers were included in the 

analysis. The authors also reported an inverse correlation between age and performance on tests 

measuring eye-hand coordination but positively correlated between age and complex reaction time. The 

study by Gibbs et al. (1999) is the first to report a lack of poorer performance on neurobehavioral tests by 

workers chronically exposed to manganese. Interestingly, the median exposure estimates for respirable 

dust in this population (0.051 mg/m3

) is slightly higher than the lowest level of respirable dust at which 

preclinical neurological effects have been seen (0.032 mg/m3

) as reported by Mergler et al. (1994). 

Gorell et al. (1999) noted a high OR of 10.51 for the development of Parkinson’s disease in individuals 

>50 years old who were occupationally exposed to manganese for >20 years, but not for those exposed 

for <20 years. However, the numbers of individuals with a >20-year exposure was rather small (n=4), 

and occupational exposures to other metals (copper, and lead-iron, lead-copper, and iron-copper 

combinations) for >20 years were also associated with increased risk for the disease. 

In a cross-sectional study of 138 (114 male and 34 female) enamels-production workers, Deschamps et al. 

(2001) administered a questionnaire about neurological symptoms; evaluated performance on 

psychological tests of similarity recognition, vocabulary (oral word association), geometrical figure 

recognition (visual gestalts), and short-term memory (digit span); and measured levels of manganese in 

blood samples. Results were compared with a control group of 137 nonexposed workers matched for age, 

educational level, and ethnic group. Exposed workers were employed for a mean duration of 19.87 years 

(SD±9) in enamels production. Mean manganese levels in 15 personal air samples and 15 stationary air 

samples collected at the plant during the year preceding the tests were 2.05 mg manganese/m3 (SD 2.52; 

range 0.5–10.2) for total dust and 0.035 mg manganese/m3 for respirable manganese (SD 0.063; range 

0.01–0.293). Symptoms of asthenia, sleep disturbance, and headache were significantly elevated in 

exposed workers, compared with controls, but no significant differences in blood levels of manganese or 

performance on the administered tests were found between the exposed and control groups of workers. 

Clinical examination of the exposed subjects revealed no cases of obvious neurological impairment, but 

sensitive psychomotor tests of simple reaction times and motor functions were not administered in this 

study. 

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In a cross-sectional study, Myers et al. (2003a) evaluated results from a health questionnaire and a battery 

of neurobehavioral tests administered to 489 workers employed as office workers, miners, surface 

processors, engineers, and other service workers from two South African manganese mines. Cumulative 

exposure indices for each subject were calculated based on total dust measurements and job history. 

Workers were employed in the mines for a mean of 10.8 years (SD=5.5 years; range 1–41 years), had an 

average cumulative exposure index of 2.2 (mg manganese/m3 per year, SD=2.2; range=0–20.8), an 

average exposure intensity of 0.21 mg manganese/m3 (SD=0.14; range, 0–0.99), and an average blood 

manganese concentration of 8.5 μg/L (SD=2.8; range, 2.2–24.1). Neurobehavioral end points included 

three tests of motor function in the Luria-Nebraska battery (tests 1, 2, and 23), mean reaction time in the 

SPES, and three cognitive tests (forward and backward digit span and digit-symbol score). Multiple 

linear regression analysis revealed no significant (p<0.05) associations between any measure of exposure 

and questionnaire or test battery outcomes. 

In another cross-sectional study, Myers et al. (2003b) evaluated neurobehavioral end points in a group of 

509 workers at a South African manganese smelter, compared with a group of unexposed workers from 

an electrical fittings assembly plant (remote from the manganese smelter). Workers were employed for a 

mean of 18.2 years (SD 7.6), compared with 9.4 years (SD 7.0) in the control group. Exposure was 

assessed from manganese determinations in dust from personal air samples, blood samples, and urine 

samples. Cumulative exposure indices were calculated for each exposed worker based on manganese 

concentrations in “inhalable” dust from personal air samples and job histories. Mean values for exposed 

workers were 16.0 mg manganese/m3 per year (SD 22.4) for cumulative exposure index, 0.82 mg 

manganese/m3 (SD 1.04) for average intensity of exposure, 12.5 μg manganese/L (SD 5.6) for blood 

manganese, and 10.5 μg manganese/L (SD 20.3) for urine manganese. Control workers had mean values 

of 6.4 μg manganese/L (SD 1.7) for blood manganese and 0.96 μg manganese/L (SD 0.81) for urine 

manganese. Neurobehavioral end points included the Swedish nervous system questionnaire and the 

following neurobehavioral test batteries: World Health Organization (WHO) neurobehavioral core test 

battery, SPES, Luria-Nebraska tests, and Danish product development tests (tests of hand steadiness, 

tremor, and body sway). Information collected for potential confounders included age, educational level, 

alcohol and tobacco consumption, neurotoxic exposures in previous work, past medical history, and 

previous head injury. Multiple linear and logistic regression analyses were conducted to examine 

possible exposure-response relationships. Several tests showed significant (p<0.05) differences between 

exposed and control workers, but no evidence of exposure-response relationships including the following: 

the Santa Ana, Benton and digit span WHO tests; hand tapping and endurance tapping SPES tests; one 

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Luria-Nebraska test (item 2L); several self-reported symptoms (e.g., tiredness, depressed, irritated); and 

increased sway under two conditions (eyes open with or without foot insulation). Results from two other 

tests (WHO digit-symbol test and Luria-Nebraska item 1R) showed differences between exposed and 

control groups and some evidence for increased deficits with increasing exposure, but the change with 

increasing exposure was greater at lower exposure levels than at higher exposure levels. Results from all 

of the remaining tests showed no significant adverse differences between the exposed and control groups. 

The authors concluded that “the most likely explanation for few, weak and inconsistent findings with 

implausible or counterintuitive exposure-response relationships is chance, and it is concluded that this is 

essentially a negative study.” 

Young et al. (2005) reanalyzed the data collected by Myers et al. (2003b) on the basis of estimated 

exposures to manganese in “respirable” dust. Exposure estimates for each worker (cumulative exposure 

indices in mg manganese/m3 per year and average intensity of exposure in mg manganese/m3

) were 

recalculated based on manganese determinations in personal air samplings of respirable dust (collected on 

37 mm, 5 μm MCEP membrane filters, as opposed to inhalable dusts of larger particle sizes used to 

estimate exposure in the earlier analyses by Myers et al. [2003b]). Results from comparisons of mean 

performances of exposed and control groups in the neurobehavioral tests and regression analyses to assess 

exposure-response relationships were similar to results from the earlier analyses by Myers et al. (2003b) 

based on manganese determinations in inhalable dust. The authors concluded that the results did not 

provide evidence that exposure estimates based on respirable dust provide a more sensitive method to 

detect manganese neurobehavioral effects. 

Bast-Pettersen et al. (2004) cross-sectionally examined neurobehavioral end points in a group of 100 male 

workers in manganese alloy plants and a group of 100 control workers (paired matched for age) from two 

plants, one producing silicon metal and microsillica and another titanium oxide slag and pig iron. 

Manganese alloy workers were employed for a mean of 20.2 years (SD 8.6; range 2.1– 41.0 years); 

comparable statistics were not reported for the control workers. Exposure was assessed from manganese 

determinations in dust from personal air samples (collected on 3 days for each subject closely before the 

neurobehavioral assessment), blood samples, and urine samples. Arithmetic means for manganese 

workers were 0.753 mg manganese/m3 inhalable dust for work room air (geometric mean 0.301; range 

0.009–11.5 mg manganese/m3

), 189 nmol manganese/L in blood (range 84–426 nmol/L), and 3.9 nmol 

manganese/mmol urine creatinine (range 0.1–126.3). The Institute of Occupational Medicine (IOM) 

personal samplers used in this study are expected to provide estimates that are approximately 2-fold 

higher than estimates using 25- or 37-mm plastic Millipore personal air samplers used in many earlier 

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studies to measure “total dust”. Mean levels of manganese in blood (166 nmol manganese/L) and urine 

(0.9 nmol manganese/mmol creatinine) of control workers were significantly lower than levels in exposed 

workers. Neurobehavioral end points included: two self-administered neuropsychiatric questionnaires; 

six tests of cognitive functions (Weschlers adult intelligence scale, digit symbol, trail making test, Stroop 

color-word recognition, digit span, and Benton visual retention); and eight tests of motor functions (static 

hand steadiness, “TREMOR” test, finger tapping, foot tapping, supination/pronation of hand, LuriaNebraska thumb/finger sequential touch, simple reaction time, and hand-eye coordination). Information 

collected for potential confounders included age, years of education, alcohol and tobacco consumption, 

and prevalence of previous brain concussions. Multiple linear regression analyses were conducted to 

examine the influence of potential confounders and exposure-response relationships for test results. No 

significant (p<0.05) effect of exposure was found in tests for cognitive functions, reaction time, or 

symptom reporting. No statistically significant (p<0.05) differences were found in tests of motor speed, 

grip strength, or reaction time. Postural tremor as measured in the hand steadiness test was significantly 

(p<0.05) increased in the exposed group compared with the controls and showed an exposure-response 

relationship when the exposed group was regrouped into three groups of increasing duration of 

employment. Results from an alternative test of tremor (“TREMOR”) did not distinguish between the 

manganese alloy group and the control group. The results indicate that the manganese-exposed group of 

workers had increased hand tremor compared with the control group, but were indistinguishable from the 

control group in other tests of motor function, cognitive function, or symptom reporting. 

Bouchard et al. (2005) reanalyzed results from neurobehavioral tests administered by Mergler et al. 

(1994) to 74 male workers in a manganese alloy plant to examine the influence of age on the tests. At the 

time of testing, workers had been employed an average of 19.3 years (range 1–27 years) and 71 of the 

workers were employed for >10 years. Based on personal air and stationary air samples 8-hour timeweighted average manganese concentrations ranged from 0.014 to 11.48 mg manganese/m3 total dust 

(geometric mean=0.225 mg manganese/m3

) and from 0.001 to 1.273 mg manganese/m3 respirable dust 

(geometric mean=0.035 mg manganese/m3

). The referent group contained 144 workers with no history of 

occupational exposure to neurotoxicants who were matched for age, educational level, smoking status, 

and number of children. Mean blood manganese levels were 11.9±5.3 μg/L (range 4.4–25.9 μg/L) in 

exposed workers and 7.2±0.3 μg/L (range 2.8–15.4 μg/L) in controls. Paired differences between 

exposed and control workers increased significantly (p<0.05) with age for one of nine tests of neuromotor 

domain (nine-hole hand steadiness test); 3 of 12 tests of cognitive domain (trail making B [test of visual 

conception and visuomotor tracking], delayed word recall [test of learning, recall and attention], and 

cancellation H [test of visuomotor tracking and concentration]); and 1 of 4 sensory domain tests 

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(vibratometer–vibrotactile perception of the index and toe). The results suggest that older workers may 

be more slightly more susceptible to the neurological effects of low-level manganese exposure than 

younger workers. 

Bouchard et al. (2007a) examined neuropsychiatric symptoms in a group of 71 male workers in a 

manganese alloy plant, 14 years after cessation of exposure, and in a group of 71 unexposed referents of 

similar age and education levels from the same geographical region. Based on personal air and stationary 

air samples during the operation of the plant, 8-hour time-weighted average manganese concentrations 

were 0.014–11.48 mg manganese/m3 total dust (geometric mean=0.225 mg manganese/m3

) and 0.001– 

1.273 mg manganese/m3 respirable dust (geometric mean=0.035 mg manganese/m3

). The mean number 

of years of occupational exposure to manganese was 15.7 (range, 7.4–17.3 years). The exposed workers 

were participants in the earlier study by Mergler et al. (1994). Neuropsychiatric symptoms were assessed 

by a self-administered questionnaire, the Brief Symptom Inventory, from which scores were determined 

for somatization (psychological distress from perception of bodily dysfunction), obsessive-compulsive 

behavior, interpersonal sensitivity (feeling of personal inadequacy), depression, anxiety, hostility, phobic 

anxiety, paranoid ideation, and psychoticism. Former, manganese workers showed significantly (p<0.05) 

higher scores (after adjustment for age, education, and alcohol consumption) for two of the nine 

neuropsychiatric symptoms (depression, anxiety), compared with controls. 

In a follow-up to the Mergler et al. (1994) study, Bouchard et al. (2007b) evaluated neurobehavioral end 

points in a group of 77 male former workers in a manganese alloy plant, 14 years after cessation of 

employment, and in a group of 81 nonexposed referents group-matched for age, education and alcohol 

consumption. The groups were initially assessed in 1990 and, for the present study in 2004, in five 

neuromotor tests, nine cognitive tests, and six mood state tests. Based on personal air and stationary air 

samples during the operation of the plant, 8-hour time-weighted average manganese concentrations were 

0.014–1.48 mg manganese/m3 total dust (geometric mean=0.225 mg manganese/m3

) and 0.001–1.273 mg 

manganese/m3 respirable dust (geometric mean=0.035 mg manganese/m3

). Mean years of occupational 

exposure to manganese was reported as 15.3 years (maximum=17.3 years). In the 1994 assessment, 

significant (p<0.05) differences between exposed and control workers were found in scores for one of 

five neuromotor tests (Luria Motor Scale), three of nine cognitive tests (cancellation H, digit span, colorword test), and one (tension-anxiety) of six mood state tests. In 2004, significant (p<0.05) differences 

between the exposed and control workers persisted for one (Luria Motor Scale) of five neuromotor tests, 

none of the nine cognitive tests, and one (confusion-bewilderment) of the six mood states. These results 

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indicate that exposure-related effects observed initially in the manganese alloy workers did not progress 

in a 14-year period following cessation of employment. 

Neurological Assessments of Environmentally Exposed Populations Exposed to Inorganic Manganese. 

Mergler et al. (1999) studied environmental exposure to manganese and its possible effect on mood 

(Bowler et al. 1999), neuromotor function (Beuter et al. 1999), and levels of the metal in biological fluids 

(Baldwin et al. 1999). The study group was a community in southwest Quebec, Canada, near which a 

former manganese alloy production plant served as a point source for environmental manganese pollution. 

Due to the presence of MMT in gasoline in Canada, inhaled manganese from car exhaust is a potential 

contributor to manganese exposures experienced in the population studied. A total of 273 persons 

comprised the test population. These individuals were selected using a stratified random sampling 

strategy from the Quebec Health Plan Register, which includes all residents. This strategy helped to 

ensure that no selection bias was introduced. These individuals were administered a test battery including 

a computerized neuromotor test, blood sampling, visual function tests from the Neurobehavioral 

Evaluation System-2, an extensive neuropsychological test battery, and diverse tests covering such areas 

as olfactory threshold, finger tapping, digit span, and postural sway. Blood sampling data for the study 

subjects (Baldwin et al. 1999) indicated that manganese levels in women (geometric mean=7.5 μg/L) 

were significantly higher than in men (6.75 μg/L). No relationship was found between the overall level of 

manganese in blood and those of lead or iron in serum. However, blood manganese levels were 

negatively correlated with serum iron in women and had a tendency to decrease with increasing age. 

Serum iron levels in men were higher than in women. The authors analyzed manganese in drinking water 

from the study subjects’ residences and analyzed air samples from four different locations for total 

manganese particulates and PM10 values. The geometric mean value for manganese in drinking water 

was 4.11 μg/L; there was no correlation between individual values in drinking water manganese and 

manganese blood levels. Intersite differences in manganese values in total particulate were not observed 

in the air samples, but intersite differences did exist for manganese in PM10 values. Two geographical 

areas were identified where manganese in air contributed to blood manganese levels; serum iron was 

negatively related to blood manganese levels in this analysis (Baldwin et al. 1999). 

The Profile of Moods State and Brief Symptom Inventory self-report scales were used to assess condition 

of mood in the study population (Bowler et al. 1999). The results from these analyses indicated that men 

who are older (>50 years) and have higher blood manganese levels (≥7.5 μg/L) showed significant 

disturbances in several mood symptoms with significantly increased values for anxiety, nervousness, and 

irritability; emotional disturbance; and aggression and hostility when compared to those with lower levels 

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of blood manganese. Neuromotor, neurological, and neurobehavioral analyses revealed that subjects with 

higher blood manganese levels (≥7.5 μg/L) performed significantly worse on a test for coordinated upper 

limb movements, with poorest performance in older men (Mergler et al. 1999). Also in men, proximal 

events on the qualified neurological examination, involving arm movements were significantly slower for 

those with higher blood manganese, and hand movements (distal events) tended to be in the same 

direction. No correlation was observed in women. Other measures of motor performance (e.g., hand-arm 

tremor and tapping movements) were not related to blood manganese levels, although a significant 

decrease in tremor frequency dispersion was observed with log MnB (manganese blood level). For both 

men and women, performance on the learning and memory tests was inversely correlated with manganese 

blood level values, although performance on individual portions of the overall test varied significantly 

with gender. For men, higher levels of manganese in blood were associated with poorer performance on 

list acquisition, delayed auditory recall, and visual recognition following a distracter. Females, in 

contrast, tended to recall fewer geometric shapes, made more errors on the visual reproduction test, but 

remembered more numbers on the digit span forward test. This study is unique in that it is the first to 

study both males and females in an exposed population, and it shows an association between elevated 

manganese blood levels linked to elevated environmental manganese and poor performance on 

neurobehavioral and neuropsychiatric tests. This study also reported that neurological effects associated 

with higher levels of blood manganese were more likely to be observed in persons >50 years of age. In 

contrast, Roels et al. (1999) reported that age was a significant factor only in performance of the visual 

reaction time test, but not for the eye-hand coordination test or the measure of hand steadiness used in 

their longitudinal studies. However, Crump and Rousseau (1999) reported that older age was a 

significant factor in poor performance in tests of short-term memory and eye-hand coordination. 

Although there were no statistically significant neurological effects associated with manganese exposure 

among workers of a metal-producing plant evaluated by Gibbs et al. (1999), these investigators also noted 

that test performance in eye-hand coordination and reaction time decreased with increasing age. 

Rodriquez-Agudelo et al. (2006) examined neurobehavioral end points in 168 women and 120 men from 

eight communities at various distances from manganese extraction or processing plants in the district of 

Molango, Mexico. Manganese levels in PM10 dust in air samples collected from 28 houses were 

determined, and the values obtained from the closest monitor were assigned to each of the 

288 participants (values ranged from 0 to 5.86 μg manganese/m3

). Concentrations of manganese in 

samples of drinking water and maize grain were mostly below detection limits, whereas soil 

concentrations ranged from about 6 to 280 mg manganese/kg, with the largest concentrations noted in 

samples collected close to the manganese industrial sites. Blood samples were collected from each 

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participant and used for manganese and lead determinations. Neuromotor tests (which were a Spanish 

adaptation of Luria diagnostic procedures) were administered, and odds ratios (ORs) were calculated for 

24 different end points involving hand motor functions using dichotomous assessments of performance 

(e.g., normal and poor) after grouping the participants based on associated manganese concentrations in 

air or blood manganese levels. No associations were found between neuromotor performance and blood 

levels of manganese or lead. After grouping the participants into those associated with air concentrations 

between 0 and 0.1 μg manganese/m3 and those with concentrations between 0.1 and 5.86 μg 

manganese/m3 (approximate midpoint=3 μg manganese/m3

), significantly (p<0.05) elevated ORs for poor 

performance were calculated for only 3 of the 24 neuromotor end points (two movement coordination, left 

hand performance [OR=1.99, 95% CI 1.15–3.43]; change of hand position, left hand performance 

[OR=1.98, 95% CI 0.99–3.95], and conflictive reaction, a test of verbal regulation of movement 

[OR=2.08. 95% CI 1.17–3.71]). Although the authors concluded that the results indicate that “there is an 

incipient motor deficit in the population environmentally exposed to large manganese levels,” a more 

likely explanation for the few and inconsistent findings is chance. This explanation is supported by the 

finding that no statistically significant associations were found between any neuromotor function end 

points and blood manganese levels. In addition, the lack of air monitoring data for individual participants 

in the study precludes assigning the “high” air concentration exposure level as a reliable LOAEL or 

NOAEL. 

In a community-based study, Lucchini et al. (2007) examined possible associations between prevalence of 

Parkinsonian disorders and levels of manganese in settled dust collected from communities in the 

vicinities of manganese ferroalloy industrial plants in the province of Brescia, Italy. Parkinsonian patients 

were identified from clinical registers from local hospitals, area neurologists, and records of exemption 

from prescription payments, as well as from records of L-Dopa prescriptions; a total of 

2,677 Parkinsonian cases were identified among 903,997 residents. SMRs for each of 206 municipalities 

were calculated based on national rates standardized for age and gender. Municipalities with the highest 

SMRs were located within 20 km and/or downwind of three manganese alloy industrial plants in the 

Valcamonica region of Brescia. An average standardized prevalence of 492 cases/100,000 residents was 

observed in the 37 municipalities of the Valcamonica region. Crude and standardized prevalence rates for 

the Valcamonica municipalities were significantly (p<0.05) higher than rates for the other 

169 municipalities of Brescia. Municipality-based SMRs for Parkinsonian disorders were significantly 

(p<0.05) associated with manganese levels in settled dust, and manganese levels in settled dust samples 

from the 37 municipalities in Valcamonica were significantly (p<0.05) higher than levels in samples for 

the other 169 municipalities. The results suggest that prolonged environmental exposure to excessive 

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manganese in the Valcamonica region of Brescia may increase the risk for Parkinsonian disorders, but the 

results do not identify a reliable NOAEL or LOAEL that can be expressed in units of manganese air 

concentrations. The authors speculated that, even though manganese-induced and Parkinsonian 

neurological disorders are expected to have two distinct target areas in the brain (the globus pallidus and 

the substantia nigra, respectively), structural and chemical interconnections between the brain areas may 

interact to cause increased risk for Parkinsonian disorders as suggested by Weiss (2006). 

Neurological Studies of Animals Exposed by Inhalation to Inorganic Manganese. In several early 

animal studies, intermediate or chronic inhalation exposure of monkeys and rats to manganese dusts has 

not produced neurological signs similar to those seen in humans (Bird et al. 1984; EPA 1983c; Ulrich 

et al. 1979a, 1979b). For example, Ulrich et al. (1979a) reported that monkeys continually exposed for 

9 months to aerosols of manganese dioxide at concentrations as high as 1.1 mg manganese/m3 showed no 

obvious clinical signs of neurotoxicity, no histopathological changes in brain tissues, and no evidence for 

limb (leg) tremor or electromyographic effects on flexor and extensor muscles in the arm. However, in a 

chronic study with Rhesus monkeys, decreased levels of dopamine were found in several regions of the 

brain (caudate and globus pallidus) (Bird et al. 1984). Behavioral tests detected signs of neurological 

effects in mice (increased open-field activity and decreased maternal pup retrieval latency), although 

these are only seen at relatively high exposure levels (60–70 mg manganese/m3

) (Lown et al. 1984; 

Morganti et al. 1985). 

Several studies provide evidence for associations between decreased neuronal cell counts in the globus 

pallidus and neurobehavioral changes (increased locomotor activity) in rats exposed by inhalation for 

13 weeks to a mixture of manganese phosphate/sulfate (at 1.05 mg manganese/m3

) or manganese sulfate 

alone (at concentration between 0.009 and 0.9 mg manganese/m3

), but not to manganese phosphate alone 

at concentrations up to 1.1 mg manganese/m3 (Normandin et al. 2002; Salehi et al. 2003, 2006; Tapin et 

al. 2006). Other 13-week rat inhalation exposure studies reported increased brain manganese 

concentrations and increased locomotor activity after exposure to 3.75 mg manganese/m3 as metallic 

manganese (St-Pierre et al. 2001) and increased brain manganese concentrations with no increases in 

olfactory bulb, cerebellar, or striatal concentrations of glial fibrillary acidic protein (GFAP) after exposure 

to 0.5 mg manganese/m3 as manganese sulfate or 0.1 mg manganese/m3 as manganese phosphate 

(Dorman et al. 2004b). GFAP is a widely acknowledged marker of damage to astrocytes. 

In male Sprague-Dawley rats, increased locomotor activity (increased distance traveled, but no change in 

resting time) was observed after up to 13 weeks of exposure to 0.03 or 3 mg of a manganese 

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phosphate/sulfate mixture/m3 (6 hours/day, 5 days/week), but not at 0.3 mg/m3 (Salehi et al. 2003). These 

exposure concentrations correspond to 0.01, 0.11, and 1.05 mg manganese/m3

. Assessment of brain 

manganese levels, hind limb tremor, and neuropathology of the brain (counts of neuronal cells) found no 

evidence for tremor at any exposure level, but rats at the highest exposure level showed significantly 

(p<0.05) increased concentrations of manganese in the frontal cortex, globus pallidus, and caudate 

putamen, as well as significantly (p<0.05) decreased neuronal cell counts in the globus pallidus and 

caudate putamen, compared with control values or to values for rats in the lower exposure groups (Salehi 

et al. 2006). 

In similar experiments with male Sprague-Dawley rats exposed to 0, 0.03, 0.3, or 3 mg manganese 

sulfate/m3 (Tapin et al. 2006) or 0, 0.03, 0.3, or 3 mg manganese phosphate/m3 (Normandin et al. 2002) 

for 13 weeks by the same exposure protocol, some differences in results were obtained. These exposure 

levels correspond to 0.009, 0.09, or 0.9 mg manganese/m3 for manganese sulfate and 0.01, 0.11, or 

1.1 mg manganese/m3 for manganese phosphate. With exposure to manganese phosphate, manganese 

levels were significantly (p<0.05) elevated (at 3 mg/m3 ) in the olfactory bulb, frontal cortex, globus 

pallidus, caudate putamen, and cerebellum regions of the brain, but no exposure-related effects were 

found on neuronal cell counts or locomotor activity (Normandin et al. 2002). In contrast, manganese 

sulfate exposure significantly (p<0.05) increased manganese levels in all regions of the brain, and 

decreased neuronal counts in the globus pallidus at 0.3 and 3 mg manganese sulfate/m3

, compared with 

controls (Tapin et al. 2006). In addition, the two highest exposure levels of manganese sulfate were 

associated with significantly (p<0.05) increased locomotor activity (distance traveled), increased resting 

time, and decreased total ambulatory counts; the lowest exposure level, 0.03 mg manganese sulfate/m3 

also increased the distance traveled end point of locomotor activity (Tapin et al. 2006). As with the 

manganese phosphate/sulfate mixture, neither manganese phosphate nor manganese sulfate exposure was 

associated with hind limb tremors in the rats. Earlier studies by the same research group, found that 

Sprague-Dawley rats exposed to 3.75 mg aerosols of metallic manganese/m3 (6 hours/day, 5 days/week 

for 13 weeks) showed significantly (p<0.05) higher manganese concentrations in various regions of the 

brain, and higher distance traveled and lower resting time in locomotor tests, compared with controls; 

neuronal counts were not assessed in this earlier study (St-Pierre et al. 2001). 

Several studies have examined the influence of inhalation exposure to manganese sulfate on biochemical 

end points associated with oxidative stress or inflammation in the brain of rats (Erikson et al. 2005, 2006; 

HaMai et al. 2006; Taylor et al. 2006) and monkeys (Erikson et al. 2007). Erikson et al. (2005, 2006) 

exposed neonatal rats to manganese sulfate (0, 0.05, or 1 mg manganese/m3

) during gestation and 

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postnatal days (PNDs) 1–18 and examined five brain regions for several biochemical end points 

associated with oxidative stress either on PND 19 (Erikson et al. 2006) or after 3 weeks without exposure 

(Erikson et al. 2005). End points included levels of glutamine synthase (GS) protein and mRNA, 

metallothionein (MT) mRNA, tyrosine hydroxylase (TH) protein and mRNA, and total reduced 

glutathione. At PND 9, increased manganese concentrations in the striatum (the most consistently 

affected region) were associated with decreases in GS, MT, and TH mRNA, and significantly decreased 

levels of glutathione (Erikson et al. 2006), but these were not apparent 3 weeks after cessation of 

exposure (Erikson et al. 2005). However, other end points (such as decreased GS protein) were changed, 

compared with control values, 3 weeks after cessation of exposure (Erikson et al. 2005). Similar end 

points, as well as levels of mRNA and protein for glutamate transporters, were examined in six brain 

regions of young male Rhesus monkeys exposed to 0, 0.06, 0.3, or 1.5 mg manganese/m3 as manganese 

sulfate for 65 days (Erikson et al. 2007). Exposure-related changes included decreased MT mRNA in 

most regions, decreased TH protein levels in the caudate and globus pallidus, increased GSH in the 

frontal cortex, and decreased GSH in the caudate. In another study, HaMai et al. (2006) exposed three 

groups of rats to 0 or 0.71 ng manganese/m3 (2 hours/day) as manganese sulfate on gestation days (GDs) 

9 and 10, on PNDs 37–47, or on GDs 9 and 10 plus PNDs 37–47 and measured brain levels of mRNA for 

gene products related to oxidative stress or inflammation. Gestational exposure was associated with 

decreased mRNA for amylid precurson (APP), cyclooxygenase-2 (COX-2), neuronal nitric oxide 

synthetase (nNOS), and GFAP, whereas adult exposure was associated with greater transcriptional 

decreases for the same gene products as well as transcriptional growth factor beta (HaMai et al. 2006). 

The results from these studies indicate that acute- or intermediate-duration inhalation exposure to 

manganese sulfate concentrations ranging from about 0.1 to 1 mg manganese/m3 can differentially affect 

brain biochemical markers of neurotoxicity, but understanding of the neurotoxic mechanism of 

manganese is inadequate to confidently define any one of the observed changes as biologically adverse. 

No studies on neurological effects from inhalation exposure to MMT in humans or animals were located. 

3.2.1.5 Reproductive Effects 

As discussed earlier (see Section 3.2.1.4), impotence and loss of libido are common symptoms in male 

workers afflicted with clinically identifiable signs of manganism attributed to occupational exposure to 

manganese for 1–21 years (Emara et al. 1971; Mena et al. 1967; Rodier 1955; Schuler et al. 1957). These 

symptoms could lead to reduced reproductive success in men. Impaired fertility (measured as a decreased 

number of children/married couple) has been observed in male workers exposed for 1–19 years to 

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manganese dust (0.97 mg/m3) at levels that did not produce frank manganism (Lauwerys et al. 1985). 

This suggests that impaired sexual function in men may be one of the earliest clinical manifestations of 

manganism, but no dose-response information was presented so it is not possible to define a threshold for 

this effect. Jiang et al. (1996b) performed a reproductive epidemiological study on 314 men in a 

manganese plant. The men, from six different factories, performed milling, smeltering, and sintering 

duties for up to 35 years. The geometric mean airborne manganese concentration (assumed to be total 

dust) was 0.145 mg/m3 as manganese dioxide. The researchers found no significant differences in 

reproductive outcomes between exposed and control workers (controls were matched for several factors, 

including age, smoking, personal hygiene, living habits, and cultural background). The incidences of 

sexual dysfunction were evaluated through researchers’ questions and judged by the occurrence of two 

positive responses to three potential conditions: impotence, abnormal ejaculation (early ejaculation or 

nonejaculation), and lack of sexual desire. Impotence and lack of sexual desire were higher in the 

exposed group than in the controls (Jiang et al. 1996b). Wu et al. (1996) reported increased semen 

liquefaction time and decreased sperm count and viability in three groups of men occupationally exposed 

to manganese: 63 miners or ore processors, 38 electric welders in mechanical fields, and 110 electric 

welders in shipbuilding. Matched controls consisted of 99 men who were employed in the same 

occupation and from the same area, but were not exposed to manganese or other reproductive toxins. The 

men had been exposed to manganese for ≥1 year. Geometric means of total manganese dust (as 

manganese dioxide) ranged from 0.14 mg/m3 for mining operations to 5.5 mg/m3 for manganese powder 

processing. Manganese fume concentrations varied; the mechanical welders were exposed to a 

concentration of 0.25 mg/m3 (geometric mean), while the shipbuilding area concentrations ranged from 

geometric means of 6.5–82.3 mg/m3

, depending on the location within the ship. The miners had a 

significant percentage (14.3%; p<0.01) of samples with increased liquefaction time, decreased sperm 

count (34.9%; p<0.01), and decreased percentage of total viable sperm (33.3% had abnormal counts; 

p<0.01) compared to controls. Welders in shipbuilding had decreased sperm viability levels that were 

significantly different from controls (p<0.01). Manganese concentrations in semen were significantly 

increased compared to controls in the mechanical welders; copper, nickel, chromium, and iron 

concentrations were also elevated in semen in welders in both mechanical and shipbuilding careers. 

Further, stepwise regression analysis of the impact of these other metals on the measured reproductive 

parameters indicated that the higher the nickel concentration, the lesser the semen volume and the greater 

the number of deformed sperm. Copper in the seminal fluid was also positively linked with the viable 

sperm percentage, sperm viability and number of sperm. Although this study indicates that manganese 

exposure can cause sperm toxicity, the presence of other metals prevents any conclusive statements 

concerning its importance. Gennart et al. (1992) performed a reproductive study on 70 male workers 

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exposed to manganese dioxide at a median concentration of 0.71 mg manganese/m3 in total dust for an 

average of 6.2 years in a dry alkaline battery plant. Results from a questionnaire answered by the workers 

and controls in the study and from analysis of birthrates of exposed and control workers revealed no 

difference in birthrates between the groups. 

These results in human studies reveal conflicting evidence for whether occupational exposure to 

manganese causes adverse reproductive effects. Effects reported may occur as a secondary result of 

neurotoxicity but do not provide information on any direct effect manganese may have on the 

reproductive organs. No information was found regarding reproductive effects in women. 

Intratracheal instillation studies in rabbits indicate that single high doses of manganese (158 mg/kg, as 

manganese dioxide) can cause severe degenerative changes in the seminiferous tubules and lead to 

sterility (Chandra et al. 1973; Seth et al. 1973). This effect did not occur immediately, but developed 

slowly over the course of 4–8 months following the exposure. Direct damage to the testes has not been 

reported in humans occupationally exposed for longer periods, suggesting that this effect may not be of 

concern under these exposure circumstances. However, it is unclear if specific studies to investigate 

possible testicular damage have been performed. 

None of the studies located reported adverse effects in female animals following inhalation exposure to 

manganese. In a study with female mice (Lown et al. 1984), the average number of pups born to exposed 

females was increased when dams were exposed to manganese dioxide before conception through 

gestation. In a report of a study of tissue manganese concentrations in lactating rats and their offspring 

following exposure to manganese sulfate aerosols at 0, 0.05, 0.5, or 1 mg manganese/m3 starting 28 days 

prior to breeding through PND 18, no mention was made of reproductive performance variables such as 

the percentage of dams that delivered or the number of pups per litter (Dorman et al. 2005a). 

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects in 

each species and duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

No studies were located concerning reproductive effects following inhalation exposure to organic 

manganese compounds in humans or animals. 

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3.2.1.6 Developmental Effects 

Very little information is available on the developmental effects of inorganic manganese from inhalation 

exposure. The incidences of neurological disorders, birth defects, and stillbirths were elevated in a small 

population of people living on an island where there were rich manganese deposits (Kilburn 1987). 

However, no conclusions could be reached on the causes of either the neurological effects or the 

increased incidence of birth defects and stillbirths because there were insufficient exposure data. Control 

data were not provided, and the study population was too small for meaningful statistical analysis. 

Although inhalation exposure was not ruled out, the route of exposure was assumed to be primarily oral. 

Lown et al. (1984) evaluated the developmental effects of inhaled manganese in mice. The study 

involved exposing dams and non-pregnant female mice to either filtered air or manganese at an average 

concentration of 61 mg/m3 (as manganese dioxide) 7 hours/day, 5 days/week, for 16 weeks prior to 

conception. The authors then exposed the mice to either air or manganese post-conception, irrespective 

of preconception exposure. Once delivered, six pups (three of each sex) were distributed to foster 

mothers and then nursed in the absence of exposure to manganese. The pups were then evaluated on 

postpartum day 7 for weight gain and gross locomotor activity and on day 45 for different behavioral 

parameters and learning performance. The authors observed that pups raised by foster mothers that had 

been exposed to manganese preconception and filtered air postconception had reduced weights compared 

to pups raised by foster mothers exposed only to filtered air. The activity data indicated that there were 

no observable differences in activity between pups who had been exposed to manganese in utero and 

those that had not. Therefore, the data did not provide evidence that manganese exposure resulted in 

adverse neurological developmental effects. 

No studies were located concerning developmental effects in humans or animals following inhalation 

exposure to organic manganese. 

3.2.1.7 Cancer 

No studies were located regarding carcinogenic effects in humans or animals after inhalation exposure to 

inorganic or organic manganese. 

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3.2.2 Oral Exposure 

Although humans are often exposed to significant quantities of inorganic manganese compounds in food 

and water (see Sections 6.4 and 6.5), reports of adverse effects in humans from ingestion of excess 

manganese are limited. Most information on the effects of oral exposure to inorganic manganese is 

derived from studies in animals. These studies are summarized in Table 3-2 and Figure 3-2, and the 

findings are discussed below. All doses are expressed as mg manganese/kg/day. 

Health effects following oral exposure to the organic manganese compound, MMT, were observed in 

animals. Studies involving oral exposure of animals to MMT are summarized in Table 3-3 and 

Figure 3-3. As discussed previously, because inhalation, oral, and dermal pathways are not a concern 

regarding exposure to mangafodipir, this compound’s studies are not presented in an LSE table or figure; 

instead, they are discussed in Section 3.2.4. 

3.2.2.1 Death 

Two studies have been located in which death in humans may have been caused by the ingestion of 

manganese-contaminated water (Hafeman et al. 2007; Kawamura et al. 1941). Kawamura et al. (1941) 

reported death from "emaciation" in two adults who ingested drinking water contaminated with high 

levels of manganese. Hafeman et al. (2007) reported high mortality among infants <1 year of age in a 

Bangladesh population where the drinking water supplied by certain local wells contained high levels of 

manganese. As discussed in detail in Sections 3.2.2.4 (Kawamura et al. 1941) and 3.2.2.5 (Hafeman et al. 

2007), several aspects of these two reports suggest that factors other than, or in addition to, high levels of 

manganese in drinking water may have been responsible for the deaths. 

In animals, most studies indicate that manganese compounds have low acute oral toxicity when provided 

in feed. In rats, daily doses of 1,300 mg manganese/kg/day (as manganese sulfate in the feed) for 14 days 

did not affect survival (NTP 1993). Survival was decreased in male rats fed 200 mg manganese/kg/day 

(as manganese sulfate) for 2 years (NTP 1993). The cause of death was attributed to increased severity of 

nephropathy and renal failure; however, female rats fed 232 mg manganese/kg/day (as manganese sulfate) 

for 2 years were not affected in this manner (NTP 1993). Similarly, doses as high as 2,251 mg 

manganese/kg/day (as manganese chloride) in the diet were tolerated by male mice (females were not 

tested) for 6 months without lethality (Gianutsos and Murray 1982). The survival of both male and 

female mice was also unaffected by feeding as much as 731 mg manganese/kg/day (as manganese sulfate) 

for 2 years (NTP 1993). 

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139

412

146

351

227

342331275

1039

642

1040

782

77

1082

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(SpragueDawley) 

once (GW) 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

412 M (LD50) 

2 Rat 

(albino) 

once (GW) 351 M (LD50) 

3 Rat 

(Wistar) 

once (GW) 342 M (LD50) 

331 F (LD50) 275 (LD50 - pups) 

4 Rat 

(Swiss albino) 

once (G) 642 M (LD50) 

5 Rat 

(Swiss albino) 

once (G) 782 M (LD50) 

6 Rat 

(Wistar) 

once (GW) 1082 (LD50) 

Reference Chemical Form 

Holbrook et al. 1975 MnCl2 Kostial et al. 1978 MnCl2 Kostial et al. 1989 MnCl2 Singh and Junnarkar 19MnCl2 Singh and Junnarkar 19MnSO4 Smyth et al. 1969 MnOAc 
234

130013006501300

1300

6501300

1300

13001300650

1300

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

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Systemic 

7 Rat 

(F344/N) 

14 d (F) Resp 1300 NTP 1993 MnSO4 

Cardio 1300 Hemato 650 M 

1300 F 

1300 M (decreased leukocyte 

and neutrophil counts) 

Hepatic 650 M 1300 M (reduced liver weight) 

1300 F 

Renal 1300 Endocr 1300 Bd Wt 650 1300 (57% decreased body 

weight in males; 20% in females) 
1002

260039002600390026003900260039002600390026003900

375

22

1058

8.8

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

14 d (F) Resp 2600 M 

3900 F 

NTP 1993 MnSO4 

Cardio 2600 M 

3900 F 

Hemato 2600 M 

3900 F 

Hepatic 2600 M 

3900 F 

Renal 2600 M 

3900 F 

Endocr 2600 M 

3900 F 

6 d (GW) 22 M (increase in dihydroxyphenylacetic 

acid and uric acid in striatum) 

Desole et al. 1994 MnCl2 

2 x/d 6 d 1 x (d 7) (GW) 

8.8 M (decrased concentrations 

of dopamine in brainstem; glutathione depletion potentiated Mn effects on dopamine as well as concentrations of DOPAC and HVA) 

Desole et al. 1997 MnCl2 

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a 

Key to Species 

Figure (Strain) 

8 Mouse 

(B6C3F1) 

Neurological 

9 Rat 

(Wistar) 

10 Rat 

(Wistar) 
235

1300

1067

13.9

384

2200

1003

1300

383

2200

147

225

44

180

449

6

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

11 Rat 

(F344/N) 

14 d (F) 1300 NTP 1993 MnSO4 

12 Rat 

(albino) 

1 d (GW) 13.9 (decreased acquisition of an avoidance reaction) Shukakidze et al. 2003 MnCl2*4H2O 

Reproductive 

13 Rat 

(SpragueDawley) 

Gd 6-17 (GW) 2200 F Grant et al. 1997 MnCl2 

14 Rat 

(Fischer- 344) 

14 d (F) 

Developmental 

15 Rat 

(SpragueDawley) 

Gd 6-17 (GW) 

INTERMEDIATE EXPOSURE Death 

16 Rat 

(Long- Evans) 

21 d (GW) 

Systemic 

17 Rat 

(Long- Evans) 

224 d (F) Hemato 

1300 M 2200 

180 M 

225 (LD50 - 21 days) 

NTP 1993 MnSO4 Grant et al. 1997 MnCl2 Rehnberg et al. 1980 Mn3O4 Carter et al. 1980 Mn3O4 

18 Rat 

(Wistar) 

1 x/d 28 d (F) 

Bd Wt 6 M (rats gained only 44% of 

amount gained by control rats with normal food consumption) 

Exon and Koller 1975 Mn3O4 

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237

40

520618520618

3315533618

52061852061877

155

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

19 Rat 

(F344/N) 

13 wk (F) Resp 

Cardio Gastro Hemato Hepatic Renal Endocr Bd Wt 

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NOAEL 

(mg/kg/day) 

520 M 

618 F 520 M 618 F 520 M 618 F 520 M 618 F 

77 F 

LOAEL 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

40 F (reduced lung weight) NTP 1993 

MnSO4 

33 M (increased neutrophil 

count) 

155 F (decreased leukocyte 

count) 

33 M (decreased liver weight) 

618 F (decreased liver weight) 155 F (11% decrease in body 

weight) 
1051

87

406

33

11

80

12

1050

277

56

205205

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

20 Rat 

(SpragueDawley) 

63 d (GW) Renal 87 M (increased incidence of glomerulosclerosis/ 

glomerulonephritis or urolithiasis [i.e., bile stone formation] in males) 

Ponnapakkam et al. 200MnOAc 

21 Rat 

(SpragueDawley) 

Gd 0-21 (GW) Endocr 33 F Szakmary et al. 1995 MnCl2 

Metab 11 F (increased cytochrome 

P450) 

22 Rat 

(white) 

10 wk (W) Hepatic 12 M Wassermann and Wassermann 1977 

MnCl2 

23 Mouse 

Swiss 

12 wk (W) Bd Wt 277 F Elbetieha et al. 2001 MnCl2 

24 Mouse 

(CD-1) 

90 d (F) Hepatic 205 M Gray and Laskey 1980 Mn3O4 

Renal 205 M 

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1004

284284

1005

284

1006

284

220

284284

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

100 d (F) Hemato 284 M (decreased red blood cell count and white blood 

cell count) 

Komura and Sakamoto MnOAc 

Bd Wt 284 M (10% decrease in body 

weight gain) 

100 d (F) Hemato 284 M (decreased hematocrit) Komura and Sakamoto 

MnCO3 

100 d (F) Hemato 284 M (decreased white blood cell count) Komura and Sakamoto 

MnO2 

100 d (F) Hemato 284 M (decreased red blood cell count and white blood 

cell count) 

Komura and Sakamoto MnCl2 

Bd Wt 284 M (10% decrease in body 

weight gain) 

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a 

Key to Species 

Figure (Strain) 

25 Mouse 

(ddY) 

26 27 

Mouse (ddY) Mouse (ddY) 

28 Mouse 

(ddY) 
248

195019509751950

1950

975

1950

9751950

1950

195019509751950

1950

361

4.4

29 30 

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

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1950 NTP 1993 

MnSO4 

1950 

975 M 1950 M (mild hyperplasia and 

hyperkeratosis of the

1950 F forestomach) 

975 1950 (decreased hematocrit, 

hemoglobin, and erythrocyte count) 

975 M 1950 M (reduced liver weight) 

1950 F 

1950 1950 

975 M 1950 M (13% lower body weight 

compared to controls)

1950 F 

4.4 M (patchy necrosis, Chandra and Imam 197

decreased ATPase, MnCl2 GTPase in stomach and small intestine) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

Mouse 13 wk (B6C3F1) (F) Gn Pig 30 d; 1 d 

(G) 

System 

Resp Cardio Gastro Hemato Hepatic Renal Endocr Bd Wt Gastro 
240

33155

1084

0.3

1061

107.5

1071

71.1

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Immuno/ Lymphoret 

31 Rat 

(F344/N) 

13 wk (F) 33 M (increased neutrophil count) NTP 1993 MnSO4 

155 F (decreased leukocyte 

count) 

Neurological 

32 Human 1 x/d 

8 wk varying dose (IN) 

0.3 F Finley et al. 2003 

MnSO4 

33 Monkey 

(Rhesus) 

4 mo during infancy (F) 

107.5 M (minimally adverse 

behavioral effects in soy and soy+Mn groups: decreased activity during sleep at 4 months and decreased play activity between 1-1.5 months) 

Golub et al. 2005 MnCl2 

34 Rat 

(SpragueDawley) 

6 wk (W) 71.1 (decreased Fe levels in caudate putamen and 

substantia nigra; decreased GABA uptake activity in striatal synaptosomes) 

Anderson et al. 2007a MnCl2 

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151

594

372

392.5

43

13

850

11

22

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

a 

Key to Species 

Figure (Strain) 

35 Rat 

(SpragueDawley) 

36 Rat 

(SpragueDawley) 

37 Rat 

(SpragueDawley) 

38 Rat 

(CD) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

2 mo (W) 594 M (increased gamma- aminobutyric acid levels) Bonilla 1978b MnCl2 

8 mo (W) 392.5 M (increased L-tyrosine hydroxylase activity in 

neostriatum, midbrain, hippocampus, and hypothalamus) 

Bonilla 1980 MnCl2 

8 mo (W) 13 M (decreased norepinephrine levels) Bonilla and Prasad 198

MnCl2 

pnd 1-49 (GW) 11 22 (increased spontaneous motor activity) Brenneman et al. 1999 MnCl2 
1072

1310

1062

1310

45

146.7

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

39 Rat 

(Wistar) 

10 wk (W) 1310 M (significantly increased open field activity, 

significantly elevated, continued interest in a novel object and increased fear; enhanced dopaminergic inhibitory control of corticostriatal excitatory transmission) 

Calabresi et al. 2001 MnCl2 

40 Rat 

(Wistar) 

10 wk (W) 1310 M (increased frequency and amplitude of 

spontaneous excitatory membrane potentials in corticostriatal slices from Mn-treated rats compared with control rats) 

Centonze et al. 2001 MnCl2 

41 Rat 

(albino) 

30 d (W) 146.7 M (increased activity and aggression, turnover of 

striatal dopamine, tyrosine and homovanillic acid, altered neurotransmitter levels) 

Chandra 1983 MnCl2 

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180

0.31

370

40

181

1

10

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) 

LOAEL 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

42 Rat 

(ITRC albino) 

60 d (GW) 

Chandra and Shukla 19MnCl2*4H2O 

0.31 M (increased monoamine 

oxidase activity in the brain, neuronal degeneration in cerebral and cerebellar cortex and caudate nucleus) 

43 Rat 

(ITRC albino) 

360 d (W) 

Chandra and Shukla 19MnCl2 

40 M (increase of dopamine, 

norepinephrine, and homovanillic acid above control levels in striatum observed at 15-60 days of treatment, followed by a decrease of all three compounds below control levels at 300-360 days of treatment) 

44 Rat 

(CD Neonatal) 

24 d (GW) 1 M Deskin et al. 1980 MnCl2 10 M (decreased dopamine levels in the 

hypothalamus, significant decrease in hypothalamic tyrosine hydroxylase activity, significant increase in hypothalamic monoamine oxidase activity) 

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360

15

20

830

11

48

390

1085

8

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg) Less Serious (mg/kg) 

LOAEL 

Serious 

(mg/kg) 

Reference Chemical Form 

45 Rat 

(CD) 

pnd 0-24 (GW) 15 20 M (increased serotonin in hypothalamus, 

decreased acetylcholinesterase in striatum) 

Deskin et al. 1981 MnCl2 

46 Rat 21 d 

1 x/d (GW) 

11 (significant increase in 

pulse elicited startle reflex at pnd 21) 

Dorman et al. 2000 MnCl2 

47 Rat 100-265 d 

(W) 390 M (increased dopamine and dopamine metabolite 

levels) 

Eriksson et al. 1987a MnCl2 

48 Rat 

(SpragueDawley) 

Gd 7- pnd 21 (F) 8 (hematological changes indicative of Fe 

deficiency in dams and pups; increased levels of the inhibitory neurotransmitter, GABA, in pup brains) 

Garcia et al. 2006 NS 

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1089

1248

62

13.8

65

150

1076

2.2

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

49 Rat 

(Long- Evans) 

20 d Gd 0-20 (W) 

1248 Kontur and Fechter 198

MnCl2 

50 Rat 

(Long- Evans) 

14-21 d (GO) 13.8 Kontur and Fechter 198

MnCl2 

51 52 

Rat Rat (SpragueDawley) 

44 d (GW) 30 d (GW) 2.2 M (redistribution of iron in body fluids associated 

with upregulation of transferritin receptor mRNA and downregulation of ferritin mRNA from the choroid plexus and striatum) 

150 (ataxia) Kristensson et al. 1986 

MnCl2 Li et al. 2006 MnCl2 

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1099

10

20

1074

15.1

26.7

1057

611

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

53 Rat 

(SpragueDawley) 

30 d (GO) 10 M 20 M (significant [p < 0.05] body weight decrease 

[~9%] and significant [p < 0.05] increase in aspartate, glutamate, glutamine, taurine and GABA in the cerebellum [~20-50%, depending upon the amino acid] of adult rats) 

Lipe et al. 1999 MnCl2 

54 Rat 

(Wistar) 

4 wk (W) 15.1 M 26.7 M (increases in striatal Mn levels in cirrhotic rats, 

striatal neurotransmitter [dopamine or homovanillic acid] increased with or without cirrhosis) 

Montes et al. 2001 MnCl2*4H2O 

55 Rat 

(Wistar) 

13 wk (W) 611 M (33% reduction in immunoreactive cells 

with glutamine synthetase in the globus pallidus) 

Morello et al. 2007 MnCl2*4H2O 

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238

520618

1090

120

1064

74.9

1065

4.4

13.1

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

13 wk (F) 520 M 

618 F 

NTP 1993 MnSO4 

Gd 1- pnd 30 (W) 120 M (significant decrease in cortical thickness; with 

high dose rats demonstrating evidence of hyperactivity [significantly increased locomotor activity and increased rearing in an open field] on pnd 17) 

Pappas et al. 1997 MnCl2 

50 d (NS) 74.9 M (increased serum levels of dopamine sulfate, 

L-Dopa, and L-p-tyrosine and decreased levels of dopamine) 

Ranasinghe et al. 2000 MnSO4 

21 d (NS) 

4.4 M 13.1 M (subtle behavioral effects 

[altered balance in the neonatal period and diminished locomotor response to cocaine in adulthood] and neurochemical effects in adulthood [decreased dopamine binding sites in the striatum]) 

Reichel et al. 2006 MnCl2 

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a 

Key to Species 

Figure (Strain) 

56 Rat 

(F344/N) 

57 Rat 

(SpragueDawley) 

58 Rat 

(SpragueDawley) 

59 Rat 

(SpragueDawley) 
1068

5.6

1077

3311

282

11.8

1054

76

153

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

30 d (F) 5.6 (severely impaired cognitive performance in 

maze) 

Shukakidze et al. 2003 MnCl2*4H2O 

13 wk (W) 3311 M (impaired ability of globus pallidus neurons to 

survive mechanical dissociation) 

Spadoni et al. 2000 (NS) 

90 d (W) 11.8 M (altered brain regional dopamine and serotonin 

levels and monoamine oxidase activity) 

Subhash and Padmash1991 MnCl2 

21 wk (GW, W) 76 M 153 M (significantly decreased open field activity among 

restrained rats, impaired spatial learning with or without restraint in a water maze) 

Torrente et al. 2005 MnCl2*4H2O 

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a 

Key to Species 

Figure (Strain) 

60 Rat 

(albino) 

61 Rat 

(Wistar) 

62 Rat 

(albino) 

63 Rat 

(SpragueDawley) 
1069

3.8

7.5

1070

7.5

1082

6.5

1078

13.8

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

20 d (GO) 3.8 7.5 (olfactory discrimination [homing test], and 

performance on a passive avoidance task; striatal dopamine concentrations were about 50% lower than control values) 

Tran et al. 2002a MnCl2 

20 d (GO) 7.5 M Tran et al. 2002b MnCl2 

22 wk (GW) 6.5 M (significant decreases in spatial memory 

performance, open field locomotor activity and acoustic startle responses; increased latency of sensory evoked potentials) 

Vezér et al. 2005, 2007 MnCl2*4H2O 

21 d (IN) 13.8 Weber et al. 2002 MnCl2*4H2O 

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a 

Key to Species 

Figure (Strain) 

64 Rat 

(SpragueDawley) 

65 Rat 

(SpragueDawley) 

66 Rat 

(Wistar) 

67 Rat 

(CD) 
52

2250.7

54

205

221

284

1086

43.7

249

1950

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

6 mo (F) 2250.7 M (decreased dopamine levels) Gianutsos and Murray 1

MnCl2 

90 d (F) 205 M (decreased locomotor activity) Gray and Laskey 1980 Mn3O4 

100 d (F) 284 M (decreased motor activity) Komura and Sakamoto 

MnCl2, MnOAc, MnCO3MnO2 

1 x/d 8 wk (GW) 

43.7 F (increased locomotor 

activity in Mn-treated mice; increased Mn content of striatum and substantia nigra; decreased striatal dopamine; increased apoptotic neurons expressing nitric oxide synthase, choline acetyltransferase and enkephalin in striatum and globus pallidus; increased astrocytes expressing evidence of nitric oxide formation) 

Liu et al. 2006 MnCl2 

13 wk (F) 1950 NTP 1993 MnSO4 

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a 

Key to Species 

Figure (Strain) 

68 Mouse 

(CD-1) 

69 Mouse 

(CD-1) 

70 Mouse 

(ddY) 

71 Mouse 

(C57BL/6N) 

72 Mouse 

(B6C3F1) 
64

624 1248

67

2055

55

180

380

620

1063

68.6

137.2

404

22

33

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

Reproductive 

73 Rat 

(Long- Evans) 

20 d Gd 0-20 (W) 

74 Rat 

(Long- Evans) 

100-224 d (F) 

624 F 

20 M 

55 F 

1248 F (decreased litter weight) 

55 M (significantly decreased 

testicular weight with low-Fe diet) 

75 Rat 

(SpragueDawley) 

Gd 1- pnd 30 (W) 620 F 

76 Rat 

(SpragueDawley) 

63 d (GW) 68.6 M 137.2 M (increased incidences of testicular degeneration in 

male rats) 

77 Rat 

(SpragueDawley) 

Gd 0-21 (GW) 22 F (increase in relative weight of liver, thymus, 

and brain) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Kontur and Fechter 198MnCl2 

180 F (significantly decreased 

[~25%] pregnancy rate) 

Laskey et al. 1982 Mn3O4 Pappas et al. 1997 MnCl2 Ponnapakkam et al. 200MnOAc*4H20 

33 F (post implantation loss) Szakmary et al. 1995 

MnCl2 

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1044

154

309

1048

44

277

55

205

250

1950

1041

2.4

4.8

1043

9.6

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) 

12 wk (W) 154 M 309 M (statistically significantly impaired male fertility) 12 wk (W) 44 F (increased uterine weights relative to body 

weight) 

277 F (implantation number 

reduced by 17% and the number of viable fetuses reduced by 19% from the control value) 

90 d (F) 205 M (delayed growth of testes and sex accessory 

glands) 

13 wk (F) 1950 1 x/d 43 d (GW) 

2.4 M 4.8 M (decreased sperm 

motility and sperm counts) 

1 x/d 43 d (GW) 

9.6 M 

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a 

Key to Species 

Figure (Strain) 

78 Mouse 

Swiss 

79 Mouse 

Swiss 

80 Mouse 

(CD-1) 

81 82 

Mouse (B6C3F1) Mouse (CD-1) 

83 Mouse 

(CD-1) 

Exposure/ LOAEL 

Duration/ 

Reference Chemical Form 

Elbetieha et al. 2001 MnCl2 Elbetieha et al. 2001 MnCl2 Gray and Laskey 1980 Mn3O4 NTP 1993 MnSO4 Ponnapakkam et al. 200MnOAc Ponnapakkam et al. 200MnOAc 
409

33

1087

107.5

1000

11

22

850

11

22

830

11

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg) Less Serious (mg/kg) 

LOAEL 

Serious 

(mg/kg) 

Reference Chemical Form 

Gd 6-20 (GW) 33 F Szakmary et al. 1995 MnCl2 

4 mo (F) 107.5 M (minimally adverse effects in soy and 

soy+Mn groups: decreased activity during sleep at 4 months and decreased play activity between 1-1.5 months) 

Golub et al. 2005 MnCl2 

pnd 1-49 (W) 11 22 (~20% decrease in body weight at pnd 49) Brenneman et al. 1999 MnCl2 

pnd 1-49 (GW) 11 22 (increased spontaneous motor activity) Brenneman et al. 1999 MnCl2 

21 d 1 x/d (GW) 

11 (significant increase in 

pulse elicited startle reflex at pnd 21) 

Dorman et al. 2000 MnCl2 

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a 

Key to Species 

Figure (Strain) 

84 Rabbit 

(New Zealand) 

Developmental 

85 Monkey 

(Rhesus) 

86 Rat 

(CD) 

87 Rat 

(CD) 

88 Rat 
1059

8

1060

8

430

150

376

120

620

1088

4.4

13.1

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Gd 7- pnd 21 (F) 8 (hematological changes indicative of Fe 

deficiency in dams and pups; increased levels of the inhibitory neurotrnasmitter, GABA, in pup brains) 

Garcia et al. 2006 NS 

17 d (F) 8 Garcia et al. 2007 NS 

44 d (GW) 150 (ataxia) Kristensson et al. 1986 MnCl2 

Gd 1- pnd 30 (W) 120 M 620 M (transient decrease (~20%) in pup body 

weight on pnd 9-24; difference not apparent on pnd 90) 

Pappas et al. 1997 MnCl2 

21 d (NS) 

4.4 M 13.1 M (subtle behavioral effects 

[altered balance in the neonatal period and diminished locomotor response to cocaine in adulthood] and neurochemical effects in adulthood [decreased dopamine binding sites in the striatum]) 

Reichel et al. 2006 MnCl2 

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a 

Key to Species 

Figure (Strain) 

89 Rat 

(SpragueDawley) 

90 Rat 

(SpragueDawley) 

91 Rat 92 Rat 

(SpragueDawley) 

93 Rat 

(SpragueDawley) 
405

33

1091

3.8

7.5

1092

7.5

1093

13.8

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg) Less Serious (mg/kg) 

LOAEL 

Serious 

(mg/kg) 

Reference Chemical Form 

Gd 0-21 (GW) 33 (increased retardation in skeletal/organ 

development) 

Szakmary et al. 1995 MnCl2 

20 d (GO) 3.8 7.5 (decreased performance in the olfactory 

discrimination [homing test] and passive avoidance task; striatal dopamine concentrations were about 50% lower 

than control values) 

Tran et al. 2002a MnCl2 

20 d (GO) 7.5 M Tran et al. 2002b MnCl2 

21 d (IN) 13.8 Weber et al. 2002 MnCl2*4H2O 

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a 

Key to Species 

Figure (Strain) 

94 Rat 

(SpragueDawley) 

95 Rat 

(SpragueDawley) 

96 Rat 

(SpragueDawley) 

97 Rat 

(CD) 
408

33

1096

0.26

241

200

242

2002326520023265

200200

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg) 

LOAEL 

Less Serious 

(mg/kg) 

Serious 

(mg/kg) 

Reference Chemical Form 

98 Rabbit 

(New Zealand) 

Gd 6-20 (GW) 

CHRONIC EXPOSURE Death 

99 Human </= 1 yr 

(W) 

33 Szakmary et al. 1995 

MnCl2 Hafeman et al. 2007 NS 

0.26 (increased fatality among 

children <1 year of age) 

100 Rat 

(F344/N) 

2 yr (F) 

NTP 1993 MnSO4 

200 M (14% survival compared 

to 49% in controls) 

Systemic 

101 Rat 

(F344/N) 

2 yr (F) Resp 200 M 

232 F 

NTP 1993 MnSO4 

Cardio Gastro Hemato Renal 

65 M 

200 M 232 F 

65 M 

200 M (increased severity of 

chronic progressive nephropathy) 

Bd Wt 200 M (body weight 10% lower 

than controls) 

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253

585731585731177226

585

732

177731

585

585731585731585731

58564

584732584223

732

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

102 Mouse 

(B6C3F1) 

2 yr (F) Resp 585 M 

731 F 

NTP 1993 MnSO4 

Cardio 585 M 

731 F 

Gastro 177 M 

226 F 

585 M (hyperplasia, erosion) 732 F (ulceration and 

inflammation of the forestomach) 

Hemato 177 M 

731 F 

585 M (increased hematocrit, 

hemoglobin, and erythrocyte counts) 

Musc/skel 585 M 

731 F 

Hepatic 585 M 

731 F 

Renal 585 M 

731 F 

Endocr 585 M (thyroid follicular 

hyperplasia and dilatation) 

64 F (thyroid follicular 

hyperplasia) 

Dermal 584 M 

732 F 

Bd Wt 584 M 

223 F 

732 F (13% lower body weight 

than controls) 

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245

200232

1007

585731

171

0.0048 0.059

1097

0.103

353

0.009

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Immuno/ Lymphoret 

103 Rat 

(F344/N) 

2 yr (F) 

NTP 1993 MnSO4 

200 M 232 F 

104 Mouse 

(B6C3F1) 

2 yr (F) 

NTP 1993 MnSO4 

585 M 731 F 

Neurological 

105 Human 50 yr 

(W) 

Kondakis et al. 1989 NS 

0.0048 0.059 (mild neurological signs) 

106 Human ~68 d 

intermittently x 5 yr (W) 

Sahni et al. 2007 NS 

0.103 F (pica, emotional lability, 

personality changes, speech impairments, loss of balance and coordination, inability to walk) 

107 Human 10 yr or more 

(W) Vieregge et al. 1995 NS 0.009 

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1098

0.04

0.07

1095

0.06

152

6.9

66

40

71

40

213

10.6

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

10 yr (W) 0.04 0.07 (significantly reduced performance on 

Full-Scale IQ test, performance and verbal tests in children) 

Wasserman et al. 2006 NS 

5 yr (W) 0.06 M (Mn possibly producing deficit in free retrieval 

skills, affecting general, verbal and visual memory and learning skills; inattentiveness; lack of focus in classroom) 

Woolf et al. 2002 NS 

18 mo (GW) 6.9 M (weakness, rigidity, neuronal loss and 

depigmentation of the substantia niagra) 

Gupta et al. 1980 MnCl2 

2 yr (W) 40 (altered neurotransmitter uptake) Lai et al. 1984 MnCl2 

65 wk (W) 40 M (increased activity) Nachtman et al. 1986 MnCl2 

3 gen (W) 10.6 (altered gait) Ishizuka et al. 1991 MnCl2*4H2O 

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a 

Key to 

Figure 

108 109 110 111 112 113 

Species 

(Strain) 

Human Human Monkey (Rhesus) Rat (Wistar) Rat (SpragueDawley) Mouse (ddY) 
1008

275

1009

275

1010

275

223

275

689

45

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

12 mo (F) 275 M (decreased locomotor activity) Komura and Sakamoto 

MnOAc 

12 mo (F) 275 M (decreased locomotor activity) Komura and Sakamoto 

MnCO3 

12 mo (F) 275 M (decreased dopamine and increased 

homovanilic acid in brain; decreased norepinephrine and epinephrine; decreased locomotor activity) 

Komura and Sakamoto MnO2 

12 mo (F) 275 M (decreased locomotor activity) Komura and Sakamoto 

MnCl2 

12 mo (F) 45 M (significant [p < 0.05] decreases in dopamine 

and homovanillic acid levels in the corpus striatum) 

Komura and Sakamoto MnCl2 

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a 

Key to Species 

Figure (Strain) 

114 Mouse 

(ddY) 

115 Mouse 

(ddY) 

116 Mouse 

(ddY) 

117 Mouse 

(ddY) 

118 Mouse 

(ddY) 
254

585731

244

200232

255

585731

1011

420

Table 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

119 Mouse 

(B6C3F1) 

2 yr (F) 585 M 

731 F 

NTP 1993 MnSO4 

Reproductive 

120 Rat 

(F344/N) 

2 yr (F) 200 M 

232 F 

NTP 1993 MnSO4 

121 Mouse 

(B6C3F1) 

2 yr (F) 585 M 

731 F 

NTP 1993 MnSO4 

Developmental 

122 Rat 

(ITRC) 

1 gen (W) 420 M (altered neurotransmitter levels) Ali et al. 1985 MnCl2*4H2O 

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a The number corresponds to entries in Figure 3-2. ATPase = adenosine triphosphatase; Bd Wt = body weight; Cardio = cardiovascular; CSF = cerebrospinal fluid; d = day(s); DA = dopamine; DOPAC = dihydroxyph

Endocr = endocrine; F = Female; (F) = feed; (G) = gavage; GABA = gamma-aminobutyric acid; Gastro = gastrointestinal; Gd = gestational day; GFAP = glial fibrillaGn pig = guinea pig; (GO) = gavage in oil; (GW) = gavage in water; GTPase = glucose-6-phosphatase; Hemato = hematological; 5-HIAA = 5-hydroxy-indoleacetic ahomovanillic acid; Immuno/Lymphoret = immunological/lymphoreticular; (IN) = ingestion; LD50 = lethal dose, 50% kill; LH = luteinizing hormone; LOAEL = lowest-observed-adverse-effect level; M = male; Metab = metabolic; mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS Resp = respiratory; TH = tyrosine hydroxylase (W) = drinking water; wk = week(s); x = time(s); yr = year(s) 
Death 

Respiratory Cardiovascular Hematological Hepatic Renal Endocrine Body Weight Neurological Reproductive Developmental 

MANGANESE

3. HEALTH EFFECTS

123

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Figure 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral
	

Acute (≤14 days)
	

Systemic 

mg/kg/day 

10000 

8m 8m 8m 8m 8m 8m 

8m 8m 8m 8m 8m 8m 

13r 15r 

7r 7r 7r 7r 7r 7r 7r 7r 7r 11r 14r 

6r 1000
	

5r
	

4r
	 7r 7r 7r 

1r

2r 3r
	

3r
	 3r 

100 

9r 

12r 

10 10r 

1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Hepatic Renal Endocrine Body Weight Metabolic Immuno/Lymphor 

MANGANESE

3. HEALTH EFFECTS

124

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Figure 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (Continued)
 

Intermediate (15-364 days)
	

Systemic 

mg/kg/day 

10000 

29m 29m 29m 29m 29m 29m 29m 29m 29m 29m 29m 

1000 29m 29m 29m 29m 

19r 19r 19r 19r 19r 19r 19r 19r 19r

25m 26m 27m 28m 23m 25m 28m

16r 24m 24m 17r 19r 19r 31r 

100 20r 19r 

19r 19r 19r 21r 31r 

22r 21r 10 

18r 

30g 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer

 Minimal Risk Level 
Neurological 

Reproductive Developmental 

MANGANESE

3. HEALTH EFFECTS

125

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Figure 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (Continued)

Intermediate (15-364 days) 

mg/kg/day 

10000 

61r 

68m 72m 81m 

39r 40r 49r 73r 

1000 

35r 55r 56r 73r 75r 92r 56r 

36r 47r 

70m 78m 79m 

69m 80m 74r

41r 51r 63r 78m 91r 76r 57r 92r 100 33k 85k

34r 58r 63r 76r 

74r 74r 

71m 43r 79m

77r 84h 94r 98h 

54r 38r 77r 86r 87r 45r 53r 74r 

45r 54r 37r 50r 59r 67r 93r 97r

38r 46r 62r 86r 87r 88r 10 44r 53r 83m 48r 64r 65r 89r 90r 95r 96r 66r 60r 

59r 82m 93r 64r 95r 

52r 82m

1 44r 

32 42r

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer

 Minimal Risk Level 
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Body Weight Immuno/Lymphor Neurological 

MANGANESE

3. HEALTH EFFECTS

126

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Figure 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (Continued)
 

Chronic (≥365 days)
	

Systemic 

mg/kg/day 

1000 

102m 102m 102m 102m 102m 102m 102m 102m 102m 104m 102m 102m 102m 102m 102m 102m 102m 102m 102m 102m 104m

114m 101r 102m 101r 102m 103r 100r 101r 101r 101r 101r 103r 102m 102m 

100 

101r 101r 102m 

113m 

110k 

10 

1 

99 

106 

108 

0.1 

109 

108 

105 

0.01 107 

105 

0.001 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer

 Minimal Risk Level 
Neurological 

Reproductive Developmental 

Figure 3-2 Levels of Significant Exposure to Inorganic Manganese - Oral (Continued)
 

Chronic (≥365 days)

MANGANESE

3. HEALTH EFFECTS

127

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mg/kg/day 

1000 

119m 121m 119m 121m

122r 

115m 116m 117m 120r 120r 

100 

118m 111r 112r 

10 

1 

0.1 

0.01 

0.001 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Level 
581

12.5

1137

15

1094

14.6

435

58

580

30

451

7.6

11.3

7.6

11.3

Table 3-3 Levels of Significant Exposure to MMT - Oral 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(SpragueDawley) 

once (GO) 

System 

NOAEL 

(mg/kg) 

Less Serious 

(mg/kg) 

LOAEL 

Serious 

(mg/kg) 

12.5 M (increase in mortality, 

LD50=50 mg MMT/kg or 13 mg Mn/kg) 

Reference Chemical Form 

Hanzlik et al. 1980a 

2 Rat 

(SpragueDawley) 

1 x 15 (LD50) Hinderer 1979 

3 Rat 

(COBS) 

1 x (GO) 14.6 (LD50) Hysell et al. 1974 

4 Mouse 

(CD-1) 

Systemic 

5 Rat 

(SpragueDawley) 

1 x (GO) once (GO) Resp 

58 F (LD50) 30 M (distended lungs with 

bloody fluid, hemorrhage, perivascular and alveolar edema) 

Hinderer 1979 Hanzlik et al. 1980a 

6 Rat 

(COBS) 

1 x (GO) Resp 7.6 11.3 (severe fibrinopurulent pneumonia with 

prominent macrophage infiltrate of lungs) 

Hysell et al. 1974 

Hepatic 7.6 11.3 (hepatic parenchymal 

necrosis and leukocytic infiltration) 

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441

11

442

11

688

11

9 

Table 3-3 Levels of Significant Exposure to MMT - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg) (mg/kg) (mg/kg) Chemical Form 

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CHRONIC EXPOSURE Systemic 

7 Mouse 1 x/d Bd Wt 11 M (>10% decrease in body Komura and Sakamoto 

12 mo (ddY) weight in exposed group) (F) 

Neurological 

8 Mouse 1 x/d 11 M (increase in spontaneous Komura and Sakamoto 

12 mo (ddY) motor activity on day 80) (F) 

Mouse 12 mo 11 M (changes in brain Komura and Sakamoto 

(ddY) (F) neurochemistry) 

a The number corresponds to entries in Figure 3-3. Bd Wt = body weight; d = day(s); (F) = feed; F = Female; GO) = gavage in oil; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = maNOAEL = no-observed-adverse-effect level; pnd = post-natal day; Resp = respiratory; x = time(s) 
Death 

Respiratory Hepatic 

MANGANESE

3. HEALTH EFFECTS

130

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Figure 3-3 Levels of Significant Exposure to MMT - Oral 

Acute (≤14 days) 

Systemic mg/kg/day 

100 

4m 

5r 

2r 3r 

1r 

6r 6r 

10 

6r 6r 

1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Body Weight 

Neurological 

MANGANESE

3. HEALTH EFFECTS

131

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Figure 3-3 Levels of Significant Exposure to MMT - Oral (Continued) 

Chronic (≥365 days) 

Systemic 

mg/kg/day 

100 

7m 8m 9m 

10 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
 

 

 

 

 

 

 

 

MANGANESE 132 

3. HEALTH EFFECTS 

In contrast to these studies, when exposure is by gavage (usually as highly concentrated solutions of 

manganese chloride in water), measured LD50 values for 1–21 days of exposure range from 225 to 

1,082 mg manganese/kg/day in mice and rats (Holbrook et al. 1975; Kostial et al. 1978, 1989; Rehnberg 

et al. 1980; Singh and Junnarkar 1991; Smyth et al. 1969). These results suggest that gavage dosing with 

a bolus of a concentrated soluble manganese compound in water may not be a good model for 

determining the toxic effects of manganese ingested by humans from environmental sources. Bolus 

dosing produced death in animals at concentrations near the daily dose levels tolerated in food or drinking 

water by the same strains and species of animals subjected to longer durations of exposure. It is possible 

that bolus dosing circumvents the homeostatic control of manganese absorption. It should be noted that 

the concentrations used in the bolus dosing studies are much higher than even excess levels to which 

certain humans are typically exposed. 

In a study where young pigs were fed a diet moderately high (1.7 mg manganese/kg/day) in manganese 

but deficient in magnesium, all eight pigs consuming the high manganese diet died within 5 weeks 

following convulsive seizures; only two of the pigs in a group without supplemental manganese died 

(Miller et al. 2000). Further studies suggested that high dietary manganese could exacerbate magnesium 

deficiency in heart muscle, thus creating a complicating factor in the deaths of the magnesium-deficient 

pigs (Miller et al. 2000). 

In conclusion, route of exposure and animal species and strain differences, as well as sex, may account for 

some of the observed variations in the lethality of manganese. In addition, deficiencies in certain 

essential nutrients, such as magnesium, may increase the lethal potential of excess manganese. 

No studies were located concerning death in humans following ingestion of MMT. 

MMT, dissolved in oil and administered by gavage, was found to have LD50 values of 15 mg 

manganese/kg in the male and female Sprague-Dawley rat and 58 mg manganese/kg in the adult female 

CD-1 mouse (Hinderer 1979). 

Hysell et al. (1974) administered via gavage increasing amounts of MMT (dissolved in oil) to adult 

COBS rats, 10 animals/group. No lethality was observed at the lowest two doses of 3.8 and 7.5 mg 

manganese/kg, but 5/10 rats died within 2–6 days postdosing at a dose of 11.3 mg manganese/kg. 

Increasing numbers of rats died at higher doses, with decreasing times of death post-dosing; complete 

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MANGANESE 133 

3. HEALTH EFFECTS 

mortality occurred at the highest dose of 37.5 mg manganese/kg. The survivors appeared normal by 

14 days. The LD50 (14-day) was estimated at 14.6 mg manganese/kg. 

Hanzlik et al. (1980a) determined the 14-day LD50 for purified MMT administered in corn oil via gavage 

to adult male Sprague-Dawley rats to be 12.5 mg manganese/kg (95% confidence interval, 9.5–16.8 mg 

manganese/kg). The animals survived similar times post-dosing as those in the Hysell et al. (1974) study. 

All LD50 values from each reliable study for death in each species and duration category are recorded in 

Table 3-3 and plotted in Figure 3-3. 

3.2.2.2 Systemic Effects 

In general, there is a lack of data concerning systemic toxic effects in humans who have ingested 

manganese. This is likely due to the strong homeostatic control the body exerts on the amount of 

manganese absorbed following oral exposure; this control protects the body from the toxic effects of 

excess manganese. Studies in humans and animals provide limited data regarding the effects of 

manganese ingestion on systemic target tissues. This information is discussed below and is organized by 

target tissue. Table 3-3 and Figure 3-3 present the highest NOAEL and all LOAEL values from each 

reliable study for these effects for each species and each duration category. 

Respiratory Effects. No studies were located regarding respiratory effects in humans after oral 

exposure to inorganic manganese. 

No respiratory effects were reported in mice fed up to 3,900 mg manganese/kg/day (as manganese 

sulfate) or rats fed 1,300 mg manganese/kg/day (as manganese sulfate) for 14 days (NTP 1993). Male 

rats fed manganese sulfate for 13 weeks showed no respiratory effects at 520 mg manganese/kg/day; 

however, females exhibited decreased lung weight at 40–618 mg manganese/kg/day (NTP 1993). No 

respiratory effects were noted in mice of either sex fed 122–1,950 mg manganese/kg/day (as manganese 

sulfate) for 13 weeks (NTP 1993), in rats fed up to 232 mg manganese/kg/day (as manganese sulfate), or 

in mice fed up to 731 mg manganese/kg/day (as manganese sulfate) for 2 years (NTP 1993). 

The lungs of adult male Sprague-Dawley rats administered one dose of MMT via gavage in corn oil 

(31.25 mg manganese/kg) showed signs of hemorrhage and alveolar and perivascular edema, with an 

accumulation of proteinaceous material in the alveoli. As early as 12 hours following gavage 

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MANGANESE 134 

3. HEALTH EFFECTS 

administration of this same dose, the lung/body weight ratio increased to 2.5 times the control value 

(Hanzlik et al. 1980). Hinderer (1979) observed dark red lungs in Sprague-Dawley rats and CD-1 mice 

administered sublethal doses (values unspecified) of MMT in an acute toxicity study. Gross necropsy of 

the lungs of COBS rats administered one dose of MMT in Wesson oil (dose range, 20–37.5 mg 

manganese/kg) revealed severe congestion and the release of a serosanguinous fluid upon sectioning; 

histopathology of lungs from rats dying within 24 hours post-exposure showed severe congestion, 

perivascular and alveolar edema, and alveolar hemorrhage (Hysell et al. 1974). Sections of lungs from 

rats surviving until 14 days post-exposure revealed extensive areas of consolidation, thickened alveolar 

septa and focal areas of alveolar macrophage activity. 

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after 

oral exposure to inorganic manganese. 

In a 1993 National Toxicology Program (NTP) study, no cardiovascular effects (pathological lesions) 

were observed in mice or rats fed 3,900 or 1,300 mg manganese/kg/day, respectively, for 14 days. No 

cardiovascular effects were observed in rats or mice exposed for 13 weeks to doses as high as 1,950 mg 

manganese/kg/day (as manganese sulfate) or for 2 years to doses as high as 731 mg manganese/kg/day (as 

manganese sulfate) (NTP 1993). 

In a study of weanling male Sprague-Dawley rats provided with a diet supplemented with 55 mg 

manganese/kg/day for 14 weeks, Kalea et al. (2006) found that the level of uronic acid in aortas of the 

manganese-supplemented group was significantly (p<0.05) higher than in a group of rats fed a diet with 

adequate manganese (5.5 mg manganese/kg/day). Among heparan sulfate glycosaminoglycans, aortas 

from manganese-supplemented rats contained higher concentrations of total galactosaminoglycans and 

decreased concentration of hyaluronan and heparan sulfate (50% less heparan sulfate) when compared to 

aortas from rats consuming diets with adequate manganese. Heparan sulfate chains of aortas from 

manganese-supplemented rats contained 41% higher concentration of non-sulfated units compared to 

those of rats fed the adequate manganese diet (Kalea et al. 2006). These results raise concern about the 

potential for manganese to influence vascular chemistry in deleterious ways, creating increased 

vulnerability to cardiovascular events. 

In the course of investigating a mechanism to explain the sudden deaths in pigs from high doses of 

manganese (Miller et al. 2000), studies were conducted in which pigs were fed either low (3.4 mg/kg/day) 

or adequate dietary magnesium (6.8 mg/kg/day) along with high (55 mg/kg/day) or low doses 

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(5.5 mg/kg/day) of manganese (Miller et al. 2004). No differences in heart muscle ultrastructure were 

observed; however, marked myocardial necrosis and mitochrondrial swelling were observed in pigs fed 

high dietary manganese in combination with low magnesium (13.9 mg magnesium/kg/day; Miller et al. 

2004). In pigs fed high manganese and adequate magnesium, no swelling of myocardial mitrochondria 

was observed. These results suggest that high manganese, when fed in combination with low magnesium, 

disrupts mitochondrial ultrastructure (Miller et al. 2004). In another related study, when rats were 

provided with high dietary manganese (13.8 mg manganese/kg/day as manganese carbonate) for 8 weeks, 

heart muscle oxygen consumption was depressed, although no effects of manganese on hematologic 

variables were observed (Miller et al. 2006). No effects of manganese were observed on heart muscle 

activities for Ca+2 ATPase, liver glutathione peroxidase, or brain glutathione peroxidase at doses as high 

as 55 mg manganese/kg/day (Miller et al. 2006). The depression in heart muscle oxygen consumption 

produced by high dietary manganese presents yet another possible mechanism by which high doses of 

manganese can produce adverse cardiovascular events. 

No studies were located regarding the cardiotoxic effects of MMT in either humans or animals following 

oral exposure. 

Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after 

oral exposure to manganese, except for one case report of a child who accidentally ingested some 

potassium permanganate (Southwood et al. 1987). This led to severe local corrosion of the mouth, 

esophagus, and stomach due to the caustic effects of potassium permanganate on the tissue, but there was 

no evidence of systemic toxicity. 

Adverse gastrointestinal effects have been reported in guinea pigs and mice but not in rats. Guinea pigs 

administered 4.4 mg manganese/kg/day (as manganese chloride by gavage) did not suffer any gross 

abnormalities in either the stomach or small or large intestines as a result of treatment but did have patchy 

necrosis and decreased adenosine triphosphatase and glucose 6-phosphatase levels in both the stomach 

and small intestine (Chandra and Imam 1973). This study differs from the others in its delivery of 

manganese (by gavage); the gavage treatment may have partially or completely contributed to the adverse 

effects seen in the stomach and small intestine of the guinea pigs. No gastrointestinal effects were 

observed in female mice fed 1,950 mg manganese/kg/day (as manganese sulfate in food) or rats fed up to 

618 mg manganese/kg/day (as manganese sulfate in food) for 13 weeks, but male mice exhibited mild 

hyperplasia and hyperkeratosis of the forestomach at 1,950 mg manganese/kg/day, also in food (NTP 

1993). 

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In a 1993 NTP study, rats fed as much as 232 mg manganese/kg/day (as manganese sulfate) for 2 years 

showed no gastrointestinal effects; however, mice treated with manganese sulfate for 2 years exhibited 

hyperplasia, erosion, and inflammation of the forestomach at 585 mg manganese/kg/day for males and 

731 mg manganese/kg/day for females. The acanthosis was judged by the authors to be a result of direct 

irritation of the gastrointestinal epithelium and to be of minor consequence. 

No studies were located concerning gastrointestinal effects following oral exposure to MMT in humans. 

Hinderer (1979) observed discolored intestinal tracts in Sprague-Dawley rats and fluid-filled intestines 

and spotting of the intestine in CD-1 mice dosed by gavage with high concentrations (values not 

provided) of MMT in a 14-day toxicity study. Hysell et al. (1974) observed that single lethal doses of 

20–37.5 mg manganese/kg (as MMT, given by gavage) produced small intestines that were distended 

with clear watery contents and thin, friable walls. 

Hematological Effects. In a dietary study with female subjects (Davis and Greger 1992), no changes 

in hematocrit, serum transferrin, or serum ferritin were reported following supplementation with 

0.25 mg manganese/kg/day for 119 days. Vieregge et al. (1995) found no effects on hemoglobin, 

ceruloplasmin, or copper and iron levels in serum for a population of 40-year-old people who had 

ingested at least 0.3 mg manganese/L in drinking water for a minimum of 10 years. These data indicate 

that exposure to increased manganese in water did not result in observable hematological toxicity. 

Alterations in hematological parameters have been reported in rats and mice, although they were found to 

vary depending on species, duration, and the form of manganese administered. No conclusive evidence 

regarding a significant functional deficit has been reported. In mice fed 284 mg manganese/kg/day for 

100 days, red blood cell count was decreased by manganese acetate and manganese chloride; white blood 

cell count was decreased by manganese acetate, manganese chloride, and manganese dioxide; and 

hematocrit was decreased by manganese carbonate (Komura and Sakamoto 1991). However, manganese 

carbonate had no effect on red blood cells or white blood cells, manganese dioxide had no effect on red 

blood cells or total hematocrit, and manganese acetate and manganese chloride had no effect on total 

hematocrit. It has been suggested that the manganese-related effects on red blood cells may be related to 

the displacement of iron by manganese. The significance of the other hematological effects was not 

noted. In a study in rats and mice dosed with manganese sulfate for 14 days, 13 weeks, or 2 years, minor 

changes in hematology parameters were reported; these changes varied depending on species, dose, and 

duration, and the study authors did not consider them to be clearly related to compound administration 

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(NTP 1993). No significant hematological effects were observed in mice exposed to 180 mg 

manganese/kg/day (as manganese tetroxide) for 224 days (Carter et al. 1980). In a study where male 

Sprague-Dawley rats were fed 55 mg manganese/kg/day as manganese carbonate for 8 weeks, 

significantly decreased hematocrit and hemoglobin levels were observed (Miller et al. 2006). However, 

an even lower level of dietary manganese carbonate (35.8 mg manganese/kg/day) fed to male SpragueDawley rats in a diet containing a relatively low concentration of magnesium (200 mg magnesium/kg 

feed/day) for 4 weeks also produced significantly decreased hematocrit and hemoglobin levels (Miller et 

al. 2006). Thus, the potential for dietary manganese to produce adverse effects on red blood cells may be 

further modulated by the relative availability of magnesium in the diet. 

No studies were located concerning hematological effects following oral exposure to MMT in humans or 

animals. 

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after 

oral exposure to inorganic manganese. 

In young rats, high concentrations of manganese chloride in the diet (218–437 mg manganese/kg/day) led 

to rickets (Svensson et al. 1985, 1987); however, this was found to be due to a phosphate deficiency 

stemming from precipitation of manganese phosphate salt (MnHPO4) in the intestine rather than to a 

direct biological effect of manganese on bone formation. No significant musculoskeletal effects were 

observed in mice or rats fed up to 731 mg manganese/kg/day for 2 years (NTP 1993). 

No studies were located concerning musculoskeletal effects following oral exposure to MMT in humans 

or animals. 

Hepatic Effects. A single study of human oral exposure of manganese investigated potential 

hepatotoxicity by analyzing liver enzymes in serum. Vieregge et al. (1995) reported no effects on 

bilirubin, alkaline phosphatase, glutamic pyruvic transaminase, glutamic oxalacetic transaminase, or 

gamma glutamyl transferase in humans, ≥40 years old, who had ingested well water containing 

≥0.30 mg/L for at least 10 years. These limited data indicate that chronic exposure to elevated levels of 

manganese did not result in observable liver toxicity in this population. 

In animals, a variety of histological changes in subcellular organelles (e.g., rough and smooth 

endoplasmic reticulum, Golgi apparatus) were observed in the livers of rats exposed to 12 mg 

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manganese/kg/day for 10 weeks (as manganese chloride) (Wassermann and Wassermann 1977). 

However, these changes were not considered to be adverse but to be adaptive, possibly in response to 

increased manganese excretion in the bile (see Section 3.4.4). Reductions in liver weight have also been 

reported in male Fischer 344 rats fed 1,300 mg manganese/kg/day (as manganese sulfate) for 14 days. 

However, these effects were not seen in B6C3F1 mice fed dosages up to 3,900 mg manganese/kg/day (as 

manganese sulfate) for 14 days (NTP 1993). In rats fed up to 618 mg manganese/kg/day (as manganese 

sulfate) for 13 weeks, decreased liver weights were reported in males at ≥33mg manganese/kg/day and 

females at 618 mg manganese/kg/day (NTP 1993). When mice were fed 122–1,950 mg 

manganese/kg/day (as manganese sulfate) for 13 weeks, the females showed no hepatic effects; however, 

the males exhibited both relative and absolute reduced liver weights at 1,950 mg manganese/kg/day (NTP 

1993). In CD-1 mice, no hepatic changes were seen in males fed 205 mg manganese/kg/day (as 

manganese tetroxide) (Gray and Laskey 1980). No significant hepatic histological changes were 

observed in either mice or rats exposed for 2 years, with rats fed up to 232 mg manganese/kg/day (as 

manganese sulfate), and mice fed up to 731 mg manganese/kg/day (as manganese sulfate) (NTP 1993). 

There are no studies concerning hepatic effects following oral exposure to MMT in humans. 

Hinderer (1979) observed mottling of the liver in CD-1 mice administered high doses (unspecified) of 

MMT via gavage in a 14-day acute toxicity study. Histological evaluation of livers of adult male 

Sprague-Dawley rats administered 31.3 mg manganese/kg/day (as MMT) revealed scattered hepatocytes 

throughout the lobule that contained cytoplasmic vacuoles (Hanzlik et al. 1980b). Twelve hours after 

administration of the same dose, no changes in plasma glutamic pyruvic transaminase (GPT) or liver 

glucose 6-phosphatase (G6P) activities were observed. After the death of 8/14 animals at this dose level 

(24 hours post-dosing), there were still no changes in plasma GPT, liver G6P, or hepatic triglycerides 

(Hanzlik et al. 1980b). Hysell et al. (1974) observed that COBS rats that were gavage-dosed with 20– 

37.5 mg manganese/kg (as MMT) once and died within 24 hours post-dosing had livers with acute 

centrolobular passive congestion. This damage progressed to hepatic parenchymal necrosis and 

leukocytic infiltration in those rats surviving 48–72 hours (15–37.5 mg manganese/kg/day), and extensive 

cytoplasmic vacuolar change in rats surviving to 14 days. 

Renal Effects. No studies were located regarding renal effects in humans after oral exposure to 

inorganic manganese. 

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In animal studies, no significant renal histopathological changes were observed in any of the following: 

mice and rats fed up to 3,900 or 1,300 mg manganese/kg/day (as manganese sulfate) for 14 days (NTP 

1993); mice exposed to 205 mg manganese/kg/day (as manganese tetroxide) in their diet for 90 days 

(Gray and Laskey 1980); mice or rats fed up to 1,950 mg manganese/kg/day for 13 weeks (NTP 1993); or 

mice fed up to 731 mg manganese/kg/day for 2 years and female rats fed 232 mg manganese/kg/day (as 

manganese sulfate) (NTP 1993). Contrary to these findings, increased severity of chronic progressive 

nephropathy was noted in male rats fed 200 mg manganese/kg/day (as manganese sulfate) for 2 years 

(NTP 1993). In addition, glomerulosclerosis/nephritis and urolithiasis (kidney stones) were observed in 

male, but not female, Sprague-Dawley rats exposed to dietary doses ≥87 mg manganese/kg/day for 

63 days (Ponnapakkam et al. 2003b). 

No studies were located concerning renal effects in humans following oral exposure to MMT. 

Hanzlik et al. (1980b) observed occasional vacuolar degeneration of proximal convoluted tubules of the 

kidney in Sprague-Dawley rats administered a single gavage dose of 31.3 mg manganese/kg (as MMT). 

Histopathologic renal effects observed within 24 hours of a gavage dose of 20–37.5 mg manganese/kg 

(Hysell et al. 1974) included hyaline droplet change, cytoplasmic vacuolation of the proximal convoluted 

tubules, and distention of the glomerular space and tubule lumens with a finely granular material that 

stained lightly basophilic. Within 48 hours post-dosing, there was severe tubular degeneration in the form 

of nuclear pyknosis and cell lysis. Animals surviving the administration of 3.75–25 mg manganese/kg 

did not have any adverse renal effects. 

Endocrine Effects. No studies were located regarding endocrine effects in humans after oral 

exposure to inorganic manganese; however, other elements of endocrine function (e.g., reproductive 

effects) following oral exposure to inorganic manganese are discussed elsewhere. 

In mice fed up to 3,900 mg manganese/kg/day (as manganese sulfate) and rats fed 1,300 mg 

manganese/kg/day (as manganese sulfate) for 14 days, no endocrine effects (pathological lesions) were 

observed (NTP 1993). The adrenal gland was assessed for atypical cells and hyperplasia. In the pituitary 

gland, the pars distalis was assessed for cyst, hyperplasia, and hypertrophy. The pars intermedia was 

checked for cysts. C-cells and hyperplasia were examined in the thyroid gland. No endocrine effects 

were observed in mice or rats fed up to 1,950 mg manganese/kg/day (as manganese sulfate) for 13 weeks. 

A 2-year study in rats fed up to 232 mg manganese/kg/day (as manganese sulfate) reported no endocrine 

effects (NTP 1993). However, in a 2-year mouse study, thyroid follicular hyperplasia and dilatation were 

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observed in males fed 584 mg manganese/kg/day, and thyroid follicular hyperplasia was observed in 

females fed 64 mg manganese/kg/day (NTP 1993). 

No studies were located regarding endocrine effects in humans or animals following oral exposure to 

MMT. 

Dermal Effects. No studies were located regarding dermal effects in humans after oral exposure to 

inorganic manganese. 

In animals, no significant dermal histopathological changes were observed in mice or rats exposed for 

2 years to doses up to 731 or 232 mg manganese/kg/day, respectively, (NTP 1993). 

No studies were located regarding dermal effects following oral exposure to organic manganese. 

Ocular Effects. No studies were located regarding ocular effects in humans after oral exposure to 

inorganic manganese. 

In animals, no significant ocular histopathological changes were observed in mice or rats exposed for 

2 years to average oral doses of 731 or 232 mg manganese/kg/day (as manganese sulfate), respectively 

(NTP 1993). 

No studies were located regarding ocular effects in humans or animals after oral exposure to organic 

manganese. 

Body Weight Effects. No studies were located regarding body weight effects in humans after oral 

exposure to inorganic manganese. 

In some animal studies, lower body weights were observed in rats and mice in manganese-dosed groups. 

For example, an NTP study (1993) reported decreases in body weight gain of 57% in male rats and 20% 

in female rats fed 1,300 mg manganese/kg/day (as manganese sulfate in food) for 14 days. Exon and 

Koller (1975) reported that rats fed daily doses of manganese tetroxide as low as 6 mg manganese/kg/day 

(mean ingestion value over the duration of the experiment) for 28 days gained only 44% as much weight 

over the course of the study as control rats. No changes in eating habits in this lowest dose group were 

observed, although rats in the highest dose group at 4,820 mg manganese/kg/day did exhibit decreased 

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weight gain due to starvation and the effects of the manganese. No histopathological changes were 

reported in the exposed animals. The authors suggested that the decrease in weight gain might have been 

due to manganese interference in metabolism of calcium, phosphorous, and iron. 

In chronic studies, a similar sex-related difference in the response to this effect was reported. By the end 

of a 2-year exposure to the maximum daily dose of 200 mg manganese/kg/day (as manganese sulfate in 

food), male rats had a final mean body weight that was 10% lower than that of controls; however, 

females’ mean body weights were not significantly different from those of controls throughout the study 

at all dose levels (232 mg manganese/kg/day was the maximum dose for female rats) (NTP 1993). Food 

intake (as mg/kg/day) was similar for exposed groups and control groups and for males and females (NTP 

1993). 

Laskey et al. (1982) investigated body weight changes in a study of adverse reproductive toxicity in male 

and female Long-Evans rats exposed to manganese. Pregnant dams were fed 0, 350, 1,050, and 3,500 mg 

manganese/kg/day (in conjunction with a low-iron diet [20 mg iron/kg/day] or a diet adequate in iron 

[200 mg iron/kg/day]); the pups were continued on their respective diets from day 14 to 15 postpartum to 

the end of the study (224 days). Manganese treatment did not have any effect on body weight, in either 

sex fed adequate iron. In iron-deficient male rats, however, body weights were significantly decreased 

from controls at 24 days postpartum in the 1,050 mg manganese/kg/day diet and at all doses at 40- and 

60-day time points. Interestingly, body weight was not significantly different in iron-deficient male rats 

fed manganese at 350 mg/kg/day at 100 days and at 224 days (no dose group had weight values 

significantly different from control at day 224). Female body weights were only significantly different in 

the highest dose at day 24 and in the remaining two manganese doses at day 60. Body weights were not 

significantly different from controls for the remainder of the study. Significant mortality in both sexes 

from the highest manganese group fed an iron-deficient diet limited the available data. 

No studies were located concerning body weight effects following oral exposure to MMT in humans. 

Hanzlik et al. (1980b) observed no significant differences in acutely exposed rats at a dose of 31.3 mg 

manganese/kg as MMT. Hinderer (1979) also observed normal weight gain in surviving Sprague-Dawley 

rats and CD-1 mice administered doses of MMT ranging from 7 to 159 mg manganese/kg in a one-dose 

14-day lethality study. 

In a chronic study, Komura and Sakamoto (1992b) administered 11 mg manganese/kg/day (as MMT) in 

chow to male ddY mice for 12 months. A 12% decrease in weight gain was observed at 9 months 

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between exposed mice and mice fed unmodified chow, increasing to a 17% difference at 12 months. All 

differences in these time points were statistically significant. There was no observed difference in food 

intake between the exposed and control groups. 

Metabolic Effects. No studies were located regarding metabolic effects following oral exposure to 

inorganic manganese in humans or animals. 

No studies were located regarding metabolic effects following oral exposure to MMT in humans or 

animals. 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological or lymphoreticular effects in humans after oral 

exposure to inorganic manganese. 

Alterations in white blood cell counts have been reported in rats and mice following oral exposure to 

manganese. One NTP study reported immunological effects in rodents treated for 13 weeks, but not in 

those treated for 2 years (NTP 1993). Mice were fed 122–1,950 mg manganese/kg/day (as manganese 

sulfate) for 13 weeks. Males exhibited decreased leukocyte counts at ≥975 mg manganese/kg/day; 

however, these effects may not have been treatment-related; females were unaffected. For 13 weeks, rats 

were fed 33–520 mg manganese/kg/day (males) and 40–618 mg manganese/kg/day (females); neutrophil 

counts were increased in males at ≥33 mg manganese/kg/day, lymphocytes were decreased in males at 

≥130 mg manganese/kg/day, and total leukocytes were decreased in females at ≥155 mg manganese/ 

kg/day (NTP 1993). Rats fed up to 232 mg manganese/kg/day (as manganese sulfate) and mice fed up to 

731 mg manganese/kg/day (as manganese sulfate) for 2 years exhibited no gross or histopathological 

changes or organ weight changes in the lymph nodes, pancreas, thymus, or spleen (NTP 1993). Komura 

and Sakamoto (1991) reported decreased white blood cell counts in mice following dosing at 284 mg 

manganese/kg/day with manganese acetate, manganese chloride, or manganese dioxide for 100 days. It is 

not known if any of these changes are associated with significant impairment of immune system function. 

No studies were located regarding immunological or lymphoreticular effects following oral exposure to 

MMT in humans or animals. 

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3.2.2.4 Neurological Effects 

Although inhalation exposure to high levels of manganese is known to result in a syndrome of profound 

neurological effects in humans (see Section 3.2.1.4, above), there is only limited evidence that oral 

exposure leads to neurological effects in humans. 

An outbreak of a disease with manganism-like symptoms was reported in a group of six Japanese families 

(about 25 people) exposed to high levels of manganese in their drinking water (Kawamura et al. 1941). 

Noted symptoms included a masklike face, muscle rigidity and tremors, and mental disturbance. Five 

people were severely affected (2 died), 2 were moderately affected, 8 were mildly affected, and 10 were 

not affected. These effects were postulated to be due to the contamination of well water with manganese 

(14 mg/L) that leached from batteries buried near the well. Although many of the symptoms reported 

were characteristic of manganese toxicity, several aspects of this outbreak suggest that factors in addition 

to manganese may have contributed to the course of the disease. First, symptoms appeared to have 

developed very quickly. For example, two adults who came to tend the members of one family developed 

symptoms within 2–3 weeks. Second, the course of the disease was very rapid, in one case progressing 

from initial symptoms to death in 3 days. Third, all survivors recovered from the symptoms even before 

the manganese content of the well had decreased significantly after removal of the batteries. Thus, while 

there is no doubt that these people were exposed to manganese, there is considerable doubt that all of the 

features of this outbreak (particularly the deaths) were due to manganese alone. 

A manganism-like neurological syndrome has been noted in an aboriginal population living on an island 

near Australia where environmental levels of manganese are high (Kilburn 1987). Symptoms included 

weakness, abnormal gait, ataxia, muscular hypotonicity, and a fixed emotionless face. Although it seems 

likely that excess manganese exposure is an etiologic factor in this disease (based on occupational 

exposure data from a study where exposure was assumed to be primarily by inhalation although oral 

exposure was not ruled out), absence of data on dose-response correlations and absence of data from a 

suitable control group preclude a firm conclusion on the precise role of manganese (Cawte et al. 1987). It 

is possible that other factors besides manganese exposure may have contributed to the neurological 

effects, including genetic factors, dietary deficiencies in antioxidants and calcium, and excess alcohol 

consumption (Cawte et al. 1989). Also, it should be noted that if manganese intake is a causal factor for 

neurological damage, exposure of the population evaluated in this study could occur not only through the 

oral route (e.g., food, water, soil), but also by inhaling manganese-containing dusts in environmental or 

workplace air (Cawte et al. 1987). 

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In another study, Kondakis et al. (1989) reported that chronic intake of drinking water containing elevated 

levels of manganese (1.8–2.3 mg/L) led to an increased prevalence of neurological signs in the elderly 

residents (average age, 67 years) of two small towns in Greece. Effects in these residents were compared 

with effects in similarly aged residents in a town where manganese levels were 0.004–0.015 and 0.082– 

0.25 mg/L. These levels are within and slightly above levels found in U.S. drinking water, respectively 

(see Section 6.4.2). Over 30 different neurological signs and symptoms were evaluated, each being 

weighted according to its diagnostic value for Parkinsonism. Based on this system, the average 

neurological scores for the residents of the control town (0.004–0.015 mg manganese/L), the town with 

mid-range levels (0.08–0.25 mg manganese/L), and the town with elevated manganese (1.8–2.3 mg 

manganese/L) were 2.7, 3.9, and 5.2, respectively. Results from this study suggest that higher-than-usual 

oral exposure to manganese might contribute to an increased prevalence of neurological effects in the 

aged population. 

However, there are a number of limitations to this study that make this conclusion uncertain. First, no 

details were reported regarding which neurological signs or symptoms were increased, so it is difficult to 

judge if the differences were due to effects characteristic of manganism or to nonspecific parameters. 

Second, the weighting factors assigned to each neurological symptom were based on the symptom’s 

diagnostic value for Parkinsonism; however, there are clinically significant differences between 

manganism and Parkinsonism. Therefore, the weighting scheme should have placed more weight on 

those symptoms (e.g., sleep disorders, emotional lability, weakness, fatigue, and irritability) reported in 

humans with manganism, such as manganese-exposed miners. The report does not indicate whether 

efforts were made to avoid bias in the examiner or in the study populations. Nonetheless, the use of the 

weighting scheme does strengthen the authors' assertion of an association between elevated manganese 

concentration in the water source and increased susceptibility to neurological symptoms in older 

populations. Although the subjective parameters included in this scoring are indicative of alterations in 

mood or emotional state, and affective disorders often accompany other more objective nervous system 

effects, the authors did not state whether individuals who experienced neurological signs did, in fact, 

ingest higher levels of manganese than unaffected individuals. The authors reported that the populations 

in the towns were very similar to each other, but they provided few data to substantiate this. In this 

regard, even small differences in age, occupational exposures, or general health status could account for 

the small differences observed. Thus, this study suggests, but does not prove, that chronic oral intake of 

high levels of manganese can lead to neurological changes in humans. 

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A study by Vieregge et al. (1995) reported no difference in performance on neurological function studies 

by people who had ingested well water with high concentrations of manganese. These individuals 

(high-exposure group), ages ≥40 years, were exposed to manganese at a minimum concentration of 

300 μg manganese/L in water for at least 10 years. The controls consisted of a matched group of people 

who ingested well water with a manganese concentration no higher than 0.05 mg/L. Mean blood 

manganese concentrations in the high-concentration group were 8.5±2.3 μg/L compared to the control 

value of 7.7±2.0 μg/L. Performance on motor coordination tests in the ‘high-exposure’ group was no 

different than the performance of the control group. The authors noted that they could not control for the 

ingestion of water from sources other than the wells described. Ingestion of manganese in food is also a 

major contributor, but the authors did not report an estimate of manganese levels ingested from 

foodstuffs. However, these possible confounders were considered negligible because no differences 

between groups were revealed in a risk factor analysis for nutritional factors performed by the authors and 

because manganese concentrations in the blood were not statistically different between the two groups. 

Manganese drinking water levels for the ‘control group’ in this study were within the range of levels 

reported in U.S. drinking water (see Section 6.4.2). As with the report by Kondakis et al. (1989), a 

limitation of this study is the use of a neurological assessment scale for ‘Parkinsonian signs’ rather than 

an evaluation of symptoms associated with manganism, though the authors observed no ‘detectable’ 

neurological impairment. 

Goldsmith et al. (1990) investigated a cluster of Parkinson's disease in the southern region of Israel. They 

reported an increased prevalence of Parkinsonism particularly among those 50–59 years old, which 

suggested early onset of the disease. The authors believed that a potential environmental cause was the 

water source common to residents in the region where the cluster of Parkinson’s disease was observed. 

Although the authors reported that the water samples examined showed a “substantial excess of aluminum 

and a smaller excess of iron and manganese,” the concentrations were not reported. Soil samples were 

reported to contain excess concentrations of manganese as well as beryllium, chromium, europium, and 

ytterbium, though no quantitative values were provided. The residents were connected to a national water 

system, so it could not be determined when the water supply may have become contaminated with excess 

levels of manganese and other metals. Moreover, there was no clear evidence that persons living in the 

region were actually exposed to a contaminated water supply. Although identified as a cluster of 

Parkinson’s disease rather than manganism, the authors suggested that the disease cluster might be related 

to an environmental source. However, the limitations in this study make it difficult to make any clear 

association between chronic oral intake of excess levels of manganese and the prevalence of neurological 

disease. 

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Iwami et al. (1994) studied the metal concentrations in rice, drinking water, and soils in Hohara, a small 

town on the Kii peninsula of Japan. This town reportedly had a high incidence of motor neuron disease. 

The researchers observed that a significantly increased manganese content in local rice and a decreased 

concentration of magnesium in drinking water were positively correlated with the incidence of motor 

neuron disease in Hohara (r2

=0.99). 

Evidence of neurological effects following oral manganese exposure has been noted in case studies of 

adults, as well. For example, in a case report of a man who accidentally ingested low doses of potassium 

permanganate (about 1.8 mg manganese/kg/day) for 4 weeks, the man began to notice weakness and 

impaired mental capacity after several weeks (Holzgraefe et al. 1986). Although exposure was stopped 

after 4 weeks, the authors reported that a syndrome similar to Parkinson's disease developed after about 

9 months. Though suggested by the appearance of a syndrome resembling Parkinsonism, it is difficult to 

prove that these neurological effects were only caused by exposure to the manganese compound. The 

authors speculated that the ingested MnO4

– was reduced to Mn(II) or Mn(III); however, while this would 

be expected, it was not measured. Since MnO4

– is a corrosive agent, it seems likely that it may have 

caused significant injury to the gastrointestinal tract (the patient did experience marked stomach pain), 

perhaps leading to a larger-than-normal gastrointestinal absorption of manganese. 

In another study, Banta and Markesbery (1977) reported on a case involving a 59-year-old man with no 

occupational or environmental exposure to manganese. The man exhibited dementia and neuromuscular 

deficiencies including bradykinesia, shuffling gait, retropulsion, and rigidity in the upper extremities. 

Masked faces with infrequent blinking and stooped posture were also observed. Manganese 

concentrations were significantly elevated in serum, urine, hair, feces, and cerebrum. Although the 

authors posit that the man may have had Alzheimer’s disease as well as manganese toxicity, they question 

how the individual could build up significant body stores of manganese in the absence of occupational 

exposure or any other known source of excess manganese. The authors suggest that the manganese 

overload may have been caused by abuse of vitamins and minerals. 

Several studies have documented the potential for adverse neurological outcomes from childhood 

exposure to manganese-contaminated drinking water and/or food. Two studies (He et al. 1994; Zhang et 

al. 1995) have reported adverse neurological effects in children (aged 11–13) who were exposed to excess 

manganese in well water and in foods fertilized with sewage water. However, these two studies have 

several flaws that preclude their use as substantial support for the link between ingestion of excess 

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MANGANESE 147 

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manganese and the incidence of preclinical neurological effects in children. These studies utilized a 

group of 92 children pair-matched to 92 controls who lived in a nearby region. The pairs were matched 

for age, sex, grade, family income level, and parental education level; in addition, all children lived on 

farms. Although the groups were well matched, the duration and amount of manganese uptake from the 

flour (from wheat fertilized with sewage) and drinking water containing excess levels was not well 

characterized. Moreover, the studies did not indicate if nutritional status, such as low iron or calcium 

intake, which could greatly enhance manganese uptake, were evaluated as potential confounding factors. 

The exposed population drank water with average manganese levels of 0.241 mg/L (He et al. 1994; Zhang 

et al. 1995). The control group drank water containing 0.04 mg manganese/L. These values were 

measured over 3 years, although it was not stated if the children were exposed during the entire 3 years, 

or what the children’s daily manganese intakes were. The exposed children performed significantly more 

poorly (p<0.01) in school and on neurobehavioral exams than control students. School performance was 

measured as mastery of the native language and other subjects; neurobehavioral performance was 

measured using the WHO core test battery. However, the report did not state what measures, if any, were 

taken to ensure that the individuals administering the tests were blind to the exposure status of the subject. 

Such safeguards would be necessary to prevent the introduction of bias in measurement and analysis of 

the performance data of the subjects. The exposed children’s hair, blood, and urine manganese levels 

were significantly increased relative to controls. A simple correlation analysis indicated the performance 

of exposed children on five of the six of the neurobehavioral tests administered (digit span, Santa Ana 

manual dexterity, digit symbol, Benton visual retention test, and pursuit aiming test) was inversely 

correlated with hair manganese levels. Although the authors reported that iron, copper, and zinc were 

measured in blood and hair, no other metals were measured in these tissues. Because the exposed group 

presumably ingested food from sources irrigated with sewage, the children may have been exposed to 

increased levels of other metals, such as lead or mercury. The authors indicate that the children were 

exposed to increased manganese in their diet from excess levels in foodstuffs and drinking water. Of the 

foodstuffs evaluated (cabbage, spinach, potatoes, eggplant, sorghum, and flour), only wheat flour 

contained excess manganese compared to that from the control area. Although the total amount of 

manganese ingested from the wheat flour and drinking water was not estimated, the authors suggest that 

the elevated manganese level in drinking water was the key factor contributing to the observed effects. 

The authors report that children ingesting food and water containing elevated manganese showed poor 

performance in neurobehavioral tests and poorer school performance when compared to children from a 

control area. Because exposure levels and duration were not well defined, these studies as reported are 

not rigorous enough to establish causality between ingestion of excess manganese and preclinical 

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MANGANESE 148 

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neurological effects in children. Nonetheless, these studies are strongly suggestive that subclinical 

neurobehavioral effects often seen in industrial workers exposed to excess manganese via inhalation are 

observed in children. 

In a recent study, a cross-sectional investigation of intellectual function was conducted on 142 10-yearold children in Araihazar, Bangladesh, who had consumed tube-well water with an average concentration 

of 793 μg manganese/L and 3 μg arsenic/L (Wasserman et al. 2006). The children received a medical 

examination and their weight, height, and head circumferences were measured. Intellectual function was 

assessed on tests drawn from the Wechsler Intelligence Scale for Children, version III, by summing 

weighted items across domains to create verbal, performance, and full-scale raw scores (the tests were 

adapted for use in this particular population). Maternal intelligence was assessed with Raven's Standard 

Progressive Matricies, a non-verbal test considered relatively free of cultural influences. Children 

provided urine specimens for measuring urinary arsenic and creatinine and provided blood samples for 

measuring blood lead, arsenic, manganese, and hemoglobin concentrations. To assess the dose-response 

relationship between manganese in well water and intellectual function, children were stratified into four 

approximately equal sized groups, based on well water manganese levels. The results of the intelligence 

tests are displayed in Table 3-4. 

The results indicated that, unadjusted for other contributors, children in group 1 (i.e., those with estimated 

mean dose of 0.006 mg manganese/kg bw/day), when compared with the other three groups, had higher 

full-scale scores; groups 2 (estimated mean dose of 0.02 mg manganese/kg bw/day) and 4 (estimated 

mean dose of 0.07 mg manganese/kg bw/day) were significantly different. The unadjusted result for 

performance scores revealed that group 2 had a significantly lower score than group 1. In the verbal test, 

group 4 had a significantly lower unadjusted score than group 1. 

After adjustment for sociodemographic factors, groups 1 and 4 were significantly different on all three 

tests, with group 4 performing more poorly (Table 3-4). Although groups 2 and 3 (estimated mean dose 

of 0.04 mg manganese/kg bw/day) performed more poorly on average than group 1, the averages from 

groups 2 and 3 were not statistically significantly different from group 1. Therefore, children consuming 

the largest amounts of manganese from well water, estimated to be on average 0.07 mg manganese/kg 

bw/day, did show significant decrements in all forms of intellectual performance tested. 

There are also individual case reports that supply further evidence of potential neurological effects from 

exposure to manganese-contaminated drinking water. Sahni et al. (2007) report a case history of a 

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Table 3-4. Scores on Intelligence Tests 

Quartiles by mean calculated dose of manganese (mg/kg bw/day)a 

Test type 0.006 0.02 0.04 0.07 

Full-scale 81.7±3.1 73.0±4.1 74.0±3.7 60.7±5.2b 

Performance 64.6±2.7 56.4±3.2 56.9±2.8 45.6±4.8b 

Verbal 17.6±0.8 16.6±0.9 17.0±1.0 14.3±1.3b 

a

Adjusted scores by four groups of water manganese for full-scale, performance, and verbal raw scores. In each 

case, adjustments were made for maternal education and intelligence, type of housing, child height, head 

circumference, and access to TV. Scores represent mean ± standard error on the mean.
 b

Adjusted score significantly different from lowest dose group, p<0.05.
 

Source: Wasserman et al. 2006 

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previously healthy Canadian 6-year-old girl who lived with her family in an urban center in Canada. 

Since 2000, the child’s family had spent summers at their nearby cottage, characterized as weekend visits 

in June, followed by full-time residence in July and August. While the municipal water used at the 

primary residence of the family had non-detectable levels of manganese, the cottage well used between 

2000 and 2003 was found to have manganese concentrations of 1.7–2.4 mg/L. A neighboring cottage 

well used in 2004 had 1.7–2.2 mg manganese/L, while spring water used in 2004 had non-detectable 

levels. The child’s estimated intake from well water exposure was 0.103 mg manganese/kg/day. In 2005, 

municipal water was brought to the cottage for drinking, but well water was used for washing and 

cooking. A food history demonstrated that the family consumed more manganese-rich foods, such as 

pineapples and leafy green vegetables, than a typical Canadian family. However, the family was not 

vegetarian. The patient and her 7-year-old, asymptomatic sister had very similar diets, with the exception 

that the sister consumed soy milk due to lactose intolerance. No inhalation exposures to manganese were 

identified. No industrial releases of manganese were reported in the vicinity of either residence. No other 

possible source of manganese involving occupational exposures, hobbies among family members, etc., 

was identified. The patient presented with pica and emotional lability in August 2004. Over the 

following months, she developed progressive behavioral and neurologic symptoms. She became 

withdrawn and less verbal, with stuttered and slurred speech. Her balance, coordination, and fine motor 

skills declined; eventually (in November 2004), she could no longer stand independently, tended to fall 

backward, and demonstrated a high steppage "cock-like" gait. An MRI indicated hyperintensity in the 

basal ganglia, indicative of high manganese accumulation. The patient demonstrated high levels of 

manganese in whole blood (39.7 μg/L). The patient also had severe iron deficiency and polycythemia, 

which was attributed to elevated cobalt. Her blood levels of lead were normal. While her liver 

manganese was elevated, her liver function was normal, as was her blood copper level. Other members of 

the family had elevated blood levels of manganese (1.9–2.8 μg/L) when tested between March and June 

2005. The patient's symptoms abated to a large degree when she was treated with phlebotomies for the 

polycythemia and ethylene-diamine tetraacetic acid chelation for the manganese overload and iron 

therapy. These treatments occurred from November 2004 through July 2005, when her iron 

supplementation stopped. By August 2005, the patient’s condition had deteriorated, with her pica 

returning; she fell frequently and needed assistance where she was previously independent. Phlebotomies 

and oral iron therapy were resumed in October 2005. The authors concluded that a metabolic disorder 

involving divalent metals (manganese, iron, and cobalt) interacting with environmental exposures was the 

most likely explanation for the patient's symptoms. 

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Woolf et al. (2002) describe the case of a 10-year-old boy whose sole source of drinking water at home 

over a 5-year period was from a well on the family's property in a Boston, Massachusetts suburb. The 

well water tested after 5 years of use had a manganese concentration of 1.21 ppm (estimated intake: 

0.06 mg manganese/kg/day). The child had elevated blood levels of manganese (serum concentration of 

0.90 μg/100 mL, compared to reference normal of <0.265 μg/100 mL) and whole-blood manganese 

concentration of 3.82 μg/100 mL (reference normal: <1.4 μg/100 mL). The child’s urinary excretion of 

manganese was found to be 8.5 μg/L over a 24-hour period (reference normal: <1.07 μg/L). Although no 

other member of the family exhibited elevated blood concentrations of manganese, the child and his 

brother each had elevated manganese levels in hair samples (the patient's level was 3,091 ppb; the 

brother's was 1,988 ppb; reference normal: <260 ppb hair). At this time, the family switched to bottled 

drinking water, but continued to use the well water for other purposes (bathing, etc.). The child exhibited 

no evidence of illness or tremors. A detailed neurologic examination was normal. His balance with his 

eyes closed was good, but he did not coordinate rapid alternating motor movement well. His fine motor 

skills were normal and he had no sensory deficits. A battery of neuropsychologic tests revealed that while 

the child's global cognitive skills were intact, he had striking difficulties in both visual and verbal memory 

(14th and 19th percentiles, respectively), suggesting a deficit in free retrieval skills, and had a general 

memory index at the 13th percentile and learning index at the 19th percentile. The child was in 5th grade 

at the time of testing and had no history of learning problems, although teachers had persistently reported 

difficulties with listening skills and following directions. The authors report that the findings from the 

neuropsychological testing are consistent with the toxic effects of manganese, although the authors 

indicate that a causal relationship cannot be inferred in this case. 

Though limited, these case reports also provide further evidence for a link between ingestion of elevated 

levels of manganese and learning problems. Other studies have found that manganese levels in hair are 

higher in learning-disabled children than in normal-functioning children (Collipp et al. 1983; Pihl and 

Parkes 1977). The route of excess exposure is not known, but is presumed to be mainly oral. These 

observations are consistent with the possibility that excess manganese ingestion could lead to learning or 

behavioral impairment in children as suggested by the results of He et al. (1994) and Zhang et al. (1995). 

However, an association of this sort is not sufficient to establish a cause-effect relationship because a 

number of other agents, including lead, might also be involved (Pihl and Parkes 1977). Moreover, other 

potentially confounding factors (e.g., health and nutritional status) must be taken into consideration in 

interpreting such studies. 

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However, a pilot study conducted by Bouchard et al. (2007c) found significant associations between hair 

levels of manganese and certain behavioral end points. The study involved a group of children (24 boys 

and 22 girls) from Quebec, Canada whose homes received drinking water from one of two wells; one well 

provided water with a relatively high level of manganese (610 μg/L; W1) and the second well provided 

water with a much lower level of manganese (160 μg/L; W2). The children, aged 9–13, had estimated 

average exposure levels of 0.02 mg manganese/kg/day (W1) and 0.007 mg manganese/kg/day (W2). The 

children with exposure to water from the high-manganese well had significantly higher (p<0.05) levels of 

manganese in their hair than those children exposed to water from the low-manganese well. Moreover, 

the children with high concentrations of manganese in their hair demonstrated significantly more (p<0.05) 

oppositional behaviors (e.g., breaking rules, getting annoyed or angered) and more hyperactivity than 

children with lower manganese hair concentrations (after adjustment of scores for age, sex, and income). 

No manganese-related differences were observed for tests related to cognitive problems (disorganization, 

slow learning, lack of concentration). Although this report is a pilot study, it nonetheless suggests the 

possibility that exposure to relatively high levels of manganese in water can influence behavior in 

children. 

Several studies report the link between hepatic encephalopathy and an increased manganese body burden 

following chronic liver disease in adults (Hauser et al. 1994; Pomier-Layrargues et al. 1998; Spahr et al. 

1996) and children (Devenyi et al. 1994) and in individuals with surgically-induced portacaval shunts 

(PCS) (Hauser et al. 1994). The manganese exposure in these studies was assumed to originate from a 

normal diet. Hepatic encephalopathy comprises a spectrum of neurological symptoms commonly 

occurring in individuals with chronic liver disease; these symptoms include varying degrees of mental 

dysfunction, although extrapyramidal symptoms may also be identified during a clinical examination 

(Spahr et al. 1996). In the Hauser et al. (1994) study, two men aged 49 and 65 years, both with chronic 

liver disease, and one 56-year-old man with cirrhosis of the liver and a portacaval shunt, showed a variety 

of neurological symptoms including bradykinesia, postural tremor of the upper extremities, and gait 

disturbances, as well as a decrease in cognitive function. These men all had significant elevations 

(p<0.05) in blood manganese as compared to healthy male and female controls, and had hyperintense 

signals in the basal ganglia bilaterally as measured by T1-weighted MRI. Similar elevations of blood 

manganese were reported in a population of 57 cirrhotic patients with an absence of clinical 

encephalopathy (Spahr et al. 1996). Blood manganese was elevated in 67% of the patients and was 

significantly higher in those patients with previous portacaval anastomoses or transjugular intrahepatic 

portosystemic shunt. MRI signal hyper intensity was observed in the globus pallidus; the elevated blood 

manganese levels were significantly correlated with the intensity of the signal in affected patients. 

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Neurological evaluation of extrapyramidal symptoms using the Columbia rating scale indicated a 

significant incidence of tremor, rigidity, or akinesia in ~89% of the patients, although there was no 

significant correlation between blood manganese level and these symptoms. 

Similar results were observed in a young girl with Alagille’s syndrome (involving neonatal cholestasis 

and intrahepatic bile duct paucity) with end-stage cholestatic liver disease who exhibited several 

neurological dysfunctions including dystonia, dysmetria, propulsion, retropulsion, and poor check 

response bilaterally (Devenyi et al. 1994). The girl had elevated blood manganese (27 μg/L compared to 

normal value of ~9.03 μg/L) and exhibited hyperintense MRI signal in the basal ganglia. After a liver 

transplant, the MRI signal abated and the blood manganese level returned to normal. This study and 

those in adults indicate that the increased manganese body burden (as evidenced by increased manganese 

blood and brain levels) may contribute to the resultant neurological symptoms and encephalopathy in 

individuals with cirrhosis or chronic liver disease. 

Rose et al. (1999) evaluated brain manganese levels in 12 autopsied cirrhotic individuals who died from 

hepatic coma and 12 control subjects with no history of hepatic, neurological, or psychiatric disorders at 

time of death. Neutron activation analysis of the brain tissue revealed an increase in manganese content 

in the cirrhotic individuals, particularly in the globus pallidus, which had 186% more manganese than that 

of controls (significant at a level of p<0.001). Significant, although less extreme, increases in manganese 

were also found in the putamen and caudate nucleus from cirrhotic patients. However, the increased brain 

manganese did not correlate with patient age, the etiology of the cirrhosis, or the history of recurrent 

hepatic encephalopathy (reported in 6 patients). 

An association has been suggested between violent behavior and excess manganese exposure; this was 

investigated by measuring the correlation between the manganese content in hair and violent behavior in 

prison subjects and controls (Gottschalk et al. 1991). The prisoners did have significantly higher hair 

manganese content than controls, but further research was indicated to determine whether manganese was 

a causative factor in violent behavior. The highest concentrations of manganese demonstrated in the hair 

samples (1.8–2.5 ppm) were, however, within the control ranges reported by Kondakis et al. (1989) (0– 

13 ppm) and Huang et al. (1989) (0.1–2.2 ppm for scalp and 0.3–9.8 ppm for pubic hair). Another factor 

to be considered in the interpretation of these results is the hair color composition within the samples 

evaluated. At least one study (Cotzias et al. 1964) has reported that manganese content was greater in 

dark hair when compared to that found in lighter colored hair. Another study showed that manganese 

accumulated in melanin-containing tissues including the melanin from human hair (Lydén et al. 1984). In 

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MANGANESE 154 

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their study of inhabitants living in Angurugu on Groote Eylandt, Australia, Stauber et al. (1987) found 

that samples of grey hair from one elderly Aborigine participant had the same manganese content as the 

individual’s black hair. The white hairs of a local dog also had the same manganese content as the dog’s 

black hairs. Based on this evidence, these investigators stated that there was no evidence to support 

previous reports that dark colored hair concentrated more manganese than light hair. The average 

manganese content in scalp hair among male and female Aborigine residents was 3.5–5-fold greater than 

the average scalp hair manganese in male and female Caucasian residents, respectively. The authors 

cautioned that interpretation of data on manganese content in scalp hair should take into consideration 

endogenous as well as potential exogenous sources. Moreover, long-term manganese exposure that may 

be associated with adverse effects may not be represented by manganese content in hair growth from only 

a few months (Stauber et al. 1987). Thus, further investigations are needed to determine whether 

manganese content can vary significantly due to hair color pigment alone. 

Manganese has also been associated with amyotrophic lateral sclerosis (ALS). In a human study, spinal 

cord samples from ALS patients were found to have higher manganese concentrations in the lateral 

fasciculus and anterior horn than in the posterior horn (Kihira et al. 1990). Also, ALS patients exhibited a 

positive correlation between manganese and calcium spinal cord content, whereas controls exhibited a 

negative correlation. It was suggested that an imbalance between manganese and calcium in ALS patients 

plays a role in functional disability and neuronal death. There was also some indication from previous 

studies that an excess intake of manganese in drinking water may have caused this imbalance, although 

data to support this were not presented. While this is suggestive of an association between manganese 

and ALS, it is equally plausible that ALS leads to an imbalance in manganese-calcium metabolism. 

No neuropsychological effects were found in a recent study by Finley et al. (2003) of healthy, 

nonsmoking, premenopausal women were studied in a research project using a crossover design to 

determine the combined effects of very low or high dietary manganese with foods containing either 

saturated or unsaturated fats on measures of neuropsychological and basic metabolic function. Women 

were fed for 8 weeks at one of two doses of manganese (0.01 or 0.3 mg manganese/kg/day), with one-half 

of the subjects receiving 15% energy as cocoa butter and the other half receiving 15% energy as corn oil. 

Blood draws and neuropsychological tests (involving tests of steadiness and ability to control muscular 

tremor, signs of Parkinson's and related neurologic diseases, as well as tests to determine a range of 

components related to hostility and anger) were given at regular intervals during the dietary periods. 

Manganese intake did not affect any neurological measures and only marginally affected psychologic 

variables. 

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There are significantly more studies on the neurological effects of manganese ingestion in animals as 

compared to humans. A few of these report observed effects that were comparable to clinical signs seen 

in people. Gupta et al. (1980) reported that monkeys given 25 mg manganese/kg/day (as manganese 

chloride) for 18 months developed weakness and muscular rigidity (however, no data were provided to 

support these observations). 

Rats dosed with 150 mg manganese/kg/day (as manganese chloride) developed a rigid and unsteady gait 

after 2–3 weeks, but this was a transient condition that was not apparent by 7 weeks (Kristensson et al. 

1986). In addition, in two separate studies, the authors reported a decrease in spontaneous activity, 

alertness, muscle tone, and respiration in mice dosed once with 58 mg manganese/kg/day by gavage 

(Singh and Junnarkar 1991) and staggered gait and histochemical changes in two third-generation mice 

treated with 10.6 mg manganese/kg/day (as manganese chloride) in drinking water (Ishizuka et al. 1991). 

As shown in Table 3-3 and Figure 3-3, changes of this sort have been reported at oral exposure levels that 

ranged from 1 to 2,270 mg manganese/kg/day (as manganese chloride, manganese acetate, or manganese 

tetroxide) (e.g., Bonilla 1978b; Bonilla and Prasad 1984; Chandra 1983; Eriksson et al. 1987a; Gianutsos 

and Murray 1982; Gray and Laskey 1980; Komura and Sakamoto 1991, 1992b; Lai et al. 1984; Nachtman 

et al. 1986; Subhash and Padmashree 1991). Thus, the database on neurological effects in adult animals 

ingesting high levels of manganese does not provide a clear picture of manganese-induced effects and the 

significance of these results is difficult to interpret. 

Rose et al. (1999) reported the effects on manganese body burden (exclusively from the diet) in rats with 

either induced cirrhosis of the liver, acute liver failure (induced by portacaval anastomosis followed by 

hepatic artery ligation), or a surgically-administered portacaval shunt (PCS). Brain manganese levels in 

these three groups of rats were compared to control rats and sham-operated rats. PCS and sham-operated 

rats were evaluated 4 weeks following surgery, while cirrhotic rats were studied 6 weeks following 

surgery. Rats with acute liver failure were studied 15–18 hours following devascularization at coma stage 

of encephalopathy. Manganese levels were statistically significantly increased as compared to nontreated controls and sham-operated controls in both cirrhotic and PCS rats in the frontal cortex, globus 

pallidus, and caudate/putamen; manganese levels were highest in the globus pallidus. For example, in the 

globus pallidus, brain manganese was increased 57% in the PCS rats as compared to the control rats 

(p<0.0001). However, the level of manganese in the globus pallidus in the PCS rats was significantly 

elevated as compared to cirrhotic rats, indicating that shunting is a strong determinant of manganese 

deposition in the brain. 

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Montes et al. (2001) also explored the potential for hepatic disease to potentiate the toxic effects of 

manganese by observing effects on levels of specific neurotransmitters. Groups of male Wistar rats were 

assigned to one of six treatments: (1) sham operated; (2) bile duct ligated (BDL); (3) sham operated with 

15.1 mg manganese/kg/day supplied as manganese chloride in drinking water; (4) BDL with 15.1 mg 

manganese/kg/day in drinking water; (5) sham operated with 26.7 mg manganese/kg/day in drinking 

water; or (6) BDL with 26.7 mg manganese/kg/day in drinking water. The BDL condition models a 

cirrhotic-type condition in the rats. Rats received this treatment for 4 weeks beginning at surgery. At the 

end of treatment, rats were weighed and killed. Total bilirubins (as well as conjugated and unconjugated 

forms) increased over control in all BDL groups, but there was no significant effect of manganese 

treatment. There was also no effect of manganese on alanine aminotransferase levels or on collagen, 

although these measures were significantly increased by BDL. However, the combination of BDL and 

manganese exposure produced 2- and 4-fold increases (p<0.001) of striatal manganese content at the 

15.1 and 26.7 mg manganese/kg/day doses, respectively, while BDL alone did not produce changes. 

Striatal DA content was significantly decreased compared to control in BDL rats; the addition of 26.7 mg 

manganese/kg/day to BDL produced an approximate 33% increase in dopamine (DA) content over BDL 

alone. The highest dose of manganese produced 2-fold striatal homovanillic acid (HVA) increases over 

control in both sham-operated and BDL rats. BDL and manganese treatment at 15.1 mg manganese/ 

kg/day each individually produced 2-fold increases over control levels in striatal DA turnover, measured 

as HVA/DA; the combination of BDL with manganese at 15.1 mg manganese/kg/day produced the same 

result as each condition individually. The sham-operated and BDL high dose rats each had HVA/DA 

levels of nearly 3 times the control level; all of these differences were significant (p<0.05). These results 

suggest that hepatic dysfunction can, indeed, potentiate the neurotoxicity of manganese. 

In another study, Montes et al. (2006) explored the potential role of hepatic dysfunction as a potentiator of 

the toxic effects of manganese on neuronal damage produced by oxidative stress. Groups of male Wistar 

rats were assigned to one of four treatments (n=6–9 in each group): (1) sham operated; (2) BDL; 

(3) sham operated with 26.7 mg manganese/kg/day (as manganese chloride) in drinking water; or 

(4) BDL with 26.7 mg manganese/kg/day in drinking water. Rats received this treatment for 4 weeks 

beginning at time of surgery. Compared with sham-operated controls, BDL treatment with or without 

manganese caused significant (p<0.05) increases (>2-fold) in gamma glutamyltranspeptidase and alanine 

aminotransferase activities, collagen, and glycogen levels, but manganese alone did not increase these 

indices of liver damage. Manganese or BDL treatments alone caused moderate, statistically significant 

(p<0.05) increases (~20%) in manganese content in the striatum and globus pallidus. Manganese contents 

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in both regions were further and markedly increased by the BDL and manganese treatment (300–400% 

increase). Levels of nitric oxide (NO) were not consistently changed in either brain region in manganesealone or BDL plus manganese-treated rats compared with sham-operated controls, with the exception that 

the NO levels in the globus pallidus were decreased (p<0.05) by ~25% in BDL and BDL plus manganese 

rats. Constitutive nitric oxide synthetase (NOS) activities in the globus pallidus were decreased (but not 

to a statistically significant degree) in BDL and BDL plus manganese-treated rats. 

Many studies in animals have explored the interplay between iron deficiency and manganese 

supplementation and its ultimate potential for modulating neurotransmission in the brain. In a study by Li 

et al. (2006) groups of 7–8-week-old male Sprague-Dawley rats were dosed by gavage with sterile saline 

(control) or manganese chloride dissolved in sterile saline at 2.2 or 6.6 mg manganese/kg/day; rats were 

dosed daily for 5 consecutive days/week (weekdays only) for 30 days. The study was conducted to 

determine the mechanism by which iron is regulated at the blood-brain barrier and the bloodcerebrospinal fluid (B-CSF) barrier and how manganese may alter these processes. Serum iron 

concentrations were found to be significantly decreased (p<0.05) at 2.2 and 6.6 mg manganese/kg/day 

(50 and 66% of control value, respectively. In contrast, iron concentrations in the cerebrospinal fluid 

(CSF) were significantly (p<0.05) increased at 2.2 and 6.6 mg manganese/kg/day (136 and 167% of 

control values). Manganese produced a dose-dependent increase of binding of IRP1 to iron-responsive 

element-containing RNA in (percentage increase of high-dose group over control indicated in 

parentheses): the choroid plexus (+70%); in capillaries of striatum (+39%), hippocampus (+56%), and 

frontal cortex (+49%); and in brain parenchyma of striatum (+67%), hippocampus (+39%), and 

cerebellum (+28%). Manganese exposure significantly increased the expression of TfR mRNA in 

choroid plexus and striatum with a reduction in the expression of Ft mRNA. The results indicate that 

intermediate-duration oral exposure to excess manganese decreased serum iron concentrations and 

increased iron concentrations in the CSF. These changes were associated with: (1) increased binding of 

iron regulatory proteins and mRNA containing iron responsive element in several brain regions and 

(2) upregulation of transferritin receptor mRNA and down-regulation of ferritin mRNA in choroid plexus 

and striatum. 

In a recent study by Anderson et al. (2007a), male and female PND 1 Sprague-Dawley rats were divided 

into groups receiving either a control diet (35 mg iron/kg, 10 mg manganese/kg diet and drinking water) 

or a diet with manganese supplementation (same as control diet with 1 g/L of manganese chloride added 

to drinking water for a final dose of 71.1 mg manganese/kg/day). Rats were sacrificed after 6 weeks of 

treatment. Additional females and males (n=6 per group) were provided with an iron-deficient diet 

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(4 mg/kg iron, 10 mg manganese/kg diet and drinking water) and an iron deficient/manganese 

supplemented diet (same iron-deficient diet plus 1 g manganese chloride/L water). Manganese exposure 

significantly (p<0.05) reduced iron concentrations in the caudate putamen and the substantia nigra from 

male and female rats. In female rats, manganese exposure also significantly reduced iron levels in the 

caudate putamen. The largest decrease was seen in the female caudate putamen, where iron levels 

dropped by approximately 66% compared to controls and the female substantia nigra, where iron levels 

dropped by approximately 75% compared to controls. Manganese concentrations in the brain were seen 

to increase over controls most prominently in the female globus pallidus (approximately 60%). A 

significant negative correlation (p<0.05) was observed between synaptosomal manganese concentration 

and 3H-GABA uptake in rats of both sexes. 3H-GABA levels were significantly reduced from controls in 

both males and females (by approximately 50%). In rats provided with an iron-deficient diet, few 

differences were observed between the iron-deficiency condition and the iron-deficiency plus manganese 

condition. In males, iron levels were approximately 10 times higher in the caudate putamen of irondeficient animals than in the animals that were iron-deficient and manganese-supplemented. 

Some studies have explored the relation between high dietary manganese and nitrous oxide synthesis as a 

means of exploring the impact of manganese on oxidative stress and, hence, neuronal injury. 

Liu et al. (2006) studied 12-week-old female C57Bl/6 mice, paired as littermates from timed pregnant 

dams, that received by gavage either water or 43.7 mg manganese/kg/day as manganese chloride for 

8 weeks prior to sacrifice. Manganese-treated mice had significantly (p<0.05) increased levels of 

manganese in the striatum and decreased locomotor activity and striatal dopamine content. Neuronal 

injury in the striatum and globus pallidus was observed, especially in regions proximal to the 

microvasculature. Neuropathological assessment revealed marked perivascular edema, with hypertrophic 

endothelial cells and diffusion of serum albumin into the perivascular space. Immunofluorescence studies 

revealed the presence of apoptotic neurons expressing neuronal NOS choline acetyltransferase, and 

enkephalin in both the striatum and globus pallidus. Soma and terminals of dopaminergic neurons were 

morphologically unaltered in either the substantia nigra or striatum. Regions with neuronal injury 

contained increased numbers of reactive astrocytes that coexpressed inducible NOS2 and localized with 

areas of increased neuronal staining for 3-nitrotyrosine protein adducts, a marker of NO formation. The 

data suggest a possible role for astrocyte-derived NO in injury to striatal-pallidal interneurons from 

manganese intoxication. 

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In a study by Weber et al. (2002), Charles River CD rat pups were dosed (by mouth with micropipette) 

according to average pup weight for each litter starting on PND 1 and continuing until PND 21 at doses of 

0 (nanopure water vehicle), 6.9, or 138 mg manganese/kg/day. Pups were sacrificed on PND 21, and 

samples of cerebellum and cerebral cortex were collected and frozen in liquid nitrogen, with manganese 

concentrations evaluated in brain tissue. Also evaluated were cerebrocortical and cerebellar 

metallothionein (MT) mRNA levels, glutamine synthetase (GS) activity, GS protein levels, and total 

glutathione (GSH) levels. High-dose manganese exposure significantly increased (p<0.05) total 

cerebrocortical GSH when compared to control without changes observed in any of the other measures. 

The same change was apparent with the high-dose manganese exposure on cerebellar GSH, although 

slight differences in the standard error of the mean prevented reaching statistical significance. However, 

it should be noted that these measures actually decreased with respect to the control in the low dose 

manganese group. Overall, data do not appear to support an effect of manganese exposure on measured 

biochemical variables indicative of oxidative stress. 

In a study by Lipe et al. (1999), groups of 30-day-old and 90-day-old male Sprague-Dawley rats were 

exposed to10 or 20 mg manganese/kg/day as manganese chloride for 30 days. A dose-dependent 

decrease in body weight gain was found in the adult, but not the weanling rats. Significant (p<0.05) 

increases were observed in concentrations of aspartate, glutamate, glutamine, taurine, and 

gamma-aminobutyric acid (GABA) in the cerebellum of the adult rats dosed with 20 mg 

manganese/kg/day; this increase also appeared to be dose dependent. A significant (p<0.05) decrease in 

the concentration of glutamine was observed in caudate nucleus and hippocampus of weanling rats dosed 

with 10 mg manganese/kg/day. A significant (p<0.05) increase in GABA concentration in the caudate 

nucleus of weanlings was observed in the 20 mg manganese/kg/day group. A significant (p<0.05) 

decrease in the concentration of glutamine in the caudate nucleus and hippocampus was found in 

weanlings of the 10 mg manganese/kg group. 

In a study by Morello et al. (2007), groups of adult male Wistar rats had free access to either normal 

drinking water or to a water solution providing 611 mg manganese/kg/day as manganese chloride, with 

treatment lasting for 13 weeks. A significant reduction in the number of immunoreactive cells for 

glutamine synthetase was observed in the globus pallidus for manganese-treated animals compared to 

controls (33% reduction). No effect of manganese was observed in the sensorimotor cortex or striatum, 

nor was there any effect observed for other manganoproteins tested. 

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In a study by Ranasinghe et al. (2000), groups of male Sprague-Dawley rats were provided daily 

with 0 (n=2), 74.9 (n=4), or 149.8 mg (n=4) mg manganese/kg/day, administered as manganese sulfate; 

another control group of two rats received 20 mg sodium/day. All animals were treated for 50 days. 

Mean manganese concentrations in liver, brain, heart, and kidney were elevated in the low- and high-dose 

groups, compared with untreated sodium controls, but statistical analyses of these data were not 

performed. A decrease was observed in dopamine serum levels in manganese-treated rats compared to 

controls; the sulfated form was increased in both dose groups compared to controls (12–13 times; from 

0.014 nmol/mL in controls to 0.179 nmol/mL in the 20 mg manganese group). Increases were also 

observed in L-dopa and L-dopa sulfate in both treatment groups. No treatment-related differences were 

observed in serum levels of L-P tyrosine or its L-P tyrosine sulfate. 

In a study by Desole et al. (1997), groups of 3-month-old male Wistar rats were given gavage doses of 

0 or 8.8 mg manganese/kg/day as manganese chloride in water for 6 days. Other groups of control or 

manganese-treated rats received 20 mg/kg buthionine (S,r) sulfoximine0ethyl ester (BSO-E) by 

intraperitoneal injection twice daily (1 hour before gavage treatment) on days 4, 5, 6, and 7. Rats were 

sacrificed on day 7, and brainstem samples were extracted for determination of concentrations of 

dopamine, dihydroxyphenylacetic acid (DOPAC), HVA, and noradrenaline (NA), as well as 

concentrations of reduced glutathione, ascorbic acid, dehydroascorbic acid, and uric acid (the latter being 

indicators of oxidative stress potential). Compared with controls, manganese treatment alone increased 

concentrations of GSH (10–14%) and uric acid (28–45%) in striatum and brainstem, without affecting 

ascorbic acid concentrations, increased concentrations of DOPAC and HVA in striatum, without affecting 

dopamine, and decreased brainstem concentrations of dopamine. As expected, BSO-E treatment alone 

decreased GSH concentrations in striatum (23%) and brainstem (35%), without affecting striatal or 

brainstem concentrations of ascorbic acid, dehydroasocrbic acid, or uric acid or striatal concentrations of 

dopamine, DOPAC, or HVA; however, brainstem concentrations of dopamine were decreased by this 

treatment. Compared with controls, manganese plus BSO-E treatment decreased concentrations of GSH 

and ascorbic acid in striatum (42 and 22%, respectively) and brainstem (23 and 22%, respectively) and 

increased concentrations of dihydroxyascorbic acid and uric acid; these results are indicative of a 

heightened oxidative stress condition. In addition, manganese plus BSO-E treatment decreased striatal 

concentrations of dopamine, DOPAC, and HVA and brainstem concentrations of dopamine and 

noradrenaline. The magnitude of the manganese plus BSO-E treatment changes were mostly larger than 

changes seen in all other experimental groups. The results indicate that the manganese treatment 

decreased brainstem concentrations of dopamine without affecting neurochemical indicators of oxidative 

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stress and that a glutathione depleted condition potentiated the effects of manganese on brainstem and 

striatal concentrations of dopamine, DOPAC, and HVA. 

The effects of manganese on a variety of behavioral assessments in rats have been conducted; these 

studies have found changes in measures related to fear, locomotor activity, and cognitive performance 

(Calabresi et al. 2001; Shukakidze et al. 2003; Torrente et al. 2005; Vezér et al. 2005, 2007). In some of 

these studies, electrophysiological changes in the brain have been associated with the behavioral changes 

(Calabresi et al. 2001; Spadoni et al. 2000; Vezér et al. 2005, 2007). 

Measures of locomotor activity, fear, and learning and memory were made on male Wistar rats treated 

with either tap water as drinking water or a solution of magnesium chloride (1,310 mg manganese/kg/day) 

as drinking water for 10 weeks (Calabresi et al. 2001). Brain manganese levels ranged from 3 to 

approximately 4 times higher than controls. Manganese-treated rats were significantly (p<0.001) more 

active than control rats in the open field. Manganese-treated rats showed progressively and significantly 

more interest in the "novel" object over three trials than the control rats (p<0.001; an average of four 

contacts for manganese-treated animals compared to an average of <2 for controls on the third trial). 

Manganese-treated animals also produced significantly (p<0.05) more fecal boluses (indicative of 

heightened fearfulness) in the open field than control rats over the three trials. No major differences were 

observed between treatment groups in the eight-arm radial maze test, with the manganese-treated animals 

taking significantly (p<0.01) more 45 degree angle turns than the control rats. An enhanced 

dopaminergic inhibitory control of the corticostriatal excitatory transmission via presynaptic D2-like 

dopamine receptors in corticostriatal slices obtained from the manganese-treated rats was observed. The 

use of agonists acting on presynaptic purinergic, muscarinic, and glutamatergic metabotropic receptors 

revealed normal sensitivity. Membrane responses recorded from single dopaminergic neurons following 

activation of D2 dopamine autoreceptors were also unchanged following manganese intoxication. The 

authors suggest that the behavioral symptoms described in the "early" clinical phase of manganism may 

be produced by an abnormal dopaminergic inhibitory control on corticostriatal inputs (Calabresi et al. 

2001). 

Spadoni et al. (2000) studied groups of male, PND 20 Wistar rats provided with either access to drinking 

water or 3311 mg manganese/kg/day in drinking water, with treatment lasting for 13 weeks. No neuronal 

loss or gliosis was detected in the globus pallidus with either treatment. However, the majority of GP 

neurons from manganese-treated rats died following brief incubation in standard dissociation media. 

Patch-clamp recordings in the whole-cell configuration were not tolerated by surviving GP neurons from 

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manganese-treated rats. Manganese-treated GP cells, but not striatal cells, demonstrated an unusual 

response to glutamate, since repeated applications appeared to produce irreversible cell damage. 

Another factor that could potentiate the neurotoxicity of manganese was explored by Torrente et al. 

(2005), with rats subjected to restraint stress along with manganese exposure. Groups of 15 adult male 

Sprague-Dawley rats (250–300 g) were dosed for 2 weeks with either plain drinking water or drinking 

water providing 38.2 mg manganese/kg/day as manganese chloride. The manganese chloride group was 

then split into two groups, with drinking water doses of 76 and 153 mg manganese/kg/day provided for 

another 19 weeks. One-half of the animals in each group were subjected to restraint stress for 2 hours 

daily by placing them in metacrilate cylindrical holders. Animals treated with 153 mg manganese/kg/day 

with restraint traveled a significantly shorter distance than control restraint animals (38% decrease; 

p<0.05). Manganese concentrations in brain and cerebellum were significantly elevated in exposed 

groups, compared with controls. Body weight and food consumption were significantly decreased 

(p<0.05) in the exposed groups, compared with control values. Terminal body weights were 86 and 51% 

of control values in the low- and high-dose unrestrained groups and 90 and 56% in the respective 

restrained groups. Open field activity was significantly decreased (p<0.05) in the high-dose restrained 

groups. Spatial learning was also impaired in high-dose rats with or without restraint); for example, 

unrestrained high-dose rats showed significantly (p<0.05) increased latency to find a hidden platform in 

the water maze test on days 1, 2, 3, 4, and 5 of testing. 

In a study by Shukakidze et al. (2003), groups of white rats were tested for cognitive performance in a 

multipath maze. Group I served as a control group, which was trained in the maze for 10 days, fed 

normal feed for 30 days, and then retested. Groups II and III, instead of receiving normal feed, received 

dosed feed at 5.6 or 13.9 mg manganese/kg/day (as manganese chloride). Groups IV and V were dosed 

the same doses as Groups II and III, respectively, but received the doses for 30 days prior to maze 

training. Groups II and III received normal feed for the next 90 days prior to retesting for 10 days. An 

additional group of animals received a single dose (undefined route) prior to 10 days of training in the 

maze. Both groups of rats dosed after training (Groups II and III) showed moderate disruption of their 

acquired skill in the maze compared to controls. Group III also demonstrated increased "aggressivity". 

Both groups that were exposed prior to training (Groups IV and V) were entirely unable to learn the 

maze. When these rats were reassessed after a 3-month period without excess manganese, they remained 

unable to learn the maze. After training, 8/12 rats in the group with the single dose (Group VI) mastered 

the maze; 4/12 required assistance from the experimenter to orient themselves. Groups of 9 (control) and 

10 (manganese-treated) rats were tested in an active avoidance of conditioned and unconditioned stimuli 

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paradigm. Manganese-treated rats received by mouth 13.9 mg manganese/kg/day (as manganese 

chloride) in water 1 hour prior to the experiment on day 1. Rats were tested over 16–17 days. Manganese 

treatment resulted in significant and reversible behavioral change, with manganese exposure leading to 

worsened acquisition of the avoidance reaction in response to unconditioned and conditioned stimuli, 

increased latent period of conditioned reflex activity, and increased numbers of errors and time taken to 

navigate a maze, beginning on day 5 of the experimental period and lasting until day 10–15, depending on 

the end point. 

Tran et al. (2002b) studied Sprague-Dawley rat pups that received dietary supplementation in the form of 

0, 0.7, 3.8, or 7.5 mg manganese/kg/day (as manganese chloride). Male and female pups were sacrificed 

during infancy and at weaning (18–24 per treatment group) for tissue analyses of trace elements. Twentyfour rats were sacrificed at PND 35 for dopamine analysis (Tran et al. 2002a). The 32 remaining rats, all 

males, no longer received treatment. Behavioral testing began with a burrowing detour test (PNDs 50– 

56) and ended with a passive avoidance test (PNDs 60–64). No statistically significant results for any 

individual treatment group for any behavioral task or striatal dopamine levels. A statistically significant 

positive trend was observed for passive avoidance (approximately 50% more footshocks in highest dose 

group compared with control). The control had approximately 2 times the striatal dopamine levels of the 

two highest dose groups on animals sacrificed on PND 65. Striatal dopamine increase observed in Tran et 

al. (2002a) at an earlier timepoint (PND 40). 

Vezér et al. (2005, 2007) examined neurobehavioral end points in young adult male Wistar rats treated by 

water gavage with 0, 6.5, or 25.9 mg manganese/kg/day for 10 weeks. Rats were tested in an eight-arm 

radial maze test (spatial learning and memory test) and an open field test (locomotor ability). Rats were 

also tested for amphetamine-induced locomotor activity, acoustic startle response, and prepulse inhibition. 

At 5 and 10 weeks of treatment, as well as at the end of the post-treatment period 8 weeks later, 

electrophysiological testing was performed, including recording of cortical evoked potentials as well as 

spontaneous electrical activity in the hippocampus. Immunohistochemistry was performed to detect 

changes in density of glial fibrillary acid protein (GFAP) immunoreactive structures in the hippocampal 

CA1region. Blood and tissue samples (from the cortex and hippocampus) were collected in the 5th and 

10th treatment and 12 post-treatment week. Blood and tissue levels of manganese were determined. 

Manganese accumulation was first seen in blood and then in brain of high-dose rats. Decreased shortand long-term spatial memory performance (at least p<0.05) and decreased spontaneous open field 

activity (p<0.05) were observed in both low- and high-dose groups compared with controls. The number 

of acoustic startle responses, as well as their associated prepulse inhibition of the acoustic startle 

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responses, were decreased in manganese-treated animals. The latency of sensory evoked potentials 

increased and their duration decreased. Manganese levels returned to normal at the end of the posttreatment period, but impairment of long-term spatial memory remained, as well as the decrease in 

number of acoustic startle responses in high-dose rats. Prepulse inhibition responses returned to normal. 

Open field activity returned to normal at the end of post-treatment, but a residual effect could be observed 

under the influence of D-amphetamine. The electrophysiological effects partially returned to normal 

during post-treatment. Significantly (p<0.05) high percentages of area showing GFAP immunoreactivity 

were observed in the dentate gyrus (but not in the striatum radiatum or striatal oriens) in the low- and 

high-dose groups, compared with controls. 

No studies regarding neurological effects following oral exposure to MMT by humans were identified. 

Komura and Sakamoto (1992b) administered 11 mg manganese/kg/day (as MMT) to ddY mice in food 

for 12 months. To measure differences in behavior between exposed and control mice that were fed 

normal chow, spontaneous motor activity was measured at regular intervals during exposure to determine 

differences in behavior between exposed and control mice fed normal chow. The authors observed a 

significant increase in spontaneous activity at day 80; no other significant differences were noted. In a 

separate study (Komura and Sakamoto 1994), the authors analyzed brain levels of different neurotransmitters and metabolites after identical MMT treatment. MMT resulted in a 66% decrease in dopamine 

(DA; p<0.05) and a 95% decrease in normetanephrine (NMN; p<0.01) in the hypothalamus; in the 

hippocampus, DA was unchanged, while the level of 3,4-dihydroxyphenylacetic acid (DOPAC) was 

reduced 41% (p<0.05), and the 3-methoxytyramine (3MT) level increased 3.5-fold (p<0.01). In the 

midbrain, the only significant changes noted were an almost 6-fold increase in 3MT (p<0.01) and a 

1.75-fold increase of homovanillic acid (HVA), a metabolite of DOPAC via conjugation by catechol-omethyl transferase (p<0.05). In the cerebral cortex, HVA was decreased by 61%, norepinephrine (NE) by 

64%, and epinephrine by 43% (all were p<0.05) due to MMT administration. In the cerebellum, DOPAC 

was decreased 51% (p<0.05), while NMN was increased 7.7-fold (p<0.01). Finally, in the medulla 

oblongata, DOPAC was decreased by 45% (p<0.05), HVA was decreased by 55% (p<0.01), and serotonin 

(5HT) was decreased 81% (p<0.01); metanephrine was increased approximately 2.75-fold in the medulla 

(p<0.05). 

Through analysis of the distribution of manganese in the different brain regions of the mice, the authors 

observed relationships between manganese content and neurotransmitter levels. For example, a weak 

relationship was found between the manganese level in the corpus striatum and the level of NE. There 

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was no relationship between the increase in HVA and the manganese levels in this same region. The 

relationship between the increase in 3MT and manganese levels in the midbrain was weak, as was the 

relationship between DOPAC and manganese levels in the cerebellum. There were no relationships 

between amines and manganese levels in the hippocampus, cerebral cortex, or medulla oblongata, 

although some changes were found. A significant correlation was found between the level of NMN and 

manganese in the cerebellum. As discussed more fully in Section 3.4.2, the cerebellum contained the 

most manganese of any brain region following MMT administration (Komura and Sakamoto 1994). 

3.2.2.5 Reproductive Effects 

Potential reproductive effects of manganese were suggested by the results of a study by Hafeman et al. 

(2007), where high infant mortality in a Bangladesh community was reported in conjunction with the 

presence of a local drinking water supply containing high levels of manganese. The Health Effects of 

Arsenic Longitudinal Study (HEALS) was conducted on 11,749 participants 18–70 years of age living in 

Araihazar, Bangladesh. Data on the reproductive history of the 6,707 women in this population were 

collected and samples were taken of drinking water from all of the wells in the study region. Manganese 

concentrations were determined for a total of 1,299 wells, representing the drinking water supply of 

3,824 infants <1 year old. Eight-four percent of infants were exposed, directly or through maternal 

intake, to water manganese levels above 0.4 mg/L with manganese concentrations ranging from 0 to 

8.61 mg/L, for an average calculated daily intake of 0.26 mg manganese/kg/day. Of the 3,837 children 

born to women who reported to drink from the same well for most of their childbearing years, 335 of 

them died before reaching 1 year of age. Infants exposed to greater than or equal to the 0.4 mg/L WHO 

(2004b) standard for manganese in drinking water had an elevated mortality risk during the first year of 

life compared to unexposed infants (OR=1.8; 95% CI, 1.2–2.6). Adjustment for water arsenic indicators 

of social class and other variables and potential confounders did not appreciably alter the results. When 

the population was restricted to infants born to recently married parents (marriage year 1991 or after), the 

elevation was larger (OR=3.4; 95% CI, 1.5–7.9). Although the results of the study suggest that the 

presence of high levels of manganese in the water may be responsible for the high infant mortality 

observed here, information provided by the authors on mechanism of manganese exposure suggests that 

infant exposure to the high levels of manganese in the water may be complex (i.e., would likely require 

direct rather than indirect or fractionated exposure, such as that occurring through breast milk or by 

in utero exposure). The authors also indicate that it is not possible to infer that the manganese is solely 

responsible for the high rate of infant mortality documented in this study 

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In a 14-day study in rats, no changes in testicular weight were reported at 1,300 mg manganese/kg/day 

(NTP 1993). However, several intermediate-duration studies in rats and mice indicate that manganese 

ingestion can lead to delayed maturation of the reproductive system in males. One study investigated the 

effect of 1,050 mg manganese (as manganese tetroxide)/kg/day, provided to weanling mice and their 

dams starting when the pups were 15 days old (Gray and Laskey 1980). On day 30, the mice were 

weaned and maintained on the high-manganese diet until killed for analysis at 58, 73, or 90 days old. The 

growth and general appearance of the weanling rats appeared normal. At time of death, preputial gland, 

seminal vesicle, testes, and body weights were measured. The high-manganese diet resulted in a 

significant decrease in growth of these reproductive tissues but no growth retardation of the body and no 

change in liver or kidney weights. 

A later study by Laskey et al. (1982) evaluated the reproductive functioning of male and female LongEvans rats that had been exposed to 0, 350, 1,050, and 3,500 mg manganese/kg/day (in conjunction with a 

low-iron diet [20 mg iron/kg/day] or a diet adequate in iron [200 mg iron/kg/day]) while in utero (dams 

were fed the described diets during gestation) and from day 14 to 15 postpartum. The rats were 

maintained on the diet throughout the remainder of the study (224 days). The rats were mated at 100 days 

postpartum and the reproductive success of these matings was evaluated. 

In males, manganese treatment resulted in decreased testes weights (testes weights analyzed with body 

weight as a covariable) observed at 40 days (at the 1,050 and 3,500 mg manganese/kg/day dose levels) 

and 100 days (at the 1,050 mg manganese/kg/day dose level) of age, only when administered with the 

low-iron diet. Hormone levels in male rats were also evaluated. No treatment-related effect was seen in 

40-day-old males. At 60 and 100 days of age, however, dose-related decreases in serum testosterone 

were observed, while serum LH (luteinizing hormone) levels remained relatively unchanged. Luteinizing 

hormone (LH) is secreted by the pituitary to stimulate testosterone production in the Leydig cells. 

Testosterone levels control LH production through a negative feedback loop. An increase in testosterone 

would normally be associated with a subsequent decrease in LH. The decrease in testosterone 

simultaneous with a stable LH levels suggests that manganese is targeting the Leydig cells. Manganese 

treatment in both iron regimens prevented the normal decrease in serum follicle-stimulating hormone 

(FSH) from 60 to 100 days. In addition, manganese only negatively affected epididymal sperm counts at 

100 days in the iron-deficient group. When serum concentrations of LH, FSH, and testosterone and 

epididymal sperm counts from the 60- and 100-day-old rats were used to predict the reproductive age of 

the males, the 60-day old animals were predicted correctly. Of the 100-day-old animals, 2/12 controls, 

7/12 at 350 mg manganese/kg, and 12/12 at 1,050 mg manganese/kg were classified as 60 days old. 

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These data indicate that manganese induced a significant maturational delay in the reproductive organs of 

the male rat (Laskey et al. 1982). 

To further assess the mechanism of toxicity of manganese in the pre-weanling rat, Laskey et al. (1985) 

dosed rats from birth to 21 days of age with particulate manganese tetroxide in 50% sucrose solution by 

gavage at doses of 0, 71, or 214 mg manganese/kg/day. They then assessed the hypothalamic, pituitary, 

and testicular functions in the rat by measuring the endogenous or stimulated serum concentrations of 

FSH, LH, and testosterone at 21 or 28 days of age. LH-releasing hormone (LH-RH) was used to 

stimulate the pituitary-testicular axis to secrete FSH, LH, and subsequently testosterone; human chorionic 

gonadotropin (hCG) was used to stimulate acutely (2-hour time period) the testicular secretion of 

testosterone and repeatedly (7-day time period) to assess the ability of the Leydig cells to maintain 

maximal testosterone synthesis and secretion. Some rats from both control and manganese-dosed groups 

were castrated to determine the effect this would have on the study end points. Manganese treatment had 

only a slight effect on body and testes weights, while no effects were observed on unstimulated or 

stimulated FSH or LH serum levels. In addition, manganese did not affect endogenous or acute 

hCG-stimulated serum testosterone concentrations, but did decrease serum testosterone level following 

repeated hCG stimulation. Liver manganese at the 71 mg/kg/day manganese dose was significantly 

elevated over controls in both castrated (8.42±7.23 mg/kg for treated vs. 1.96±0.22 mg/kg for controls) 

and noncastrated (3.36±0.91 mg/kg for treated vs. 1.81±0.11 mg/kg for controls) rats. In addition, 

hypothalamic manganese concentrations were significantly increased at the 71 mg/kg/day dose in both 

castrated (6.10±3.0 mg/kg in treated vs. 0.59±0.11 mg/kg in controls) and noncastrated (3.73±1.18 mg/kg 

in treated vs. 0.65±0.057 mg/kg in controls) rats. The authors speculate that since their earlier results had 

shown changes in male reproductive development in postpubertal animals with minimal manganese 

concentrations in tissues (Gray and Laskey 1980; Laskey et al. 1982), it seemed likely that the changes in 

this later study (Laskey et al. 1985) would result from high manganese concentrations in the 

hypothalamus, pituitary, or testes, with the tissue with the highest manganese concentration being the site 

of the toxic reproductive effect. However, the results from this latest study reveal that manganese had no 

effect on the hypothalamus or pituitary to produce LH or FSH in pre-weanling rats, despite the increased 

manganese concentrations. Rather, the data indicate that it is delayed production of testosterone, shown 

by the inability of the Leydig cells to maintain maximum serum concentrations of the hormone, which 

results in the delayed sexual maturation. This delay in testosterone was not significant enough, however, 

to impair rodent fertility at manganese doses as high as 1,050 mg/kg/day (Laskey et al. 1982). 

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A slight decrease in pregnancy rate was observed in rats exposed to 3,500 mg manganese/kg/day (as 

manganese tetroxide) in the diet for 90–100 days prior to breeding (Laskey et al. 1982). Since both sexes 

were exposed, it is not possible to conclude whether the effect was in males, females, or both. However, 

this exposure regimen did not have significant effects on female reproductive parameters such as ovary 

weight, litter size, ovulations, or resorptions (Laskey et al. 1982). 

Manganese was found to affect sperm formation and male reproductive performance in other 

intermediate-duration oral studies (Elbetieha et al. 2001; Joardar and Sharma 1990; Ponnapakkam et al. 

2003a, 2003c). Joardar and Sharma (1990) administered manganese to mice, as potassium permanganate 

or manganese sulfate, at 23–198 mg/kg/day by gavage for 21 days. The treatment resulted in sperm head 

abnormalities, and the percentage of abnormal sperm was significantly elevated in all exposed mice as 

compared to controls. Increased incidences of testicular degeneration occurred in male Sprague-Dawley 

rats exposed for 63 days to doses ≥137.2 mg manganese/kg/day as manganese acetate, but not at 

68.6 mg/kg/day (Ponnapakkam et al. 2003c). Impaired male fertility was observed in male mice exposed 

to manganese chloride in drinking water for 12 weeks before mating with unexposed females at a daily 

dose level of 309 mg manganese/kg/day, but not at doses ≤154 mg manganese/kg/day (Elbetieha et al. 

2001). In the 309-mg/kg/day group, 17 pregnancies occurred in 28 mated females, compared with 

26 pregnancies out of 28 females mated with controls. At lower dose levels in another study, decreased 

sperm motility and sperm counts were observed in male CD-1 mice after 43 days of exposure to 

manganese acetate at doses of 4.6 or 9.6 mg manganese/kg/day, but these doses did not impair the ability 

of these males to impregnate unexposed females (Ponnapakkam et al. 2003a). 

In another intermediate feeding study, Jarvinen and Ahlström (1975) administered varying doses of 

manganese sulfate, from nutritionally deficient levels to excess amounts, to Sprague-Dawley female rats 

for 8 weeks prior to mating. The rats were continued on manganese diet (0.75, 4.5, 10, 29, 94, or 187 mg 

manganese/kg/day) until GD 21. The authors found no effect of manganese on maternal weight gain, 

implantation number, resorptions, or percentage of dead fetuses. The authors did observe that manganese 

doses of 94 mg manganese/kg/day and higher resulted in significant increases in liver manganese 

concentrations, whereas nonpregnant females had liver manganese concentrations that were unchanged, 

irrespective of dose. These data suggest that pregnancy allows the female to develop significant liver 

manganese stores, and it is possible these stores may be mobilized during gestation or at a future time. 

The authors also noted that pregnant rats had consistent liver iron concentrations, whereas nonpregnant 

rats developed a dose-dependent decrease in liver iron concentrations. Further, the highest dose in dams 

caused a significant increase in fetal manganese content. 

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Szakmáry et al. (1995) studied the reproductive effects of manganese chloride, administered by gavage to 

pregnant rabbits and rats at concentrations of 0, 11, 22, and 33 mg manganese/kg/day on GDs 6–20 in the 

rabbit and throughout gestation in the rat. Manganese did not result in any reproductive effect in the 

rabbit, but the highest manganese dose did cause an increase in postimplantation loss in the rat. In 

13-week dietary studies, no gross or histopathological lesions or organ weight changes were observed in 

reproductive organs of rats fed up to 618 mg manganese/kg/day or mice fed 1,950 mg manganese/kg/day, 

but the reproductive function was not evaluated (NTP 1993). 

More recent oral studies indicate that ingested manganese does not result in female reproductive toxicity 

when rat dams were exposed during pregnancy, but impaired female fertility was observed when female 

mice were exposed to manganese in drinking water for 12 weeks before mating with unexposed males. 

The first study involved a dose of 22 mg manganese/kg/day administered as manganese chloride by 

gavage to female rats on days 6–17 of gestation (Grant et al. 1997a). No treatment-related mortality, 

clinical signs, changes in food or water intake, or body weights were observed in the dams. In the second 

study (Pappas et al. 1997), manganese chloride was provided to pregnant rats in drinking water at doses 

up to 620 mg manganese/kg/day throughout gestation. The manganese did not adversely affect the health 

of the dams, litter size, or sex ratios of the pups. More extensive analyses of female reproductive organs 

were not performed. Similarly, Kontur and Fechter (1985) found no significant effect on litter size in 

female rats exposed to manganese chloride in drinking water except at concentrations so high (1,240 mg 

manganese/kg/day) that water intake by the dams was severely reduced. In contrast, Elbetieha et al. 

(2001) reported that decreased numbers of implantations and viable fetuses were observed in female 

Swiss mice exposed to manganese chloride in drinking water at a dose level of 277 mg manganese/kg/day 

for 12 weeks before mating with unexposed males. 

In a 2-year NTP study, no adverse reproductive effects (lesions in reproductive organs) from manganese 

sulfate exposure were reported for rats at up to 232 mg manganese/kg/day or mice at up to 731 mg 

manganese/kg/day (NTP 1993). 

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects in 

each species and duration category are recorded in Table 3-3 and plotted in Figure 3-3. 

No studies were located regarding reproductive effects in humans or animals following oral exposure to 

MMT. 

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3.2.2.6 Developmental Effects 

Very little information is available on the developmental effects of manganese in humans. The incidences 

of neurological disorders and the incidences of birth defects and stillbirths were elevated in a small 

population of people living on an island where there were rich manganese deposits (Kilburn 1987); 

however, the lack of exposure data, the small sample sizes, and the absence of a suitable control group 

preclude ascribing these effects to manganese. The route of exposure was assumed to be primarily oral, 

but inhalation exposure was not ruled out. 

As discussed in Section 3.2.2.4, two studies have evaluated adverse neurological results in children 

exposed to increased manganese concentrations in both water and food. The first study (He et al. 1994), 

evaluated 92 children, aged 11–13, who drank water containing manganese at average levels of at least 

0.241±0.051 mg/L for 3 years or more and who also ate foodstuffs (wheat flour) with excess manganese 

(due to the high concentration of the metal in sewage water used to irrigate/fertilize the fields). These 

children were compared to 92 children from a nearby village whose manganese concentration in water did 

not exceed 0.040±0.012 mg/L (controls). The children who consumed higher manganese concentrations 

performed more poorly on the WHO neurobehavioral core tests (the emotional status test was omitted) 

than the control children. Further, the blood and hair manganese concentrations of exposed children were 

significantly higher than those of the control population. The negative results on the tests were correlated 

with hair manganese concentration. Zhang et al. (1995) reported that the children with increased 

manganese exposure also performed more poorly in school (as measured by mastery of their native 

language, mathematics, and overall grade average), and their serum levels of serotonin, norepinephrine, 

dopamine, and acetylcholinesterase were significantly decreased compared to controls. In the second 

study, Wasserman et al. (2006) cross-sectionally evaluated intellectual function in 142 10-year old 

children in Bangladesh who had been consuming well water with an average concentration of 793 μg 

manganese/L and 3 μg arsenic/L. Intellectual function was assessed using Weschler’s Intelligence Scale 

for Children, from which raw scores for verbal, performance, and full scale were calculated. After 

grouping children into four groups based on manganese concentrations in the wells (<200, 200–499, 500– 

999, and ≥1,000 μg/L), regression analyses indicated that children in the highest exposure group (with 

estimated daily intakes of 0.07 mg manganese/kg/day in drinking water) had statistically significantly 

lower verbal, performance, and full scale scores compared with children in the lowest exposure group. 

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In animals, classical developmental toxicity studies have not found distinct effects on fetal survival, gross 

fetal malformations, or skeletal or visceral malformations or alterations. For example, acute 

administration of manganese chloride by gavage to pregnant rats at a dose of 22 mg manganese/kg/day on 

GDs 6–17 resulted in no adverse fetal developmental effects, measured as weight gain, gross 

malformations, or skeletal malformations (Grant et al. 1997a). In another study, Szakmáry et al. (1995) 

studied the developmental toxicity of manganese in the rabbit and rat. The metal, as manganese chloride, 

was administered by gavage during the whole period of gestation in the rat, and during organogenesis 

(day 6–20) in the rabbit at concentrations of 0, 11, 22, and 33 mg/kg/day. In the rabbit, manganese 

treatments did not result in decreases in fetal weights, skeletal retardation, or extra ribs, or in an increase 

in fetuses afflicted with major anomalies. In the rat, the highest dose resulted in retardation of 

development of the skeleton and internal organs. In addition, manganese at the highest dose caused a 

significant increase in external malformations, such as clubfoot. However, when pups from dams treated 

at the same dose were allowed to grow for 100 days after birth, no external malformations were observed, 

indicating that these effects were self-corrected. No significant differences were found in any of the 

groups concerning the development of the ears, teeth, eyes, forward motion, clinging ability, body posture 

correction reflex, or negative geotaxis reflex. 

Many developmental toxicity studies in animals orally exposed to excessive manganese have focused on 

possible effects on development of reproduction functions and neurological functions. 

Several animal studies of the effects of manganese on reproductive development show developmental 

effects. 

One study involved pre-weanling mice (Gray and Laskey 1980) that were fed 1,050 mg manganese/ 

kg/day (as manganese tetroxide) beginning on PND 15. On days 58, 73, and 90, mice were sacrificed and 

reproductive organ (preputial gland, seminal vesicle, and testes) weights and body weights were 

measured. The manganese decreased the growth of these reproductive organs, but had no effect on body 

growth or liver or kidney weights. 

In another study, Laskey et al. (1982) evaluated the effect of dietary manganese exposure on rats during 

gestation and continued during nursing and after weaning at doses of 0, 350, 1,050 or 3,500 mg 

manganese/kg/day. The manganese was given in combination with either 20 or 200 mg iron/kg/day (the 

former is deficient in iron, the latter is adequate). Manganese treatment was lethal at the highest dose in 

the iron-deficient diet, but had no effect on male or female body weight at any age in animals receiving an 

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iron-sufficient diet. In the iron-poor diet, body weights of males were significantly depressed (p<0.05) 

through day 100 of the study, whereas the females’ body weights were depressed only through day 60. 

Select females and males were mated at day 90–100 of the study and the reproductive outcomes were 

analyzed. The manganese treatment did not have any significant adverse effects at any dose except to 

significantly decrease the number of pregnancies at the highest dose (p<0.05). Litter size, ovulations, 

resorptions, preimplantation deaths, and fetal weights were unaffected by the metal. Testes weights in 

males were significantly decreased from controls only when administered manganese in conjunction with 

an iron-poor diet: at day 40 at 1,050 and 3,500 mg manganese/kg/day and at day 100 at 1,050 mg/kg/day. 

Hormone levels in male rats were also evaluated. No effect was seen from manganese treatment in 

40-day-old male rats. At 60–100 days of age, however, dose-related decreases in serum testosterone were 

observed, when age-related increases were expected and no increase in serum LH was observed. 

Manganese given in both iron regimens prevented the normal decrease in serum follicle-stimulating 

hormone (FSH) from 60 to 100 days. Manganese decreased epididymal sperm count only when given 

with the iron-poor diet as measured at 100 days. 

A third study involved gavage administration of 0, 71, or 214 mg manganese/kg/day (as manganese 

tetroxide) to pre-weanling rats from birth to 21 days of age (Laskey et al. 1985). Functioning of the 

hypothalamus, pituitary, and testicular tissues were measured by assaying endogenous or stimulated 

serum concentrations of FSH, LH, and testosterone at days 21 or 28. No manganese-related effects were 

observed on unstimulated or stimulated FSH or LH serum levels. In addition, manganese did not affect 

endogenous or acute hCG-stimulated serum testosterone concentrations but did decrease serum 

testosterone level following chronic hCG stimulation. Liver and hypothalamic manganese concentrations 

were significantly increased in treated rats given the 71 mg/kg/day dose over controls. The authors 

hypothesized that the manganese had an unknown affect on the testicular Leydig cell that resulted in the 

delayed production of testosterone. This delayed production was presumably causing the delayed 

reproductive maturation seen in the earlier study (Gray and Laskey 1980), but was not enough to affect 

fertility outcomes at doses as high as 1,050 mg/kg/day (Laskey et al. 1982). 

Many animal studies have examined neurological end points in animals repeatedly exposed during 

gestations and/or neonatal or juvenile stages of life. End points evaluated have included brain chemistry, 

neurobehaviors, and neuropathology. 

Studies of manganese in Rhesus monkeys by Golub et al. (2005) were prompted by the observation that 

soy-based formulas provided to human infants contain relatively high levels of manganese and thus may 

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pose a potentially toxic hazard to early neurological development. Groups of eight male infant Rhesus 

monkeys were fed a commercial cow's milk based formula (Similac containing 50 μg manganese/L as 

control, providing 17.5 mg manganese/kg/day), a commercial soy protein based formula (soy containing 

300 μg manganese/L, providing 107.5 mg manganese/kg/day), or the same soy formula with added 

manganese chloride for a final concentration of 1,000 μg manganese/L (soy plus manganese, providing 

328 mg manganese/kg/day). Formulas were exclusively fed to infants starting on the day of birth and 

extending through 4 months of age, at which time monkeys were transitioned to standard laboratory diet. 

A behavioral test battery was administered over an 18-month period. The battery included measures of 

motor, cognitive, and social skills, as well as tests related to the dopamine system (reward delay, fixed 

interval dopamine drug response). Infants that did not generate sufficient data in each test to permit 

evaluation were excluded from data analyses. Growth and levels of the dopamine metabolite HVA and 

the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) in CSF at 4, 10, and 12 months of age were 

also measured. No significant differences between groups were observed for body weights and levels of 

dopamine and serotonin metabolites in cerebrospinal fluid. 

Monkeys fed soy supplemented with manganese were consistently more active during 12 weekly 

7-minute observation periods, compared with control and soy monkeys. "Motor behaviors" were 

observed in seven of eight soy plus manganese monkeys, compared with three of eight in soy monkeys 

and three of eight in control monkeys. Assessment of gross motor maturation during these observation 

periods did not detect clear differences between the groups. Both soy and soy plus manganese groups 

showed some changes in activity/sleep patterns. Compared with controls at 4 months, the 4-month 

monkeys fed soy plus manganese showed 50% less activity (p<0.05) during the sleep portion of the 

sleep/wake cycle (this change was not seen at 8 months). At 8 months (but not at 4 months), both soy and 

soy plus manganese monkeys showed significantly (p<0.05) longer sleep periods and shorter longest time 

inactive during awake periods than controls. Social interactions were assessed during 16 sessions in 

which each monkey was paired with another monkey in the study. In these sessions, both soy and soy 

plus manganese monkeys demonstrated ~66% less time (p<0.05) in chase or rough play and more time in 

clinging activity compared with control monkeys. 

Significant group differences were not consistently observed in more highly structured tests to assess 

cognitive functions including learning, memory, and attention than controls (p<0.05 for 328 mg 

manganese/kg/day and p<0.01 for 107.5 mg manganese/kg/day). For example, a response latency 

decrease was observed in a reward delay response task in the soy group by 50% compared to control, but 

no significant difference (although a 20% reduction) was observed in the soy plus manganese group. The 

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authors noted that more formal tests of cognitive functions would be most appropriately administered at 

more mature ages. 

Other studies in neonatal animals have detected neurostructural and neurochemical changes at doses 

similar to or slightly above dietary levels (1–10 mg manganese/kg/day) (Chandra and Shukla 1978; 

Deskin et al. 1980), suggesting that young animals might be more susceptible to manganese than adults. 

Kristensson et al. (1986) investigated the developmental effects of manganese chloride on 3-day-old male 

rat pups. The authors dosed the pups with 150 mg manganese/kg/day by gavage in water for 41 days. 

The pups developed a transient ataxia on days 15–22, which was resolved by the end of the dosing period. 

The exposed pups also had increased levels of manganese in the blood and the brain (7–40-fold increase 

in 15- and 20-day-old rats, with cortex and striatum concentrations being relatively equal). In 43-day-old 

rats, the increases in brain manganese levels were less than those observed in younger rats (i.e., 

approximately 3 times the control levels), but the striatal levels were higher than in the cortex. 

Manganese treatment decreased the concentration of homovanillic acid (metabolite of dopamine) in the 

striatum and the hypothalamus, but not in other brain regions. No other monoamines and metabolites 

were affected. In a similar study, neonatal rats given bolus doses of manganese chloride in water of 

0.31 mg manganese/kg/day for 60 days suffered neuronal degeneration and increased brain monoamine 

oxidase on days 15 and 30 of the study, but did not show any clinical or behavioral signs of neurotoxicity 

(Chandra and Shukla 1978). 

Deskin et al. (1980, 1981) also found changes in brain chemistry in rat pups dosed with manganese. In 

the first study, male rat pups were administered 0, 1, 10, or 20 mg manganese/kg/day (as manganese 

chloride) via gavage in 5% sucrose solution for 24 days postnatal. The authors observed that the two 

highest doses resulted in decreased dopamine levels in the hypothalamus, while the highest dose resulted 

in a significant decrease in brain tyrosine hydroxylase activity and a significant increase in monoamine 

oxidase activity in the hypothalamus. Hypothalamic norepinephrine was unaffected by any manganese 

dose, and no significant changes in neurochemistry were noted in the corpus striatum. The authors 

suggested that the observed effects were probably due to decreased activity of tyrosine hydroxylase and 

increased levels of monoamine oxidase. 

The second study (Deskin et al. 1981) involved dosing male rat pups with 0, 10, 15 or 20 mg 

manganese/kg/day (as manganese chloride) via gavage in 5% sucrose solution, for 24 days starting at 

birth. The authors performed neurochemical analyses of hypothalamus and corpus striatum as before and 

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observed that serotonin was increased in the hypothalamus at the highest dose, but was not elevated 

significantly in the striatum. Acetylcholinesterase levels were significantly decreased in the striatum at 

the highest dose, but were unchanged in the hypothalamus. The authors believed that the decrease in 

acetylcholinesterase to be of minor functional significance given that other mechanisms can also regulate 

acetylcholine metabolism. 

Lai et al. (1984) studied the effect of chronic dosing of 40 mg manganese/kg/day (as manganese tetroxide 

given in drinking water) to neonatal rats that were exposed from conception, throughout gestation, and up 

to 2 years of age. The authors found that manganese treatment led to small decreases in choline 

acetyltransferase activities in cerebellum and midbrain of 2-month-old rats. The regional distribution of 

glutamic acid decarboxylase or acetylcholinesterase was unchanged. 

An intermediate drinking water study in pregnant rats (Pappas et al. 1997) investigated the developmental 

neurotoxicity of manganese chloride doses of either 120 or 620 mg manganese/kg/day given on GDs 1– 

21. Following birth, the dams were continued on manganese until weaning at PND 22. When the dams 

were removed, the pups were continued on the same manganese doses until PND 30. Male pups were 

observed on several days subsequent to exposure in a number of behavioral tests that measured 

spontaneous motor activity, memory, and cognitive ability. The manganese-treated rats’ performance 

was not significantly different from control rats. Pups from the highest-dose group exhibited a 

significantly decreased weight gain on several days post-dosing, as well as an increased activity level on 

PND 17 that was no longer evident by PND 30. The high-dose rats were not overactive on other days, 

and the decreased weight gain was resolved by PND 90. Neurochemical analyses of the brains from 

treated pups indicated that brain manganese concentrations were significantly elevated in the high-dose 

group, as compared to controls. Brain enzyme and dopamine concentrations were not significantly 

different between groups, but cortical manganese concentrations were significantly elevated in the highdose group. Cortical thickness was significantly different in several areas of the brains of pups in the 

high-dose group but was only found to be significantly different in one area of the low-dose group. The 

significance of the cortical thinning is not clear. 

While the Szakmáry et al. (1995) and Pappas et al. (1997) studies did not observe any changes in behavior 

due to manganese, many other studies have explored the potential for oral manganese exposure during 

early development to produce effects on later behavior and have frequently observed subtle changes in 

behavior attributable to manganese exposure (Ali et al. 1983a; Kontur and Fechter 1988; Reichel et al. 

2006; Tran et al. 2002a). 

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A study by Kontur and Fechter (1988) reported no difference in levels of monoamines and related 

metabolites in neonatal rats at 22 mg manganese/kg/day as manganese chloride (14–21 days), although 

Dorman et al. (2000) reported elevated striatal DA and DOPAC in 21-day-old rats administered the same 

high daily dose used by Kontur and Fechter (1988) from PND 1 to 21. Effect of manganese treatment on 

neurobehavior was also evaluated in this study. There was a significant decrease in body weight gain in 

pups at the highest manganese exposure dose. Although there were no statistically significant effects on 

motor activity or performance in the passive avoidance task in the neonates, manganese treatment induced 

a significant increase in amplitude of the acoustic startle reflex at PND 21. However, in adult rats, the 

amplitude of the acoustic startle reflex was significantly decreased compared to the control at the lowest 

dose tested. 

Reichel et al. (2006) studied the effects of manganese in male Sprague-Dawley rats that were born and 

dosed daily with an oral dose of 0, 4.4 or 13.1 mg manganese/kg/day as manganese chloride on 

postpartum days 1–21. Locomotor activity was assessed (distance traveled horizontally; PNDs 10–14), as 

was olfactory orientation (PNDs 9–13), negative geotaxis (PNDs 8–12) and balance and coordination 

(PND 90). Day of eye opening, pinna detachment, and incisor eruptions was also evaluated. Mean body 

weights at PND 21 were decreased by about 2 and 3% in the low- and high-dose groups, respectively, 

compared with controls. Manganese concentrations in striatum were elevated in the high dose group, 

compared with control, at PND 14 (~4-fold) and PND 21 (~2-fold), but not at PND 90. Manganese levels 

were not measured in the low-dose group. No exposure-related effects were noted on developmental 

landmarks (eye opening, pinna detachment, incisor eruption), basal motor activity during the neonatal 

period (PNDs 10–14) and adulthood (PND 90), or olfactory discrimination of home cage bedding during 

the neonatal period. The only behavioral end point affected during the neonatal period was a significant 

(p<0.05) increase in mean latencies to rotate 180° on the inclined plane of a negative geotaxis task. At 

PND 90, dopamine transporter binding sites in the striatum were decreased by about 20 and 60% in the 

low- and high-dose groups, respectively; only the high-dose value was significantly different (p<0.05) 

from the control. At PND 90, the locomotor activating effects of 20 mg/kg cocaine were significantly 

(p<0.05) decreased in the neonatally exposed manganese high dose group, compared with controls. The 

results indicate that neonatal exposure of rats to excess manganese caused subtle behavioral effects 

(altered balance in the neonatal period and diminished locomotor response to cocaine in adulthood) and 

neurochemical effects in adulthood (decreased dopamine binding sites in the striatum). 

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In a study by Tran et al. (2002a), Sprague-Dawley PND 1 litters were culled to 10–12 pups per dam and 

then were supplemented from PNDs 1–20 with 0, 0.7, 3.8, or 7.5 mg manganese/kg/day as manganese 

chloride provided by mouth. Male and female pups were used. Righting test (PND 6), homing test 

(olfactory discrimination; PND 10), and passive avoidance (PND 32) were performed. Striatal dopamine 

levels were also determined after sacrifice on PND 40. Tissue analyses (on brain, liver, kidneys, spleen, 

and small intestine) for iron, copper, zinc, and manganese content were performed on animals sacrificed 

on PNDs 14, 21, and 40. Animals were not dosed after PND 20. The two highest dose groups of rats 

took approximately twice as long (2 seconds) as control and 0.7 mg manganese/kg/d (approximately 

1 second) to right themselves; this result was not statistically significant. In the homing test of olfactory 

discrimination, the 7.5 mg manganese/kg/day group took significantly longer to reach their goal 

compared to controls and the 3.8 mg manganese/kg/day group (the 0.7 mg manganese/kg/day group 

performed similarly to the control). The control group required approximately 40 seconds; the high-dose 

group required 75 seconds (an 88% increase in the high-dose group over the control). In the passive 

avoidance task, there was a positive linear trend, with the highest dose group showing a 3-fold increase in 

the number of footshocks received over the control. The 3.8 mg manganese/kg/d group showed a 2-fold 

increase in the number of footshocks over the control. A negative linear relationship was also observed in 

striatal dopamine concentrations, with the high-dose group having approximately half the dopamine 

concentration of the control. No dose-related trends over time points were observed in manganese 

content of tissues. The highest dose group showed some statistically significant (p<0.05) increases in 

manganese in body tissues (brain, small intestine, kidney) at different time points. An increase (p<0.05) 

was observed in the high dose group for iron in the small intestine on PND 40. No changes were seen in 

copper or zinc tissue concentration. Both males and females were used in behavioral tests since 

ANOVAs showed no interactive effects of treatment or sex. 

Ali et al. (1983a) conducted a gestational study investigating the neurological effects of excess 

manganese in drinking water on rats maintained on either a normal or low-protein diet. Manganese 

exposure originated 90 days prior to mating and continued throughout gestation and nursing. The 

offspring of rats who drank the equivalent of 240 mg manganese as manganese chloride/kg/day had pups 

with delayed air righting reflexes. No treatment-related effects were observed in body weight or brain 

weight in pups from dams fed the normal amount of protein. Significant delays in age of eye opening and 

development of auditory startle were observed only in the pups of dams fed protein-deficient diets. In a 

recent study, Dorman et al. (2000) evaluated the effects of oral manganese treatment in neonatal CD rats. 

Pups were administered manganese chloride in water at 11 or 22 mg manganese/kg for 21 days by mouth 

with a micropipette and were dosed starting after birth (PND 1) until weaning (PND 21). At PND 21, the 

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effect of manganese treatment on motor activity, learning and memory (passive avoidance task), evoked 

sensory response (acoustic startle reflex), brain neurochemistry, and brain pathology was evaluated. 

Manganese treatment at the highest dose was associated with decreased body weight gain in pups, 

although the authors indicated that absolute brain weight was not significantly altered. There were no 

statistically significant effects on motor activity or performance in the passive avoidance task. However, 

manganese treatment induced a significant increase in amplitude of the acoustic startle reflex. Significant 

increases in striatal DA and DOPAC concentrations were also observed in the high-dose treated neonates. 

No pathological lesions were observed in the treated pups. The authors indicated that these results 

suggest that neonatal rats are at greater risk than adults for manganese-induced neurotoxicity when 

compared under similar exposure conditions. 

In a longer-duration intermediate study, Jarvinen and Ahlström (1975) fed female rats up to 187 mg 

manganese/kg/day (as manganese sulfate) for 8 weeks prior to conception. The rats were continued on 

manganese treatment until the 21st day of gestation. The unborn pups from dams administered 94 mg 

manganese/kg/day had significantly decreased weights as compared to the other groups. No gross 

malformations were observed in the fetuses, and alizarin-stained bone preparations revealed no 

abnormalities in any dose group. However, fetuses from dams fed the highest manganese dose had 

significantly higher concentrations of manganese in their bodies than fetuses from the other groups. 

These data indicate that a level of 187 mg manganese/kg/day overwhelmed the rat’s homeostatic control 

of manganese and the metal accumulated in the fetus. The highest manganese dose also resulted in a 

significant decrease in the iron content of the fetuses. 

Garcia et al. (2006, 2007) studied the relationship between dietary manganese and dietary iron on brain 

chemistry and neurotransmission. In one study, groups of 5–7 dams were fed diets containing 35 ppm 

iron (control) or 8 mg manganese/kg/day and 35 ppm iron (manganese-supplemented) from GD 7 through 

PND 7 (Garcia et al. 2006). On PND 4, pups born to control dams were pooled and randomly crossfostered to dams fed one of the two diets such that initial mean litter weights were equivalent. Pups were 

exposed to each of these diets via maternal milk from PND 4 to 21 as well as via direct ingestion of chow 

(beginning around PND 11) and were euthanized on PND 21. In the dams, the high manganese diet 

induced changes in hematological parameters similar to those seen with iron-deficiency: 50% decrease in 

plasma iron (without significant decreases in hemoglobin) and increased plasma transferrin and total iron 

binding capacity. Compared with controls, manganese-exposed pups showed decreased hemoglobin 

(about 20%), decreased plasma levels of iron (about 70%), increased plasma tranferrin and total iron 

binding capacity (about 10%), increased brain concentrations of manganese, chromium, and zinc, 

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decreased brain iron levels, increased protein expression of divalent metal transporter-1 (DMT-1) and 

transferrin receptor (TfR) in all brain regions, increased GABA concentrations, and increased ratios of 

GABA to glutamate concentrations. Because GABA is an inhibitory amino acid and glutamate is an 

excitatory amino acid, the authors suggested that the manganese treatment induced enhanced inhibitory 

transmission in the brain of the pups. The results indicate that manganese treatment altered transport and 

distribution of iron in developing rat pups and induced perturbations in brain levels of the 

neurotransmitter, GABA. 

In a further study by Garcia et al. (2007), groups of 5–7 GD7 timed–pregnant Sprague-Dawley rats were 

fed one of three experimental diets: control (35 mg Fe/kg diet; 10 mg manganese/kg diet), low iron (3 mg 

Fe/kg diet; 10 mg manganese/kg diet), or low iron with supplemented manganese (3 mg Fe/kg diet, 

100 mg manganese/kg diet). On PND 4, pups born to the control dams were pooled and randomly 

cross-fostered to dams fed one of the two iron-deficient diets, such that initial mean litter weights were 

approximately equivalent. The pups received these diets via maternal milk from PND 4 to 21, at which 

time the pups were sacrificed. Levels of essential metals in the brain were measured (in cerebellum, 

cortex, hippocampus, striatum, and midbrain) by inductively coupled plasma-mass spectrometry. 

Increases in brain levels in low iron/manganese-treated rats (compared to control and low iron) were seen 

for the following metals: copper, manganese (~50%), chromium (~150%), cobalt (~150%), molybdenum 

(~25%), zinc (~130%), aluminum (~130), and vanadium (~150%). A decrease in brain iron levels was 

observed for low iron animals; low iron/manganese-treated rats had iron levels significantly higher than 

the low iron animals. 

No studies of developmental effects following oral exposure to MMT in humans or animals were located. 

3.2.2.7 Cancer 

No studies were located regarding carcinogenic effects in humans after oral exposure to inorganic 

manganese. 

Chronic (2-year) feeding studies in rats and mice have yielded equivocal evidence for the carcinogenic 

potential of manganese. For example, rats exposed to up to 232 mg manganese/kg/day as manganese 

sulfate for 2 years showed no increases in tumor incidence (NTP 1993). Mice fed up to 731 mg 

manganese/kg/day as manganese sulfate for 2 years had a marginally increased incidence of thyroid gland 

follicular cell adenomas (high-dose animals) and a significantly increased incidence of follicular cell 

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hyperplasia (NTP 1993); this was considered by NTP to be "equivocal evidence of carcinogenic activity 

of Mn(II) sulfate monohydrate in male and female B6C3F1 mice" (there was "no evidence of carcinogenic 

activity" in rats in this study). 

No studies were located regarding carcinogenic effects in humans or animals following oral exposure to 

MMT. 

3.2.3 Dermal Exposure 

For inorganic manganese compounds, dermal exposure is not a typical pathway of exposure because 

manganese does not penetrate the skin readily. For organic manganese, dermal exposure is a possibility 

with all compounds discussed in this profile. This exposure pathway is most likely, however, with MMT, 

where occupational workers (mechanics, workers in the gasoline industry, pesticide manufacturers and 

sprayers) are likely to handle large quantities of these compounds. 

No studies were located regarding the any health effects in humans or animals after dermal exposure to 

inorganic manganese. 

3.2.3.1 Death 

No studies were located regarding death in humans from dermal exposure to MMT. 

Hinderer (1979) reported LD50 values for rabbits (strain and sex were unreported) that were administered 

varying doses of “neat” commercial MMT on abraded skin in the trunk area for 24 hours. These values, 

generated by four different laboratories, ranged from 140 to 795 mg/kg. Although this dose range is 

wide, the author reported that it was analogous to the wide oral LD50 range given for the compound in 

other reports. 

3.2.3.2 Systemic Effects 

Respiratory Effects. No studies were located regarding respiratory effects in humans or animals 

following dermal exposure to MMT. 

Cardiovascular Effects. No studies concerning cardiovascular effects following dermal exposure to 

MMT in humans or animals were located. 

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Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans 

following dermal exposure to MMT. Hinderer (1979) observed bloody diarrhea in rabbits exposed 

dermally to MMT; the compound was obtained as commercial grade, “neat,” and applied to shaved skin 

for 24 hours. No histopathology was performed to ascertain the presence of lesions on the gastrointestinal 

tract. 

Hematological Effects. No studies were located regarding hematological effects in humans or 

animals following dermal exposure to MMT. 

Musculoskeletal Effects. No studies regarding musculoskeletal effects in humans or animals 

following dermal exposure to MMT were located. 

Hepatic Effects. Hinderer (1979) observed that rabbits that underwent dermal application of a 

commercial “neat” solution of MMT for 24 hours on shaved skin had discoloration of the liver and 

swollen liver. No histopathology was performed. 

Renal Effects. Hinderer (1979) observed that rabbits that underwent dermal application of a 

commercial “neat” solution of MMT for 24 hours on shaved skin had discoloration of the kidneys and 

swollen and congested kidneys. No histopathology was performed. 

Endocrine Effects. No studies were located regarding endocrine effects in humans or animals 

following dermal exposure to MMT. 

Dermal Effects. No studies were located regarding dermal effects in humans following dermal 

exposure to MMT. Hinderer (1979) observed that rabbits exposed dermally to commercial “neat” MMT 

on shaved skin for 24 hours developed edema and erythema. Further dermal irritation tests performed 

showed that MMT is a moderate skin irritant. Campbell et al. (1975) exposed male albino rats dermally 

to MMT for 24 hours on closely clipped dorsolateral aspects of the trunk that were either abraded or 

allowed to remain intact; skin reactions were evaluated and scored at 24 hours and again 48 hours later. 

By comparing skin reactions following exposure to a test rating that categorized irritancy levels, MMT 

was determined to be safe for intact or abraded skin contact. However, the authors note that MMT in 

concentrated form is absorbed through the skin, and dermal absorption or interactions with other materials 

or factors were not incorporated into their study. 

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Ocular Effects. No studies were located regarding ocular effects in humans or animals following 

dermal exposure to inorganic manganese. 

Hinderer (1979) performed a standard Draize irritation test with commercial “neat” MMT in rabbits and 

found the compound not to be an eye irritant. 

Body Weight Effects. No studies were located regarding body weight effects in humans or animals 

following dermal exposure to inorganic manganese. 

Rabbits exposed dermally to commercial “neat” MMT exhibited slight body weight loss, although the 

actual amount was not reported (Hinderer 1979). 

Metabolic Effects. No studies were located regarding metabolic effects in humans or animals 

following dermal exposure to inorganic manganese. 

No studies were located regarding metabolic effects in humans or animals following dermal exposure to 

MMT. 

3.2.3.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological and lymphoreticular effects following dermal exposure 

to inorganic manganese in either humans or animals. 

No studies regarding immunological and lymphoreticular effects following dermal exposure to MMT in 

humans or animals were located. 

3.2.3.4 Neurological Effects 

No studies were located regarding neurological effects following dermal exposure to inorganic 

manganese in either humans or animals. 

Rabbits exposed to “neat” commercial grade MMT on shaved areas of their trunks for 24 hours 

experienced the following reported symptoms: polypnea, vocalization, excitation, ataxia, tremors, 

cyanosis, and convulsions (Hinderer 1979). 

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3.2.3.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans or animals following dermal exposure 

to inorganic manganese. 

No studies were located regarding reproductive effects in humans or animals following dermal exposure 

to organic manganese. 

3.2.3.6 Developmental Effects 

No studies were located regarding reproductive effects in humans or animals after dermal exposure to 

inorganic manganese. 

No studies were located in humans or animals concerning developmental effects following dermal 

exposure to MMT. 

3.2.3.7 Cancer 

No studies were located regarding carcinogenic effects in humans or animals after dermal exposure to 

inorganic manganese. 

No studies were located regarding carcinogenic effects in humans or animals after dermal exposure to 

MMT. 

3.2.4 Diagnostic Uses 

Manganese is a paramagnetic element that can contain up to five unpaired electrons in its ionic form. The 

unpaired electrons can facilitate T1 relaxation (in MRI) by interacting with hydrogen nuclei of water 

molecules (Earls and Bluemke 1999). This T1 relaxation provides a contrast in signal during MRI from 

normal cells and tumor cells because normal cells will take up the metal, whereas the cancerous cells take 

up little or no manganese (Toft et al. 1997a). The Mn2+ ion is the ion of choice because it is most readily 

found in the body. However, because increased amounts of other sources of Mn2+, especially manganese 

chloride, were found to have a high acute toxicity (as discussed in the previous sections), it is necessary to 

chelate the Mn2+ ion with another molecule that might decrease the toxic nature of the free ion. One such 

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chelate is the fodipir molecule, or dipyridoxal diphosphate. The result is mangafodipir, Mn(II)-N,N’-dipyridoxylethylendiamino-N,N;-diacetate-5,5'-bis(phosphate), or manganese dipyridoxal diphosphate 

(MnDPDP). This clinical imaging agent is primarily used in the detection of hepatobiliary tumors, as it is 

preferentially taken up by parenchymatous cells. However, as other organs have parenchymatous cells, 

the compound is also useful in the detection of kidney, pancreas, and adrenal gland tumors (Earls and 

Bluemke 1999). 

This section will discuss the adverse effects of administration of mangafodipir. This section will not 

discuss the efficacy of mangafodipir as a contrast agent in the identification of abdominal cancer. 

Because this compound is used primarily in the detection of liver and other parenchymatous tumors, it is 

found exclusively in hospitals and other clinical settings. It is only administered intravenously; therefore, 

all subsequent studies discussed entail an intravenous exposure route. Because the toxicity of 

mangafodipir is mediated by manganese, the doses will be in mg manganese/kg body weight, rather than 

in terms of the parent compound. 

3.2.4.1 Death 

There are no reports of lethality in humans following administration of mangafodipir. 

Administration of mangafodipir can occur either all at once (bolus) or over a specific timed period 

necessary to give the entire amount of a precalculated dose (slow infusion). The latter method has been 

found to be better tolerated in a clinical setting (Bernardino et al. 1992; Lim et al. 1991; Padovani et al. 

1996). 

Mangafodipir was found to cause lethality in both sexes of Swiss-Webster mice with an LD50 of 2,916 mg 

manganese/kg after slow infusion of 15 seconds (Larsen and Grant 1997). The compound had an LD50 of 

103 mg/kg in both sexes of the same rodent when administered in a bolus dose (Larsen and Grant 1997), 

showing the increased toxicity in the bolus administration. When given as a slow infusion over 5 minutes 

in both sexes of the CD-1 mouse, the compound had an LD50 value of 157 mg/kg, and when given at a 

rate of 1.2 mL/second in BOM:NMRI male mice, the LD50 was 211 mg/kg. In another study, the LD50 in 

both sexes of the Swiss-Webster mouse was found to be 290 mg/kg, when given as a slow infusion over 

approximately 2.5 minutes (Elizondo et al. 1991). One male and one female beagle dog given a single 

slow infusion (lasting ~110 seconds) of 160 mg/kg mangafodipir, as well as the one male given 

120 mg/kg, died prior to the second day of the experiment; the remaining female given 120 mg/kg was 

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sacrificed due to a moribund condition on day 3 of the experiment (Larsen and Grant 1997). Dogs of both 

sexes given 83 or 99 mg/kg survived the 14-day observation period. A single slow infusion (lasting 

5 minutes) at a dose of 160 mg/kg did not result in lethality in the Sprague-Dawley rat (Larsen and Grant 

1997). 

Death was not observed in Sprague-Dawley rats administered nine doses of 16 mg manganese/kg/day (as 

mangafodipir) given over 3 weeks (Elizondo et al. 1991; Larsen and Grant 1997). Moribund condition 

prompted the sacrifice of one male and one female beagle dog on days 12 and 21, respectively, of a 

21-day exposure period in which the animals were administered 5.4 mg/kg/day manganese (as 

mangafodipir), whereas a lower dose of 1.6 mg/kg/day did not result in death or sacrifice of any treated 

dogs (Larsen and Grant 1997). Moribund condition also prompted the sacrifice of a single male 

Cynomolgus monkey on day 18 of a mangafodipir-dosing regimen involving 16 mg manganese/kg/day 

doses also given 3 times/week for 3 weeks (Larsen and Grant 1997). The authors did not indicate the 

precise cause of lethality in the sacrificed dogs; however, they noted the dogs’ livers showed histological 

signs of cholangiohepatitis, fibroplasia, bile duct proliferation, and hepatocyte necrosis, with cortical 

tubular necrosis in the kidneys. The sacrificed monkey had a serum chemistry profile indicative of renal 

failure and associated liver toxicity. 

3.2.4.2 Systemic Effects 

Respiratory Effects. No reports were located concerning respiratory effects in humans following 

dosing with mangafodipir. 

A single dose of 160 mg manganese/kg as mangafodipir in Sprague-Dawley rats of both sexes resulted in 

dyspnea (Larsen and Grant 1997). 

Cardiovascular Effects. Mangafodipir, when administered to humans in timed doses in clinical 

studies has resulted in transient facial flushing and increased blood pressure at doses as low as 0.2 mg 

manganese/kg (facial flushing) (Bernardino et al. 1992; Lim et al. 1991; Padovani et al. 1996; Wang et al. 

1997). 

Slow infusion of mangafodipir at doses of 16.5 mg manganese/kg resulted in no cardiotoxicity in mongrel 

dogs of either sex (Karlsson et al. 1997). The dogs suffered from medically-induced acute ischaemic 

heart failure; cardiotoxicity was measured as the depression of cardiovascular function, with specific 

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measured end points being aortic pressure, pulmonary artery pressure, right atrial pressure, cardiac output, 

and heart rate (Karlsson et al. 1997). Sprague-Dawley rats suffered no cardiotoxicity (as measured by 

histomorphological evaluation) after a single administration of mangafodipir at doses as high as 63 mg/kg 

(Larsen and Grant 1997). 

Rats administered nine doses (3 times/week for 3 weeks) of 16 mg manganese/kg did not suffer any 

adverse cardiovascular effects as measured by histomorphological analyses (Larsen and Grant 1997). 

Twenty-one days of daily administration of 5.4 mg manganese/kg in beagle dogs resulted in reduced heart 

rate by the end of the treatment (Larsen and Grant 1997). Cynomolgus monkeys administered 16 mg/kg 

for 3 days/week for 3 weeks resulted in flushing of the face, but no other measured cardiovascular effects 

(Larsen and Grant 1997). 

Gastrointestinal Effects. Incidences of gastrointestinal effects in humans following injection with 

mangafodipir have been limited to rare complaints of nausea or vomiting that are short-lived (15 seconds 

to 5 minutes in length) and not dose- or administration rate-dependent (bolus vs. infusion) (Bernardino et 

al. 1992; Lim et al. 1991; Padovani et al. 1996; Wang et al. 1997). A dose of 81 mg manganese/kg as 

mangafodipir in beagle dogs of both sexes resulted in vomiting, diarrhea, and decreased food 

consumption (Larsen and Grant 1997). 

Vomiting was observed in Cynomolgus monkeys of both sexes after administration of nine doses of 

16 mg manganese/kg, given 3 times/week for 3 weeks (Larsen and Grant 1997). No other gastrointestinal 

effects in animals were reported. 

Hematological Effects. No hematological changes (versus pretreatment values) were noted in three 

different studies that included 13 healthy males (Wang et al. 1997), 54 healthy males (Lim et al. 1991), or 

96 human volunteers of both sexes with known or suspected focal liver tumors (Bernardino et al. 1992) 

administered up to 1.4 mg manganese/kg as mangafodipir (either via bolus or slow infusion). 

A single dose of 63 mg manganese/kg as mangafodipir in both sexes of Sprague-Dawley rats resulted in 

no adverse hematological effects (Larsen and Grant 1997). Intermediate studies of adverse effects were 

also negative. Doses as high as 16 mg/kg given 3 times/week for 3 weeks to Sprague-Dawley rats 

(Elizondo et al. 1991; Larsen and Grant 1997) or Cynomolgus monkeys, or 5.4 mg/kg in beagle dogs 

dosed daily for 21 days, failed to induce any adverse hematological effects (Larsen and Grant 1997). 

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Musculoskeletal Effects. No reports of musculoskeletal effects in humans or animals following 

mangafodipir administration were located. 

Hepatic Effects. Blood chemistry analyses revealed no significant changes in liver enzymes in 

several volunteers, either with or without tumors, given mangafodipir at doses up to 1.4 mg 

manganese/kg (Bernardino et al. 1992; Lim et al. 1991; Wang et al. 1997). Three individuals dosed with 

0.55 mg manganese/kg and one dosed with 1.4 mg/kg had increased serum alanine aminotransferase; 

however, there was no dose response with these results and the maximum increase in the enzyme was to 

70 International Units (IU)/l (the upper limit of the normal range is 45 IU/l) (Lim et al. 1991). 

A single dose of up to 63 mg manganese/kg administered to both sexes of Sprague-Dawley rats did not 

produce any adverse hepatic effects as observed by histomorphological analyses (Larsen and Grant 1997). 

The administration of nine total doses of mangafodipir, three per week, at 16 mg manganese/kg/day per 

dose, resulted in an increased incidence (relative amount unreported) in hepatic microgranulomas in 

female Sprague-Dawley rats, but no effect on liver enzymes as measured by serum chemistry (Elizondo et 

al. 1991; Larsen and Grant 1997). Twenty-one daily doses of 1.6 mg/kg/day resulted in an increase in 

serum enzymes (alanine aminotransferase, ornithine carbamyl transferase, glutamine dehydrogenase, 

alkaline phosphatase, gamma-glutamyl transferase), as well as bilirubin and cholesterol, in both sexes of 

beagle dogs, while a higher dose of 5.5 mg/kg/day resulted in increased liver enzymes and liver weight 

and changes in liver pathology (cholangiohepatitis, fibroplasia, bile duct proliferation, and hepatocyte 

necrosis) (Larsen and Grant 1997). The authors noted that altered serum albumin:globulin ratios and 

increased prothrombin time were indicative of decreased liver protein synthesis. When dogs at this high 

dose were allowed a 4-week recovery period, healing of the liver was observed; specific measures of 

healing were not provided, although resolution of lesions in other affected organs, such as the kidneys, 

was mentioned. The authors also noted that increased serum levels of liver enzymes and decreased liver 

protein synthesis were reversible effects in dogs allowed a recovery period. Doses of 0.54 mg/kg/day did 

not have any effect on the liver (Larsen and Grant 1997). In both sexes of the Cynomolgus monkey, nine 

total doses of 16 mg/kg/day given 3 times/week for 3 weeks, resulted in increases in liver enzymes 

(alanine aminotransferase, gamma-glutamyl transferase), as well as increases in bilirubin and relative 

liver weights in males, and focal hepatitis/cholangiolitis in one male at the end of the dosing period. 

When the monkeys were given a 2-week recovery period following a 3-week administration of the 

highest dose, only one male had a liver lesion, which was in the process of healing. Doses of 

1.6 mg/kg/day in this primate did not cause any adverse hepatic effects (Larsen and Grant 1997). 

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Renal Effects. Administration of mangafodipir at up to 1.4 mg manganese/kg in a few human studies 

has not resulted in any adverse renal effects as measured by blood chemistry or urinalysis (Bernardino et 

al. 1992; Wang et al. 1997). 

Single doses of mangafodipir up to 63 mg manganese/kg given to Sprague-Dawley rats did not cause 

renal effects as measured by blood chemistry, urinalysis, gross necropsy, and histopathology (Larsen and 

Grant 1997). Sprague-Dawley rats of both sexes given nine doses (thrice weekly for 3 weeks) of 

16 mg/kg manganese did not show any adverse renal effects as measured by urinalysis, blood chemistry, 

and histomorphological analysis (Elizondo et al. 1991; Larsen and Grant 1997). Daily administration of 

mangafodipir over 21 days in both sexes of the beagle dog at concentrations up to 6 mg/kg resulted in 

cortical tubular necrosis of the kidneys at this highest dose, as well as decreased glomerular filtration rate, 

as indicated by high serum carbamide and creatinine levels. There were no measurable effects at 

≤1.6 mg/kg (Larsen and Grant 1997). Administration of nine doses of mangafodipir, also given thrice 

weekly for 3 weeks, at individual concentrations of 16 mg manganese/kg to Cynomolgus monkeys of 

both sexes resulted in increased kidney weights and enzymes, as well as creatinine, urea, and other 

inorganic ions. Doses of 1.6 mg/kg over the same time period did not result in any adverse effect (Larsen 

and Grant 1997). 

Endocrine Effects. No studies were located regarding endocrine effects in humans or animals 

following administration of mangafodipir. 

Dermal Effects. No studies were located regarding dermal effects in humans or animals following 

intravenous administration of mangafodipir. 

Ocular Effects. No studies were located concerning ocular effects in humans following 

administration of mangafodipir. 

Cynomolgus monkeys administered nine individual doses at 16 mg/kg over 3 weeks and beagle dogs 

given up to 6 mg/kg daily for 21 days did not have any adverse ocular effects from the mangafodipir 

treatment (Larsen and Grant 1997). 

Body Weight Effects. No reports were located concerning body weight effects in humans following 

mangafodipir dosing. 

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Mice given acute doses of mangafodipir as high as 275 mg manganese/kg and rats administered a dose of 

160 mg/kg did not suffer any body weight effects (Larsen and Grant 1997). 

Rats (Elizondo et al. 1991; Larsen and Grant 1997) and monkeys (Larsen and Grant 1997) administered 

nine doses of mangafodipir over 3 weeks at doses as high as 16 mg manganese/kg did not have any 

treatment-related effects on body weight. Dogs administered 21 daily doses of the compound suffered 

decreased body weight (unspecified decrease) at 5.4 mg/kg, but no effect at 1.6 mg/kg (Larsen and Grant 

1997). There were no significant treatment-related adverse effects on body weight of male and female 

rats or female rabbits used in reproductive studies with mangafodipir (Blazak et al. 1996; Grant et al. 

1997a; Treinen et al. 1995), except for a transient decrease in body weight during weeks 2–5, 9, and 10 in 

male rats administered 6 mg manganese/kg/day for 85 days (Grant et al. 1997a). The authors noted that 

the decrease was significant when compared to controls, but did not report actual data. 

Metabolic Effects. No studies were located regarding metabolic effects in humans or animals 

following administration of mangafodipir. 

3.2.4.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological or lymphoreticular effects in humans following 

exposure to mangafodipir. 

Injection of mangafodipir 3 times/week for 3 weeks in Sprague Dawley rats at doses of 1.6, 6.3, or 16 mg 

manganese/kg resulted in eosinophilia in females only at the highest dose, but had no effect in males. The 

authors stated they are unsure of the clinical importance of this effect as it was only seen at repeated high 

doses (Larsen and Grant 1997). Daily dosing of mangafodipir in beagle dogs of both sexes at doses of 

1.6 mg manganese/kg for 21 days resulted in a decrease in eosinophils and an increase in toxic 

neutrophils (absolute amounts not reported) (Larsen and Grant 1997). A lower dose of 0.54 mg/kg had no 

immunological effect. 

3.2.4.4 Neurological Effects 

No statistically significant increases in adverse neurological effects in humans following mangafodipir 

administration were reported. In one study, four subjects given doses ranging from a low of 0.17 mg/kg 

to a high of 1.4 mg/kg complained of light-headedness or dizziness (Lim et al. 1991). Five of 96 patients 

administered mangafodipir complained of a headache following dosing; only two of these five, given 

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varying doses of mangafodipir ranging from 0.17 to 1.4 mg manganese/kg, could be attributed to the 

contrast agent (Bernardino et al. 1992). No other neurological effects were reported in human studies. 

Single doses of mangafodipir ranging from 8.3 to 275 mg manganese/kg in mice and a single dose of 

160 mg/kg in rats, resulted in decreased activity and abnormal gait and stance (Larsen and Grant 1997). 

Mongrel dogs infused once with mangafodipir at doses of 0.55, 3.3, or 16.5 mg manganese/kg did not 

have any treatment-related changes in plasma catecholamines or physiological signs of sympathetic 

activation as compared to the undosed controls (Karlsson et al. 1997). In a separate study, beagle dogs 

receiving either single doses ranging from 83 to 160 mg/kg or 21 daily doses at 5.4 mg manganese/kg 

suffered decreased appetite as measured by decreased food consumption; when the dogs were allowed a 

recovery period following the repeated dosing, the food consumption normalized within the first 2–3 days 

(Larsen and Grant 1997). 

Rats and monkeys administered nine doses of up to 16 mg/kg each did not have any observable 

neurotoxic effects (Larsen and Grant 1997). 

Grant et al. (1997a) did observe behavioral changes in the pups of Sprague-Dawley dams exposed to 0, 

0.6, 1.1, or 2.2 mg manganese/kg on GDs 6–17. Although no significant effects were observed at the 

lowest dose, the exposed pups suffered a significant decrease in grasp/holding time and a 10–11% 

decrease in body weight at PNDs 4 and 7 at the 1.1 mg/kg dose. At the highest dose, pup weight was 

significantly decreased at PNDs 4, 7, 14, and 21; performance on grasp/holding, negative geotaxis, and 

surface righting tests was also significantly impaired. In addition, postnatal survival was decreased on 

days 0–4 (56 vs. 95.9% in the control group) and 4–21 (78.9 vs. 100% in the control group) at the highest 

dose (Grant et al. 1997a). 

Current studies do not provide evidence on the potential for neurotoxicity following clinical exposure to 

mangafodipir. In general, studies on neurological effects in humans or animals following mangafodipir 

exposure did not involve a long observation period. Because deposition of manganese in the brain can be 

significantly delayed following exposure, it is possible that the studies to date were terminated prior to the 

onset of potential neurotoxicity. However, neurotoxicity in humans or animals has not been reported 

following single exposures to manganese, even at high doses. Studies on toxicokinetics of other 

manganese compounds also indicate that a single exposure is not likely to result in significant 

neurological effects. For further information on distribution, refer to Section 3.4 Toxicokinetics. 

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3.2.4.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans following administration of 

mangafodipir. 

A single dose of 160 mg/kg in male Sprague-Dawley rats resulted in no adverse effects in testes as 

measured by organ weight and histomorphological analysis (Larsen and Grant 1997). 

Male Sprague-Dawley rats dosed nine times in 3 weeks with 16 mg manganese/kg as mangafodipir 

suffered a decrease in absolute testes weights, but no relative decrease in weight and no 

histomorphological effects (Larsen and Grant 1997). 

Injection of pregnant Sprague-Dawley rats with up to 4.4 mg manganese/kg as mangafodipir, on GDs 6– 

8, 9–11, 12–14, or 15–17 (all during organogenesis) resulted in no evidence of reproductive toxicity as 

measured by pregnancy rate, numbers of corpora lutea, implantations or resorptions (Treinen et al. 1995). 

Further, daily intravenous administration of doses up to 2.2 mg manganese/kg throughout GDs 6–17 did 

not result in any significant changes in pregnancy rate, corpora lutea, implantations, or resorptions 

(Treinen et al. 1995). However, Grant et al. (1997a) observed a >50% rate of post-implantation loss in 

pregnant Sprague-Dawley rats administered 2.2 mg manganese/kg as mangafodipir during GDs 6–17. 

Doses of 0.6 and 1.1 mg/kg resulted in postimplantation loss rates that were similar to that of the control 

group. There were no obvious differences in compound administration or animal husbandry between the 

two studies that would indicate why such disparate results would occur. Intravenous dosing of New 

Zealand white rabbits with up to 1.1 mg manganese/kg/day on GDs 6–17 did not cause reproductive 

toxicity in one study (Grant et al. 1997a), but a dose of 3.3 mg manganese/kg/day during GDs 6–18 in the 

same species resulted in a significant increase (3-fold) in post-implantation loss (Blazak et al. 1996). This 

latter dose corresponds to a 12-fold increase over the one-time human clinical dose (Earls and Bluemke 

1999). 

Mangafodipir dosing in female Sprague-Dawley rats for 22 total days, starting prior to conception and 

ending on the 7th day of gestation at a dose of up to 6 mg manganese/kg, did not result in any adverse 

reproductive effects (Grant et al. 1997a). 

Male Sprague-Dawley rats dosed for 84–85 days with 0, 0.6, 2, or 6 mg manganese/kg as mangafodipir 

did not show any signs of reproductive toxicity as measured by histomorphological analyses. Although 

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MANGANESE 192 

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absolute testes weights in the intermediate dose group were reduced compared to controls, relative 

weights were not, and in the absence of histopathological findings, this reduction is not considered an 

adverse effect. The treated rats were bred with females to determine if mangafodipir dosing had any 

effect on fertility. Pregnancy rates, and the number of corpora lutea, implantations, or resorptions were 

unaffected by parental treatment (Grant et al. 1997a). 

3.2.4.6 Developmental Effects 

No studies were located regarding developmental effects in humans following intravenous exposure to 

mangafodipir. 

Treinen et al. (1995) tested the sensitivity of different gestational periods to the administration of 

mangafodipir in Sprague-Dawley rats. Pregnant rats were dosed with 0, 1.1, 2.2, or 4.4 mg manganese/kg 

on 3 consecutive days: GDs 6–8, 9–11, 12–14, or 15–17. The 1.1 mg/kg dose given on days 15–17 

resulted in a significant increase in skeletal malformations in fetuses (10/113 fetuses vs. 0/106 in the 

control group; p<0.05). A higher dose of 2.2 mg/kg also caused a significant increase in malformations 

when given on GDs 12–14 (10 out of 104 fetuses affected) and days 15–17 (21/143) (both p<0.05), and 

the 4.4 mg/kg dose caused increases in malformations when given on days 9–11(5/83), 12–14 (45/128), 

and 15–17 (98/129) (all p<0.05). The malformations seen in this study included angulated or irregularly 

shaped clavicle, femur, fibula, humerus, ilium, radius, tibia, ulna, and/or scapula (Treinen et al. 1995). 

The offspring of Sprague-Dawley rats dosed with 0, 0.1, 0.3, or 1 mg manganese/kg as mangafodipir 

daily throughout GDs 6–17 had a significant increase (p<0.05) in abnormal limb flexures (38/270 fetuses 

affected) and skeletal malformations (141/270 fetuses affected) only at the highest dose (Treinen et al. 

1995). These malformations included the same ones listed for the segmented teratology study above. In 

a separate experiment evaluating the teratology of mangafodipir administration on GDs 6–17 in pregnant 

Sprague-Dawley rats, Treinen et al. (1995) observed a significant increase (p<0.05) in skeletal 

malformations in offspring of rats dosed with 2.2 mg manganese/kg (86/92 fetuses affected) compared to 

controls. In both the segmented and continuous teratology studies, no maternal toxicity was observed. 

Fetuses from Sprague-Dawley females dosed with 0, 0.6, 1.1, or 2.2 mg manganese/kg on GDs 6–17 

exhibited a statistically significant increase in wavy ribs at 0.6 mg/kg (20.5% of the viable fetuses 

impacted vs. 0.7% at the control dose; p<0.05). At the intermediate dose, there was a statistically 

significant increase in the number of fetuses with abnormalities (20 out of 159 viable fetuses) including 

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distortion or misshaping of one or more of the following bones: humerus, radius, ulna, scapula, clavicle, 

femur, tibia, and fibula; in addition, 56.6% of the viable fetuses had wavy ribs and the fetuses weighed 

14% less than controls (p<0.05). At 2.2 mg/kg, there was a significant decrease in fetal viability 

(56% decrease; p<0.05), a greater increase in fetuses with abnormalities (45 out of 64 viable fetuses,) and 

a greater percentage (85.9%) with wavy ribs (Grant et al. 1997a). These effects were observed in the 

absence of maternal toxicity. By contrast, when the mangafodipir was administered for 22 days prior to 

conception and up to GD 7 in the same species at doses of 0, 0.6, 2, and 6 mg manganese/kg/day, no 

adverse effects on the number of viable fetuses, fetal weight, or the number of fetuses with abnormalities 

were reported (Grant et al. 1997a). These teratogenic studies indicate that developmental toxicity 

resulting from mangafodipir dosing is highly dependent on the time-frame of administration. 

Grant et al. (1997a) also observed behavioral changes in the offspring of Sprague-Dawley dams 

administered 0, 0.6, 1.1, or 2.2 mg manganese/kg on GDs 6–17. The exposed pups suffered a significant 

decrease in grasp/holding time and a 10–11% decrease in body weight at PNDs 4 and 7 at the 1.1 mg/kg 

dose, but no significant effects at the lower dose (Grant et al. 1997a). At the highest dose, pup weight 

was significantly decreased at PNDs 4, 7, 14, and 21, and performance on grasp/holding, negative 

geotaxis, and surface righting tests was significantly impaired. In addition, postnatal survival was 

decreased on days 0–4 (56 vs. 95.9% in the control group) and 4–21 (78.9 vs. 100% in the control group) 

at the highest dose (Grant et al. 1997a). These effects occurred at doses that did not cause observable 

maternal toxicity. 

Mangafodipir administration in New Zealand white rabbits at doses of 0, 0.3, 0.55, or 1.1 mg 

manganese/kg on GDs 6–18 resulted in incomplete ossification of the sternebrae at 1.1 mg/kg in one 

study (Grant et al. 1997a), but no significant effects on fetotoxicity or fetal weight; this dose did not result 

in any maternal toxicity. In a separate study, mangafodipir at doses as high as 3.3 mg manganese/kg in 

the same strain of rabbit for the same period of exposure did not result in any significant increases in 

external, skeletal, or visceral malformations in a separate teratology study (Blazak et al. 1996). This dose 

did result in an 11% decrease in fetal weight (although this value was not statistically significant in the 

study, it is considered a significant developmental effect) and a 20% decrease in the number of viable 

fetuses (also not statistically significant). It is not readily apparent why two studies with similar dosing 

regimens would obtain such conflicting results. A comparison between rat and rabbit gestational studies 

indicates that the rabbit is a much less sensitive model for reproductive and developmental toxicity 

induced by mangafodipir. 

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3.3 GENOTOXICITY
 

There is some evidence from a study on occupationally exposed welders that manganese may cause 

chromosomal aberrations; the welders were exposed to other potentially toxic compounds including 

nickel (known to cause chromosomal aberrations) and iron; therefore, the observed increase in 

chromosomal aberrations cannot be attributed solely to manganese (Elias et al. 1989). Mutagenicity 

studies in both bacteria and mammalian strains are equivocal. While manganese sulfate was shown to not 

be mutagenic to Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537 either in the 

presence or absence of S9 from Aroclor 1254-induced liver from rats or Syrian hamsters (Mortelmans et 

al. 1986), it was shown to be mutagenic to strain TA97 elsewhere (Pagano and Zeiger 1992). In yeast 

(Saccharomyces cerevisiae strain D7), a fungal gene conversion/reverse mutation assay indicated that 

manganese sulfate was mutagenic (Singh 1984). Manganese chloride was reportedly not mutagenic in 

S. typhimurium strains TA98, TA100, and TA1535, but it was mutagenic in strain TA1537, and 

conflicting results were obtained for TA102 (De Méo et al. 1991; Wong 1988). 

In vitro assays in mammalian cells also gave conflicting results concerning manganese mutagenicity. 

Manganese chloride produced gene mutations in cultured mouse lymphoma cells (Oberly et al. 1982). 

Manganese chloride caused DNA damage in vitro using human lymphocytes at a concentration of 25 μm 

without metabolic activation, but not at the lower tested concentrations of 15 and 20 μm (Lima et al. 

2008). The compound also caused DNA damage in human lymphocytes using the single-cell gel assay 

technique in the absence of metabolic activation, but caused no DNA damage when S9 was present 

(De Méo et al. 1991). Manganese sulfate induced sister chromatic exchange in Chinese hamster ovary 

(CHO) cells in both the presence and absence of S9 from Aroclor 1254-induced rat liver (Galloway et al. 

1987). In a separate assay, manganese sulfate also induced chromosomal aberrations in CHO cells in the 

absence of S9 but not in its presence (Galloway et al. 1987). Manganese chloride caused chromosome 

aberrations in human lymphocytes without metabolic activation, but only when treated in the G2 phase of 

the cell cycle; treatment in the G1, G1/S, and S1 phases of the cell cycle did not result in chromosome 

aberrations (Lima et al. 2008). The compound was also found to be clastogenic in root tip cells of Vicia 

faba (Glass 1955, 1956), but not in cultured FM3A cells in the absence of metabolic activation (Umeda 

and Nishimura 1979). Potassium permanganate caused chromosomal aberrations in FM3A cells (Umeda 

and Nishimura 1979), but not in a primary culture of cells from Syrian hamster embryos when tested in 

the absence of metabolic activation (Tsuda and Kato 1977). Manganese chloride caused cell 

transformation in Syrian hamster embryo cells (Casto et al. 1979). A list of in vitro study results is given 

in Table 3-5. 

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Table 3-5. Genotoxicity of Manganese In Vitro 

Results 

Species (test 

system) Compound End point Strain 

With 

activation 

Without 

activation Reference 

Inorganic manganese compounds 

Prokaryotic 

organisms: 

Salmonella 

typhimurium 

(plate 

incorporation 

assay) 

MnCl2 Gene mutation TA98 TA 102 

TA1535 

TA1537 

– 

– 

– 

– 

– 

– 

– 

+ 

Wong 1988 

MnSO4 Gene mutation TA98, TA100, 

TA1535, 

TA1537, TA97 

– – Mortelmans 

et al. 1986 

S. typhimurium 

(preincubation 

assay) 

MnSO4 Gene mutation TA97 No data + Pagano and 

Zeiger 1992 

MnCl2 Gene mutation TA102 No data 

+ 

DeMéo et al. 

1991 

TA100 No data DeMéo et al. 

– 1991 

MnCl2 Gene mutation TA102 No data 

+ 

DeMéo et al. 

1991 

TA100 No data DeMéo et al. 

– 1991 

Photobacterium 

fischeri 

(bioluminescence 

test) 

MnCl2 Gene mutation 

(restored 

luminecence) 

Pf-13 (dark 

mutant) 

No data + Ulitzur and 

Barak 1988 

Escherichia coli MnCl2 Gene mutation KMBL 3835 No data + Zakour and 

Glickman 

1984 

Bacteriophage 

(E. coli lysis) 

MnSO4 Gene mutation T4 No data + Orgel and 

Orgel 1965 

Bacillus subtilis 

(recombination 

assay) 

MnCl2 

Mn(NO3)2 

MnSO4 

Mn(CH3C00)2 

KmnO4 

Inhibition of 

growth in 

recombination 

deficient mutant 

(Rec-

) compared 

to wild type 

(Rec+) 

M45 (Rec-) No data 

+ 

+ 

+ 

+ 

– 

Nishioka 

1975 

B. subtilis 

(recombination 

assay) 

MnCl2 

Mn(NO3)2 

Mn(CH3C00)2 

Inhibition of 

growth in 

recombination 

deficient mutant 

M45 (Rec-) No data 

– 

– 

– 

Kanematsu 

et al. 1980 

(Rec-

) compared 

to wild type 

(Rec+) 

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Table 3-5. Genotoxicity of Manganese In Vitro 

Results 

Species (test With Without 

system) Compound End point Strain activation activation Reference 

Eukaryotic organisms: 

Fungi: 

Saccharomeyces MnSO4 Gene D7 No data + Singh 1984 

cervisiae conversion, 

reverse mutation 

Mammalian cells: 

Mouse lymphoma 

cells 

MnCl2 Gene mutation L5178Y TK+/­ No data + Oberly et al. 

1982 

Syrian hamster MnCl2 Enhancement of No data + Casto et al. 

embryo cells SA7 1979 

transformation 

Human MnCl2 DNA damage lymphocyte – + DeMéo et al. 

lymphocytes 1991 

(Single-cell gel 

assay) 

Chinese hamster MnSO4 Chromosomal + + NTP 1993 

ovary cells aberrations/ 

sister chromatid 

exchange 

Human MnCl2 Chromosomal No data + Lima et al. 

lymphocytes aberrations (G2 2008 

phase) 

Human MnCl2 DNA damage No data + Lima et al. 

lymphocytes 2008 

Organic manganese compounds 

Prokaryotic organisms: 

E. coli and S. MnDPDP Gene mutation E. coli: – – Larsen and 

typhimurium WP2uvrA­ Grant 1997 

S. typhimurium: 

TA100, 

TA1535, TA98, 

TA1537 

Eukaryotic organisms: 

CHO cells MnDPDP Forward – – Larsen and 

mutation Grant 1997 

MnDPDP Chromosomal – – Larsen and 

aberration Grant 1997 

– = negative result; + = positive result; ± = weakly positive result; CHO = Chinese hamster ovary;
 

DNA = deoxyribonucleic acid; Mn(CH3COO)2 = manganese acetate; MnCI2 = manganese chloride;
 

MnDPDP = mangafodipir; Mn(NO3)2 = manganese nitrate; MnSO4 = manganese sulfate; Rec = recombination
 

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Manganese chloride did not produce somatic mutations in Drosophila melanogaster fruit flies in one 

study (Rasmuson 1985), and manganese sulfate did not induce sex-linked recessive lethal mutations in 

germ cells of male D. melanogaster (Valencia et al. 1985). 

In vivo assays in mice showed that oral doses of manganese sulfate or potassium permanganate caused 

micronuclei and chromosomal aberrations in bone marrow (Joardar and Sharma 1990). In contrast, oral 

doses of manganese chloride did not cause chromosomal aberrations in the bone marrow or 

spermatogonia of rats (Dikshith and Chandra 1978). A list of in vivo study results is given in Table 3-6. 

The results of in vitro studies show that at least some chemical forms of manganese have mutagenic 

potential. However, as the results of in vivo studies in mammals are inconsistent, no overall conclusion 

can be made about the possible genotoxic hazard to humans from exposure to manganese compounds. 

Genotoxicity data concerning MMT was not available. 

One study was located regarding genotoxic effects in humans following inhalation exposure to 

manganese. In this study, the incidences of chromosomal aberrations in three groups of welders with 

occupational exposures (10–24 years) to metals including manganese, nickel, and chromium were 

examined (Elias et al. 1989). An increase in chromosomal aberrations was found in the group working 

with the metal active gas welding process; however, since their exposures included nickel as well as 

manganese, the authors could not attribute the results to any one metal exposure (nickel is known to cause 

chromosomal aberrations by the inhalation route). The median manganese concentrations during the 

survey were 0.18 mg/m3 for respirable dust and 0.71 mg/m3 for total dust. No information was available 

regarding the genotoxicity of manganese alone. 

No studies were located regarding genotoxic effects in humans after oral exposure to inorganic 

manganese. 

In male Swiss albino mice, manganese sulfate and potassium permanganate have both been found to be 

clastogenic, and their effects were found to be dependent primarily on the concentration (not duration) of 

exposure (Joardar and Sharma 1990). In this in vivo study, oral doses were administered at varying levels 

over a 3-week period. The manganese sulfate doses were 10.25, 20.25, and 61 mg/100 g body weight, 

and the potassium permanganate doses were 6.5, 13, and 38 mg/100 g body weight. Sperm head 

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Table 3-6. Genotoxicity of Manganese In Vivo 

Species (test system) Compound End point Route Results Reference 

Inorganic manganese compounds 

Nonmammalian systems: 

Drosophila MnSO4 Sex-linked Feeding – Valencia et al. 1985 

melanogaster recessive lethal injection 

D.melanogaster MnCl2 Somatic mutation Soaking – Rasmuson 1985 

larvae 

Mammalian systems: 

Albino rat MnCl2 Chromosomal Oral – Dikshith and Chandra 

(bone marrow cells) aberrations 1978 

(spermatogonial cells) 

Albino mouse MnSO4 Chromosomal Oral + Joardar and Sharma 

aberrations 1990 

Albino mouse KMnO4 Chromosomal Oral + Joardar and Sharma 

aberrations 1990 

– = negative result; + = positive result; KMnO4 = potassium permanganate; MnCl2 = manganese chloride; 

MnSO4 = manganese sulfate 

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abnormalities and the frequency of chromosomal aberrations in bone marrow cells and micronuclei were 

significantly increased. In male rats, repeated oral doses of 0.014 mg manganese/kg/day (as manganese 

chloride) for 180 days did not produce any significant chromosomal damage in either bone marrow or 

spermatogonial cells (Dikshith and Chandra 1978). 

No studies were located regarding genotoxic effects in animals after inhalation exposure to inorganic 

manganese. 

No studies were located concerning genotoxic effects in humans or animals following inhalation or 

exposure to MMT. 

3.4 TOXICOKINETICS 

Manganese is required by the body and is found in virtually all diets. As discussed in Chapter 6, adults 

consume between 0.7 and 10.9 mg of manganese per day in the diet, with higher intakes for vegetarians 

who may consume a larger proportion of manganese-rich nuts, grains, and legumes than non-vegetarians 

(WHO 2004b). Manganese intake from drinking water is substantially lower than intake from food. 

Exposure to manganese from air is considered negligible as compared to intake from diet, although 

persons in certain occupations may be exposed to much higher levels than the general public (see 

Section 6.7). 

Even though daily dietary intake of manganese can vary substantially, adult humans generally maintain 

stable tissue levels of manganese through the regulation of gastrointestinal absorption and hepatobiliary 

excretion (Andersen et al. 1999; Aschner and Aschner 2005; Aschner et al. 2005; Roth 2006). Following 

inhalation exposure, manganese can be transported into olfactory or trigeminal presynaptic nerve endings 

in the nasal mucosa with subsequent delivery to the brain, across pulmonary epithelial linings into blood 

or lymph fluids, or across gastrointestinal epithelial linings into blood after mucociliary elevator clearance 

from the respiratory tract (Aschner and Dorman 2006; Dorman et al. 2006a; Roth 2006). Manganese is 

found in the brain and all other mammalian tissues, with some tissues showing higher accumulations of 

manganese than others. For example, liver, pancreas, and kidney usually have higher manganese 

concentrations than other tissues (Dorman et al. 2006a). The principal route of elimination of manganese 

from the body is fecal elimination via hepatobiliary excretion; contributions from pancreatic, urinary, and 

lactational elimination are expected to be small (Dorman et al. 2006a). Excess manganese is expected to 

be eliminated from the body rapidly. For example, following the intravenous bolus injection of 

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manganese chloride in rats, manganese concentrations in plasma return to normal levels within 12 hours 

(Zheng et al. 2000). 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

No studies were located regarding the absolute amount of manganese that is absorbed by humans or 

animals after inhalation exposure to manganese dusts. 

In general, the extent of inhalation absorption is a function of particle size, because size determines the 

extent and location of particle deposition in the respiratory tract. Manganese from smaller particles that 

are deposited in the lower airway is mainly absorbed into blood and lymph fluids, while manganese from 

larger particles or nanosized particles deposited in the nasal mucosa may be directly transported to the 

brain via olfactory or trigeminal nerves. Alternatively, particles deposited in the upper or lower 

respiratory tract may be moved by mucociliary transport to the throat, where they are swallowed and enter 

the stomach. The latter process is thought to account for clearance of a significant fraction of manganesecontaining particles initially deposited in the lung. Thus, manganese may be absorbed in the nasal 

mucosa, in the lung, and in the gastrointestinal tract following inhalation of manganese dust. However, 

the relative amounts absorbed from each site are not accurately known. 

Absorption of manganese deposited in the lung is expected to be higher for soluble forms of manganese 

compared with relatively insoluble forms of manganese (Aschner et al. 2005). Evidence in support of this 

hypothesis comes from studies in which 3-month-old male Sprague-Dawley rats were given intratracheal 

doses (1.22 mg manganese/kg) of relatively soluble (manganese chloride) or insoluble (manganese 

dioxide) forms of manganese (Roels et al. 1997). Peak concentrations of manganese in blood were 

observed earlier after manganese chloride intratracheal administration (0.5 hour) compared with 

manganese dioxide (168 hours after administration). Peak concentration of manganese in blood were 

about 4-fold higher in rats exposed to manganese chloride than in rats exposed to manganese dioxide 

(Roels et al. 1997). Confirmatory evidence has been presented by Dorman et al. (2001a, 2004b). For 

example, rats exposed to manganese sulfate (0.1 mg manganese/m3

, 6 hours/day, 5 days/week for 

13 weeks) showed higher olfactory bulb and striatum manganese concentrations than rats exposed to 

0.1 mg manganese/m3 manganese phosphate (hureaulite) (Dorman et al. 2004b). 

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Results consistent with nasal uptake of manganese and transport to the brain along neuronal tracts have 

been obtained in several animal studies (Brenneman et al. 2000; Dorman et al. 2001a, 2002a; Elder et al. 

2006; Fechter et al. 2002; Henriksson et al. 1999; Lewis et al. 2005; Normandin et al. 2004; Tjälve and 

Henriksson 1999; Tjälve et al. 1996; Vitarella et al. 2000). For example, following intranasal 

administration of 4 μg/kg 54Mn (as manganese chloride) to weanling Sprague-Dawley rats, whole-body 

autoradiography showed that the olfactory bulb contained the vast majority of measured manganese at 1, 

3, and 7 days post-dosing (90, 69, and 47%, respectively) with values decreasing to a low of 16% at 

12 weeks (Tjälve et al. 1996). Significant uptake of manganese by other brain regions was not observed 

until the third day, when the basal forebrain, cerebral cortex, hypothalamus, and striatum had 21, 2, 3, and 

1% of the measured label, respectively (Tjälve et al. 1996). Subsequent experiments with varying doses 

of manganese chloride showed that the uptake of manganese into the olfactory epithelium and the transfer 

to the brain olfactory bulb leveled off at the highest doses, indicating that these are saturable processes 

(Henriksson et al. 1999). Following single, 90-minute, nose-only inhalation exposures of 8-week old 

male CD rats to aerosols of manganese chloride (0.54 mg 54Mn/m3

; Brenneman et al. 2000) or manganese 

phosphate (0.39 mg 54Mn/m3

; Dorman et al. 2002a), peak concentrations of radioactivity in the brain 

olfactory bulb (at 1–3 days after exposure) were about 20- or 4-fold higher, respectively, than peak 

concentrations in the striatum at 21 days after exposure. Results consistent with transport of manganese 

to the brain along olfactory neurons have also been obtained in rats exposed to manganese phosphate 

aerosols in inhalation chambers (0, 0.03, 0.3, or 3 mg manganese/m3

) 6 hours/day for up to 14 days 

(Vitarella et al. 2000). Elevated concentrations of manganese were observed in the olfactory bulb, 

striatum, and cerebellum at the 0.3 and 3 mg manganese/m3 exposure levels, compared with control 

levels, and concentrations in the olfactory bulb were about 1.4–2.4-fold higher than concentrations in the 

striatum (Vitarella et al. 2000). Elevated manganese concentrations were also found in the olfactory bulb, 

striatum, and cerebellum, following 90 days of inhalation chamber exposure (6 hours/day, 5 days/week) 

of young (6 weeks old at start) male or female CD rats or aged (16 months old at start) male CD to 

aerosols of either manganese sulfate or manganese phosphate (“hureaulite”) at an exposure concentration 

of 0.1 mg manganese/m3 (Dorman et al. 2004b). Regardless of age or gender, the olfactory bulb showed 

the highest elevation in manganese concentration, compared with other brain tissues, and concentrations 

in the olfactory bulb were higher in rats exposed to soluble manganese than in rats exposed to relatively 

insoluble manganese phosphate (Dorman et al. 2004a). Following 12 days of inhalation exposure of rats 

to ultrafine manganese oxide particles (30 nm diameter; about 0.5 mg manganese dioxide/m3

), Elder et al. 

(2006) reported that manganese concentrations in the olfactory bulb were increased by 3.5-fold over 

controls, compared with 2-fold increased concentrations in lungs. Lung lavage analysis showed no signs 

of pulmonary inflammation following 11 days of exposure, but several markers of inflammation were 

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noted in the olfactory bulb including increase tumor necrosis factor-α mRNA and protein. Elder (1996) 

argued that these results are consistent with the direct transport of the nanosized particles from the nasal 

mucosa via the olfactory neuronal tract to the olfactory bulb, noting that when the right nares were 

occluded, manganese only accumulated in the left olfactory bulb. 

Elevated concentrations of manganese have also been observed in the trigeminal ganglia of rats and mice 

at 0, 7, and 14 days following nose-only inhalation exposure to aerosols of manganese chloride at a 

concentration of about 2 mg manganese/m3

, 6 hours/day, 5 days/week for 2 weeks (Lewis et al. 2005). 

The latter results are consistent with uptake of manganese in the nasal respiratory epithelium and 

subsequent transport to the brain via trigeminal neurons. In Rhesus monkeys exposed to 1.5 mg 

manganese/m3 manganese sulfate for 65 days, olfactory epithelium, olfactory bulb, and trigeminal nerve 

manganese concentrations were increased by about 17-, 8-, and 2-fold over concentrations in air control 

monkeys (Dorman et al. 2006a). These results are consistent with the hypothesis that the nasal olfactory 

transport route may be more important than the trigeminal neuron transport route in nonhuman primates. 

The relative importance of the nasal route of manganese absorption (and delivery to the brain) in humans 

has not been quantified, but it may be less important in humans than in rats because the olfactory bulb 

accounts for a larger part of the central nervous system and the olfactory epithelium accounts for a larger 

proportion of the nasal mucosa in rats compared with humans (Aschner et al. 2005; Dorman et al. 2002a). 

Using a pharmacokinetic model describing the olfactory transport and blood delivery manganese in rats, 

Leavens et al. (2007) calculated that 21 days or 8 days following acute inhalation exposure of rats to 

54MnCl2 or 54MnHPO4, respectively direct olfactory transport accounted for the majority of label in the 

olfactory bulb, but only a small percentage (≤3%) of the label in the striatum. 

Absorption of manganese deposited in the lung or nasal mucosa of rats is expected to be influenced by 

iron status, with enhanced absorption under iron-deficient conditions and diminished absorption under 

iron-excess conditions. Following intratracheal administration of 54Mn-manganese chloride, 54Mn blood 

concentrations were lower in male Sprague-Dawley rats fed a high-iron diet (about 10,000 ppm Fe), 

compared with concentrations in rats fed a control iron (210 ppm Fe) diet (Thompson et al. 2006). These 

results are consistent with diminished pulmonary absorption of manganese under iron-loaded conditions. 

Supporting this interpretation, 4 hours after 54Mn administration, levels of 54Mn (expressed as a 

percentage of the instilled dose) were higher in the lungs of high-iron rats, compared with control rats, but 

generally lower in other tissues in high-iron versus control rats (Thompson et al. 2006). In rats fed the 

high-iron diet, mRNA levels for divalent metal transporter 1 (DMT1—a transport protein that facilitates 

membrane transport of divalent iron and manganese) were decreased in the bronchus-associated 

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MANGANESE 203 

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lymphatic tissue of high-iron rats, compared with control rats (Thompson et al. 2006). In Belgrade rats, 

homozygous (b/b) for a mutation in DMT1 that impairs transport function and fed 500 ppm Fe in the diet, 

54Mn blood levels following intranasal administrations of 54Mn-manganese chloride were markedly (2– 

5-fold) lower than those in blood of anemic heterozygous (+/b) rats fed a 20 ppm Fe diet (Thompson et al. 

2007). For example, levels of 54Mn remaining in the blood 4 hours after administration were 0.022 and 

0.115% of the instilled dose in the homozygous (b/b) and anemic heterozygous (+/b) rats, respectively (a 

5-fold difference). Intermediate levels of 54Mn in blood were found in heterozygous (+/b) rats fed the 

500 ppm Fe diet (Thompson et al. 2007). In Sprague-Dawley rats, levels of DMT1 protein in the 

olfactory epithelium were 1.5- to 2.5-fold greater under anemic conditions (20 ppm Fe in diet for 

3 weeks), compared with iron-sufficient conditions, 200 ppm Fe in diet for 3 weeks (Thompson et al. 

2007). These results are consistent with the hypothesis that up- and down-regulation of DMT1 plays a 

role in enhanced nasal absorption of manganese under iron-deficient conditions and diminished 

absorption under iron-excess conditions, respectively. 

No studies were located regarding the absorption of organic manganese compounds following inhalation 

exposure in either humans or animals. 

3.4.1.2 Oral Exposure 

The amount of manganese absorbed across the gastrointestinal tract in humans is variable, but typically 

averages about 3–5% (Davidsson et al. 1988, 1989a; Mena et al. 1969). Data were not located on the 

relative absorption fraction for different manganese compounds, but there does not appear to be a marked 

difference between retention of manganese ingested in food (5% at day 10) or water (2.9% at day 10) 

(Davidsson et al. 1988, 1989a; Ruoff 1995). In humans, manganese absorption tends to be greater from 

manganese chloride (in demineralized water) than from foods (labeled intrinsically or extrinsically with 

54Mn); however, the biological half-life of manganese from either manganese chloride or food is the same 

(EPA 1995b; Johnson et al. 1991). In human adults, supplementation of the diet with manganese sulfate 

for 12–35 weeks at a level approximately 2 times the normal dietary intake caused a 30–50% decrease in 

absorption of a tracer dose of 54MnCl2 (Sandstrom et al. 1990). 

Results from animal studies indicate that the gastrointestinal absorption of manganese is rapid and 

expected to be higher for soluble forms of manganese compared with relatively insoluble forms of 

manganese. Following a single gavage dose of 6 mg manganese/kg as manganese chloride to rats, 

maximal plasma concentrations were attained rapidly (Tmax=15 minutes) (Zheng et al. 2000). From 

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analysis of time course of plasma concentrations following oral and intravenous administration, the oral 

bioavailability for manganese was calculated to be 13.9% (Zheng et al. 2000). Roels et al. (1997) noted 

that in 3-month-old male rats, gavage administered manganese chloride (24.3 mg manganese/kg) reached 

a maximal level in blood, 7.05 μg/100 mL, within the first 30 minutes post-dosing (first time point 

measured), whereas manganese from manganese dioxide, administered in the same fashion, did not reach 

a maximal level in blood of 900 ng/100 mL until 144 hours (6 days) post-dosing. Following four weekly 

gavage doses of manganese chloride at 24.3 mg manganese/kg per dose, significant increases in 

manganese concentration were observed in blood and the cerebral cortex, but not cerebellum or striatum, 

as compared to controls; for identical doses of manganese dioxide, manganese levels were significantly 

increased only in blood. The lack of significant increase in manganese levels in any brain region 

following administration of the dioxide is likely due to the delayed uptake of manganese in the blood. 

One study showed that, in full-term infants, manganese is absorbed from breast milk and cow’s milk 

formulas that were either unsupplemented or supplemented with iron, copper, zinc, and iodine (Dorner et 

al. 1989). Manganese intake was greater in the formula-fed infants than in the breast-fed infants due to 

the higher manganese content of the formula. However, breast-fed infants retained more of their daily 

intake of manganese (40%) than did the formula-fed infants (20%). It must be noted that the full-term 

infants evaluated in this study were 2–18 weeks old, and the data did not stratify intake and retention 

amounts by age. Further, the data did not indicate if there were similar proportions of manganese taken 

up from breast milk as compared to the formulas. A study by Davidson and Lönnerdal (1989) 

demonstrated the in vitro receptor-mediated uptake of manganese from lactoferrin; the authors speculated 

that this may lead to the absorption of manganese from breast milk in human infants. 

There is some evidence to suggest that gastrointestinal absorption of manganese is age-dependent. 

Dorner et al. (1989) have shown that infants, especially premature infants, retain a higher proportion of 

manganese than adults. Animal studies also support this finding. For example, Rehnberg et al. (1980, 

1981, 1982) dosed 1-day-old rat pups with up to 214 mg manganese/kg/day (as manganese tetroxide) for 

up to 224 days, then measured manganese concentrations in tissues. The authors noted that intermediate 

and chronic exposure of rats to manganese tetroxide in water or food resulted in much larger increases in 

tissue levels in young rats (1–15 days in intermediate studies, 24–40 days in chronic study) than in older 

rats. These increases in neonates were judged to be due to the neonates' greater absorption of manganese 

as a result of a slower rate of transport through the gut (Rehnberg et al. 1985). Similar results have been 

reported in rats exposed to manganese chloride (Kostial et al. 1978). However, such age-dependent 

differences in tissue retention of manganese could also be due to differences in excretory ability (Cotzias 

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et al. 1976; Miller et al. 1975) or to age-related changes in dietary intake levels of iron and manganese 

(Ballatori et al. 1987). Dorner et al. (1989) found that both pre-term and full-term infants had active 

excretion of manganese; in fact, some infants had negative manganese balances. Animal studies show 

that absorption and/or retention of manganese is higher in neonates, but returns to the level of older 

animals at approximately post-GD 17–18 (Kostial et al. 1978; Lönnerdal et al. 1987; Miller et al. 1975; 

Rehnberg et al. 1981). Available studies (Dorner et al. 1989) do not provide adequate data to determine 

when this transition takes place in human infants. 

One of the key determinants of absorption appears to be dietary iron intake, with low iron levels leading 

to increased manganese absorption. Mena et al. (1969) administered oral 54Mn and 39Fe to subjects with 

iron-deficiency anemia (ranging in age from 13 to 44 years old) and measured manganese and iron uptake 

with whole-body autoradiography. The uptake of manganese by anemic subjects was 7.5% while in nonanemic subjects, it was 3.0%. This is probably because both iron and manganese are absorbed by the 

same transport system in the gut. The activity of this system is inversely regulated by dietary iron and 

manganese intake levels (Chandra and Tandon 1973; Diez-Ewald et al. 1968; Rehnberg et al. 1982; 

Thomson et al. 1971). Interaction between iron and manganese occurs only between nonheme iron and 

manganese. Davis et al. (1992a) demonstrated that increasing dietary intakes of nonheme iron, but not 

heme iron, depressed biomarkers of manganese status (i.e., serum manganese concentrations and 

lymphocyte manganese-dependent superoxide dismutase activity). 

Studies of oral absorption of manganese in animals have yielded results that are generally similar to those 

in humans. Manganese uptake in pigs, which have similar gastrointestinal tracts to humans, has been 

measured using labeled manganese administered orally (Finley et al. 1997). The mean absorption rates 

for different times post-dosing were 5% 1–6 hours post-dosing, 7% 6–12 hours post-dosing, and 3.8% 

12–24 hours post-dosing. Gastrointestinal uptake of manganese chloride in rats has been estimated to be 

2.5–8.2% (Davis et al. 1993; Pollack et al. 1965). Uptake is increased by iron deficiency (Pollack et al. 

1965) and decreased by preexposure to high dietary levels of manganese (Abrams et al. 1976a; Davis et 

al. 1992b). In a rat study, the intestinal transfer of the calcium ion and manganese ion was found to be 

competitive, and the authors suggested that there is a common mechanism for their transfer in the 

intestines (Dupuis et al. 1992). High dietary intakes of phosphorus (Wedekind et al. 1991) and calcium 

(Wilgus and Patton 1939) have also been demonstrated to depress manganese uptake in chicks. 

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Manganese absorption has also been found to vary according to manganese intake; in rats with 

manganese-deficient diets, absorption was at least 2-fold higher than in rats whose diets contained an 

adequate amount of manganese (as manganese carbonate) (Davis et al. 1992b). 

Two studies in suckling rat pups found differing absorptions of manganese from different milks and 

formulas. The first study (Lönnerdal et al. 1987) found that the percent of 54Mn (added to the food source 

as an extrinsic label) retained (measured as whole-body retention) in 14-day-old pups fed breast milk, 

cow milk, cow milk formula, and soy formula, was 82, 90, 77, and 65%, respectively. 

The latter study (Lönnerdal et al. 1994) found that 13-day-old rat pups fed 54Mn (from manganese 

chloride that was incubated with the food for at least 24 hours prior to feeding) in breast milk, cow milk, 

and several different manufacturers’ cow milk formulas had similar absorption values. These pups 

absorbed (measured as whole-body retention) 80% of the label from breast milk, 83% from cow milk, and 

63–90% from the cow milk formulas, with the two lowest retention values being significantly lower than 

the others. In this latter study, manganese absorption from soy formulas was significantly lower than the 

other milks and formulas tested, ranging from 63 to 72%. 

The inherent concentration of manganese in each of these food sources from the first study was 0.01, 

0.04, 0.05, and 0.30 μg/mL, respectively (Lönnerdal et al. 1987). Therefore, when the retention of the 

label was multiplied by the actual manganese concentration of the food, the total amounts of absorbed 

manganese were 0.004, 0.018, 0.019, and 0.097 μg/dose fed, respectively. These data indicate that infants 

fed cow milk formula may retain 5 times more manganese, and infants fed soy formula may retain 

25 times more manganese than breast-fed infants. Although the latter results differ significantly from 

those observed earlier, the researchers report that the similar relative values for manganese absorption 

were indicative of significant efforts made to optimize both the relative concentrations and the 

bioavailability of minerals and trace elements in the manufactured formulas. 

No studies were located regarding absorption of manganese following oral exposure to MMT in humans. 

Several studies (Hanzlik et al. 1980a, 1980b; Hinderer 1979; Hysell et al. 1974; Komura and Sakamoto 

1992a, 1992b) indicate that absorption is occurring because toxicity is observed following MMT 

exposure; however, no absorption rates or relative amounts were provided in these studies. The plasma 

temporal pattern of manganese following oral administration of MMT has been studied in male SpragueDawley rats (Zheng et al. 2000). Following oral gavage of 20 mg MMT/kg, manganese appears in the 

plasma with a Cmax between 2 and 12 hours after dosing. When nearly equivalent oral doses of MMT 

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(5.6 mg manganese/kg) or manganese chloride (6 mg manganese/kg) were administered, the Cmax 

(0.93 mg manganese/mL) following oral MMT was about 3-fold higher than that following oral 

manganese chloride (0.30 mg manganese/mL) (Zheng et al. 2000). 

3.4.1.3 Dermal Exposure 

The only available human study regarding dermal exposure to manganese discussed a case report of a 

man burned with a hot acid solution containing 6% manganese. The authors speculated that manganese 

absorption had occurred across the burn area (Laitung and Mercer 1983) because the man had slightly 

elevated urinary manganese levels (11–14 vs. 1–8 mg/L). In most cases, manganese uptake across intact 

skin would be expected to be extremely limited. 

No studies were located regarding absorption of organic manganese in humans or animals following 

dermal exposure. 

3.4.2 Distribution 

Manganese is a normal component of human and animal tissues and fluids. In humans, most tissue 

concentrations range between 0.1 and 1 μg manganese/g wet weight (Sumino et al. 1975; Tipton and 

Cook 1963), with the highest levels in the liver, pancreas, and kidney and the lowest levels in bone and fat 

(see Table 3-7). Manganese levels in the blood, urine, and serum of healthy, unexposed subjects living in 

the Lombardy region of northern Italy were 8.8±0.2, 1.02±0.05, and 0.6±0.014 μg/L, respectively (Minoia 

et al. 1990). Serum manganese concentrations in healthy males and females in Wisconsin were 1.06 and 

0.86 μg/L, respectively (Davis and Greger 1992; Greger et al. 1990). Although precise inhalation 

exposure data were not available for humans, chronic occupational exposure studies have shown that 

higher levels of inhalation exposure generally correspond with higher blood or urine manganese levels for 

groups, but that individual measurements may not correspond to individual exposure or be reliable 

exposure predictors (Abdel-Hamid et al. 1990; Alessio et al. 1989; Jarvisalo et al. 1992; Roels et al. 1992; 

Siqueira et al. 1991). 

Studies investigating manganese levels in human fetal tissues or fluids are very few. Widdowson et al. 

(1972) measured manganese in fetal livers from 29 unborn infants (ranging in gestational age from 20 to 

41 weeks) and from 5 adults. The fetal manganese levels ranged from 0.09 to 0.23 mg/100 g wet weight 

with a mean of 0.14 mg/100g wet weight, while the mean of the five adults was 0.18 mg/100 g wet 

weight (range of values not reported). The highest fetal manganese value of 0.23 mg/100 g wet weight 

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Table 3-7. Manganese Levels in Human and Animal Tissues 

Tissue concentrations (μg manganese/g wet weight) 

Humans Rats Rabbits 

Tipton and Sumino et al. Rehnberg et al. Fore and 

Tissue Cook (1963) (1975) (1982) Morton (1952) 

Liver 1.68 1.2 2.6–2.9 2.1 

Pancreas 1.21 0.77 No data 1.6 

Adrenals 0.20 0.69 2.9 0.67 

Kidney 0.93 0.56 0.9–1.0 1.2 

Brain 0.34 0.30a 0.4 0.36 

Lung 0.34 0.22 No data 0.01 

Heart 0.23 0.21 No data 0.28 

Testes 0.19 0.20 0.4 0.36 

Ovary 0.19 0.19 No data 0.60 

Muscle 0.09 0.09 No data 0.13 

Spleen 0.22 0.08 0.3 0.22 

Fat No data 0.07 No data No data 

Bone (rib) No data 0.06 No data No data 

Pituitary No data No data 0.5 2.4 

a

Average of cerebrum and cerebellum 

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was from one of the two infants at 41 gestational weeks of age when analyzed. The data indicate that 

fetal liver manganese levels throughout the latter half of gestation are comparable to those in the adult. 

Concentrations of manganese also have been measured in the blood of pregnant women, as well as in the 

plasma of cord blood of preterm and full-term infants (Wilson et al. 1991). Manganese concentrations in 

full-term (37–42 weeks gestation) infants were 5.5±1.5 μg/L, slightly higher than the preterm (27– 

36 weeks gestation) infants’ values of 5.0±1.1 μg/L, but the difference was not statistically significant. 

There were no correlations between the levels in infants and mothers. The higher manganese levels in 

cord blood of gestationally older infants, along with the higher manganese level in the oldest fetus from 

the Widdowson et al. (1972) study, suggest that manganese levels may rise slightly as the fetus 

approaches birth; however, there are inadequate data points to make a strong argument for this possibility. 

Serum manganese values of 180 healthy Venezuelan infants decreased consistently from a high value of 

0.45 μg/L (mean of 22 infants) at 5 days of age to a low value of 0.29 μg/L (mean of 40 infants) at 

12 months of age (Alarcón et al. 1996). The level of manganese at 12 months was the only measurement 

that was statistically different than the 5-day value. The values were not statistically different between 

the sexes. Rükgauer et al. (1997) obtained very different results in their analyses of serum manganese 

levels in German children, adolescents, and adults. The authors evaluated 137 children (aged 1 month– 

18 years); the mean serum manganese level for all children was 1.4 μg/L (range 0.17–2.92 μg/L). When 

the children were separated by age, the serum manganese values were found to decrease from a mean 

value of 2.12 μg/L (age 0–1 year) to a minimum of 0.98 μg/L (age 14–18 years). Adults (age 22– 

75 years) had a mean value of 0.79 μg/L. These data indicate that children had much higher manganese 

levels in serum than those levels shown by the other studies. It is unknown why this latter study indicates 

results that are vastly different from those reported in the earlier studies. Rükgauer et al. (1997) took 

precautions to prevent manganese contamination of their experimental materials during sampling and 

analysis. Also, the authors reported that the subjects were healthy and were not suffering from nutritional 

diseases or metabolic disorders and were not taking medicines containing trace elements. However, the 

children and adolescent subjects were chosen from a pediatric hospital after seeking medical attention on 

non-nutrition related matters. Therefore, this population may not be a representative sample of the 

general population. Animal studies, by contrast, suggest that distribution of manganese in the infant and 

young child may be very different from the adult. 

Levels in tissues from animals fed a normal diet are generally similar but, perhaps are slightly higher than 

those in humans (Fore and Morton 1952; Rehnberg et al. 1982). Levels of manganese in the milk of rats 

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fed a normal diet averaged 0.054 μg/g (Miller et al. 1975). Data on changes in tissue levels following 

acute exposures to excess manganese are presented in exposure-specific subsections later in this chapter. 

Manganese is also found in breast milk for the continuing metabolic nutrition of the infant. One study 

reported manganese concentrations from 82 normal, healthy French women of 12±5.6 μg/L at postpartum 

day 2 in human colostrum decreasing to 3.4±1.6 μg/L at postpartum day 6 in breast milk (Arnaud and 

Favier 1995). Another study reported an average manganese concentration in breast milk of 6.2 μg/L 

using 2,339 samples from mothers of 20 full-term and 6 preterm infants (Dorner et al. 1989). Collipp et 

al. (1983) have reported concentrations of manganese in breast milk of 10 μg/L. These reports, however, 

did not address the dietary manganese intake of the nursing mothers. It is unknown whether mothers 

exposed to increased concentrations of manganese have higher-than-usual levels of the metal in breast 

milk. 

Manganese is distributed throughout all cells in the body; therefore, it is present in germ cells. However, 

existing studies in humans and animals are not sufficient to predict if distribution of excess manganese 

into germ cells might result in heritable genetic changes. Manganese is constantly present in human 

tissues and, therefore, is able to enter germ cells. One human study involving inhalation exposure to 

nickel and manganese observed chromosomal aberrations in welders working with these metals (Elias et 

al. 1989). However, the presence of nickel is a confounding factor, as it is known for causing 

chromosomal changes. Studies in animals are equivocal; there are not enough data to make predictions as 

to the likelihood for excess exposures of manganese to cause heritable genetic changes. 

Concentrations of manganese in select human and animal tissues are presented in Table 3-7 and 

concentrations of manganese in plasma and serum in infants of differing ages and adults are presented in 

Table 3-8. 

3.4.2.1 Inhalation Exposure 

Following inhalation exposure of mice to manganese dust, for a short period of time the concentration of 

manganese in the lung is approximately proportional to the concentration of manganese in the air (Adkins 

et al. 1980c). However, as noted earlier, some of the particles that are deposited in the lung are 

transported to the gastrointestinal tract (Mena et al. 1969). The rate of particle transport from the lungs 

has not been quantified in humans, but half-times of elimination in animals range from 3 hours to 1 day 

(Adkins et al. 1980c; Bergstrom 1977; Newland et al. 1987). 

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Table 3-8. Manganese Levels in Human Serum/Plasma 

Concentration (μg/L) (mean±2 standard deviations)
	

Age Serumc Plasma 

5 Daysa 0.45±0.12 (22)
 

1 Month 0.41±0.11 (20)
 

3 Months 0.39±0.13 (22)
 

5 Months 0.39±0.10 (14)
 

7 Months 0.38±0.09 (20)
 

10 Months 0.37±0.11 (20)
 

11 Months 0.36±0.12 (22)
 

12 Months 0.29±0.10 (40)
 

1 Month–18 yearsb 1.4±1.25
 

22–75 Years 0.79±0.63
 

a

Data from infants 5 days–12 months in age are from Alarcón et al. (1996). Data are from mixed-sex groups. No 

statistically significant differences in manganese concentrations were found between sexes.

b

Data from Rükgauer et al. (1997).
 c

Value in parentheses is the number of subjects.
 

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The relative increases in tissue levels of manganese following inhalation exposure to inorganic forms of 

manganese have received considerable investigation in animals. 

Increases of 20–60% in manganese levels in the kidney and spleen were noted in mice 24–48 hours after 

exposure to manganese dioxide (Adkins et al. 1980c). Rats exposed to an aerosol containing 0.0003 mg 

54Mn/m3 for 1 hour had manganese levels in the liver, lung, kidney, and brain of 0.0495, 0.1366, 0.0141, 

and 0.0014 ng 54Mn/organ, respectively, 5 days after exposure (Wieczorek and Oberdörster 1989b). 

Sheep exposed to welding fumes for 3 hours exhibited a 40-fold increase in lung manganese content 

(Naslund et al. 1990). Preferential accumulation of manganese in specific locations of the brain 

(including the caudate nucleus, globus pallidus, and substantia nigra) was noted in one monkey exposed 

to an aerosol of manganese chloride (20–40 mg/m3

) several hours/day for 3–5 months (Newland et al. 

1989). This preferential uptake could play a role in the characteristic neurological effects of manganese 

(see Section 3.5). 

Roels et al. (1997) investigated the distributional differences in rats exposed to manganese in two forms 

(manganese chloride and manganese dioxide) administered via intratracheal injection (intended to 

simulate inhalation), by gavage (oral administration) and via intraperitoneal injection. When 

administered intratracheally once a week for 4 weeks, 1.22 mg manganese/kg as manganese chloride 

resulted in a 68% steady-state increase in blood manganese concentration after the dosing period. This 

dose also resulted in significantly increased concentrations of manganese in the rat cerebellum (27% 

increase that approached statistical significance), striatum (205% increase), and cortex (48% increase), 

compared with control rats. 

When rats were administered the same amount of manganese under the same dosing regimen, with 

manganese in the form of manganese dioxide, similar, but less striking, results were observed (Roels et al. 

1997). Manganese concentrations in the blood were increased by 41%, and in the cerebellum, striatum, 

and cortex by 31, 48, and 34%, respectively, over the control rats. 

Tjälve et al. (1996) investigated the distribution of manganese in brain tissues, liver, and kidneys of 

young male rats following intranasal injection of 54MnCl2. Radiography data indicated that 1 day after 

dosing, the olfactory bulb contained 90% of the manganese (measured as μg/100g wet weight) in the 

measured tissues, while the basal forebrain contained 6% of the manganese. Concentrations of 

manganese in the basal forebrain increased to 21 and 28% of the measured total at 3 and 7 days post­

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dosing, respectively. Manganese in the cerebral cortex, hypothalamus, striatum, and hippocampus were 

also maximal at 7 days post-dosing. Manganese values in liver and kidneys were approximately 1% of 

the total measured for the first 7 days, and then decreased steadily until 12 weeks. These results were 

compared to distribution of manganese following intraperitoneal injection, in which no brain region 

showed preferential distribution at 1, 7, or 21 days post-dosing (Tjälve et al. 1996). In another study, 

Gianutsos et al. (1997) found a dose-dependent accumulation of manganese in the olfactory bulb and 

tubercle following intranasal injection of manganese chloride into one nostril. Injection of 200 μg 

manganese resulted in maximally elevated levels in the olfactory bulb (400% higher than the uninjected 

side), with levels in the tubercle half that in the bulb within 12 hours post-exposure; these levels remained 

elevated for 3 days. Two injections of 200 μg manganese doubled the level of manganese in the striatum 

compared to saline-injected controls; single doses did not increase tissue manganese levels. No other 

brain regions were noted and blood manganese levels were not changed with any treatment. These data 

indicate that the olfactory mucosa is an important pathway for distribution of manganese into the brain. 

Vitarella et al. (2000) exposed adult rats to airborne doses of particulate manganese, as manganese 

phosphate, at 0, 0.03, 0.3, 3 mg manganese/m3

. The particles had a mean diameter of 1.5 μm. Exposures 

lasted for 6 hours/day for either 5 days/week (10 exposures) or 7 days/week (14 exposures). The 

following tissues were analyzed for manganese content using neutron activation analysis: plasma, 

erythrocytes, olfactory bulb, striatum, cerebellum, lung, liver, femur, and skeletal muscle. Increased 

manganese concentrations were reported in olfactory bulb, lung, femur, and skeletal muscle following 

exposure to 3 mg/m3 (after either dosing regiment); a lower dose of 0.3 mg/m3 resulted in increased 

manganese concentrations in olfactory bulb, and lung (14-day dose regimen only). Striatal manganese 

levels were increased at the two highest doses only after 14 days of exposure. However, concentrations in 

the cerebellum were similarly elevated, which was interpreted by the authors to indicate that 

accumulation of manganese was not selective for the striatum. Red blood cell and plasma manganese 

levels were increased only in rats exposed to the highest dose for the 10-day exposure period. These data 

indicate that even at lower doses manganese can accumulate in the olfactory bulb and that the neuronal 

pathway to the brain is significant for inhaled manganese in rodents. 

Although the results from the studies by Tjälve et al. (1996) and Vitarella et al. (2000) indicate that 

manganese can be transported via the olfactory neural pathway from the nasal mucosa to the olfactory 

bulb of the brain and, to a limited degree, to other brain regions in rodents, the relative importance of this 

pathway to the delivery of manganese to basal ganglia sites of neurotoxicity is uncertain. Statistical 

mapping of functional olfactory connections in rat brains using MRI following nasal administration of 

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manganese chloride could readily detect connections to the olfactory bulb, but could not detect 

connections to other brain regions (Cross et al. 2004). Mainstream manganese entry into the brain from 

blood occurs through capillary endothelial cells of the blood-brain barrier and through the cerebral spinal 

fluid via the choroid plexuses (Bock et al. 2008; Crossgrove and Yokel 2005). A number of transport 

mechanisms (including facilitated diffusion, active transport, transferrin-mediated transport, divalent 

metal transporter-1 mediation, store-operated calcium channels) have been proposed to transport 

manganese across the blood barrier, but current understanding is inadequate to determine the predominant 

mechanism of transport (Aschner et al. 2005; 2007; Crossgrove and Yokel 2004, 2005; Roth 2006). 

A concern that inhaled manganese, compared with ingested manganese, may more readily result in 

manganese accumulation in the brain, a principal toxicity target of manganese, has led to recent detailed 

investigations of manganese concentrations in various brain regions and in other tissues following 

inhalation exposure of animals to environmentally relevant forms of manganese. These studies have 

investigated manganese concentrations in tissues of young male and female CD rats exposed by 

inhalation to manganese sulfate or manganese tetroxide for 14 days at concentrations of 0, 0.03, 0.3, or 

3 mg manganese/m3 (Dorman et al. 2001a), young male CD rats given low- (2 ppm), sufficient- (10 ppm), 

or high-manganese (100 ppm) diets for 67 days, followed by inhalation exposure to manganese sulfate for 

14 days at concentrations of 0, 0.092, or 0.92 mg manganese/m3 (Dorman et al. 2001b), young male and 

female CD rats or aged male CD rats after 90 days of inhalation exposure to manganese sulfate at 0.01, 

0.1, or 0.5 mg manganese/m3 or manganese phosphate at 0.1 mg manganese/m3 (Dorman et al. 2004a), 

maternal CD rats and offspring after inhalation exposure to manganese sulfate at 0, 0.05, 0.5, or 1.0 mg 

manganese/m3 starting 28 days prior to breeding through PND 18 (Dorman et al. 2005a, 2005b), and 

young male Rhesus monkeys after inhalation exposure to manganese sulfate at 0.06, 0.3 or 1.5 mg 

manganese/m3 for 15, 33, or 65 exposure days (Dorman et al. 2006a). 

The results from these animal studies indicate that tissue manganese concentrations in the brain depended 

on aerosol concentration, exposure duration, and brain region. Tissue manganese concentrations 

generally increased with increasing air concentrations and durations of exposure. With repeated 

exposures at the highest air concentrations (≥0.92 mg manganese/m3

), manganese concentrations in brain 

regions were elevated, compared with control animals, showing the following order: olfactory 

bulb>striatum>cerebellum. Illustrative data for maternal CD rats (Dorman et al. 2005a) and young 

Rhesus monkeys (Dorman et al. 2006a) exposed to manganese sulfate are shown in Tables 3-9 and 3-10, 

respectively. Comparison of manganese concentrations across tissues shows the following order in 

exposed maternal rats: liver > pancreas > olfactory bulb > lung > striatum ≈ femur > milk > cerebellum 

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Table 3-9. Terminal Mean (±Standard Error on the Mean) Tissue Manganese
 

Concentrations (μg Manganese/g Tissue Wet Weight) in Maternal CD Rats 

Exposed to Aerosols of Manganese Sulfate 6 Hours/Day, 7 Days/Week
 

Starting 28 Days Prior to Breeding Through Postnatal Day 18
 

Exposure concentration (mg manganese/m3) 

Tissue 0 0.05 0.5 1.0 

Whole blood 0.08±0.04 0.06±0.02 0.06±0.01 0.05±0.01 

Olfactory bulb 0.56±0.05 0.71±0.04a 1.40±0.07a 1.73±0.07a 

Striatum 0.51±0.02 0.54±0.02 0.74±0.02a 0.89±0.02a 

Cerebellum 0.50±0.02 0.52±0.02 0.60±0.01a 0.61±0.03a 

Lung 0.22±0.03 0.37±0.02 0.86±0.07a 1.05±0.06a 

Liver 3.21±0.15 3.04±0.09 3.37±0.15 4.28±0.76a 

Femur 0.62±0.07 0.61±0.04 077±0.05 0.89±0.06a 

Pancreas 1.66±0.13 1.80±0.19 1.29±0.28 1.91±0.23 

Milk 0.21±0.08 0.20±0.06 0.47±0.06 0.77±0.10a 

Group size (n) 8 10 9 8 

a

Significantly (p<0.05) different from control mean value. 

Source: Dorman et al. 2005a 

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Table 3-10. Mean (±Standard Error on the Mean) Tissue Manganese 

Concentrations (μg Manganese/g Tissue Wet Weight) in Young 

Male Rhesus Monkeys Exposed to Aerosols of Manganese 

Sulfate (1.5 mg Manganese/m3

) 6 Hours/
 

Day, 5 Days/Week for Up to 65 Days
 

Exposure to air 1.5 mg manganese/m3 

Exposure (days) 65 15 33 65 65 (+45)a 65 (+90)a 

Tissue 

Olfactory tissues 

Olfactory 0.49±0.01 6.10±0.39b 7.34±0.70b 7.10±2.01b 0.65±0.04 0.69±0.11 

epithelium 

Olfactory bulb 0.31±0.01 2.19±0.44b 2.29±0.26b 2.40±0.18b 0.35±0.02 0.31±0.02 

Olfactory tract 0.30±0.06 0.77±0.19b 0.84±0.11b 1.12±0.08b 0.18±0.02 0.22±0.02 

Olfactory cortex 0.19±0.01 0.43±0.04b 0.45±0.01b 0.42±0.01b 0.26±0.01 0.21±0.01 

Brain 

Globus pallidus 0.48±0.04 1.92±0.40b 2.41±0.29b 2.94±0.23b 1.09±0.03b 0.59±0.12 

Putamen 0.36±0.01 1.01±0.08b 1.50±0.14b 1.81±0.14b 0.58±0.03b 0.44±0.02 

Caudate 0.34±0.02 0.93±0.11b 1.37±0.13b 1.72±0.10b 0.57±0.03 0.43±0.02 

Frontal cortex 0.25±0.03 0.36±0.01b 0.52±0.03b 0.47±0.02b 0.26±0.01 0.23±0.01 

Cerebellum 0.44±0.01 0.85±0.06b 0.96±0.05b 1.10±0.11b 0.66±0.04 0.61±0.10 

Pituitary 0.84±0.12 3.79±0.38b 5.60±0.33b 6.19±0.61b 3.01±0.91b 1.54±0.18 

Trigeminal nerve 0.17±0.05 0.27±0.02 0.51±0.14b 0.42±0.08b 0.18±0.01 0.17±0.02 

Organs 

Femur 0.13±0.02 0.27±0.04b 0.13±0.03 0.20±0.03 0.12±0.02 0.09±0.01 

Heart 0.16±0.03 0.25±0.05 0.50±0.03b 0.62±0.05b 0.23±0.3 0.27±0.01 

Kidney 1.14±0.12 2.65±0.14b 3.04±0.09b 2.61±0.30b 1.38±0.13 1.27±0.14 

Liver 2.49±0.09 2.96±0.34 3.28±0.22 3.52±0.45b 2.88±0.27 2.04±0.06 

Lung 0.15±0.03 0.39±0.06b 0.35 ±0.02b 0.33±0.04b 0.09±0.01 0.06±0.01 

Pancreas 1.59±0.11 2.89±0.14b 2.38±0.34b 2.95±0.24b 1.41±0.270. 1.53±0.10 

Skeletal muscle 0.15±0.03 0.22±0.03 0.22±0.02 0.58±0.19b 19±0.02 0.12±0.01 

Parietal bone 0.08±0.04 0.48±0.16b 0.56±0.18b 0.25±0.04 0.17±0.03 0.16±0.04 

Testis 0.26±0.03 0.41±0.06 0.50±0.04b 0.39±0.07 0.36±0.04 0.31±0.02 

Fluids 

Bile 0.89±.22 7.38±.78b 4.40±.89b 7.60±1.68b 1.17±0.28 0.77±0.13 

0.010±.00 0.016±.06 0.022±.002 0.026±0.00 0.021±0.00 0.013±.00 Blood a 1 3b 2b 1 

0.000±.00 0.000±.000 0.001±.000 0.005±0.00 0.000±0.00 0.000±.00 Urine 0 1b 0 0 

Group size (n) 6 4 4 4 4 4 

a

These monkeys were sacrificed 45 or 90 days after the 65-day exposure period. b

Significantly (p<0.05) greater than mean value for air control rats. 

Source: Dorman et al. 2006a 

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>> whole blood (Table 3-9). In young Rhesus monkeys after 65 days of exposure, the order was: bile > 

olfactory epithelium > pituitary > liver > pancreas ≈ globus pallidus > olfactory bulb > kidney > putamen 

> caudate > cerebellum > heart >skeletal muscle > frontal cortex > lung > parietal bone ≈ femur >> blood 

(Table 3-10). 

Brain tissues from the monkeys were dissected into more regions than the rat brains and, immediately 

following 65 days of exposure to the highest exposure concentration, showed the following order of 

elevated manganese concentrations: pituitary>globus pallidus>olfactory bulb>putamen>caudate> 

cerebellum>frontal cortex>trigeminal nerve (see Table 3-10). These results are consistent with the 

evidence that the human striatum, globus pallidus, and substantia nigra are the primary neurotoxicity 

target for manganese (Aschner et al. 2005; Pal et al. 1999). Three- to 5-fold increases (over air control 

values) in mean manganese tissue concentrations were found in the globus pallidus, putamen, and caudate 

in monkeys exposed to 1.5 mg manganese/m3 manganese sulfate for 65 days, but levels were <3-fold 

increased in the frontal cortex and cerebellum, two brain regions not generally associated with manganese 

neurotoxicity (Dorman et al. 2006a; Table 3-10). 

Comparison with the rat results in Table 3-9 suggests that rodents do not accumulate manganese in the 

basal ganglia (i.e., the collection of deep regions of the brain including the striatum [comprised of the 

caudate and putamen]) to the same relative degree as primates, a difference that may be related to findings 

that overt signs of manganese neurotoxicity are more readily detected in nonhuman primates than rodents 

(Aschner et al. 2005; Bock et al. 2008; Newland 1999). Recent corroborative findings showed that 

marmosets, a nonhuman primate, accumulated more manganese in the brain (especially in the basal 

ganglia and the visual cortex) than rats following intravenous injection of equivalent mg/kg body weight 

doses of manganese chloride (Bock et al. 2008). The mechanisms by which manganese accumulates in 

the basal ganglia of primates are poorly understood (Aschner et al. 2005; Bock et al. 2008; Brenneman et 

al. 1999; Dorman et al. 2006b), but Bock et al. (2008) have hypothesized that primates may accumulate 

relatively more manganese in the basal ganglia than rodents because of a relatively larger cerebral spinal 

fluid space in lateral ventricles adjacent to the basal ganglia. 

The high concentrations of manganese in bile sampled from manganese-exposed monkeys (compared 

with air control values in Table 3-10) are reflective of the hepatobiliary excretion of manganese. It is 

currently unknown whether or not the high manganese concentrations attained in the pituitary glands of 

these monkeys has any effect on normal pituitary function; in this study, exposed monkeys showed no 

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MANGANESE 218 

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difference in serum levels of luteinizing hormone (LH), a hormone that stimulates production of 

testosterone by the Leydig cells of the testes (Dorman et al. 2006a). 

In pregnant rats repeatedly exposed to inhaled manganese, the placenta appears to partially limit the 

transport of manganese to the developing fetus (Dorman et al. 2005b). After inhalation exposure to 

manganese sulfate at 0, 0.05, 0.5, or 1.0 mg manganese/m3 starting 28 days prior to breeding through 

PND 18, samples of maternal tissues (whole blood, lung, pancreas, liver, brain, femur, and placenta) and 

fetal tissues (whole blood, lung, liver, brain, and skull cap) were collected and analyzed for manganese 

concentrations. Elevated (p<0.05) manganese concentrations were observed in exposed maternal rats 

(compared with air control rats) in the following tissues: brain and placenta at 0.5 and 1.0 mg 

manganese/m3 and lung at 0.05, 0.5, and 1.0 mg manganese/m3

. In contrast, statistically significant 

elevations of manganese concentrations in sampled fetal tissues were observed only in the liver at 0.5 and 

1.0 mg manganese/m3

. In pups born and allowed to live up to PND 19 (and sampled for tissue 

evaluations at PNDs 1, 14, and 19), statistically significant (p<0.05) elevated manganese concentrations 

(compared with air control values) were observed in blood, liver, and bone samples from exposed 

neonatal rats at concentrations ≥0.05 mg manganese/m3

, starting at PND 1 (Dorman et al. 2005a). As 

shown in Table 3-11, elevated brain manganese concentrations were observed in exposed neonates 

starting at PND 14 (but not at earlier time points); tissue concentrations increased with increasing 

exposure concentration (Dorman et al. 2005a). At PND 19, mean manganese concentration in the 

striatum was about 2.6-fold higher in offspring exposed to 1 mg manganese/m3

, compared with air control 

means (Table 3-11). In contrast, the mean striatum concentration at PND 19 in maternal rats exposed to 

1 mg manganese/m3 was about 1.7-fold increased, compared with controls (Table 3-11). The results from 

this study suggest that the brain in developing fetuses is partially protected from excess manganese by the 

placenta, and that the neonatal period, compared with adulthood, is relatively more susceptible to 

increased manganese concentration in brain tissues with inhalation exposure to manganese sulfate aerosol 

concentrations between 0.05 and 1 mg manganese/m3

. 

In an examination of the distribution of manganese in young adult male and female CD rats (28 days at 

start) and aged male CD rats (16 months at start) following 90-day inhalation exposure to manganese 

sulfate or manganese phosphate, no evidence was found for a gender or age effect on delivery of 

manganese to the striatum or on the order of manganese concentrations in tissues (pancreas> olfactory 

bulb > femur > testes), but gender or age-related differences in tissue manganese concentrations in other 

brain regions, as well as in the lung, pancreas, femur, and testis, were noted (Dorman et al. 2004a). 

Following a 90-day inhalation exposure to 0.5 mg manganese/m3 manganese sulfate, young adult male 

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Table 3-11. Manganese Concentrations in Brain Tissues of Lactating CD Rats and
 

Offspring Exposed to Aerosols of Manganese Sulfate
 

Mean maternal concentrations at Mean offspring concentrations 

PND 18 (μg manganese/g)b (μg manganese/g)c 

Ai Olfactory r levela 

Brain/striatum Cerebellum bulb (mg Olfactory 

manganese/m3) Striatum Cerebellum bulb PND 1 PND 14 PND 19 PND 19 PND 19 

0 0.51±0.02 0.50±0.02 0.56±0.04 0.39 0.19 0.37 0.34 0.36 

0.05 0.54±0.02 0.52±0.02 0.71±0.04d 0.42 0.35d 0.63d 0.51d 0.52d 

0.5 0.74±0.02d 0.60±0.01d 1.40±0.07d 0.45 0.59d 0.83d 0.64d 0.70d 

1 0.89±0.02d 0.61±0.03d 1.73±0.07d 0.50 0.55d 0.97d 0.72d 0.76d 

a

Rats were exposed for 6 hours/day starting 28 days prior to breeding through postnatal day (PND) 18 as reported by
 

Dorman et al. (2005a, 2005b).

b

Mean±SEM from Table 3 in Dorman et al. (2005a).
 c

Means from Figure 4 in Dorman et al. (2005a). Bar graphs were digitized to obtain numerical estimates of means for
 

male and female offspring combined. At PNDs 1 and 14, whole brain tissues were analyzed. At PND 19, brains were 

dissected into striatum, cerebellum, and olfactory bulb before analysis.

d

Significantly (p<0.05) different from air control mean.
 

PND = postnatal day; SEM = standard error of the mean 

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rats had significantly (p<0.05) higher olfactory bulb, blood, femur, and pancreas manganese 

concentrations than aged male rats, and aged male rats had significantly higher testis manganese 

concentrations than young male rats. Young male rats exposed to 0.5 mg manganese/m3 had significantly 

higher olfactory bulb, blood, and lung manganese concentrations than similarly exposed female rats, and 

female rats exposed to 0.5 mg manganese/m3 had significantly higher cerebellum manganese 

concentrations than control females. Young male and female rats exposed to 0.5 mg manganese/m3 for 

90 days had increased 54Mn clearance rates than air-exposed controls, but similarly-exposed aged male 

rats did not display increased 54Mn clearance rates, compared with controls (Dorman et al. 2004a). No 

age-related effects were observed on the order of manganese concentrations in the various tissue. 

No studies were located regarding distribution of manganese in human or animals following inhalation 

exposure to MMT or mangafodipir. 

3.4.2.2 Oral Exposure 

Excess manganese uptake has occurred in humans following oral exposure, presumably via the diet, when 

the individuals suffered from chronic liver disease or some other liver dysfunction (cirrhosis, portacaval 

shunt, etc.). In these instances, excess manganese was shown to accumulate in certain regions of the 

brain, as determined by T1-weighted MRI or neutron activation analysis (Devenyi et al. 1994; Fell et al. 

1996; Hauser et al. 1994, 1996; Pomier-Layrargues et al. 1998; Rose et al. 1999; Spahr et al. 1996). 

These studies show that manganese preferentially accumulates in the basal ganglia, especially the globus 

pallidus, and the substantia nigra. 

Rats given a single oral dose of 416 mg manganese/kg body weight (as manganese chloride tetrahydrate) 

exhibited little tissue accumulation of manganese 14 days later (Holbrook et al. 1975). Studies in animals 

indicate that prolonged oral exposure to manganese compounds results in increased manganese levels in 

all tissues, but that the magnitude of the increase diminishes over time (Kristensson et al. 1986; Rehnberg 

et al. 1980, 1981, 1982). Table 3-12 provides illustrative data based on rats exposed to 214 mg 

manganese/kg(body weight)/day (as manganese tetroxide) for up to 224 days. As the data reveal, large 

increases in tissue levels of manganese compared to the controls occurred in all tissues over the first 

24 days, but levels tended to decrease toward the control levels as exposure was continued. This pattern 

is thought to be due to a homeostatic mechanism that leads to decreased absorption and/or increased 

excretion of manganese when manganese intake levels are high (Abrams et al. 1976a; Ballatori et al. 

1987; Mena et al. 1967). Davis et al. (1992b) and Malecki et al. (1996b) demonstrated that rats fed 

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Table 3-12. Manganese Levels in Rat Tissue After Oral Exposure 

Tissue concentrations (percent of control)a 

Tissue 24 days 60 days 224 days 

Liver 810 137 138 

Kidney 430 102 128 

Brain 540 175 125 

Testes 260 125 100 

a

Values presented are the ratio (expressed as a percentage) of tissue levels of manganese in animals receiving 

3,550 ppm manganese in the diet (as manganese tetroxide) compared to animals receiving a normal diet 

(50 ppm). 

Source: Rehnberg et al. 1980 

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elevated levels of manganese for several weeks had increased tissue manganese concentrations, despite 

increased gut endogenous losses of manganese, as biliary manganese. This reflected several factors. 

Although the percentage of manganese absorbed decreased, the total amount of manganese absorbed 

increased when higher levels of manganese were fed. Moreover, although the total amount of manganese 

lost in bile increased when manganese intake increased, the percentage of manganese intake lost in bile 

remained constant at ~1% of manganese intake (Malecki et al. 1996b). Table 3-9 contains a summary of 

manganese levels measured in rat tissue. 

A study measuring the retention of a single oral dose of radiolabeled manganese in adult and neonatal rats 

indicated that retention of the label 6 days after exposure was much greater in pups (67%) than in adults 

(0.18%); the addition of manganese to the animals' drinking water decreased radiolabel retention in pups 

and adults (Kostial et al. 1989). 

The distributional differences in rats exposed to either manganese chloride or manganese dioxide by 

gavage were investigated by Roels et al. (1997). After administration of 24.3 mg manganese/kg body 

weight (as manganese chloride) once weekly for 4 weeks, the authors analyzed blood and brain 

concentrations of the metal. Manganese concentrations were significantly elevated in the blood 

(approximately 83% increase over controls) and the cortex of the brain (approximately 39% increase over 

controls). Gavage administration of manganese dioxide, by contrast, did not significantly increase the 

amount of manganese in blood or any section of the brain. In addition, administration of manganese as 

manganese chloride by gavage caused roughly the same amount of increased manganese in the blood as 

intratracheal administration of manganese in the same form; it did not cause as significant an increase of 

manganese in the cortex (Roels et al. 1997). These data indicate that inhalation exposure to manganese in 

the form of manganese chloride or manganese dioxide causes accumulation of manganese in the brain 

more readily than oral exposure. 

Acute manganese exposure in drinking water was found to alter brain regional manganese levels in 

neonatal rats; after 5 days of exposure, the highest level was in the striatum (12.05 μg/g wet weight) and 

the lowest level was in the cerebral cortex (0.85 μg/g wet weight) (Chan et al. 1992). After 10 days, the 

highest concentrations were in the pons and medulla and the lowest were in the hypothalamus. Regional 

manganese differences were less pronounced in weanling and adult rats. A study by Lai et al. (1991) 

confirms that intermediate exposure to manganese in drinking water increases brain manganese 

concentrations; rats exposed from conception to 120 days at 0.04 or 0.4 mg manganese/kg/day had mean 

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brain manganese levels of 0.36–0.72 μg/g in the low-dose animals and 0.62–1.35 μg/g in the high-dose 

animals, compared to 0.21–0.38 μg/g in controls. 

In a dietary study, elevated manganese levels were found in the organs of male mice fed manganese 

chloride, manganese acetate, manganese carbonate or manganese dioxide at 284 mg manganese/kg/day 

for 100 days; levels of manganese in the liver and kidney were significantly higher in the animals exposed 

to manganese acetate or manganese carbonate than in those exposed to manganese chloride or manganese 

dioxide (Komura and Sakamoto 1991). In a 1993 NTP study, mice and rats chronically fed manganese 

sulfate generally exhibited elevated tissue levels of manganese; the manganese levels in the liver and 

kidney were higher than the levels in the brain. 

No studies were located concerning disposition of manganese in humans or animals following oral 

exposure to MMT or mangafodipir. 

3.4.2.3 Dermal Exposure 

No studies were located regarding tissue distribution of manganese in humans or animals after dermal 

exposure to inorganic manganese. 

No studies were located regarding tissue distribution of manganese in humans or animals after dermal 

exposure to organic manganese. 

3.4.2.4 Other Routes of Exposure 

No studies were located regarding tissue distribution of inorganic manganese in humans after exposure 

via other routes of exposure. 

A number of studies have been conducted that investigated various facets of the distribution of inorganic 

manganese in animal models. The studies utilized a number of routes of administration, and the results 

suggested that route may play an important role in distribution. In an intraperitoneal study performed in 

monkeys, manganese was reported in all tissues studied. The highest levels were found in the pancreas, 

liver, and kidney, and the lowest levels were found in the blood; levels in the central nervous system were 

found to decrease more slowly than those in other tissues (Dastur et al. 1971). Calves injected 

intravenously with 54Mn were found to have 3-fold higher liver manganese concentrations and 13-fold 

higher pancreatic manganese concentrations than calves fed manganese (Carter et al. 1974). Davis et al. 

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(1993) observed that rats injected intraportally with free 54Mn or 54Mn complexed with transferrin and rats 

injected intraperitoneally with free 54Mn accumulated more manganese in the pancreatic tissue and less in 

the liver than those rats that were either fed 54Mn or injected intravenously in the portal vein with an 

albumin-54Mn complex. The similarity in the distribution of the injected manganese-albumin complex 

and the free manganese in the diet when compared to the distribution of manganese when it was 

administered by other routes or complexed with other proteins suggests that the route of administration 

and type of complexed protein may cause differences in the transport of manganese in the sera. 

Roels et al. (1997) studied the effect of intraperitoneal administration of manganese chloride and 

manganese dioxide on distributional differences of manganese in rats. Doses of 1.22 mg manganese/kg 

as manganese chloride given once per week for 4 weeks resulted in significant increases (when compared 

to controls) in blood (approximately 60%), striatum (34%), and cortex (36%) concentrations of 

manganese; no changes were observed in the cerebellum. Identical dosing of rats with manganese 

dioxide resulted in significant increases in manganese levels in blood (79%), cerebellum (40%), striatum 

(124%), and cortex (67%) over those in controls. These data indicate that administration of manganese 

dioxide by this route resulted in greater accumulation of manganese in the brain than did manganese 

chloride. 

The distribution of manganese in the brain was investigated using Cebus (Newland and Weiss 1992; 

Newland et al. 1989) and Macaque (Newland et al. 1989) monkeys given intravenous injections of 

manganese chloride that reached a cumulative dose of 10–40 mg manganese/kg. Magnetic resonance 

images indicated hyper-intensity of the globus pallidus and substantia nigra consistent with an 

accumulation of manganese in these areas (Newland and Weiss 1992; Newland et al. 1989). Substantial 

accumulation of manganese was also noted in the pituitary at low cumulative doses (Newland et al. 1989). 

London et al. (1989) reported a rapid localization of manganese in the choroid plexus observed on MRI; 

similarly, radiotracer studies of manganese injected into the intracerebroventricular space revealed that 

radiolabeled manganese was located in the choroid plexus within 1 hour and was located in the rat dentate 

gyrus and CA3 of the hippocampus 3 days post-dosing (Takeda et al. 1994). 

No studies were located regarding disposition of MMT in humans following other routes of exposure, but 

toxicokinetics of MMT following parenteral administration has received some research attention in 

animals. 

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Young adult male rats were administered MMT dissolved in propylene glycol via subcutaenous injection 

at a dose of 1 mg manganese/kg (McGinley et al. 1987). Control rats received vehicle alone. The rats 

were sacrificed 1.5, 3, 6, 12, 24, 48, or 96 hours post-injection. Levels of manganese in the control 

animals were measured in the blood (0.09±0.01 mg/kg), lung (1.51±0.22 mg/kg), liver 

(2.49±0.36 mg/kg), kidney (1.29±0.23 mg/kg), and brain (0.45±0.01 mg/kg). These values were assumed 

by the authors to originate from the feed given to the rats and were subtracted from similar values 

analyzed for MMT-treated rats to determine the amount of manganese in these tissues and fluids that 

originated from MMT. Maximum accumulation of MMT-derived manganese was measured 3 hours after 

dosing and was found primarily in the following four tissues: lung (~9 mg/kg); kidney (3.9 mg/kg); liver 

(2.75 mg/kg); and blood (~0.75 mg/kg). Concentrations of manganese in these four tissues was still 

elevated (~1 mg/kg) at 96 hours post-dosing. Brain manganese concentrations were not significantly 

elevated over control levels in MMT-treated animals (McGinley et al. 1987). 

Gianutsos et al. (1985) administered 0, 11, or 22 mg manganese/kg as MMT (dissolved in propylene 

glycol) to male adult mice via subcutaneous injection to determine distribution of manganese. Control 

mice received vehicle alone. Mice were sacrificed at different time points after dosing. The experiment 

was divided into an acute study (one dose) or a “chronic study” (ten doses). The brain manganese level 

24 hours after the single dose of MMT at 11 mg/kg was 0.93±0.07 μg/g; the value after 22 mg/kg was 

1.35±.09 μg/g. Both values were significantly different from the control value of 0.61±0.08 μg/g. The 

brain manganese level in the mice administered 10 doses of 11 mg/kg each was 1.37±0.27 μg/g; after 

10 doses of 22 mg/kg, the value was 3.33±0.15 μg/g; both were significantly greater than the control 

value of 0.64±0.06 μg/g, and were significantly different than the levels reported after the acute exposure. 

Manganese levels in the brains of mice given a single dose of MMT at 22 mg manganese/kg were 

compared with those following injection of the same manganese dose as manganese chloride; mice were 

sacrificed at different time points from 1–24 hours post-dosing. The brain manganese levels following 

MMT exposure increased from a low at 1 hour to a maximum at 24 hours of ~1.4 μg/g wet weight. The 

manganese level in brain after manganese chloride exposure followed the same increasing trend over the 

24 hour analysis period, but was higher at each time point, with a maximum value of >2.0 μg/g wet 

weight (Gianutsos et al. 1985). 

Clinical studies involving cancer patients or healthy volunteers have analyzed the usefulness of 

mangafodipir as a contrast agent for the identification of certain abdominal tumors. Although these 

studies do not necessarily quantify the amount of manganese, or mangafodipir, in particular tissues, they 

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are useful tools in identifying the location of the metal; also relative proportions of manganese among two 

or more tissues that contain the metal can be observed by differences in signal from these imaging studies. 

Several studies have shown the qualitative presence of manganese in the liver due to increased signal in 

that organ following mangafodipir administration of 0.17–0.83 mg manganese/kg upon T1-weighted MRI 

(Bernardino et al. 1992; Lim et al. 1991; Padovani et al. 1996; Wang et al. 1997). Two studies show that 

the human liver takes up more of the manganese from mangafodipir than any other organ: the signal from 

the liver was roughly 2 times the amount from the spleen after dosing with 0.55 mg manganese/kg (Lim 

et al. 1991); the liver signal after dosing with 0.55 mg manganese/kg had reached a 100% increase over 

baseline signal by 20 minutes following post-dosing, whereas the maximal signal from other organs was 

only 80% in the pancreas, ~30% in the spleen, ~90% in the renal medulla, and 50% in the choroid plexus, 

all at the same dose. The renal cortex was the only other tissue to reach a 100% increase over baseline 

signal at 0.55 mg manganese/kg. Dosing with 0.25 mg manganese/kg (the clinically used dose for current 

MRI testing of patients) resulted in a similar distribution pattern, although the signal was decreased 

compared to the higher dose. The signal from the renal cortex at the lower dose had a maximum of 80% 

over baseline, whereas the signal in the liver at this dose was ~75% of the baseline value (Wang et al. 

1997). 

Several studies have determined the distribution of manganese in tissues of animals following intravenous 

administration of mangafodipir. Grant et al. (1994) reported that in rats injected with 2 times the clinical 

dose of [54Mn] mangafodipir (0.55 mg manganese/kg), the carcass retained 8% of the label and the tissues 

retained 7% of the label; individual tissue concentrations of manganese were not reported. 

Gallez et al. (1997) injected adult male mice once with 0.25 mg manganese/kg as [54Mn] mangafodipir 

(clinical dose) and determined the tissue manganese content at time points ranging from 15 minutes to 

3 months post-dosing. Brain concentration of 54Mn did not reach a maximum value of 0.26±0.04 (value 

is the percent of injected dose/g tissue) until 24 hours post-dosing; this value was not different than the 

brain manganese content of mice injected with manganese chloride. This maximum value was still 

observed in the brain 2 weeks post-dosing, but measurements taken at 1 and 3 months post-dosing were 

below the detection limit. By contrast, manganese from manganese chloride was still detectable, although 

not at maximal levels, at 3 months’ time. Liver manganese reached a maximum value of 7.5±1.4 (percent 

dose/g tissue) 15 minutes post-dosing and then decreased to below the detection limit 1 month later. 

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Male and female Sprague-Dawley rats injected with [54Mn] mangafodipir at a dose of 5.5 mg 

manganese/kg had the following distribution of labeled manganese 30 minutes post-dosing (values are 

given in percent injected dose/g tissue): liver, 1.3; kidney, 1.2; heart, 0.25; spleen, 0.2; blood, 0.3; small 

bowel, 1.3; large bowel, 0.5; muscle, 0.1; and brain, negligible. Distribution of manganese in tissues of 

rats injected with labeled manganese chloride was compared to the previous results, and for all tissues, the 

label was greater after administration with the chloride than from the mangafodipir, with the exception of 

kidney and large bowel, but these differences were not significant (Elizondo et al. 1991). 

The distribution of label in male and female Sprague-Dawley rats injected with either [54Mn] or [14C] 

mangafodipir at a dose of 0.39 or 0.55 mg manganese/kg, respectively, was studied by Hustvedt et al. 

(1997). The plasma concentration of labeled manganese reached a peak of 10.2 μg/mL at 5 minutes postdosing and was quickly distributed into the following organs (values given as μg equivalents of 

compound/g): pancreas, 10.2; liver, 4.0; kidneys, 3.6; testes/ovaries, 1.7; spleen, 1.0; heart, 0.9; and 

brain, 0.69. When the bile duct was cannulated, the distribution of an equivalent dose of mangafodipir 

showed an increased retention of labeled manganese in all organs but the brain (0.62): pancreas, 17.2; 

liver, 12.3; kidneys, 10.1; testes/ovaries, 5.6; small intestine, large intestine and heart, 2.1; and spleen, 

1.9. By contrast, tissue retention of 14C from radiolabeled mangafodipir was very low: pancreas, 0.016; 

liver, 0.045; kidneys, 0.067; testes/ovaries, 0.015; spleen, 0.023; small intestine, 0.012; large intestine, 

0.019; heart, 0.017; and brain, 0.009. These data indicate that manganese dissociates from the fodipir 

moiety after mangafodipir administration and partitions into the tissues listed above. 

The tissue distribution of normal and bile-cannulated dogs following administration of [54Mn] or [14C] 

mangafodipir was also studied (Hustvedt et al. 1997). Doses of 0.55 manganese/kg were used except for 

the normal dogs when the manganese was labeled; the dose in this case was 0.38 mg/kg. The general 

pattern of distribution of manganese and carbon was similar to that seen with rats, except the 

concentrations were increased in the dog. The values for normal dogs were taken 168 hours post-dosing 

for both forms of labeled mangafodipir; the bile-cannulated dogs were analyzed 24 hours post-dosing. 

The maximum concentration of 54Mn in the plasma following dosing was 13.1 μg/mL at the end of the 

infusion period. The plasma concentrations declined rapidly with a terminal half-life of approximately 

15 minutes. In the normal dog and bile-cannulated dog, the tissue distribution was as follows (the values 

for the bile-cannulated dog are given in parentheses; all values are in μg equivalents of compound/g): 

liver, 8.7 (79.8); pancreas, 8.1 (2.5); kidneys, 6.6 (37.5); bile, 5.9 (no sample); testes/ovaries, 2.2 (3.2); 

brain, 0.79 (1.1); spleen, 0.65 (26.6); and heart, 0.62 (3.1). The distribution of labeled carbon in normal 

(or bile-cannulated dogs) was the following: kidneys, 0.79 (4.1); liver, 0.13 (0.48); bile, 0.059 (no 

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sample); testes/ovaries, 0.05 (0.079); pancreas, 0.015 (0.11); heart, 0.015 (0.035); spleen, 0.007 (0.15); 

and brain, not detected (not detected). These data indicate that in the dog, as in the rat, the manganese 

cation is retained by the tissues, but the fodipir moiety is not. 

Distribution of 54Mn and 14C following mangafodipir administration was also studied in the pregnant rat 

(Hustvedt et al. 1997). Whole-body autoradiography of a section of the rat made at different time points 

revealed that the kidney had retained the highest amount of labeled manganese; later time points showed a 

distribution similar to those seen in the rat and dog studies mentioned previously with the pancreas and 

liver causing the most intense signal upon autoradiography. By 24 hours, fetal livers and bones were 

clearly seen, but placental radioactivity had decreased substantially. Fat deposits also contained a 

significant amount of the radioactivity at 24 hours. By contrast, radioactivity from labeled carbon in the 

mangafodipir was relatively uniformly distributed throughout the pregnant rat at 5 minutes and 1 hour 

post-dosing, with the highest levels in the kidneys. At 24 hours, virtually all tissues were 

indistinguishable from background. 

The human distribution studies have involved much shorter observation times than the animal studies, 

with maximal increase in MRI signal in human studies observed in minutes following administration. 

These studies have shown the liver to accumulate the highest amount of manganese from the administered 

dose of mangafodipir. This is an important limitation since the brain, the primary target of manganese 

neurotoxicity, may not accumulate a significant amount of manganese until much later, possibly after the 

current experiments in humans and animals were truncated. Experiments in rats and dogs, both normal 

and bile-cannulated, indicate that the brain does not accumulate a significant amount of manganese 

following administration of mangafodipir at levels much higher than the recommended clinical dose of 

the agent (Hustvedt et al. 1997), even at 168 hours post-dosing in the dog. Gallez et al. (1997) reported 

that manganese accumulation in the brain of adult mice following injection of a clinical dose of 

mangafodipir did not reach maximal levels until 24 hours post-dosing. This would indicate that the 

human distribution studies were terminated prematurely. However, while brain accumulation of 

manganese following mangafodipir administration is similar to that from manganese chloride, the 

manganese is not present after 2 weeks, whereas manganese from the inorganic compound was present, 

although at a decreased amount, 3 months following dosing (Gallez et al. 1997). These data indicate that 

single, clinical doses of mangafodipir are not likely to cause persistent accumulation of manganese in the 

brain. 

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3.4.3 Metabolism 

Manganese is capable of existing in a number of oxidation states, and limited data suggest that manganese 

may undergo changes in oxidation state within the body. Circumstantial support for this hypothesis 

comes from the observation that the oxidation state of the manganese ion in several enzymes appears to 

be Mn(III) (Leach and Lilburn 1978; Utter 1976), while most manganese intake from the environment is 

either as Mn(II) or Mn(IV) (see Chapter 6). Another line of evidence is based on measurements of 

manganese in tissues and fluids using electron spin resonance (ESR), which detects the unpaired electrons 

in Mn(II), Mn(III), and Mn(IV). When animals were injected with manganese chloride, levels of 

manganese increased in bile and tissues, but only a small portion of this was in a form that gave an ESR 

signal (Sakurai et al. 1985; Tichy and Cikrt 1972). This suggests that Mn(II) is converted to another 

oxidation state (probably Mn(III)), but it is also possible that formation of complexes between Mn(II) and 

biological molecules (bile salts, proteins, nucleotides, etc.) results in loss of the ESR signal without 

oxidation of the manganese ion. 

Evidence by Gibbons et al. (1976) suggests that oxidation of manganese occurs in the body. It was 

observed that human ceruloplasmin led to the oxidation of Mn(II) to Mn(III) in vitro, and although the 

process was not studied in vivo, it is a likely mechanism for manganese oxidation in the blood. These 

authors also noted that manganese oxidation led to a shift in manganese binding in vitro from α2-macroglobulin to transferrin and that in vivo clearance of Mn(II)-α2-macroglobulin from cows was much more 

rapid than the clearance of Mn(III)-transferrin (Gibbons et al. 1976). This suggests that the rate and 

extent of manganese reduction/oxidation reactions may be important determinants of manganese retention 

and toxicity in the body. 

As demonstrated in a study by Komura and Sakamoto (1991), tissue levels of manganese in rats were 

affected by the form in which the manganese was administered in the diet; levels of manganese were 

significantly higher in animals fed manganese acetate or manganese carbonate than in animals fed 

manganese chloride or manganese dioxide. 

Reaney et al. (2006) compared brain concentrations of manganese, dopamine, and gamma amino butyric 

acid in female retired breeder Long Evans rats exposed to cumulative intraperitoneal doses of 0, 30, or 

90 mg manganese/kg of Mn(II) chloride or Mn(III) pyrophosphate. Rats were given intraperitoneal doses 

of 0, 2, or 6 mg manganese/kg, 3 times/week for 5 weeks. In Mn(III)-treated rats, brain manganese 

concentrations (analyzed in the striatum, globus pallidus, thalamus, and cerebrum regions) and blood 

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concentrations were higher than brain concentrations in Mn(II)-treated rats. The only other marked 

changes in end points between the two treatment groups was that the highest Mn(III) exposure group 

showed a 60% increased dopamine level in the globus pallidus (compared with controls), whereas the 

comparably treated Mn(II) rats showed a 40% decrease in globus pallidus dopamine level. These results 

suggest that manganese valence state can influence tissue toxicokinetic behavior, and possibly toxicity. 

MMT. Following intravenous administration in the male rat, MMT was metabolized to hydroxylmethylcyclopentadienyl manganese tricarbonyl (CMT-CH2OH) and carboxycyclopentadienyl manganese 

tricarbonyl (CMT-COOH), both of which are present in urine (Hanzlik et al. 1980a). Metabolites are also 

present in the bile, as indicated by the fecal recovery of 3

H from the ring structure in MMT following 

intravenous or intraperitoneal administration of radiolabeled compound to rats (Hanzlik et al. 1980a, 

1980b). After intravenous dosing of MMT in rats, 11% of the radiolabel was recovered in feces within 

30 minutes (Hanzlik et al. 1980b). These metabolites have not been characterized; however, the 

administration of phenobarbitol to the rat doubled the biliary excretion of the metabolite (Hanzlik et al. 

1980a). 

In vitro studies showed that rat liver microsomes activated with NADPH and molecular oxygen 

metabolized MMT (Hanzlik et al. 1980b). Preliminary studies with pooled liver microsomes from 5 to 

6 normal or phenobarbital-induced rats showed that reaction rates of metabolism were linear for the first 

20 minutes. MMT and aminopyrine, a positive control compound that is metabolized exclusively by 

cytochrome P450, showed parallel responses to changes in incubation conditions (i.e., NADPH 

dependence, inhibition by carbon monoxide, induction by phenobarbital). Liver microsomes metabolized 

MMT with an estimated KM of 78 μM and a Vmax of 3.12 nmol/mg protein/minute. When the studies 

were done with liver microsomes from phenobarbital-treated rats, the KM remained the same, but the Vmax 

doubled (Hanzlik et al. 1980b). Lung microsomes were equally capable of metabolizing MMT, but 

phenobarbital induction did not enhance the response. 

In humans, an infusion of the clinical dose of MnDPDP (5 μmol/kg or 0.25 mg/kg) is rapidly 

dephosphorylated to manganese dipyridoxyl monophosphate (MnDPMP). This metabolite has been 

measured in human blood as quickly as 18 minutes after the beginning of infusion of the contrast agent, 

and is still measurable 1.3 hours after the start of the infusion (Toft et al. 1997a). MnDPMP was not 

observed in the blood after the first 18 minutes. The monophosphate is then fully dephosphorylated to 

manganese dipyridoxyl ethylenediamine (MnPLED); this compound has been isolated in blood from 

18 minutes after the start of an infusion until 40 minutes after the start. Transmetallation of either 

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MnDPDP, MnDPMP, or MnPLED with zinc can occur, forming ZnDPDP, ZnDPMP, or ZnPLED. 

ZnDPDP has been identified in the bloodstream during the first 18 minutes of an infusion of 0.25 mg 

manganese/kg as MnDPDP. ZnDPMP has been detected in the blood from 18 to 40 minutes following 

the start of the infusion, and ZnPLED has been measured in the blood from 18 minutes to 8.33 hours 

following the start of the infusion. The major metabolite detected in urine was ZnPLED (Toft et al. 

1997a). Figure 3-4 depicts the metabolism of mangafodipir in the human. 

To study mangafodipir metabolism in the dog, Toft et al. (1997c) injected three male and female beagles 

with 0.55, 1.7, or 5.5 mg manganese/kg and took timed blood samples post-dosing to analyze for the 

presence of metabolites. Mangafodipir was rapidly metabolized by dephosphorylation and 

transmetallation at all three doses. After infusion with 0.55 mg/kg, MnPLED was the primary metabolite 

observed in the bloodstream 1 minute after the end of the infusion period, and MnDPDP was present at a 

concentration lower than the five metabolites. At 30 minutes post-dosing, ZnPLED was the main 

metabolite. However, at 5.5 mg/kg, MnPLED was the main metabolite at all sampling times (1, 5, and 

30 minutes). The authors estimated that the ratios of manganese metabolites to zinc metabolites were 1, 

2, and 3.5 at doses of 0.55, 1.7, or 5.5 mg manganese/kg, respectively; these data are consistent with the 

authors’ hypothesis that the limited availability of free or loosely bound plasma zinc governs the initial 

transmetallation reaction (Toft et al. 1997c). 

In vitro experiments with radiolabeled MnDPDP and whole blood or plasma from human donors indicate 

that mangafodipir undergoes a rapid transmetallation with zinc that is nearly complete within 1 minute 

after the start of incubation, followed by a relatively slow dephosphorylation process. The primary 

metabolite after a 90-minute incubation of whole blood with MnDPDP was MnDPMP, followed by 

CaDPDP/DPDP, Mn(III)DPDP (suggested as an artifact due to high pH and oxygen), and MnPLED. 

Experiments using 14C-DPDP indicate that this chelate cannot enter red blood cells; therefore, the zinc 

contained within the cells is unavailable for binding to this compound. Binding of manganese ion to 

serum proteins was observed as well, indicating that dissociation of the metal from the chelate had 

occurred during incubation (Toft et al. 1997b). 

3.4.4 Elimination and Excretion 

In humans, absorbed manganese is removed from the blood by the liver where it conjugates with bile and 

is excreted into the intestine. Biliary secretion is the main pathway by which manganese reaches the 

intestines where most of the element is excreted in the feces (Bertinchamps et al. 1965; Davis et al. 1993; 

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Figure 3-4. Metabolism of MnDPDP 

PO -

4 PO4 

MnDPDP MnDPMP MnPLED 

ZnDPDP ZnDPMP ZnPLED 

-

PO4 

PO4 - -

PO4 

-

H2O H2O 

H2O H2O H2O 

H H2O

2O 

- PO4

- PO4 

Source: Toft et al. 1997c 

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MANGANESE 233 

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Malecki et al. 1996). However, some of the manganese in the intestine is reabsorbed through 

enterohepatic circulation (Schroeder et al. 1966). 

Small amounts of manganese can also be found in urine, sweat, and milk (EPA 1993b). Urinary excretion 

of manganese by healthy males was 7.0 nmole/g creatinine (7.0 nmole=385 ng=0.385 μg) (Greger et al. 

1990). Similarly, urinary manganese excretion by women was 9.3 nmole/day. Moreover, urinary 

excretion of manganese was not responsive to oral intake of manganese (Davis and Greger 1992). Dorner 

et al. (1989) showed that some infants fed breast milk and formula suffered negative manganese balances 

due to high fecal excretion. However, animal studies indicate that in the young, excretion is not welldeveloped and may result in increased retention of the element. For example, in mice, rats, and kittens, 

there is an almost complete absence of excretion during the neonatal period (Cotzias et al. 1976). 

However, data in neonatal rats indicate that manganese retention rates decrease to rates observed in adult 

animals. This is indirect evidence that excretion may mature during the end of the neonatal period though 

the exact time frame across species is unknown. 

3.4.4.1 Inhalation Exposure 

In humans who inhaled manganese chloride or manganese tetroxide, about 60% of the material originally 

deposited in the lung was excreted in the feces within 4 days (Mena et al. 1969). Chronically exposed 

male workers were reported to have urine manganese levels that were significantly higher than unexposed 

persons; for example, male foundry workers had a mean manganese level of 5.7 μg/L compared to 

0.7 μg/L in unexposed controls (Alessio et al. 1989). Other studies have reported significantly increased 

levels of urinary manganese in men occupationally exposed to airborne manganese dusts and fumes 

(Lucchini et al. 1995; Roels et al. 1987a, 1992). Mergler et al. (1994) did not report a significant 

difference in urinary manganese levels between the exposed and control groups in their occupational 

study. The differences in urinary excretion may be due to differences in duration or extent of exposure. 

A listing of these occupational studies that measured exposure levels of manganese and the resultant 

levels of the metal in biological samples is provided in Table 3-13. 

Rats exposed to either manganese chloride or manganese tetroxide by intratracheal instillation excreted 

about 50% of the dose in the feces within 3–7 days (Drown et al. 1986). Monkeys exposed to an aerosol 

of 54MnCl2 excreted most of the manganese, with a half-time of 0.2–0.36 days (Newland et al. 1987). 

However, a portion of the compound was retained in the lung and brain. Clearance of this label was 

slower, occurring with half-times of 12–250 days. These data do not provide information on how much 

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Table 3-13. Levels of Manganese in Exposed and Non-Exposed Workers 

Biological samples 

Occupational study 

Mean age 

(years) Mn in air (mg/m3) 

Mn-blood 

μg/100 mL 

Mn-urine μg/g 

creatinine 

Roels et al. (1987b) 

Exposed 34.3±9.6 0.97a (total dust) 1.36b±0.64 (1.22)c 4.76b (0.4)c 

Non-exposed 38.4±11.3 0.57b±0.27 (1.59)c 0.30b (0.15)c 

Roels et al. (1992) 

Exposed 31.3±7.4 0.179a (respirable dust) 0.81c 0.84c 

Non-exposed 29.3±8.0 0.68c 0.09c 

Chia et al. (1993a) 

Exposed 36.6±12.2 1.59b (total dust) 2.53c 6.1c (μg/L) 

Non-exposed 35.7±12.1 2.33c 3.9c (μg/L) 

Mergler et al. (1994) 

Exposed 43.4±5.4 0.032a (respirable dust) 1.12b (1.03)c 1.07b (0.73)c 

Non-exposed 43.2±5.6 0.72b (0.68)c 1.05 (0.62)c 

Lucchini et al. (1999) 

Exposed 42.1±8.3 0.0967 (respirable dust) 0.97b (0.92)c 1.81b (1.53)c 

(CEI/years) 

Non-exposed 42.6±8.8 0.6b (0.57)c 0.67b (0.40)c 

a

Median b

Arithmetic mean c

Geometric mean 

CEI = cumulative exposure index 

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of the manganese excreted in the feces after inhalation exposure was first absorbed and then excreted via 

the bile versus the amount simply transported directly from the lung to the gastrointestinal tract where it 

may have been absorbed. In addition, because these investigators measured manganese using gamma 

spectrometry techniques, the relatively long elimination half-times from the brain may have been 

influenced by manganese present in skull bones. In monkeys exposed to 1.5 mg manganese/m3 

manganese sulfate for 65 days, manganese concentrations were elevated (compared with air control 

values) in many brain regions and other tissues; 45 days following cessation of exposure, concentrations 

remained elevated in the olfactory cortex, globus pallidus, putamen, pituitary gland, and blood, but 

returned to air control values by 90 days after exposure (Dorman et al. 2006a). Based on these data, 

Dorman et al. (2006a) calculated elimination half-lives of about 15–16 days for the globus pallidus and 

putamen, suspected neurotoxicity targets of manganese. 

Rat studies have demonstrated that urinary excretion of manganese 1 day following inhalation exposure 

was increased 200- and 30-fold when the animals were treated with the chelating agents 

1,2-cyclohexylene-aminetetraacetic acid (CDTA) and diethylene triamine pentaacetic acid (DTPA), 

respectively, but fecal excretion was not altered (Wieczorek and Oberdörster 1989b). 

No studies were located regarding excretion of manganese in either humans or animals following 

inhalation exposure to organic manganese. 

3.4.4.2 Oral Exposure 

Humans who ingested tracer levels of radioactive manganese (usually as manganese chloride) excreted 

the manganese with whole-body retention half-times of 13–37 days (Davidsson et al. 1989a; Mena et al. 

1969; Sandstrom et al. 1986). The route of manganese loss was not documented, but was presumed to be 

mainly fecal after biliary excretion. Serum manganese concentrations in a group of healthy men and 

women in Wisconsin were 1.06 and 0.86 μg/L, respectively (Davis and Greger 1992; Greger et al. 1990). 

Urinary excretion of manganese by men was 7.0 nmole/g creatinine (Greger et al. 1990). Similarly, 

urinary manganese excretion of women was 9.3 nmole/day. Moreover, urinary excretion of manganese 

was not responsive to oral intake of manganese (Davis and Greger 1992). 

In a more recent study, young rats fed 45 mg manganese/kg/day were found to absorb 8.2% of the 

manganese ingested and to lose approximately 37% of the absorbed manganese through endogenous gut 

secretions (Davis et al. 1993). 

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The daily excretion of manganese from mice ingesting 11 mg manganese/kg as MMT in their daily diet 

was 5.4% of their daily intake (Komura and Sakamoto 1992b). In a comparison of plasma manganese 

kinetics following oral administration of MMT or manganese chloride in male rats, MMT-derived 

manganese was eliminated extremely slowly, having an average elimination half-time of 55.2 hours, 

compared with 4.56 hours for manganese chloride (Zheng et al. 2000). Rats receiving MMT showed an 

apparent oral clearance (CL/F) of 0.09 L.hours-1.kg-1, which was about 37-fold less than the oral clearance 

of manganese chloride (CL/F = 3.2 L.hours-1.kg-1). Accordingly, the AUC in MMT rats was about 

37-fold higher than that in manganese chloride rats who received equivalent dose of manganese. A 

gender difference in manganese toxicokinetics following oral MMT exposure was also observed; female 

rats showed higher mean AUC and longer half times of plasma manganese than male rats (93.1 versus 

51.8 mM hours and 68.4 versus 42.0 hours, respectively (Zheng et al. 2000). 

No other studies were located regarding excretion of manganese from organic manganese compounds in 

either humans or animals. 

3.4.4.3 Dermal Exposure 

No studies were located regarding excretion of inorganic or organic manganese in humans or animals 

after dermal exposure to manganese. 

3.4.4.4 Other Routes of Exposure 

No studies were located regarding excretion of manganese by humans after exposure to inorganic 

manganese via other routes of exposure. 

Rats exposed to manganese chloride by intravenous injection excreted 50% of the dose in the feces within 

1 day (Klaassen 1974) and 85% by day 23 (Dastur et al. 1971), indicating that biliary excretion is the 

main route of manganese clearance. Only minimal levels were excreted in urine (<0.1% of the dose 

within 5 days) (Klaassen 1974). Direct measurement of manganese levels in bile revealed concentrations 

up to 150-fold higher than in plasma, indicating the existence of either an active transport system 

(Klaassen 1974) or some sort of trapping mechanism (Tichy and Cikrt 1972). Based on the difference in 

blood levels following portal or femoral injection, Thompson and Klaassen (1982) estimated that about 

33% of the manganese burden in blood is removed in each pass through the liver. Apparently, some 

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manganese can cross directly from the blood to the bile (Bertinchamps et al. 1965; Thompson and 

Klaassen 1982), but most appears to be secreted into the bile via the liver (Bertinchamps et al. 1965). 

The chemical state of manganese in bile is not known, but a considerable fraction is bound to bile 

components (Tichy and Cikrt 1972). This material is apparently subject to enterohepatic recirculation, 

since biliary manganese is reabsorbed from the intestine more efficiently than free Mn(II) (Klaassen 

1974). The amount of manganese that contributes to total body burden following reabsorption from 

enterohepatic recirculation is not known. 

While biliary secretion appears to be the main pathway by which manganese is excreted into the 

intestines, direct transport from blood across the intestinal wall may also occur (Bertinchamps et al. 1965; 

Garcia-Aranda et al. 1984). The relative amount of total excretion attributable to this pathway was not 

quantified by Bertinchamps, but it appears to be only a fraction of that attributable to biliary secretion 

(Bertinchamps et al. 1965). 

Manganese originating from mangafodipir administered at clinical (0.25 mg/kg) and more than twice the 

clinical dose (0.55 mg/kg) is primarily excreted in the feces via the bile in both humans and animals 

(Grant et al. 1994; Hustvedt et al. 1997; Toft et al. 1997a; Wang et al. 1997). In contrast to the chelate, 

DPDP, manganese is incompletely cleared from the body 24 hours after administration, and roughly 7– 

8% of a dose is still retained in the body after 1 week (Hustvedt et al. 1997). 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

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tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-5 shows a conceptualized representation of a PBPK model. 

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MANGANESE 239 

3. HEALTH EFFECTS 

Figure 3-5. Conceptual Representation of a Physiologically Based
 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance
 

Inhaled chemical Exhaled chemical 

Ingestion 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax 

Km GI 

Tract 

Feces 

Urine

 Chemicals 

contacting skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan and Andersen 1994 

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MANGANESE 240 

3. HEALTH EFFECTS 

If PBPK models for manganese exist, the overall results and individual models are discussed in this 

section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species 

extrapolations. 

PBPK models for manganese are discussed below. 

No PBPK models have been developed for manganese in humans, but several recent reports are available 

on the development of models for manganese in rats. 

Initial Conceptual PBPK Model for Manganese (Andersen et al. 1999). A qualitative PBPK model for 

manganese disposition in humans and animals was initially developed by Andersen et al. (1999). This 

model represented the current understanding of manganese nutrition and toxicology, and because several 

data gaps existed concerning manganese pharmacokinetics, this model is anticipated to change with time 

(Andersen et al. 1999). The model, shown in Figure 3-6, was not designed to be quantitative in nature. 

The authors indicated that several data gaps prevented such an evaluation of manganese uptake, 

distribution, and excretion. For instance, there were inadequate data concerning oxidation rates for 

manganese in blood, uptake rates of protein-bound forms by the liver, neuronal transfer rates within the 

central nervous system, and quantitative data on systems controlling manganese uptake via the intestines 

and liver (such as transport mechanism in the intestines) (Andersen et al. 1999). Andersen et al. (1999) 

suggested that an approach to setting acceptable exposure levels for an essential, but neurotoxic, nutrient 

such as manganese could be based on predicting exposure levels by any route that would increase brain 

manganese concentrations to a small fraction (e.g., 10–25%) of the variation observed in the general 

human population. Reliable and validated multiple-route PBPK models for multiple species, including 

humans, are needed to take this approach to setting acceptable exposure levels. Efforts to develop such 

models in rats have been recently described (Leavens et al. 2007; Nong et al. 2008; Teeguarden et al. 

2007a, 2007b, 2007c). 

Whole-Body PBPK Models (Nong et al. 2008; Teeguarden et al. 2007a, 2007b, 2007c). Utilizing 

pharmacokinetic and tissue manganese concentration data from several published studies of manganese in 

rats and mice, recent efforts have developed PBPK models for manganese in rats that include processes 

involved in homeostatic regulation of tissue levels of manganese taken up by ingestion and by inhalation 

(Nong et al. 2008; Teeguarden et al. 2007a, 2007b, 2007c). Two PBPK model structures were developed 

and evaluated for their ability to account for kinetics of manganese in the liver and brain striatum 

following inhalation and dietary administration of soluble forms of inorganic manganese. The data sets 

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[

Mn3+

MANGANESE 241 

3. HEALTH EFFECTS 

Figure 3-6. Qualitative PBPK Model for Manganese 

Liver 

Intestine 

Mn in Diet] Intestinal Lumen 

[Airborne Mn] 

Lung Deposition 

Arterial Blood 

Matrix 

Bone 

Tissues 

CNS Targets 

Blood-Brain Barrier 

Capillary Blood 

Feces 

bile 

Mn3+ 

Inhaled Mn 

Nose 

Source: Andersen et al. 1999 

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MANGANESE 242 

3. HEALTH EFFECTS 

used to evaluate the models were: (1) tissue manganese concentrations in rats receiving diets containing 2, 

10, or 100 ppm manganese for 13 weeks and elimination kinetics for an intravenous tracer dose of 54Mnmanganese chloride (Dorman et al. 2001b); (2) tissue manganese concentrations and tracer kinetics in rats 

fed a 100-ppm diet and exposed to 0, 0.03, 0.3 or 3 mg manganese/m3 manganese sulfate 6 hours/day for 

14 consecutive days (Dorman et al. 2001a); and (3) tissue manganese concentrations (sampled at 0, 45, 

and 90 days after exposure) in rats fed a 10-ppm diet and exposed to 0, 0.1 or 0.5 mg manganese/m3 for 

6 hours/day, 5 days/week for 90 days (Dorman et al. 2004b). 

Structures of the models are shown in Figure 3-7. Model A is based on regulation of tissue 

concentrations by simple partitioning with slow inter-compartmental transfer from free manganese in 

tissues to deeper tissue stores of manganese (“diffusion-controlled tissue partitioning”; Nong et al. 2008; 

Teeguarden et al. 2007a, 2007b, 2007c). Model B features saturable binding of manganese in liver and 

brain with equilibrium binding constants defined by slow association and dissociation rate constants 

(Nong et al. 2008). Both models contain a submodel for deposition and absorption in the nose and lung 

shown schematically in Figure 3-8 (Teeguarden et al. 2007c). 

Nong et al. (2008) Model A Description and Development. Model A contains six compartments: the 

respiratory tract, brain striatum, liver, kidneys, bone, and slowly perfused tissues (Figure 3-7). The 

respiratory tract is divided into two subcompartments: nasopharyngeal tissues and lung (Figure 3-8). 

Table 3-14 lists parameters of Model A as described by Teeguarden et al. (2007c). Each of the six 

compartments is subdivided into a conventional flow-limited compartment connected to the blood and 

tissue stores that are not readily equilibrated with blood moving through the tissue compartment. Firstorder clearance rate constants (e.g., kInBrnC and koutBrnC) determine the transfer of manganese from 

the flow-limited compartment to the deep compartment of each tissue. The clearance rate constants, 

together with the blood flow to the tissue (e.g., QBrnC) and the tissue partition coefficients (e.g., PBrn), 

determine the steady-state concentrations and the rate of change manganese in each of the tissues, 

according to differential equations that are described in detail by Teeguarden et al. (2007c). 

Physiological parameters were taken from the literature and included values for blood flows, organ 

volumes, and food intake rate (Table 3-14). The initial (basal) concentrations of manganese in the tissues 

(Table 3-14) were taken from literature values as described by Teeguarden et al. (2007c). Remaining 

model parameters were estimated by fitting the model to experimental data. Fractions of manganese in 

the shallow versus deep compartments of each tissue (e.g., fBrn and FDBrn, Table 3-14) were calibrated 

to obtain the best fit to intraperitoneal 54Mn clearance data collected by Furchner et al. (1966). Partition 

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MANGANESE 243 

3. HEALTH EFFECTS 

Figure 3-7. Schematic Structures of Nong et al. (2008) PBPK Models A and B for 

Manganese in CD Rats* 

Model A Model B 

Inhaled Mn Inhaled Mn 

Diet Bile Diet 

Lung and nose 

Brain 

Bone 

Kidney 

Rest of body 

Liver 

Deep Brain 

(striatum) 

Deep Bone 

Deep Kidney 

Deep Body 

Deep Liver 

QLiv 

QBody 

QKid 

QBone 

QBrn 

QC 

klnBone kOutBone 

kInBrn kOutBrn 

kInKid kOutKid 

kInBody kOutBody 

kInLiv kOutLiv 

Arterial blood 

Venous blood 

Lung and nose 

Brain blood 

PA12 PA21 

Brain tissue (striatum) 

Kdbrain 

Mnbound Mnfree 

kabrain 

Bone 

Kidney 

Rest of body 

Liver 

Kdliver 

Mnbound Mnfree 

kaliver 

Deep Bone 

Deep Kidney 

Deep Body 

QLiv 

QBody 

QKid 

QBone 

QBrn 

QC 

klnBone kOutBone 

kInKid kOutKid 

kInBody kOutBody 

Bile Arterial blood 

Venous blood 

*Values and descriptions of model parameters are in Tables 3-14, 3-15, and 3-16. 

Source: Nong et al. 2008 

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MANGANESE 244 

3. HEALTH EFFECTS 

Figure 3-8. Schematic of Models for Nasopharyngeal and Lung Deposition of
 

Manganese and Transport to Blood in the Nong et al. (2008) PBPK
 

Models A and B for Manganese in CD Rats
 

Inhaled Mn 

(klnh) 

Nasopharyngeal 

Deposited 

Deep NP 

Shallow NP 

Deposited 

Deep Lung 

Shallow Lung 

kInLung kOutLung 

kDepSLc kDepDLc 

fdepLu Lung 

kInNP kOutNP 

fdepNP 

kDepSNc 

kNPBIc 

venous 

kdepDNc 

arterial 

Source: Teeguarden et al. 2007c 

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MANGANESE 245 

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Table 3-14. Parameter Values in the Teeguarden et al. (2007c) PBPK Model for
 

Manganese in CD Rats (Nong et al. 2008) Model A
 

Parameter Valuea 

BW Body weight (kg) 0.325b 

QCC Cardiac output (L/hour for 1-kg animal) 14.6 

QPC Alveolar ventilation (L/hour for 1-kg animal) 30.0 

Blood flows (fraction of cardiac output) 

QSlowC Slow 0.534 

QBoneC Bone 0.122 

QBrnC Brain 0.02 

QKidC Kidneys 0.141 

QLivC Liver 0.183 

Tissue volumes (fraction of body weight) 

VArtC Arterial blood 0.0224 

VBldC Blood 0.0676 

VSlowC Slow 0.738 

VBoneC Bone 0.021 

VDBoneC Bone deep compartment 0.052 

VBrnC Brain 0.006 

VKidC Kidneys 0.007 

VLivC Liver 0.034 

VLungC Lung 0.007 

VNasPhaCc Nasopharyngeal 0.0038 

VTraBroCc Tracheobronchial 0.01107 

VPulmonC Pulmonary 0.01107 

VVenC Venous blood 0.0452 

Partition coefficients 

Pslow Slow 0.4 

PBone Bone 30 

PBrn Brain 0.1 

PKid Kidneys 1.25 

PLiv Liver 5.0 

PLung Lung 0.3 

Pnaspha Nasopharyngeal 0.3 

Clearance rates 

kBile0C Biliary excretion (L/hour-kg body weight) 2.0 

kFeces Loss in feces (L/hour-kg body weight) 0.0001 

Clearance rates (/h) 

kInSlowC Into deep slow compartment 0.017 

kInBoneC Into deep bone compartment 0.105 

kInBrnC Into deep brain compartment 0.011 

kInKidC Into deep kidney compartment 0.146 

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MANGANESE 246 

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Table 3-14. Parameter Values in the Teeguarden et al. (2007c) PBPK Model for
 

Manganese in CD Rats (Nong et al. 2008) Model A
 

Parameter Valuea 

kInLivC Into deep liver compartment 0.621 

kInNPC Into deep nose compartment 0.035 

kInLungC Into deep lung compartment 0.035 

kOutSlowC Out of deep slow 0.0035 

kOutBoneC Out of deep bone 0.00085 

kOutBrnC Out of deep brain 0.00056 

kOutKidC Out of deep kidneys 0.0034 

kOutLivC Out of deep liver 0.007 

kOutNPC Out of deep nose 0.0035 

kOutLungC Out of deep lung 0.0035 

Initial concentrations of manganese (μg/L) 

CArt0 Arterial blood 10.0 

CBld0 Blood 10.0 

CSlow0 Slow 110.0 

CDSlow0 Deep slow 110.0 

CBone0 Bone 650.0 

CDBone0 Deep bone compartment 650.0 

CBrn0 Brain 450.0 

CDBrn0 Deep brain 450.0 

CKid0 Kidneys 1000.0 

CDKid0 Deep kidneys 1000.0 

CLiv0 Liver 2600.0 

CDLiv0 Deep liver 2600.0 

CLung0 Lung 250.0 

CDLung0 Deep lung 250.0 

CNose0 Nose 0.0 

CDNose Deep nose 0.0 

CVen0 Venous blood 10.0 

Fractional coefficients 

fDepNPc Particles deposited nasopharyngeal 0.2 

fDepTBc Particles deposited tracheobronchial 0.21 

fDepPuc Particles deposited pulmonary 0.07 

Fraction of manganese in shallow versus deep tissued 

(ratios of volumes; not separately estimated model parameters) 

fSlow Slow 0.5 

fDSlow Deep slow 0.5 

fBrn Brain 0.05 

fDBrn Deep brain 0.95 

fKid Kidneys 0.25 

fDKid Deep kidneys 0.75 

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Table 3-14. Parameter Values in the Teeguarden et al. (2007c) PBPK Model for
 

Manganese in CD Rats (Nong et al. 2008) Model A
 

Parameter Valuea 

fLiv Liver 0.4 

fDLiv Deep liver 0.6 

fLung Lung 0.1 

fDLung Deep lung 0.9 

FDNose Deep nose 0.9 

fDBody Body 0.5 

Dosing parameters 

InFac1 Dietary intake factor for first diet 0.05 

FDietUp Fraction of manganese in diet that is absorbed 0.008 

a

Physiological parameters are consistent with those reported by Brown et al. (1997). Rate constants were fit to 

available experimental data on the kinetics of Mn in the various tissues. Rate constants fitted to the control steadystate Mn tissue concentrations reported by Furchner et al. (1966) and used to simulate ip and inhalation experiments 

are shown. 

b

Default body weight. Some body weights were lower (0.25) to represent study conditions. 

c

The deposition lung region of the lung is the sum of the tracheobronchial and pulmonary tissue 

(fDepLu=fDepTB+fDepPu; VDepLuC=VTraBroC+VPulmonC).

d

This fraction is not an independently estimated variable. Instead, the fraction represents the ratio of the two rate 

constants, kin and kout, for each tissue. 

Source: Teeguarden et al. 2007c 

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MANGANESE 248 

3. HEALTH EFFECTS 

coefficients (e.g., PBrn, Table 3-14) and clearance rate constants into and out of deep compartments (e.g., 

kInBrnC, kOutBrnC) were calibrated with 54Mn kinetic data collected by Furchner et al. (1966) and 

steady-state tissue manganese concentration data collected by Wieczorek and Oberdörster (1989c). The 

fraction of manganese absorbed from the gut (FDietUp) was assumed to be 0.8%. The rate of biliary 

excretion from liver (kBile0C) was determined by matching the rate of manganese excreted from liver 

against the amount of manganese taken up from the diet, while maintaining steady-state levels of 

manganese in all tissues and matching the turnover of 54Mn for each tissue (Teeguarden et al. 2007c). For 

inhaled manganese, fractional depositions in the nasopharyngeal (fDepNP = 0.2), tracheobronchial 

(fDepTB = 0.21), and pulmonary (fDeppu = 0.07) regions were taken from the EPA (1994a) respiratory 

tract deposition model for 1.1-μm aerosols. The model assumed that deposited aerosols dissolved 

immediately and that there was no clearance from the airway lumen to the gut via mucociliary transport; 

this assumption is valid for soluble manganese forms such as manganese chloride and manganese sulfate, 

but would not be valid for less-soluble forms of manganese such as manganese phosphate (Nong et al. 

2008; Teeguarden et al. 2007c). 

Nong et al. (2008) described further refinements to model A parameters shown in Table 3-15. Daily 

manganese dietary intake (FDietUp) and biliary elimination rate constants (kBileC) were first calibrated for 

different levels of manganese in the diet (2, 10, 100, and 125 ppm; Table 3-15) by fitting the model to the 

observed steady-state tissue manganese concentration data for rats exposed to 2, 10, or 100 ppm 

manganese in the diet for 13 weeks (Dorman et al. 2001b). After this refinement, clearance rates for the 

liver and brain striatum (kIn and kOut values shown in Table 3-15) were refined by fitting the model to 

tissue manganese concentration data from the 14-day inhalation study by Dorman et al. (2001a). 

Nong et al. (2008) Model B Description and Development. Model B contains a similar structure to 

Model A, except that manganese concentrations in the liver and brain striatum are dependent on capacitylimited binding of manganese (Figure 3-7). In addition, uptake from striatal blood to striatal tissues is 

described with diffusion terms (PA12 and PA21, Figure 3-7). The diffusion terms were included to account 

for observations of preferential increases in some brain regions compared with other tissues, such as liver 

or blood, following inhalation exposure to manganese (see Dorman et al. 2006a for review). The 

diffusion terms are thought to reflect movement of manganese across the blood-brain barrier (Nong et al. 

2008). In Model B, the total amounts of manganese in the liver and brain striatum tissues are dependent 

on concentrations of free circulating manganese, the binding capacity of the tissue, and the concentrations 

of bound manganese in tissue stored (Nong et al. 2008). Differential equations to describe changes (with 

time) in amounts of free or bound manganese in the liver and the brain striatum are described in detail by 

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MANGANESE 249 

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Table 3-15. Refined Parameter Values in Nong et al. (2008) Model A 

Parametera Manganese level in diet Biliary excretion (/h/kg) 

kBileC 2 ppm manganese 0.19 

10 ppm manganese 0.28 

100 ppm manganese 0.60 

125 ppm manganese 0.60 

Tissue clearance rates (/h/kg) 

kInLivC Into deep liver compartment 0.621 

kInBrnC Into deep brain compartment 0.011 

kOutLivC Out of deep liver compartment 0.007 

kOutBrnC Out of deep brain compartment 0.00039 

Dosing parameters: diet level Fraction of manganese in diet that is 

of manganese absorbed 

FDietUp 2 ppm manganese 0.044 

10 ppm manganese 0.018 

100 ppm manganese 0.004 

125 ppm manganese 0.003 

a

The remaining parameters are described in Teeguarden et al. (2007c). Clearance rates are scaled to the body 

weight (BW−0.25). 

Source: Nong et al. 2008 

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MANGANESE 250 

3. HEALTH EFFECTS 

Nong et al. (2008). Table 3-16 lists binding rate constants (e.g., kaBrnC, kdBrnC), binding capacities 

(Bmax,Brain, Bmax.Liver), brain diffusion constants (PA12 and PA21), and partition coefficients in Model B. 

Liver and brain striatum binding capacity levels were first determined by fitting the model to steady-state 

tissue concentration data from the 13-week dietary study by Dorman et al. (2001b), using starting values 

for the tissue binding parameters that were estimated based on clearance rate values (kIn and kout) for 

liver and brain striatum in Model A. Tissue binding parameters (e.g., kaBrnC, kdBrnC) and brain 

diffusion constants (PA12 and PA21) were then refined by fitting the model to the 14-day-inhalation tissue 

concentration data from Dorman et al. (2001a). 

Evaluation of Nong et al. (2008) Models A and B. Nong et al. (2008) compared the abilities of Models 

A and B to predict: (1) whole-body elimination kinetics of 54Mn in rats fed a 100-ppm diet for 13 weeks 

(data from Dorman et al. 2001b); (2) liver and brain striatum manganese concentration data in rats 

exposed to 0.03, 0.3, or 3 mg manganese/m3 for 6 hours/day for 14 consecutive days (Dorman et al. 

2001a); (3) whole-body elimination kinetics of 54Mn in rats following 14-day inhalation exposure to 3 mg 

manganese/m3

; and (4) liver and brain striatum manganese concentrations in rats during and following a 

90-day inhalation exposure period to 0.1 or 0.5 mg manganese/m3 (Dorman et al. 2004b). Both models 

adequately predicted observed 54Mn elimination kinetics data, but Model B much more accurately 

predicted liver and brain striatum manganese concentration data during and following 14- or 90-day 

inhalation exposures. Model A consistently overestimated liver and brain striatum manganese 

concentration, particularly at concentrations of 0.1, 0.3, or 0.5 mg manganese/m3 (as shown in Figures 4 

and 7 of Nong et al. 2008). Nong et al. (2008) concluded that the evaluation of the models “highlighted 

the importance of tissue binding in maintaining relatively constant tissue concentrations across a wide 

range of inhaled concentrations.” Nong et al. (2008) mentioned that the next steps in model development 

would be to extend tissue binding in Model B to all other tissues in the models for which appropriate data 

are available for calibrating tissue-specific binding rate constants. 

PBPK Model for Manganese Transport from the Olfactory Mucosa to Striatum (Leavens et al. 2007). 

Leavens et al. (2007) developed a pharmacokinetic model describing the olfactory transport and blood 

delivery of manganese to the striatum in rats following acute inhalation exposure to manganese chloride 

or manganese phosphate. Figure 3-9 shows the structure of the model, which presumes that manganese 

undergoes axonal transport from the olfactory mucosa (OM) to the olfactory bulb (OB), followed by 

serial transport to the olfactory tract and tubercle (OTT) and then to the striatum (S). Tables 3-17 and 

3-18 list values of the model parameters for soluble manganese chloride and relatively insoluble 

manganese phosphate, respectively. Each of the compartments in the model (containing a left and right 

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MANGANESE 251 

3. HEALTH EFFECTS 

Table 3-16. Parameter Values in Nong et al. (2008) Model B 

Parametersa Values 

Tissue binding rate constantsa 

kaBrnC Association striatum constant (/h/μg/kg) 0.000176 

kaLivC Association liver constant (/h/μg/kg) 0.06772 

kdBrnC Dissociation striatum constant (/h/kg) 0.00002 

kdLivC Dissociation liver constant (/h/kg) 0.0054196 

Tissue binding constants (μg/kg) 

Bmax,brain Maximal binding striatum constant 3,300 

Bmax,liver Maximal binding liver constant 1,000 

Brain diffusion constants (/hour/kg) 

PA12 Influx brain tissue constant 1 

PA21 Efflux brain tissue constant 0.16 

Partition coefficient 

Pbrain Brain (striatum):blood 1.0 

Pliver Liver:blood 1.08 

a

The remaining parameters are described in Teeguarden et al. (2007c). b

Rate constants are scaled to the BW-0.25 and maximal binding capacities are scaled to BW-0.75 .
 

Source: Nong et al. 2008 

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MANGANESE 252 

3. HEALTH EFFECTS 

Figure 3-9. Schematic of the Leavens et al. (2007) Model to Describe Olfactory 

and Blood Delivery of Manganese to the Left Side of the Brain Isilateral to the 

Olfactory Mucosa (OM) in the Left Nasal Cavity* 

Blood 

Bound Bound Bound Bound 

Left Muscosa Left Bulb 

Left Tract & 

Tubercule Left Striatum 

Free Free 

ClOM 

blood kblood 

OM ClOB 

blood k blood 

OB ClOTT 

blood kblood 

OTT Cls 

blood ks 

blood 

kOM 

f:b kOM 

b:f 

kOM 

el 

kOB 

f:b kOB 

b:f 

kOB 

el 

kOTT 

f:b kOTT 

b:f 

f s · kOTT 

el 

(1- f s)· k OTT 

el 

Free Free 

kS 

f:b kS 

b:f 

*The model structure for the right side is identical. Values and descriptions of model parameters are in Tables 3-16, 

3-17, and 3-18. 

Source: Leavens et al. 2007 

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MANGANESE 253 

3. HEALTH EFFECTS 

Table 3-17. Parameter Values for Manganese Chloride in the Leavens et al. (2007)
 

PBPK Model for Olfactory Transport of Manganese in Rats
 

Parameter Description Value Units Source 

Compartment volumes 

V Left OM L 

OM 0.059 mL Measureda 

V Left OB L 

OB 0.031 mL Measureda 

V OTT Left OTT L 0.030 mL Measureda 

V Left striatum L 

S 0.032 mL Measureda 

V Right OM R 

OM 0.065 mL Measureda 

V Right OB R 

OB 0.038 mL Measureda 

V OTT Right OTT R 0.046 mL Measureda 

V Right striatum R 

S 0.042 mL Measureda 

Blood clearance into olfactory compartments 

Cl Influx to OM OM 

blood 4x10-4 mL/hour Estimated 

Cl Influx to OB OB 

blood 1x10-5 mL/hour Estimated 

Cl Influx to OTT OTT 

blood 6x10-4 mL/hour Estimated 

Cl blood Influx to striatum S 3x10-5 mL/hour Estimated 

Rate constants for olfactory compartments efflux to blood 

k Efflux from OM to blood blood 

OM 1x10-6 hour-1 Estimated 

k Efflux from OB to blood blood 

OB 1x10-6 hour-1 Estimated 

k Efflux from OTT to blood blood 

OTT 0.0 hour-1 Estimated 

k S Efflux from striatum to blood blood 1x10-6 hour-1 Estimated 

Olfactory transport rate constants 

k OM to OB OM 

el 0.022 hour-1 Estimated 

k OB to OTT OB 

el 0.037 hour-1 Estimated 

k OTT to striatum OTT 

el 0.094 hour-1 Estimated 

f Fraction of OTT loss rate to striatum S 0.001 Unitless Estimated 

Binding rate constants in olfactory compartments 

k OM free to bound OM 

f:b 0.006 hour-1 Estimated 

k OB free to bound OB 

f:b 0.0047 hour-1 Estimated 

k OTT free to bound OTT 

f:b 0.0043 hour-1 Estimated 

k Striatum free to bound S 

f:b 0.0026 hour-1 Estimated 

k OM bound to free OM 

b:f 1x10-6 hour -1 Constantb 

k OB bound to free OB 

b:f 1x10-6 hour-1 Constantb 

k OTT bound to free OTT 

b:f 1x10-6 hour-1 Constantb 

k Striatum bound to free S 

b:f 1x10-6 hour-1 Constantb 

a

Unpublished results measured in CD rats used in Brenneman et al. (2000) study. Plugged and unplugged exposure 

data were averaged together because they were not significantly different.

b

Not possible to estimate both constants for the binding; therefore, the rate constants for the bound to free
 

manganese were set to a low rate to allow slow removal of manganese tracer from the bound compartment.
 

Source: Leavens et al. 2007
 

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MANGANESE 254 

3. HEALTH EFFECTS 

Table 3-18. Parameter Values for Manganese Phosphate in the Leavens et al. 

(2007) PBPK Model for Olfactory Transport of Manganese in Rats 

Parameter Description Value Units Source 

Compartment volumes 

V Left OM L 

OM 0.085 mL Measureda 

V Left OB L 

OB 0.038 mL Measureda 

V OTT Left OTT L 0.025 mL Measureda 

V Left striatum L 

S 0.05 mL Measureda 

V Right OM R 

OM 0.074 mL Measureda 

V Right OB R 

OB 0.038 mL Measureda 

V OTT Right OTT R 0.04 mL Measureda 

V Right striatum R 

S 0.035 mL Measureda 

Blood clearance into olfactory compartments 

Cl Influx to OM OM 

blood 0.0017 mL/hour Estimated 

Cl Influx to OB OB 

blood 0.0018 mL/hour Estimated 

Cl Influx to OTT OTT 

blood 0.0016 mL/hour Estimated 

Cl blood Influx to striatum S 1.8x10-5 mL/hour Estimated 

Rate constants for olfactory compartments efflux to blood 

k Efflux from OM to blood blood 

OM 3x10-6 hour-1 Estimated 

k Efflux from OB to blood blood 

OB 0.0 hour-1 Estimated 

k Efflux from OTT to blood blood 

OTT 1x10-6 hour-1 Estimated 

k S Efflux from striatum to blood blood 1.5x10-5 hour-1 Estimated 

Olfactory transport rate constants 

k OM to OB OM 

el 0.011 hour-1 Estimated 

k OB to OTT OB 

el 0.036 hour-1 Estimated 

k OTT to striatum OTT 

el 0.099 hour -1 Estimated 

f Fraction of OTT loss rate to striatum S 0.033 Unitless Estimated 

Binding rate constants in olfactory compartments 

k OM free to bound OM 

f:b 0.00086 hour-1 Estimated 

k OB free to bound OB 

f:b 0.0014 hour-1 Estimated 

k OTT free to bound OTT 

f:b 0.0031 hour-1 Estimated 

k Striatum free to bound S 

f:b 0.024 hour-1 Estimated 

k OM bound to free OM 

b:f 1x10-6 hour-1 Constantb 

k OB bound to free OB 

b:f 1x10-6 hour-1 Constantb 

k OTT bound to free OTT 

b:f 1x10-6 hour-1 Constantb 

k Striatum bound to free S 

b:f 1x10-6 hour-1 Constantb 

a

Unpublished results measured in CD rats used in Dorman et al. (2000) study. Plugged and unplugged exposure 

data were averaged together because they were not significantly different.

b

Not possible to estimate both constants for the binding; therefore, the rate constants for the bound to free
 

manganese were set to a low rate to allow slow removal of manganese tracer from the bound compartment.
 

Source: Leavens et al. 2007
 

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nasal cavity) is connected by blood and each is comprised of pools of free and bound manganese. The 

rates of transport between tissue compartments and between bound and free pools are modeled as firstorder transport processes. Tables 3-17 and 3-18 show measured values for compartment volumes, values 

for blood clearance into olfactory compartments (e.g., ClOM/blood), values for rate constants for efflux from 

compartments to blood (e.g., kblood/OM), values for transport rate constants between compartments (e.g., 

kOM/el), and binding rate constants in the olfactory compartments (e.g., OM free to bound, kOM/f.b and 

OM bound to free, kOM/b.f). Equations for mass balance, clearance, and free concentrations of manganese 

for each of the compartments are described in detail by Leavens et al. (2007). 

Model parameters were estimated by optimization procedures using kinetics data from rats exposed noseonly for 90 minutes to 54Mn-manganese chloride (Brenneman et al. 2000) or 54Mn-manganese phosphate 

(Dorman et al. 2002a). In each experiment, one group was exposed with both nostrils unplugged, while a 

second group was exposed with the right nostril plugged. Blood concentrations were not measured in 

either of these studies, but 54Mn concentrations in the kidney, liver, and pancreas were measured and 

reported. The mean concentration in these three organs is used to represent blood concentration in the 

model, and the data were used to obtain parameters for equations describing first-order absorption and 

elimination into a single compartment; values for the parameters under plugged and unplugged 

conditions, obtained through model optimization procedures, are listed in Table 3-19. The optimized 

model was used to predict the percentage of 54Mn that was transported into each compartment either via 

direct olfactory transport or blood delivery. For manganese chloride, olfactory transport was predicted to 

deliver >97–99% of the tracer in the left or right olfactory bulbs, 40–76% of the tracer in the left or right 

olfactory tract and tubercle, and only 4–8% of the tracer in the left or right striatum under plugged or 

unplugged conditions. For manganese phosphate, the respective predictions were 38–59% in the 

olfactory bulbs, 86–90% in the olfactory tract and tubercle and 77–83% in the striatum. Leavens et al. 

(2007) cautioned against the predictions for the striatum, since the model overpredicted striatum 

concentrations at the later time points for the plugged exposures to manganese chloride or manganese 

phosphate and the unplugged exposures to manganese phosphate (Figures 4–7 in Leavens et al. 2007). 

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Table 3-19. Parameter Values for Describing Blood Concentrations
 

in the Leavens et al. (2007) PBPK Model for
 

Olfactory Transport of Manganese in Rats
 

Value 

Parametera Description Plugged Unplugged Units Source 

Manganese chloride exposures 

CӨ Initial deposited 

concentrationb 

261 791 ng/g Estimated 

ka First-order absorption 0.0068 0.005 hour-1 Estimated 

K First-order elimination rate 0.057 0.063 hour-1 Estimated 

constant 

Manganese phosphate exposures 

CӨ Initial deposited 

concentrationb 

171 376 ng/g Estimated 

ka First-order absorption 0.0035 0.0034 hour-1 Estimated 

K First-order elimination rate 0.083 0.124 hour-1 Estimated 

constant 

a

Estimated pharmacokinetic parameters for mean of liver, kidney, and pancreas concentration reported in 

Brenneman et al. (2000). See text for equation and details.
 b

Equal to FX0/Vb, where X0 is initial dose, F is fraction dose bioavailable for absorption, and Vb is the blood volume.
 

Source: Leavens et al. 2007 

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3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Absorption. Manganese absorption occurs primarily through the diet; however, absorption via the 

lungs can be significant for occupationally exposed persons or for those exposed to excess levels of 

airborne manganese, such as downwind of a manganese point source. Manganese absorption through the 

gut may occur through a nonsaturable simple diffusion process through the mucosal layer of brush border 

membranes (Bell et al. 1989) or via an active-transport mechanism that is high-affinity, low-capacity, and 

rapidly saturable (Garcia-Aranda et al. 1983). Manganese particles that are too large to enter the alveoli 

(>10 microns in diameter) remain in the upper respiratory tract, where they are coughed up by 

mucociliary transport and swallowed. Differences in solubility of manganese compounds deposited in the 

alveolar regions may impact the rate at which manganese will be absorbed, but manganese is bioavailable 

when deposited in these regions (Drown et al. 1986). 

Diets high in iron have been shown to suppress manganese absorption, and conversely, iron-poor diets 

increase manganese uptake (Lönnerdal 1997, Lönnerdal et al. 1994). Phosphorus (Wedekind et al. 1991) 

and calcium (Wilgus and Patton 1939) have also been found to decrease manganese uptake. 

Distribution. Review articles by Aschner and Aschner (1991) and Aschner et al. (2005; 2007) 

summarize some of the available data regarding the distribution of manganese. Dietary manganese, 

thought to be absorbed as Mn(II), enters portal circulation from the gastrointestinal tract and is bound to 

α2-macroglobulin or albumin in the plasma. After delivery to the liver, the major portion of Mn(II) is 

secreted in the bile, but some may be oxidized by ceruloplasmin to Mn(III). The Mn(III) enters systemic 

circulation conjugated with plasma transferrin; once this complex enters a neuron, it dissociates, and from 

there, the manganese is transported to axon terminals. For example, Sloot and Gramsbergen (1994) 

observed that radiolabeled manganese injected into the striatum or substantia nigra of rat brain is 

transported in an anterograde direction through both γ-amino-butyric acid-producing striato-nigral and 

dopaminergic nigro-striatal fibers. 

Other studies, however, argue for the transport of Mn(II) into the brain. For example, Murphy et al. 

(1991) measured the kinetics of manganese transport in the brains of adult male rats using a perfusion 

technique. The rats were infused with increasing concentrations of [54Mn]Cl2; blood and brain samples 

were analyzed for manganese at varying time points. The data indicated a saturable mechanism for 

transporting Mn(II) into the choroid plexus, and influx into the cerebral cortex was also near saturation at 

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the highest plasma concentration of manganese used. Influx into other brain regions (e.g., caudate 

nucleus, hippocampus, hypothalamus) and cerebrospinal fluid (CSF) showed non-saturable transport of 

the cation. The authors suggested that the non-saturable transport into these brain regions resulted from 

passive diffusion of manganese down a concentration gradient from ventricular cerebrospinal fluid 

because some of these brain regions have components adjacent to the ventricles and manganese 

concentrations in these regions were below levels in the CSF. The authors also noted that at all plasma 

manganese concentrations tested (from 0.8 to 78 nmol/mL), the transfer coefficient for manganese uptake 

into the choroid plexus was significantly higher than in any other area of the central nervous system. For 

example, at 0.08 nmol/mL, the transfer coefficients for the CSF and the choroid plexus were 

16.2±2.43x10-6 mL/second*g and 23,800±2,910x10-6 mL/second*g, respectively. Even after correcting 

for differences in compartment size, influx of manganese into the choroid plexus was an order of 

magnitude greater than influx into CSF. 

Rabin et al. (1993) also measured transport of [54Mn]Cl2 in adult rats using a similar technique. In this 

study, the authors used three perfusates (whole blood, plasma/serum, and saline) to determine brain 

uptake in environments that facilitated or prevented protein binding of the metal. The authors reported 

that uptake of manganese into the cortex, hippocampus, caudate nucleus, and choroid plexus was greater 

and more rapid when saline was used rather than with whole blood. When EDTA-saline was used as the 

perfusate, uptake was not significantly different than zero, indicating that divalent manganese was the 

form taken up by the brain. The transfer coefficients of Mn(II) from saline in the different regions of the 

brain (frontal, parietal, and occipital cortex regions; hippocampus; caudate nucleus; and thalamushypothalamus) ranged from 5 to 10x10-5 mL/second*g, whereas that of the choroid plexus was 

727x10-3 mL/second*g. The authors noted that the transfer coefficients were greater than that expected 

for passive diffusion and suggested a facilitated blood-brain barrier transport by a channel or carrier 

mechanism (Rabin et al. 1993). These findings of a rapid uptake mechanism and concentrated uptake into 

the choroid plexus are consistent with results reported by Murphy et al. (1991). Separate binding studies 

performed by the authors determined that albumin, transferrin, α2-macroglobulin added to the manganese 

during perfusion significantly decreased brain uptake of the cation in all brain regions. The authors were 

uncertain whether Mn(II) in the form of low-molecular mass solutes was taken up at the blood-brain 

barrier. However, based on other literature and their own unpublished results, they suggest that the free 

ion is the species transported. 

Other studies have also revealed the rapid appearance of manganese in the choroid plexus. Ingersoll et al. 

(1995) demonstrated that manganese levels in the lateral choroid plexus were 44 and 24 times higher than 

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levels in CSF, and blood, respectively, 4 hours after intraperitoneal injection of 10 mg manganese/kg. 

However, manganese concentration in the choroid plexus did not change significantly following 

intrathecal administration of this same dose. This demonstrated that manganese in the blood could be 

sequestered by the choroid plexus, whereas little to no transfer of manganese from CSF to the choroid 

plexus occurred. Intrathecal administration of manganese increased manganese concentrations in all 

brain regions examined while there were only slight changes in brain manganese concentrations after 

intraperitoneal administration. Moreover, intrathecal administration of manganese decreased spontaneous 

motor activity with no effect on motor activity following intraperitoneal dosing. The authors suggested 

that these results indicated that the brain is protected from high concentrations of manganese through 

sequestering in the choroid plexus, but this mechanism could become overwhelmed with rising levels of 

blood manganese such that manganese could then “leak’ from the choroid plexus into CSF and thereby 

enter the brain. This interpretation appears to be consistent with the findings of London et al. (1989). In 

these studies, 50 and 100 mg/kg manganese was administered intraperitoneal doses 5 and 10 times that 

used by Ingersoll et al. (1995). Using MRI images, these doses were shown to concentrate in the 

ventricles, the pineal gland, and the pituitary gland and the authors indicated that this high concentration 

of manganese appeared in the ventricular CSF because it crossed the barrier of the choroid plexus. 

Takeda et al. (1994) used autoradiography to also show that manganese in selected brain regions was 

taken up via the CSF from the choroid plexus. Moreover, Zheng et al. (1998) observed that, in a 

subchronic manganese intoxication rat model, the increases in manganese concentrations observed in 

targeted brain regions were closely related in magnitude to that of CSF manganese, but not to that of 

serum manganese. The observations of Takeda et al. (1994) and Zheng et al. (1998) support the view that 

manganese in the CSF serves as the main source for manganese distribution in brain tissues. 

Recent reviews of the state of the science have emphasized that manganese can enter the brain via three 

pathways: (1) from the nasal mucosa to the brain olfactory bulb via olfactory neural connections; 

(2) from the blood through capillary endothelial cells of the blood-brain barrier; and (3) from the blood 

through the cerebral spinal fluid via the choroid plexuses (Aschner et al. 2005; Bock et al. 2008; 

Crossgrove and Yokel 2005). Current understanding is inadequate to determine which of these pathways 

may predominate in cases of severe manganism or cases of subtle neurological impairment in nonhuman 

primates or humans. A number of transport mechanisms (including facilitated diffusion, active transport, 

transferrin-mediated transport, divalent metal transporter-1 mediation, store-operated calcium channels) 

have been proposed to transport manganese across the blood barrier or into the choroid plexus, but current 

understanding is inadequate to determine the predominant molecular mechanism of transport in either of 

the pathways (Aschner et al. 2005, 2007; Crossgrove and Yokel 2004, 2005; Roth 2006). 

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3.5.2 Mechanisms of Toxicity 

The central nervous system is the primary target of manganese toxicity. Although it is known that 

manganese is a cellular toxicant that can impair transport systems, enzyme activities, and receptor 

functions, the principal manner in which manganese neurotoxicity occurs has not been clearly established 

(Aschner and Aschner 1991; Aschner et al. 2007). 

Mn(III) has been found to be more cytotoxic to human neural cells as a manganese pyrophosphate 

complex (MnPPi) than as a manganese-transferrin complex (MnTf) (Suarez et al. 1995). Specifically, 

human neuroblastoma cells (cell line SH-SY5Y) grown in culture showed effects of cytotoxicity from 

30 μM MnPPi but did not show the same signs of cytoxicity from MnTf (membrane damage and cell 

granulation and aggregation) until concentrations of 60 μM were reached (Suarez et al. 1995). Both 

manganese complexes inhibited mitochondrial enzyme activity, but MnTf was slightly more toxic than 

MnPPi in this respect (Suarez et al. 1995). 

Neuropathological changes are detectable in the basal ganglia of humans with manganism, and the 

specific area of injury appears to be primarily in the globus pallidus; the substantia nigra is sometimes 

affected, but generally to a lesser extent (Katsuragi et al. 1996; Yamada et al. 1986). Studies in 

nonhuman primates have produced similar findings (Newland and Weiss 1992; Newland et al. 1989). 

Limited evidence suggests that dopamine levels in the caudate nucleus and putamen are decreased in 

manganism patients (Bernheimer et al. 1973). Similarities in the behavior of manganism patients to those 

with Parkinson’s disease have prompted some to refer to manganism as "manganese-induced 

Parkinsonism" or "Parkinson-like disease." Further, the two diseases do affect functional related regions 

of the brain, but Parkinsonism is believed to be due to the selective loss of subcortical neurons whose cell 

bodies lie in the substantia nigra and whose axons terminate in the basal ganglia (which includes the 

caudate nucleus, the putamen, the globus pallidus, and other structures). These nigral neurons use 

dopamine as their neurotransmitter, and treatment of Parkinson patients with levo-dopa (the metabolic 

precursor to dopamine) often relieves some of the symptoms of Parkinson's disease (Bernheimer et al. 

1973). Some investigators have reported that oral levo-dopa can temporarily improve symptoms of 

manganese-induced neurotoxicity (Barbeau 1984). However, most studies show that manganism patients 

typically do not respond to levo-dopa treatment (Calne et al. 1994; Chu et al. 1995; Huang et al. 1989), 

indicating that they have likely suffered degeneration of the receptors and neurons that normally respond 

to this neurochemical (Chu et al. 1995). 

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The precise biochemical mechanism by which manganese leads to this selective destruction of 

dopaminergic neurons is not known, but many researchers believe that the manganese ion, Mn(II), 

enhances the autoxidation or turnover of various intracellular catecholamines, leading to increased 

production of free radicals, reactive oxygen species, and other cytotoxic metabolites, along with a 

depletion of cellular antioxidant defense mechanisms (Barbeau 1984; Donaldson 1987; Garner and 

Nachtman 1989b; Graham 1984; Halliwell 1984; Liccione and Maines 1988; Parenti et al. 1988; Verity 

1999). Oxidation of catechols is more efficient with Mn(III), than with Mn(II) or Mn(IV) (Archibald and 

Tyree 1987). Formation of Mn(III) may occur by oxidation of Mn(II) by superoxide (O2

-

) In cases of 

exposure to Mn(VII), it is likely that a reduction to the Mn(II) or Mn (III) state occurs (Holzgraefe et al. 

1986), but this has not been demonstrated. 

Hussain et al. (1997) studied the effects of chronic exposure of manganese on antioxidant enzymes, 

including manganese superoxide dismutase (MnSOD). MnSOD is an antioxidant enzyme located 

primarily in the mitochondria that contains manganese as a functional component. MnSOD protects 

against oxidative injury by catalyzing the dismutation of O2

-

, Hussain et al. (1997) found that 

administration of 0, 1.1, and 2.2 mg manganese/kg/day (as manganese chloride), 5 days/week for 

3 months, resulted in increased MnSOD in the hippocampus, cerebellum, and brainstem. Other areas of 

the brain were not affected and other antioxidant enzymes, such as Cu,ZnSOD and glutathione peroxidase 

(GPx), were not increased. The researchers suggest that since a critical role of MnSOD is to protect 

against oxidative injury, the increase of this enzyme after manganese exposure may reduce the risk of 

oxidative stress induced by that exposure. Thus, this protective mechanism would have to be 

overwhelmed in cases of manganese toxicity. Additionally, the authors suggest that, since MnSOD was 

altered while Cu,ZnSOD and Gpx were unchanged, manganese may not affect cytosolic enzymes like 

Cu,ZnSOD. In support of this point, the authors also mention other reports that suggest that these 

antioxidant enzymes are independently regulated (Mossman et al. 1996; Warner et al. 1993; Yen et al. 

1996). 

Supporting evidence for the hypothesis that high levels of manganese exert neurotoxicity through 

oxidation is provided by Desole et al. (1994). The authors observed that 22 mg manganese/kg/day (as 

manganese chloride) administered orally in 6-month-old rats resulted in increased concentrations of 

DOPAC (an oxidation product of DA) and uric acid, but left DA levels unchanged. Daily doses of 44 or 

66 mg manganese/kg/day resulted in significantly decreased concentrations of DA, glutathione, ascorbic 

acid, and DOPAC, and increased concentrations of uric acid in the rat striatum when compared to 

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controls. The researchers also measured levels of these metabolites in the rat striatal synaptosomes, 

which were used as a model for neuronal terminals. Here, DA levels were unchanged at 22 mg 

manganese/kg/day but were decreased at the two highest doses. DOPAC levels remained constant at all 

three dose levels. Thus, the DOPAC/DA ratio was significantly increased at 44 and 66 mg 

manganese/kg/day in the synaptosomes. While the authors suggest that these data support other findings 

that manganese oxidizes dopamine (Segura-Aguilar and Lind 1989), the decrease in DA could be the 

result of decreased production or release of the chemical, rather than increased oxidation. Catabolism of 

adenosine triphosphate (ATP) forms xanthine and hypoxanthine, both of which are metabolized by 

xanthine oxidase. The products of this metabolism are uric acid and superoxide radical anion (Desole et 

al. 1994). The increase in uric acid production in rat striatum following oral dosing with 44 or 66 mg 

manganese/kg (as manganese chloride) suggests that manganese induces oxidative stress mediated by 

xanthine oxidase. Desole et al. (1995) expanded their studies to investigate the protective effect of 

allopurinol, a xanthine-oxidase inhibitor, to 3-month-old rats exposed to manganese. In this study, 

allopurinol was administered by gavage at a dose of 300 mg/kg/day for 4 days. Manganese 

(87 mg/kg/day) was also administered by gavage, for 7 days, either alone or with allopurinol; the 

allopurinol decreased the striatal ratio of DOPAC and homovanillic acid (HVA) to dopamine. When 

given in conjunction with manganese, allopurinol antagonized the manganese-induced increase in 

DOPAC levels and the (DOPAC + HVA)/DA ratio. Together, the two studies suggest that manganeseinduced oxidative stress through the formation of reactive oxygen species may be a mechanism for 

manganese neurotoxicity, and allopurinol may protect against this oxidative stress in the striatum and 

brainstem of young rats. 

Experiments such as the one by Desole et al. (1994) indicate that overexposure of rats to manganese 

results in increased dopamine turnover in the rat striatum. However, patients with basal ganglia 

dysfunction caused by manganese had normal striatal fluorodopa uptake on PET scan, indicating that the 

nigrostriatal pathway was intact (Wolters et al. 1989). Seven intravenous injections of manganese 

chloride into Rhesus monkeys resulted in an extrapyramidal syndrome characterized by bradykinesia, 

facial grimacing, and rigity, with gliosis of the globus pallidus and the substantia nigra par reticularis 

(Olanow et al. 1996). These intravenous injections, however, would have resulted in a highly elevated 

but transient increase in blood manganese levels. Striatal dopamine and homovanillic acid levels were 

within normal ranges; yet, there was clear evidence of manganese-induced neurotoxicity. Interestingly, 

none of the symptoms improved after levo-dopa administration, supporting findings in humans that 

manganism does not respond to levo-dopa treatment (Chu et al. 1995; Huang et al. 1989). 

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While there are a number of studies that support the hypothesis that manganese exerts its neurotoxicity 

through oxidation, a study by Sziráki et al. (1999) has demonstrated atypical antioxidative properties of 

manganese in iron-induced brain lipid peroxidation and copper dependent low density lipoprotein 

conjugation. However, the underlying mechanisms of the antioxidant effects are not clear. Brenneman et 

al. (1999) measured reactive oxygen species (ROS) in the brains of neonatal rats administered up to 

22 mg manganese/kg/day for up to 49 days (dosing was only 5 days/week from day 22 to 49). On PND 

21, no increase in ROS was seen in the striatum, hippocampus, or hindbrain of exposed rats at any dose, 

compared to controls administered water only. In the cerebellum, ROS levels were significantly 

increased to the same extent at both dose levels, as compared to controls. Manganese levels were not 

increased significantly in the cerebellum at any dose level, but were increased in the striatum, and the rest 

of the brain at the high dose level, when measured at PND 49. Mitochondrial manganese was not 

significantly elevated in the cerebellum or striatum, but was elevated in the rest of the brain at this high 

dose level, also at PND 49. These data do not support the hypothesis that oxidative damage is a 

mechanism of action in manganese-induced neurotoxicity in the rat. 

As reviewed Taylor et al. (2006), the available literature contains results both in support of and 

inconsistent with oxidative stress involvement in manganese neurotoxicity. Recent support for oxidative 

stress involvement includes the finding that co-treatment of rats with the antioxidant, N-acetylcysteine, 

and intraperitoneal injections of high doses of manganese chloride (50 mg/kg, once or daily for 4 days) 

prevented the development of pathological changes observed following injection of manganese chloride 

alone (Hazell 2006). Likewise, mouse catecholaminergic cells (CATH.a) were protected from the 

cytotoxicity of 50–1000 μM manganese by supplementation of the culture media with 5 mM glutathione 

or 10 mM N-acetylcysteine (Stredrick et al. 2004). In contrast, in a series of studies of neonatal rats, adult 

male and female rats, or senescent male rats exposed by inhalation to manganese sulfate or manganese 

phosphate at concentrations up to 3 mg manganese/m3 with acute exposure durations or 1 mg 

manganese/m3 with subchronic exposure durations (Dorman et al. 2001a, 2004a, 2005a), no consistent 

exposure-related changes were found in the following markers of oxidative stress in various brain regions: 

glutathione, metallothionein, and glutamine synthetase (Taylor et al. 2006). 

Mn(II) may also be involved in neurotoxicity. The neurotoxicity of Mn(II) has been linked to its ability 

to substitute for Ca(II) under physiological conditions (Aschner and Aschner 1991), and the intestinal 

transfers of Ca(II) and Mn(II) have been shown to be competitive in vivo (Dupuis et al. 1992). Although 

the mechanism for Mn(II) transport into brain cells is uncertain, Mn(II) preferentially accumulates in the 

mitochondria in the areas of the brain that are associated with manganism and neurological symptoms. 

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Manganese is taken up into mitochondria via the calcium uniporter, and once there, Mn(II) inhibits 

mitochondrial oxidative phosphorylation. Gavin et al. (1992) observed that Mn(II) can inhibit 

mitochondrial oxidative phosphorylation when incubating isolated mitochondria with Mn(II) at 

concentrations >1 μM. Recently, it has also been shown that intramitochondiral Mn(II) can inhibit the 

efflux of Ca(II), which may result in a loss of mitochondrial membrane integrity (Gavin et al. 1999). At 

the same time, intramitochondrial Mn(II) can also inhibit oxidative phosphorylation and decrease energy 

production. However, Brouillet et al. (1993) has suggested that the impaired oxidative metabolism 

induced by manganese is indirectly linked to an excitotoxic process that results in neuronal degeneration. 

Because manganese accumulates in the mitochondria and is associated with impaired energy production, 

these authors compared the effects of intrastriatal injection of manganese with effects produced by known 

mitochodral toxins, aminooxyacetic acid and 1-methyl-4-phenylpyridinium. Lesions produced by these 

compounds can be blocked through an inhibition of the glutamatergic N-methyl-D-aspartate (NMDA) 

receptor or by the removal of the cortical glutamatergic input into the striatum by decortication. Thus, 

these lesions are termed “excitotoxic lesions.” It was shown that decortication or pre-treatment with the 

NMDA noncompetitive antagonist, MK-801, could reverse or ameliorate neurochemical changes induced 

by intrastriatal injection of manganese. These authors also showed that intrastriatal manganese treatment 

also interfered with energy metabolism, ATP concentrations were significantly reduced by 51% and 

lactate levels were increased by 97%. There is additional evidence that the glutamatergic excitatory 

system may play a role in manganese toxicity. Recent studies in genetically epilepsy-prone rats have 

suggested that there are abnormalities in manganese-dependent enzymes. Although the manganesedependent enzymes are believed to be unrelated to seizure activity in these animals, it is suggested that 

there is a link between the low manganese concentrations in glial cells and elevated glutamate levels due 

to low glutamine synthetase activity (Critchfield et al. 1993). 

Mn(II) (from manganese chloride) has also been shown to inhibit mitochondrial aconitase activity to a 

significant level in the frontal cortex of male rats dosed with 6 mg manganese/kg/day for 30 days (Zheng 

et al. 1998). Aconitase levels in striatum, hippocampus, and substantia nigra were decreased in treated 

rats, but not to a significant extent. Aconitase, which catalyzes the interconversion of L-citrate to 

isocitrate, via cis-aconitate, requires iron as a cofactor at its active center (Zheng et al. 1998). When the 

authors incubated brain mitochondrial fractions with Mn(II), aconitase activity was decreased; the 

addition of excess iron [Fe(II)] revived the enzyme activity. These data suggest that the similarity of 

manganese and iron facilitates their proposed interaction at the subcellular level; however, the data do not 

prove that Mn(II) is the form of manganese that is exerting the inhibitory effect. 

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Conversely, Suarez et al. (1995) did not observe cytotoxicity in cultured cells exposed to 100 μM Mn(II). 

The discrepancy noted in this study, and that of Gavin et al. (1992) may have occurred because of a 

protective effect of the cell membrane; if the cell membrane protects the cytosol, which typically has a 

low manganese concentration, then the Mn(II) concentration may be too low to affect the mitochondria 

through uniport uptake (Suarez et al. 1995). Another explanation is that mitochondrial uptake of Mn(II) 

occurs, but toxic effects require that cells be exposed much longer than isolated mitochondria (Suarez et 

al. 1995). It has also been established that manganese accumulation in the brain varies between regions, 

particularly in developing animals; this region-specific accumulation may alter the metabolism and 

homeostasis of manganese (Chan et al. 1992). In addition, it has been demonstrated that the manganese 

concentration in the central nervous system, in particular the ventral mesencephalon, can be reduced by 

cocaine, a dopamine reuptake inhibitor, or by reserpine, a dopamine depleting agent (Ingersoll et al. 

1999). This suggests that the dopamine reuptake carrier is linked to a transport mechanism for 

manganese. 

In vitro studies of rat brain mitochondria have demonstrated that there is no apparent mechanism for 

Mn(II) clearance other than the slow Na+ independent mechanism; it is suggested that Ca(II) and Mn(II) 

may accumulate in the brain mitochondria during manganese intoxication (Gavin et al. 1990). Other 

theories regarding the mode of neurotoxicity for manganese (and other metal ions) include toxicity caused 

by the formation of hydroxyl radicals during the manganese-catalyzed autooxidation of hydrazines (Ito et 

al. 1992). 

It has been suggested that the mechanism of manganese neurotoxicity may in part involve complex 

interactions with other minerals (Lai et al. 1999). In a developmental rat model of chronic manganese 

toxicity, administration of manganese in drinking water was associated with increased levels of iron, 

copper, selenium, zinc, and calcium in various regions of the brain. Moreover, the subcellular distribution 

of various minerals was differentially altered following manganese treatment. Iron deficiency is 

associated with increased manganese burden in the central nervous system of rats, while administration of 

excess iron significantly decreases manganese uptake (Aschner and Aschner 1990). The biochemical 

mechanisms underlying the interactions between manganese and other minerals are unclear. 

Subtle deficits in fine motor and cognitive function in chronically exposed young adult male 

Cynomologus macaques monkeys have been associated with manganese impairment of in vivo 

amphetamine-induced dopamine release in the striatum, without detectable changes in markers of striatial 

dopamine terminal integrity, and with decreased cerebral cortex N-acetylaspartate/creatine ratio (Guilarte 

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et al. 2006a, 2006b; Schneider et al. 2006). In these studies, four monkeys (5–6 years old at the start) 

were given intravenous injections of manganese sulfate, 10–15 mg/kg or 3.26–4.89 mg manganese/kg, 

once per week for an average of 34.2 weeks. Three additional monkeys without excess manganese 

exposure or behavioral evaluations were used as a control group for post-mortem analyses of the brain 

(Guilarte et al. 2006a). Prior to manganese exposure, the monkeys were trained to perform tests for 

cognitive and motor function; overall behavior was assessed by ratings and videotaped analysis 

(Schneider et al. 2006). By the end of the exposure period, monkeys developed deficits in spatial working 

memory, showed modest decreases in spontaneous activity and manual dexterity, and showed increased 

frequency of compulsive-type behaviors such as compulsive grooming (Schneider et al. 2006). At study 

termination, mean manganese concentrations were elevated in exposed monkeys, compared with control 

monkeys, in the following brain regions: globus pallidus (3.30 versus 0.72 μg/g tissue); caudate 

(1.18 versus 0.38 μg/g tissue); putamen (1.5 versus 0.48 μg/g tissue); and frontal white matter 

(0.57 versus 0.17 μg/g tissue) (Guilarte et al. 2006b; Schneider et al. 2006). Positron emission 

tomography (PET) analysis found changes in amphetamine-induced release of dopamine in the striatum 

(up to 60% decrease compared with baseline values), but no significant changes in striatal dopamine 

receptor binding potentials (Guilarte et al. 2006a). Post-mortem chemical and immunohistochemical 

analysis of caudate and putamen tissue found no evidence for exposure-related changes to levels of 

D2-dopamine receptor (D2-DAR), dopamine receptor (DAT), tyrosine hydroxylase, or dopamine and its 

metabolite, homovanillic acid (Guilarte et al. 2006a). Using 1

H-magnetic resonance spectroscopy, 

concentrations of creatine (Cr), N-acetylaspartate (NAA), choline, and myo-inositol were measured. 

Decreases (relative to baseline) in the NAA/Cr ratio were measured in the parietal cortex and frontal 

white matter, but not in the striatum (Gulilarte et al. 2006b). Guilarte et al. (2006b) suggested that the 

changes in the NAA/Cr ratio are indicative of neuronal degeneration or dysfunction in the parietal cortex 

that may also be associated with the neurobehavioral changes noted in the monkeys. Subsequent gene 

expression profiling in the frontal cortex of these monkeys found changes consistent with cellular stress 

responses that the investigators proposed may help to explain the subtle cognitive effects noted (Guilarte 

et al. 2008). The collective results from these studies suggest that subtle neurobehavioral changes noted 

in epidemiological studies of chronically exposed workers (see Section 3.2.1.4 and Appendix A) may be 

similar to those noted in these monkeys and may be related to manganese-induced functional changes and 

gene expression changes noted in the striatum and the cerebral cortex. 

As reviewed by Fitsanakis et al. (2006), most mechanistic research on manganese neurotoxicity has 

focused on perturbations of the dopaminergic system, but there is evidence to suggest that early 

consequences of manganese neurotoxicity may involve perturbations of other neurotransmitters including 

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GABA and glutamate in the basal ganglia and other brain regions. For example, there is evidence to 

suggest that manganese decreases the ability of astrocytes to clear glutamate from extracellular space 

(Erikson and Aschner 2002, 2003), increases the sensitivity of glutamate receptors to glutamate (see 

Fitsanakis and Aschner 2005 and Fitsanakis et al. 2006 for review), and perturbs glutamine-glutamateGABA interconversions in frontal cortex and basal ganglia of rats (Zwingmann et al. 2004, 2007). When 

rat striatum was perfused with artificial cerebrospinal fluid with 200 nM manganese, GABA levels in the 

perfusate were decreased by about 60% compared with controls, but no effects on levels of glutamate, 

aspartate or glycine in the perfusate were observed (Takeda et al. 2003). In the perfused rat hippocampus, 

200 nM manganese caused a 50% decrease in the levels of GABA, glutamate, and aspartate in the 

perfusate (Takeda et al. 2002). The results from the studies of Takeda et al. (2002, 2003) suggest that 

there are differential regional effects of manganese on the release of different neurotransmitters. 

Fitsanakis et al. (2006) concluded that additional research is needed to better understand the 

interdependence of neurotransmitters, including dopamine, glutamate, and GABA and their relationships 

to manganese neurotoxicity. 

3.5.3 Animal-to-Human Extrapolations 

As discussed in Section 3.2, the available literature on toxicological analysis of manganese in humans and 

animals is quite extensive. However, due to the wide dose ranges administered, the variety of responses, 

and the differences in measured end points, comparisons of effects across species is not straightforward. 

Rodent models have primarily been used to study manganese neurotoxicity. These studies have reported 

mostly neurochemical, rather than neurobehavioral, effects (Brouillet et al. 1993; Chandra 1983; Chandra 

and Shukla 1978, 1981; Daniels and Abarca 1991; Deskin et al. 1980, 1981; Eriksson et al. 1987a; 

Gianutsos and Murray 1982; Parenti et al. 1986; Singh et al. 1979; Subhash and Padmashree 1991), as 

very few studies investigated neurobehavioral effects. It has been suggested that this focus may reflect 

difficulties in characterizing behavioral changes following basal ganglia damage in the rodent (Newland 

1999). Other techniques, such as those used to identify basal ganglia damage as a result of exposure to 

neuroleptics (Newland 1999), may be refined to further exploit the rodent model as a predictor of 

neurobehavioral change in the human. The usefulness of the rat model for manganese neurotoxicity is 

also limited because the distribution of manganese in brain regions is dissimilar to that of the human 

(Chan et al. 1992; Brenneman et al. 1999; Kontur and Fechter 1988; Pappas et al. 1997). Studies to date 

have used exposure routes such as inhalation, intravenous, intraperitoneal, or subcutaneous, with few 

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exceptions (Brenneman et al. 1999; Dorman et al. 2000, 2002, 2004a, 2005a, 2006b; Lown et al. 1984; 

Morganti et al. 1985; Pappas et al. 1997). 

The rabbit has also been used as a model for manganese toxicity in a few studies (Chandra 1972; 

Szakmáry et al. 1995). The only available neurotoxicity study using the rabbit (Chandra 1972) reported 

that the species, when dosed intratracheally with 253 mg manganese/kg body weight (inferred as a onetime dose), developed hindlimb paralysis (a response not typically observed in humans exposed to excess 

manganese) after an observation period of 18 months. The animals also exhibited wide-spread neuronal 

degeneration in the brain. This study suggests that rabbits and humans may be qualitatively similar in the 

manifestation of neurobehavioral effects. However, further studies are needed to determine if the two 

species manifest comparable symptoms within the same dose range. 

The nonhuman primate has been a useful model for predicting neurotoxicity in the human as the monkey 

presents neurobehavioral responses to toxicants that are very similar to those observed in humans 

(Eriksson et al. 1987b; Golub et al. 2005; Gupta et al. 1980; Newland and Weiss 1992; Olanow et al. 

1996). Further, the monkey also undergoes neurochemical changes (Bird et al. 1984) as a result of 

manganese exposure. Studies have shown that monkeys exposed to manganese injected either 

intravenously or subcutaneously exhibit symptoms very similar to those observed in miners and others 

exposed to manganese, including ataxia, bradykinesia, unsteady gait, grimacing, and action tremor 

(Eriksson et al. 1992a, 1992b; Newland and Weiss 1992; Olanow et al. 1996). In addition, monkeys 

exhibiting these effects show accumulation of manganese in the basal ganglia as observed by MRI 

(Eriksson et al. 1992b; Newland and Weiss 1992), as do humans who are either exposed to, or are unable 

to clear, excess manganese (Devenyi et al. 1994; Fell et al. 1996; Hauser et al. 1994; Ono et al. 1995; 

Pomier-Layrargues et al. 1998; Rose et al. 1999; Spahr et al. 1996). However, primate studies showing 

these neurobehavioral effects have involved routes of administration that do not mimic environmental 

exposures, and although the effects in monkeys are qualitatively similar, it is currently unknown whether 

the effects are seen at the same dose metric as those in humans. Newland (1999) proposes using MRI 

techniques to relate the administration of certain amounts of manganese with a corresponding MRI signal 

in the brain and the resultant neurobehavioral effects. This technique might be very useful in developing 

a true dose-response relationship for manganese neurotoxicity in both the monkey and human. 

Mechanisms of manganese toxicity in vivo are likely to be comprised in part by unique characteristics of 

the exposed individual, as well as by general physiology and exposure route. Therefore, further studies 

are needed to develop appropriate animal models for human populations identified as susceptible (e.g., 

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children, elderly adults, nutritionally-compromised children and adults) using appropriate animal 

modalities. Such techniques may lead to a more complete evaluation of the pathways and circumstances 

by which manganese exposure can result in toxicity. Additional research to further develop PBTK 

models in rats that have been recently described (Leavens et al. 2007; Nong et al. 2008; Teeguarden et al. 

2007a, 2007b, 2007c) and extend them to populations of potentially susceptible individuals (in rodents, 

nonhuman primates, and primates) may be useful to increase understanding of interspecies differences in 

manganese neurotoxicity and provide support for extrapolations of dose-response relationships in animals 

to humans. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

The potential hazardous effects of certain chemicals on the endocrine system are of current concern 

because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals with this 

type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

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for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 

Studies of endocrine effects in humans following manganese exposure are very limited. Alessio et al. 

(1989) reported the elevation of serum prolactin and cortisol in chronically-exposed workers, while no 

changes in prolactin, FSH, or LH levels were observed in an occupational study involving shorter 

exposure periods (Roels et al. 1992). Lucchini et al. (1995) reported elevated serum prolactin levels in 

ferromanganese workers; 20 of those workers still showed elevated prolactin levels 5 years later after 

exposure to consistent levels of airborne manganese (Smargiassi and Mutti 1999). In fact, the serum 

prolactin levels had increased significantly over the previous values. Although these changes are minor, 

changes in prolactin secretion may have effects on different physiological functions, including loss of 

libido and impotence in men, and infertility and change in menstrual cycle in women. 

No studies of endocrine effects in animals following airborne manganese exposure were located. Shortterm animal studies and some of the long-term animal studies were negative for endocrine effects 

following oral exposure to manganese (NTP 1993). One intermediate study reported a decrease in 

circulating testosterone and a significant increase in substance P in the hypothalamus and neurotensin in 

the pituitary in rats dosed intraperitoneally with 6.6 mg manganese/kg/day as manganese chloride (Hong 

et al. 1984). Two other studies in rats reported that manganese tetroxide in food, given at a dose of 

350 mg manganese/kg/day for 224 days (starting on day 1 of gestation and continuing for 224 days) 

(Laskey et al. 1982) and 214 mg manganese/kg/day given up to 28 days (Laskey et al. 1985), resulted in 

reduced testosterone levels in male rats. The biological significance of this effect is unknown because the 

decrease had no result on fertility in the latter study (Laskey et al. 1985), and there were no observed 

effects on the hypothalamus or pituitary. 

A current interest in endocrine effects of manganese revolves around the possibility that developmental 

manganese exposure may influence the timing of puberty. One study performed on 23-day-old female 

rats in which manganese was provided by a single, intraventricular administration of 0, 0.01, 0.02, 0.04, 

or 0.17 mg manganese/kg as manganese chloride found that, at the three highest doses, manganese 

stimulated a dose-responsive increase in luteinizing hormone (LH) levels (Pine et al. 2005). A dose of 

2 mg manganese/kg/day, provided to another group of female pups by daily gavage from PND 12 to 29 

significantly advanced the average age of puberty (by approximately 1 day) as well as produced 

significant increases in serum levels of LH, follicule stimulating hormone (FSH), and estradiol (E2) (Pine 

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et al. 2005). These results suggest a role for manganese in regulating the timing of puberty in female rats 

and suggests that excess manganese exposure may accelerate the onset of puberty. Manganese also 

appears to have pubertal effects in male rats; an oral gavage dose of 11 mg manganese/kg/day provided 

daily on PNDs 15–48 or 15–55 produced significantly increased LH, FSH, and testosterone at 55 days of 

age (Lee et al. 2006). Increases in both daily sperm production and efficiency of spermatogenesis were 

also observed, suggesting that manganese may be a stimulator of prepubertal LHRH/LH secretion and 

thus facilitate the onset of male puberty. In vitro experiments using medial basal hypothalamic implants 

from adult male Sprague-Dawley rats showed that manganese at 500 μM increased luteinizing hormonereleasing hormone (LHRH) release, nitric oxide synthase activity, and the content of cyclic cGMP in the 

medial basal hypothalamus (Prestifilippo et al. 2007). The inhibition of nitric oxide synthase with a 

competitive inhibitor prevented the manganese-induced increase in LHRH release. The results of these in 

vitro studies provide added evidence of the ability of manganese to modulate levels of LHRH, even in 

adult animals (Prestifilippo et al. 2007). 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

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because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

Children as a group have typically not been studied for the adverse effects of overexposure to inorganic 

manganese. Manganese results in adverse respiratory effects, as well as neurological effects; the latter 

effects have been the most investigated. As discussed previously, manganism has typically been observed 

in occupational settings, as in manganese miners, or in isolated cases of extreme exposure to inhaled or 

ingested manganese. In general, these exposure scenarios do not pertain to children. Reports do exist, 

however, of incidences of overexposure to inorganic manganese resulting in respiratory illness. Two 

studies exist that investigated increased respiratory complaints and symptoms at a junior high school 

situated 100 m from a manganese alloy plant in Japan (manganese concentrations in total dust at a 

200 meter perimeter around the plant were 0.004 mg/m3 [3.7 μg/m3

]) (Kagamimori et al. 1973; Nogawa et 

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al. 1973). The initial study showed that the incidences of self-reported respiratory illnesses among 

children in the exposed school were much higher than those of a control school 7 km away from the plant 

(Nogawa et al. 1973). Further, evaluations of respiratory fitness showed significant decreases in several 

parameters. When the installation of dust catchers resulted in a decreased manganese concentration in 

total dust, complaints of illness decreased, and the test results improved (Kagamimori et al. 1973). These 

respiratory effects were not unique from those observed in adults exposed to airborne manganese. 

Further, it was not reported if other compounds were present in the dust generated by the plant, which 

might have contributed to or caused the reported illnesses. It is possible that these effects might have 

been triggered by the dust and were not specific to manganese. 

Studies on potential neurological effects in children from inhalation exposure to excess inorganic 

manganese are limited. One study showed that a native population living on an island with rich 

manganese deposits suffered increased neurological disorders and incidences of birth defects (Kilburn 

1987); their exposure was most likely via inhalation and oral routes. This study involved small sample 

sizes and lacked exposure concentrations and a suitable control group; these limitations preclude 

ascribing these effects to manganese alone. 

Children who have been exposed to elevated levels of inorganic manganese presumably through diet 

(either a normally ingested diet or through total parenteral nutrition, TPN) have shown signs of motor 

disorders (e.g., dystonia, dysmetria, propulsion, retropulsion, poor check response bilaterally) similar to 

those observed in cases of frank manganism (Devenyi et al. 1994; Fell et al. 1996). In a few of the cases, 

the presence of liver dysfunction indicated a decreased ability to clear excess manganese (Devenyi et al. 

1994; Fell et al. 1996), but some of the children with apparently normal livers also exhibited motor 

disorders (Fell et al. 1996). Several children also exhibited hyperintense signals on MRI resulting from 

increased exposure to manganese due to cholestatic end-stage liver disease (Devenyi et al. 1994) and from 

high concentrations of the element in TPN, either in the presence (Fell et al. 1996) or absence (Fell et al. 

1996; Ono et al. 1995) of liver disease. The Ono et al. (1995) study involved a child on TPN for more 

than 2 years; although this child did have increased blood manganese and hyperintense signals in the 

basal ganglia as shown by MRI, the authors did not report any observable signs of neurotoxicity. A 

similar lack of observable neurotoxicity was reported in two siblings fed TPN with high manganese 

concentrations (0.2 mmol manganese/kg/day) for several months (the brother for 63 months total starting 

at age 4 months; the sister for 23 months total starting at age 1 month) (Kafritsa et al. 1998). Both 

children had elevated blood manganese levels and showed hyperintense signals in the basal ganglia 

(especially the globus pallidus and subthalamic nuclei) on MRI. Reduction of manganese concentration 

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in the TPN resulted in a gradual loss of signal on MRI analysis (becoming comparable to normal scans) 

and a decrease in blood manganese levels as measured in three subsequent annual exams. These 

equivocal results indicate that there are considerable differences in susceptibility to the neurotoxic effects 

of excess manganese in children. 

Four reports of manganese neurotoxicity in children have been published recently including: (1) severe 

manganism-like neurotoxic symptoms (inability to stand independently, tendency to fall backward, and 

development of a “cock-like” walk) in a previously healthy 6-year-old female that were associated with 

elevated drinking water concentrations of manganese (1.7–2.4 mg manganese/L), pica, a diet high in 

manganese-rich foods, and elevated levels of plasma manganese (Sahni et al. 2007); (2) inattentiveness 

and lack of focus in the classroom and low-percentile performance in tests of memory in a 10-year-old 

male with no history of learning problems associated with elevated manganese in drinking water (1.21 mg 

manganese/L) (Woolf et al. 2002); (3) a statistically significant relationship for decreasing intelligence 

scores with increasing manganese levels in drinking water in a cross-sectional epidemiological study of 

142 10-year-old children in Bangladesh (Wasserman et al. 2006); and (4) a statistically significant 

relationship between increased levels of oppositional behaviors and hyperactivity and increased levels of 

manganese in drinking water in an epidemiological study of 46 children (ages 6–15 years) in Quebec, 

Canada (Bouchard et al. 2007c). These results provide added weight to the evidence for the neurotoxic 

potential of excessive manganese in children, but the following uncertainties associated preclude the 

establishment of causal relationships between the observed effects and manganese exposure: (1) whether 

or not the observed effects were solely due to excess manganese alone or could have been influenced by 

other drinking water or dietary components; (2) the lack of information about manganese levels in food 

and air; and (3) the small sample sizes. 

Two other earlier studies show that children who drank water containing manganese at average 

concentrations of at least 0.241 mg/L (Zhang et al. 1995) and ate food with increased manganese content 

(He et al. 1994) for 3 years performed more poorly in school (as shown by mastery of their native 

language, mathematics, and overall grade average) and on the WHO neurobehavioral core test battery 

than those students who drank water with manganese ≤0.04 mg/L. These neurobehavioral tests are 

among those administered to workers occupationally exposed to manganese to determine the presence of 

early neurological deficit (Chia et al. 1993a; Iregren 1990; Lucchini et al. 1995; Mergler et al. 1994; 

Roels et al. 1987a, 1992). These concentrations are much lower than the ones to which adults were 

exposed in the Kondakis et al. (1989) study. In this study, ingestion of drinking water with excess 

manganese (1.8–2.3 mg/L) was linked to the onset of unspecified neurological symptoms in an aged 

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population (average age, over 67 years). Though there are limitations, this and other environmental 

studies in adults (Baldwin et al. 1999; Beuter et al. 1999; Goldsmith et al. 1990; Kawamura et al. 1941; 

Kondakis et al. 1989; Mergler et al. 1999) and two studies in children (He et al. 1994; Zhang et al. 1995) 

indicate that both adults and children can manifest similar neurological deficits that are potentially linked 

to ingesting excess manganese. However, these reports are lacking well-characterized and quantitative 

exposure data that would indicate whether children and adults experience neurological effects at the same 

or different exposure levels. Existing studies do not allow estimations of the quantitative susceptibility of 

children to the preclinical effects of excess manganese exposure. They do indicate, though, that children 

can develop symptoms of neurotoxicity after oral exposure to manganese that are similar to those effects 

seen in adults environmentally or occupationally exposed to the metal. Further, these studies indicate that 

neurological effects may be a concern for children exposed to excess manganese from the environment or 

from a hazardous waste site. 

The investigations by He et al. (1994) and Zhang et al. (1995) showed that children with poorer school 

performance had higher manganese hair content than children from the control area. Other studies have 

found that manganese levels in hair are higher in learning disabled children than in normal children 

(Collipp et al. 1983; Pihl and Parkes 1977). The route of excess exposure is not known, but it is 

presumed to be mainly oral. These observations are consistent with the possibility that excess manganese 

ingestion could lead to learning or behavioral impairment in children. However, an association of this 

sort is not sufficient to establish a cause-effect relationship since a number of other agents, including lead, 

might also be involved (Pihl and Parkes 1977). 

Developmental studies in animals following inhalation exposure to manganese are sparse. One study 

exists (Lown et al. 1984) in which pregnant mice were exposed to a high concentration of airborne 

manganese or filtered air for 17 days preconception and then exposed to either the same concentration of 

manganese or filtered air postconception. Their pups were then fostered to adult females who had 

experienced the same inhalation exposures as the mothers (no manganese exposure, pre- or postconception exposure, or both). The pups of exposed mothers had decreased body weight, but exhibited 

no differences in activity compared to pups from mothers exposed to air, irrespective of exposure history. 

In neonatal rats orally exposed to 25 or 50 mg manganese/kg/day from PNDs 1 through 21, manganese 

concentrations in various brain regions were about 2-fold higher than brain manganese concentrations in 

adult rats exposed to the same oral dose levels for 21 days (Dorman et al. 2000). At the highest dose 

level, neonatal rats showed an increased acoustic startle response, but exposure-related changes in other 

neurological end points (clinical signs, motor activity, and passive avoidance) were not found (Dorman et 

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al. 2000). In another recent study, inhalation exposure of female CD rats to manganese sulfate, starting 

28 days prior to breeding through PND 18, caused elevated manganese concentrations in exposed 

maternal rats (compared with air control rats) in the following tissues: brain and placenta at 0.5 and 

1.0 mg manganese/m3 and lung at 0.05, 0.5, and 1.0 mg manganese/m3 (Dorman et al. 2005a). In 

contrast, statistically significant elevations of manganese concentrations in sampled fetal tissues were 

observed only in the liver at 0.5 and 1.0 mg manganese/m3

, and elevated brain manganese concentrations 

were only observed in offspring after PND 14. The results from this study suggest that the brain in 

developing fetuses is partially protected from excess manganese by the placenta, and that the neonatal 

period is sensitive to increased manganese concentration in brain and other tissues under exposure to 

elevated airborne manganese concentrations. 

Oral studies in animal models, whether involving the dosing of pregnant dams or sucklings, reveal a 

variety of neurochemical and physiological changes as a result of manganese exposure. The majority of 

studies have involved manganese chloride. One study in rats reported that pups exposed in utero 11 days 

during gestation to a relatively low concentration of manganese chloride (22 mg/kg; by gavage in water) 

did not have any observable decrease in weight gain, nor any gross or skeletal malformations upon 

necropsy (Grant et al. 1997a). Another study (Szakmáry et al. 1995) that also administered manganese 

chloride in water by gavage to pregnant rats at the slightly higher concentration of the 33 mg 

manganese/kg/day throughout the entire gestation period reported a delay of skeletal and organ 

development as well as an increase in skeletal malformations, such as clubfoot, in unborn pups. These 

malformations, however, were self-corrected in pups allowed to grow to 100 days of age. In addition, the 

same dose and route did not result in any observable developmental toxicity in the rabbit (Szakmáry et al. 

1995). Rat pups exposed during gestation and after birth to manganese at relatively high concentrations 

of 120–620 mg/kg in drinking water suffered no observable adverse effects at the low dose and only 

transient adverse effects (decrease in weight and hyperactivity) at the high dose (Pappas et al. 1997). 

Similar transient body weight decreases and increases in motor activity were observed in neonatal rats 

administered 22 mg manganese/kg/day (as manganese chloride), by mouth or gavage, for up to 49 days 

(Brenneman et al. 1999; Dorman et al. 2000). 

Rat pups from a generational study in which the male and female parents were exposed to 240–715 mg 

manganese/kg/day (as manganese chloride in drinking water) in either a diet adequate or deficient in 

protein (Ali et al. 1983a) suffered a delayed air righting reflex (independent of protein content of diet) and 

showed significant alterations in the age of eye opening and development of auditory startle when 

produced by parents fed low-protein diets with 240 mg manganese/kg/day in water. Kontur and Fechter 

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(1988) administered up to 1,240 mg manganese/kg/day as manganese chloride in drinking water to 

pregnant rats during days 0–20 of gestation. Although the authors found increased manganese levels in 

the fetus, there were no measurable effects on dopamine or norepinephrine turnover in the pup brain, or in 

the development of a startle response. In a more recent study, an increased amplitude in acoustic startle 

reflex was observed at PND 21 in neonatal rats administered 22 mg manganese/mg/day (as manganese 

chloride) by mouth from PND 1 to 21 (Dorman et al. 2000). Significant increases in brain dopamine and 

DOPAC concentrations in select brain regions in these animals as well as increased brain manganese 

concentrations were reported. This study demonstrated that neonates treated with manganese showed 

neurological changes, whereas no effects were observed in the adult animals treated similarly. Jarvinen 

and Ahlström (1975) fed pregnant rats varying doses of manganese sulfate in food for 8 weeks prior to 

and during gestation. Fetuses taken at 21 days did not show gross abnormalities, but did have 

significantly increased body burdens of manganese from mothers fed 187 mg/kg/day. 

Neonatal rats given manganese chloride in drinking water for 44 days at a dose of 150 mg manganese/ 

kg/day developed a transient ataxia on days 15–20 of the treatment and had decreased levels of 

homovanillic acid in the hypothalamus and striatum on day 15 but not day 60 (Kristensson et al. 1986). 

Neonatal rats given bolus doses of manganese chloride in water of 1 mg manganese/kg/day for 60 days 

suffered neuronal degeneration and increased monoamine oxidase on days 15 and 30 of the study, but did 

not show any clinical or behavioral signs of neurotoxicity (Chandra and Shukla 1978). Similarly, 

neonatal rats given bolus doses of manganese chloride in 5% sucrose at doses of 0, 1, 10 or 20 mg 

manganese/kg/day for 24 days after birth showed decreased levels of dopamine, but not norepinephrine, 

in the hypothalamus (Deskin et al. 1980); doses of 20 mg/kg/day caused a decrease of tyrosine 

hydroxylase activity and an increase in monoamine oxidase activity in the hypothalamus. In a follow-up 

study, Deskin et al. (1981) gave 0, 10, 15 and 20 mg manganese/kg/day (as manganese chloride in 5% 

sucrose by gavage) to neonatal rats from birth to age 24 days. The authors found that the highest dose 

resulted in increased serotonin in the hypothalamus and decreased acetylcholinesterase in the striatum. 

However, the authors did not indicate that the acetylcholinesterase decrease was important given other 

mechanisms involved in the metabolism of this neurochemical. Other recent findings from rat studies 

include increased locomotor activity when dosed with 10 mg/kg cocaine in adulthood (but no increased 

locomotor activity without cocaine challenge) following oral exposure to 13.1 mg manganese/kg/day (but 

not 4.4 mg manganese/kg/day) on PNDs 1–21 (Reichel et al. 2006); and impaired olfactory-mediated 

homing ability and passive avoidance of footshocks in male Sprague-Dawley rats exposed to oral doses of 

17.2 mg manganese/kg/day (but not 8.6 mg manganese/kg/day) as manganese chloride on PNDs 1–20 

(Tran et al. 2002a, 2002b). 

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Several studies evaluated the effects of manganese in the diet on reproductive development in the preweanling rodent. Gray and Laskey (1980) fed mice 1,050 mg manganese/kg/day (as manganese 

tetroxide) in the diet beginning on PND 15 and continuing for 90 days. The manganese caused decreased 

growth of the testes, seminal vesicles, and preputial gland. Later studies evaluated the effect of excess 

manganese via the diet and gavage on development of the rat (Laskey et al. 1982, 1985). These studies 

reported that 350 mg manganese/kg/day (as manganese tetroxide in food fed to pregnant rats and resulting 

male offspring for a total of 224 days) (Laskey et al. 1982) or 214 mg manganese/kg/day (as manganese 

tetroxide by gavage in water given for 28 days) (Laskey et al. 1985) reduced testosterone levels in 

developing rats. 

Studies involving intravenous or subcutaneous exposure routes of pregnant dams indicate that doses of 

manganese chloride as low as 1.1 mg manganese/kg/day administered on GDs 6–17 in the rat (Grant et al. 

1997a; Treinen et al. 1995) and 14 mg/kg/day administered on GDs 9–12 in the mouse (Colomina et al. 

1996) can result in decreased fetal body weight and skeletal abnormalities. 

The data indicate that animals may suffer adverse developmental effects after inhalation, oral, and 

intravenous exposures of their pregnant mothers, but results are mixed. Taken together, the evidence 

from environmental studies in humans and studies in animals suggests that younger children can be 

affected by exposures to excess manganese. Only one study is available that compared the incidence of 

adverse neurological effects in neonates and adults exposed to excess manganese (Dorman et al. 2000). 

Another recent study (Dorman et al. 2005b) showed that fetal brains were protected from excess 

manganese when their mothers were exposed to air concentrations as high as 1 mg manganese/m3 

manganese sulfate for 28 days before mating through PND 18, but increased brain manganese 

concentrations developed in the offspring by PND 14. Additional information may help to quantitatively 

characterize the potential differences in susceptibility to manganese-induced effects in young and adult 

animals. 

No studies currently exist on the health effects arising in children as a result of exposure to organic 

manganese. Therefore, predictions concerning potential effects must be made from extrapolations from 

existing animal studies. 

Weanling mice who ingested 11 mg manganese/kg/day as MMT for 12 months exhibited a significant 

increase in spontaneous activity at day 80, but no other behavioral differences throughout the exposure 

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period (Komura and Sakamoto 1992b). Concentrations of certain neurotransmitters and dopamine 

metabolites were modified in different brain regions, but the relationship to manganese levels in the 

affected regions was weak to none (Komura and Sakamoto 1994). 

Developmental studies in rats involving intravenous exposure of pregnant dams to mangafodipir during 

organogenesis (days 6–17) indicate that the compound targets the skeletal system, resulting in irregularly 

shaped bones at doses as low as 1 mg manganese/kg/day (Grant et al. 1997a; Treinen et al. 1995). 

Further, application of specific doses of the compound during segmented time periods in organogenesis 

causes the same skeletal defects (Treinen et al. 1995). When the compound is administered from 22 days 

prior to conception until GD 7, at up to 6 mg manganese/kg/day, no developmental effects were observed 

(Grant et al. 1997a). These data further indicate that animals developing during organogenesis are 

particularly susceptible to developmental toxicity from mangafodipir exposure. Further, behavioral 

changes and significant decreases in body weight were observed in rat pups delivered from dams dosed 

with 1.1 mg manganese/kg/day, while decreased survival was observed in pups from dams given 2.2 mg 

manganese/kg/day on GDs 6–17. 

In contrast to the rat, available studies suggest that the rabbit is far less susceptible to the developmental 

effects of mangafodipir. One study reported only decreased ossification in fetal sternebrae at 1.1 mg 

manganese/kg/day when given to dams on GDs 6–17 (Grant et al. 1997a); a similar study in the same 

species reported no observable developmental toxicity at 2.2 mg manganese/kg/day, but a significant 

decrease in fetal weight and viable fetuses, with no skeletal abnormalities, at a dose of 3.3 mg manganese/ 

kg/day also given during organogenesis (Blazak et al. 1996). 

In total, these developmental studies indicate that organic manganese can induce adverse developmental 

effects in the unborn and young, with effects ranging from slight biochemical changes in the brain to 

structural changes to changes in functional development. However, the majority of studies have involved 

very high exposure doses. 

The developmental toxicity of elemental manganese has been shown in large part by comparison studies 

between manganese chloride and mangafodipir (Blazak et al. 1996; Grant et al. 1997a; Treinen et al. 

1995). While these studies have provided much information as to the targeted teratogenicity of 

manganese during organogenesis, they have generally involved intravenous exposures, which are not 

particularly relevant to the general population. Further, it is likely that the majority of women who may 

be exposed to mangafodipir are beyond child-bearing age, since clinical subjects with suspected liver 

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tumors that merit use of the compound to assist in diagnosis are often over 50 years old (mean values; 

Bernardino et al. 1992). Should child-bearing women be exposed to the compound in a clinic 

environment, the doses required to induce developmental toxicity in animals greatly exceed the clinical 

dose (Blazak et al. 1996; Grant et al. 1997a; Treinen et al. 1995). 

The pharmacokinetics of manganese in infants is known to be different than in adults. Balance studies, 

although limited, show that there is high retention of manganese during the neonatal period (Dorner et al. 

1989). Formula-fed infants had an apparent manganese absorption of around 20% (Davidsson et al. 1988; 

1989b), compared to absorption in adults, which is shown to be around 3–5% (Mena et al. 1969). The 

increased absorption may be a compensatory mechanism due to the low concentration of manganese in 

mother’s milk (Collipp et al. 1983; Dorner et al. 1989; Lönnerdal et al. 1987) and to the increased 

metabolic needs of infants as compared to adults, since manganese is required for adequate bone 

mineralization, as well as for connective tissue synthesis (Hurley and Keen 1987). Alternatively, the 

increased absorption may be due to decreased excretion in the very young (Kostial et al. 1978; Lönnerdal 

et al. 1987; Miller et al. 1975; Rehnberg et al. 1981), although at least one study indicates that both preterm and full-term infants actively excrete manganese (Dorner et al. 1989). Some studies have indicated 

that infants, who acquire all of their manganese in the first 4 months of life from human milk or milk 

formulas, ingest very different amounts of manganese due to the differing manganese content of these 

food sources. More specifically, studies showed that due to the low manganese concentration of human 

milk (4–10 μg/L) and its higher concentration in cow’s milk formulas (30–75 μg/L) and soy formulas 

(100–300 μg/L) (Dorner et al. 1989; Lönnerdal et al. 1987), more manganese was absorbed from the 

formula (with absorption rate from all sources being roughly equal). Recent changes in nutritional status 

of infant formulas have resulted in a more nutritionally balanced absorption of manganese when 

compared to human milk and cow’s milk formulas (~80–90%), with absorption of manganese from soy 

milk formulas being slightly lower (~70%; Lönnerdal et al. 1994). However, given the existing 

differences in inherent manganese concentrations between the different food sources, reports still suggest 

that infant intake of manganese from milk formulas is 10–50 times that of a breast-fed infant (Lönnerdal 

1997). Animal studies show that absorption and/or retention of manganese is similar to that of older 

animals at approximately post-gestational day 17–18 (Kostial et al. 1978; Lönnerdal et al. 1987; Miller et 

al. 1975; Rehnberg et al. 1981). However, when this transition takes place in human infants has not been 

clearly defined. 

Animal studies also show increased absorption of manganese in the young. For example, Kostial et al. 

(1989) found that rat pups retained a greater proportion (67%) of a single oral dose of radiolabeled 

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manganese than adult rats (0.18%). Bell et al. (1989) found that manganese absorption in rat pups (using 

isolated brush border membrane vesicles from the intestine) is nonsaturable and appears to occur 

primarily by diffusion. In the older rat, however, a high affinity, low capacity, active-transport 

mechanism for manganese absorption appears to be present (Garcia-Aranda et al. 1983). 

Several elements, including iron (Davis et al. 1992a), phosphorus (Wedekind et al. 1991), and calcium 

(Wilgus and Patton 1939) are known to decrease manganese absorption in adults and animals. Iron-poor 

diets result in increased manganese absorption in humans (Mena et al. 1969) and in rats (Pollack et al. 

1965). These interactions have not been studied in infants or children, but are expected to occur. 

Manganese is known to cross the placenta and has been detected in cord blood in healthy full-term and 

pre-term infants. It is unknown whether mothers exposed to increased concentrations of manganese will 

pass on toxic amounts of the metal to their unborn children via the blood. However, as manganese is an 

essential nutrient and is part of the human body at all times, it is expected to be found in all tissues and 

fluids of the infant. Manganese is also naturally found in breast milk (typical concentrations in mature 

milk range from 4 to 10 μg/L) (Collipp et al. 1983). No studies exist concerning breast milk 

concentrations of mothers exposed to increased concentrations of manganese, but milk manganese 

concentrations increased with increasing exposure levels in lactating female rats exposed by inhalation to 

manganese sulfate at 0.05, 0.5, or 1 mg manganese/m3 for 28 days before mating through PND 18 

(Dorman et al. 2005a). The mean milk concentration was statistically significantly increased, compared 

with air control levels, however, only at the highest exposure level. It is unclear if manganese stored in 

the brain, bone, or in another depot, in excess amounts, could be mobilized to affect a developing fetus. 

However, one study by Jarvinen and Ahlström (1975) showed that pregnant rats fed 94 mg manganese/ 

kg/day (as manganese sulfate) for 8 weeks accumulated the metal in their livers in contrast to nonpregnant females. Further, at a daily dose of 187 mg/kg/day, increased manganese concentrations were 

found in 21-day-old fetuses. These data suggest that homeostatic control of pregnant mothers regulated 

the distribution of the metal at lower concentrations, but this control was circumvented at high daily 

concentrations, resulting in liver excesses and distribution in the developing fetus. Although the fetuses 

in this study showed no physical abnormalities, no neurochemical or neurobehavioral studies were 

performed to determine potential adverse effects on these relevant end points. 

Transferrin is one of the proteins responsible for binding and transporting both iron and manganese 

throughout the body. One study (Vahlquist et al. 1975) reported no correlation between infant cord blood 

and maternal blood transferrin levels. The same study reported an increase in plasma transferrin from 

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1.68±0.60 mg/mL in blood from infants at 6 weeks of age, to a peak of 2.60±0.27 mg/mL at 10 months, 

with values stabilizing at these adult levels throughout 16 years of age. The authors did not comment as 

to the statistical difference, if any, of these values. 

There are no established biomarkers consistently used as indicators for overexposure to manganese in 

either adults or children. Elevated blood concentrations and hyperintense signals in the globus pallidus on 

T1-weighted MRI have been observed in children with increased exposure to manganese (Devenyi et al. 

1994; Fell et al. 1996; Kafritsa et al. 1998; Ono et al. 1995). However, the same limitations of these 

indicators of overexposure in adults (wide range of blood manganese in normal populations, high cost 

and, hence, low availability of MRI) apply to children. Blood manganese has generally been poorly 

related to current levels of exposure or cumulative exposure index (Smargiassi and Mutti 1999). Elevated 

blood manganese alone does not constitute an adequate indicator of manganese overexposure. There are 

no pediatric-specific biomarkers of exposure or effect. See Section 3.8.1 for further information. 

Studies suggest that children may differ from adults in their susceptibility to the toxic effects of 

manganese due to toxicokinetic differences (i.e., increased absorption and/or retention). Qualitative 

similarities exist between respiratory and neurological effects seen in adults and children suffering from 

extreme manganese exposure. While infant and animal studies indicate that the young have an increased 

uptake of manganese, and distribution of the element in certain tissues may differ with age, studies that 

reveal quantitative levels of manganese associated with discrete frank effects in both adults and children 

are lacking. The studies to date (namely absorption, distribution and excretion studies in animals) suggest 

a pharmacokinetic susceptibility to manganese that is different in children than in adults. 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 

A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction 

between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment 

of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance 

itself, substance-specific metabolites in readily obtainable body fluid(s), or excreta. However, several 

factors can confound the use and interpretation of biomarkers of exposure. The body burden of a 

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substance may be the result of exposures from more than one source. The substance being measured may 

be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from 

exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., 

biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and 

all of its metabolites may have left the body by the time samples can be taken. It may be difficult to 

identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids 

(e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to 

manganese are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by manganese are discussed in Section 3.8.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10, Populations That Are Unusually Susceptible. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Manganese 

Manganese can be measured with good sensitivity in biological fluids and tissues (see Section 7.1), and 

levels in blood, urine, feces, and hair have been investigated as possible biomarkers of exposure. As a 

group, workers exposed to a mean concentration of 1 mg manganese/m3 had higher levels of manganese 

in the blood and the urine than unexposed controls (Roels et al. 1987b). The group average levels in 

blood appeared to be related to manganese body burden, while average urinary excretion levels were 

judged to be most indicative of recent exposures. A study by Lucchini et al. (1995) is the only evidence 

that suggests that blood and urine levels were correlated with manganese exposure on an individual basis. 

This study differed from others in that it involved exposure to manganese dioxide and measured adverse 

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effects in workers after exposure ceased, whereas other studies involved current exposures, and some, like 

Roels et al. (1987b) involved exposure to numerous manganese compounds (salts and oxides). The 

findings of Lucchini et al. (1995) suggest that blood and urine levels of manganese, on an individual 

basis, are positively correlated with exposure levels in the few weeks following cessation of exposure. In 

a study of chronically exposed workers who were evaluated while exposure was ongoing, Lucchini et al. 

(1999) found a positive correlation between manganese levels in total dust and in blood of exposed 

workers. This correlation did not exist for cumulative exposure index and blood levels of the metal. 

Other studies have indicated that on an individual basis, the correlation between the level of workplace 

exposure and the levels in blood or urine is not a reliable predictor of exposure (Jarvisalo et al. 1992; 

Roels et al. 1987b, 1992; Smyth et al. 1973). However, two studies (Jarvisalo et al. 1992; Roels et al. 

1992) suggest that blood and urinary manganese levels may be used to monitor group exposure, such as 

exposure in an occupational setting. Also, a study (Siqueira et al. 1991) of ferromanganese workers 

indicated that exposed workers had elevated levels of plasma and urinary urea and decreased levels of 

urinary calcium, HDL cholesterol, and plasma inorganic phosphate. The study authors concluded that 

measurement of these parameters may be useful in the early detection of manganese poisoning. Although 

manganese may play a role in a metabolic pathway or other biological function involving these products, 

it is unclear what physiological significance these parameters have as related to manganese toxicity. 

There was no significant correlation between fecal excretion of manganese and occupational exposure to 

the metal (Valentin and Schiele 1983). A recent study on environmental exposure to manganese 

(Baldwin et al. 1999) in southwest Quebec, Canada, indicates that significantly higher levels of blood 

manganese are correlated with high levels of airborne manganese. In this study, air samples were taken in 

four geographic areas around a former ferroalloy plant (point source for airborne manganese). The air 

samples, which were for total dust and PM10 levels, were taken for 3 consecutive days in the summer. 

Using a geometric algorithm, 297 blood manganese values from nearby residents in seven postal zones 

were separated into two geographical areas corresponding to the point source. Higher blood manganese 

values in men and women were located in the geographic area with the higher airborne manganese values. 

It is notable that the air samples taken were limited in number and were taken only in the summer. 

However, the authors mentioned that the data were consistent with samples taken in an adjacent urban 

area and were consistent with potential exposure sources. Further, at the time of sampling, the ferroalloy 

plant was not in use and exposure data indicated that airborne levels of manganese decreased dramatically 

at a point 25 km downwind of the plant after the plant closed (Zayed et al. 1994). Thus, manganese 

exposure of the population in the Baldwin et al. (1999) study is likely to have been greater in the past; 

current blood manganese levels may be analogous to those observed in occupational workers undergoing 

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a forced layoff (Lucchini et al. 1995). These data, combined with the occupational studies, indicate that 

there may be a plateau level of homeostatic control of the metal. At low levels, blood manganese 

concentrations would be related to intake from food, water, and air; large differences in individual blood 

manganese levels would be observed. At high exposure levels, such as in occupational environments, a 

higher but still non-toxic level of blood manganese may be maintained by homeostatic control (i.e., a 

plateau level is reached); alternatively, that level may be exceeded. 

These data also indicate that blood manganese levels can be an indicator of exposure to environmental 

manganese. These data indicate that manganese in blood or urine may be useful in detecting groups with 

above-average current exposure, but that measurements of manganese in these body fluids in individuals 

may only be related to exposure dose after the exposure has ceased. 

In addition to individual variability, another factor that limits the usefulness of measuring manganese in 

blood, urine, or feces as a measure of excess manganese exposure is the relatively rapid rate of 

manganese clearance from the body. As discussed in Section 3.4, excess manganese in blood is rapidly 

removed by the liver and excreted into the bile, with very little excretion in urine (Klaassen 1974; 

Malecki et al. 1996b). Thus, levels of manganese in blood or urine are not expected to be the most 

sensitive indicators of exposure. 

Serum prolactin (PRL) has been shown to be a possible biomarker of manganese action of dopamine 

neurotransmission (Smargiassi and Mutti 1999). Manganese acts on the tuberoinfundibular dopaminergic 

system, which exerts tonic inhibition of PRL secretion. Serum PRL levels observed in workers 

occupationally exposed to manganese were shown to be consistent with mechanistic studies as they were 

distinctly higher than unexposed workers. It is still unclear whether or not serum PRL levels indicate 

recent or cumulative exposure. The value of PRL as a biomarker is called into question by the Roels et al. 

(1992) study in which serum PRL levels were not increased in workers chronically exposed to airborne 

manganese. 

Lymphocyte manganese-dependent superoxide dismutase activity increases with increased manganese 

uptake (Yiin et al. 1996). It has been suggested that this enzyme, in conjunction with serum manganese 

levels, may be helpful in assessing low and moderate levels of manganese exposure (Davis and Greger 

1992; Greger 1999). MnSOD has been shown to be elevated in women ingesting 15 mg of supplemental 

manganese/day, while levels have been shown to be depressed in the heart and liver of manganese 

deficient animals. MnSOD is important as a possible biomarker because its levels can be related to 

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oxidative damage. Its sensitivity as a biomarker depends on factors that induce oxidative stress or effect 

manganese bioavailability including diets high in polyunsaturated fatty acids and strenuous physical 

exercise (Greger 1999). 

Brain MRI scans and a battery of specific neurobehavioral tests (Greger 1998) may be useful in assessing 

excessive manganese exposure even among industrial workers exposed to airborne manganese (Nelson 

et al. 1993). These scans also have been successfully used to identify accumulation of manganese in the 

brains of children exposed to excess manganese (Devenyi et al. 1994; Fell et al. 1996; Ihara et al. 1999; 

Kafritsa et al. 1998; Ono et al. 1995; Sahni et al. 2007). Levels in feces could be useful in evaluating 

relatively recent high-level exposures but would not be expected to be helpful in detecting chronic lowlevel exposures. These methods are potentially useful biomarkers, but require additional evaluation to 

determine their validity. 

While it is well established that exposure to excess manganese can result in increased tissue levels in 

animals, the correlations among exposure levels, tissue burdens, and health effects have not been 

thoroughly investigated in humans or animals. Also, since homeostatic mechanisms largely prevent 

fluctuations of manganese concentration in whole blood and since manganese is mainly excreted by the 

biliary route, it is not believed possible to identify a biological marker to assess the intensity of exposure 

or concentration in the target organ (Lauwerys et al. 1992). As noted by Rehnberg et al. (1982), 

manganese levels in tissues are subject to homeostatic regulation via changes in absorption and/or 

excretion rates. While exposure to very high levels may overwhelm these mechanisms, continuous 

exposure to moderate excesses of manganese does not appear to cause a continuous increase in tissue 

levels (Rehnberg et al. 1982). Moreover, even if tissue levels are increased in response to above-average 

exposure, levels are likely to decrease toward the normal level after exposure ceases. For example, the 

level of manganese in the brain of a subject with severe manganism was not different from the normal 

level (Yamada et al. 1986). For these reasons, measurement of tissue levels of manganese at autopsy or 

possibly biopsy may be of some value in detecting current exposure levels but is not useful in detecting 

past exposures. Evaluation of manganese exposure by analysis of tissue levels is also not readily 

applicable to living persons except through the collection of biopsy samples. 

MRI has been used to track manganese distribution in the brains of monkeys (Dorman et al. 2006b; 

Newland and Weiss 1992; Newland et al. 1989) and humans (Kafritsa et al. 1998; Klos et al. 2005; Nolte 

et al. 1998; Park et al. 2003; Rose et al. 1999; Uchino et al. 2007; Wolters et al. 1989). In addition, it has 

been used to assay hyperintense signaling in the globus pallidus and other brain areas of individuals with 

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chronic liver disease (Devenyi et al. 1994; Hauser et al. 1994, 1996; Klos et al. 2005; Nolte et al. 1998; 

Park et al. 2003; Pomier-Layrargues et al. 1998; Spahr et al. 1996; Uchino et al. 2007), individuals on 

chronically-administered TPN (Kafritsa et al. 1998; Nagatomo et al. 1999; Ono et al. 1995), and 

individuals with symptoms characteristic of manganism (Nelson et al. 1993). Although data addressing 

the sensitivity and specificity of MRI as an indicator for body burden or exposure are limited, the 

technique is being used to identify individuals who are likely to have increased stores of manganese in 

brain and potentially in other tissues, as well. For example, the hyperintense signaling in the brain is 

typically coincident with elevated blood manganese levels (Devenyi et al. 1994; Hauser et al. 1994, 1996; 

Kafritsa et al. 1998; Klos et al. 2005; Nagatomo et al. 1999; Nolte et al. 1998; Ono et al. 1995; Park et al. 

2003; Pomier-Layrargues et al. 1998; Spahr et al. 1996; Uchino et al. 2007). Dorman et al. (2006b) 

evaluated the use of the pallidal index (PI—ratio of hyperintensities in the globus pallidus and the 

adjacent subcortical frontal white matter) and the T1 relaxation rate (R1) from MRI to reflect manganese 

concentrations determined by analytical chemistry in brain regions of monkeys repeatedly exposed by 

inhalation to aerosols of manganese sulfate at several concentrations ≥0.06 mg. Increases in the PI and 

R1 were correlated with the pallidal manganese concentration, but increased manganese concentrations in 

white matter confounded the PI measurements. Dorman et al. (2006b) suggested that R1 can be used to 

estimate regional brain manganese concentrations and that this technique may be used as a reliable 

biomarker of occupational manganese exposure. 

Neutron activation has been shown to be a possible means of in vivo measurement of manganese in the 

liver and possibly other tissues and organs, including the brain (Arnold et al. 1999; Rose et al. 1999). 

Minimum detection levels are low enough to distinguish between normal and elevated concentrations. 

Scalp hair has also been investigated as a possible biomarker of manganese exposure. While some 

studies have found a correlation between exposure level and manganese concentration in hair (Collipp 

et al. 1983), use of hair is problematic for several reasons. For example, exogenous contamination may 

yield values that do not reflect absorbed doses, and hair growth and loss limit its usefulness to only a few 

months after exposure (Stauber et al. 1987). Manganese has also been reported to have a strong affinity 

for pigmented tissues (Lydén et al. 1984), and Hurley and Keen (1987) and Sturaro et al. (1994) have 

reported that manganese concentrations in hair vary with hair color. Further, hair may be contaminated 

by dye, bleaching, or other materials. Thus, it is not surprising that other studies have found no 

correlation between individual hair levels and the severity of neurological effects in manganese-exposed 

persons (Stauber et al. 1987). A study that investigated the correlation between potentially toxic metal 

content in hair and violent behavior found an association between manganese and violent behavior, but it 

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was not conclusively established that manganese was the causative factor (Gottschalk et al. 1991). He 

et al. (1994) observed that poor performance in school and on neurobehavioral tests was inversely 

correlated with hair levels of manganese. The manganese exposure in this study was via drinking water 

and certain foods. Several studies have found that manganese levels in hair are higher in learning 

disabled children than in nondisabled children (Collipp et al. 1983; Pihl and Parkes 1977). The route of 

excess exposure is not known but is presumed to be mainly oral. However, an association of this sort is 

not sufficient to establish a cause-effect relationship since a number of other agents, including lead, might 

also be involved (Pihl and Parkes 1977). Other studies have found statistically significant associations 

between hair manganese levels and behavioral deficits (Bouchard et al. 2007c; Wright et al. 2006). These 

studies suggest that hair manganese levels can provide meaningful exposure assessments. 

Clara cell protein CC16 is a potential biomarker for exposure to MMT, because the protein decreases in 

both BALF and serum following MMT exposure (Bernard and Hermans 1997; Halatek et al. 1998), 

possibly due to decreased synthesis and/or protein secretion due to loss of producing cells (Halatek et al. 

1998). The protein can be quantified in serum or urine, but no dose-response studies on the potential 

biomarker have been performed. 

There are no known biomarkers of exposure that are specific for children; any biomarkers applicable for 

use in adults should be applicable for children. For example, manganese-induced hyperintense signals on 

MRI have been seen in children (Devenyi et al. 1994; Kafritsa et al. 1998; Ono et al. 1995; Sahni et al. 

2007) as well as adults (Hauser et al. 1994, 1996; Nagatomo et al. 1999; Pomier-Layrargues et al. 1998; 

Spahr et al. 1996). 

3.8.2 Biomarkers Used to Characterize Effects Caused by Manganese 

The principal adverse health effects associated with exposure to manganese are respiratory effects (lung 

inflammation, pneumonia, reduced lung function, etc.) and the neurological syndrome of manganism and 

preclinical neurological effects. Although the respiratory effects are similar in many different exposure 

studies (Kagamimori et al. 1973; Lloyd Davies 1946; Nogawa et al. 1973), there are no specific 

biomarkers of effect other than reduced lung function. The fully developed disease can be diagnosed by 

the characteristic pattern of symptoms and neurological signs (Mena et al. 1967; Rodier 1955), but the 

early signs and symptoms are not specific for manganese. Careful neurological and psychomotor 

examination in conjunction with known exposure to manganese may be able to detect an increased 

incidence of preclinical signs of neurological effects in apparently healthy people (Iregren 1990; Roels 

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et al. 1987a). However, these signs are not sufficiently specific for preclinical effects of manganese to 

reliably identify whether an individual has been exposed to excess levels for a prolonged period. In 

addition, no biochemical indicator is currently available for the detection of the early neurotoxic effects of 

manganese. There are no specific biomarkers that would clearly indicate long-term exposure to excess 

manganese. 

Idiopathic Parkinsonism and manganism can be difficult to distinguish due to some similarity in the 

symptoms (Kim et al. 1999). Idiopathic Parkinsonism is marked by neurodegeneration in the 

dopaminergic nigrostriatal pathway, while manganism induced damage occurs postsynaptic to the 

nigrostriatal system. PET with 18F-dopa afforded a differentiation between manganism and idiopathic 

Parkinsonism in isolated patients with manganese exposure by indexing the integrity of the dopaminergic 

nigrostriatal pathway. 

Measurement of altered levels of dopamine and other neurotransmitters in the basal ganglia has proven to 

be a useful means of evaluating central nervous system effects in animals (e.g., Bonilla and Prasad 1984; 

Eriksson et al. 1987a, 1987b), and these changes are often observed before any behavioral or motor 

effects are apparent (Bird et al. 1984). No noninvasive methods are currently available to determine 

whether there are decreased dopamine levels in the brain of exposed humans, but decreased urinary 

excretion of dopamine and its metabolites has been noted in groups of manganese-exposed workers 

(Bernheimer et al. 1973; Siqueira and Moraes 1989). However, the relationship between manganese 

effects on peripheral versus central dopamine levels has not been clearly defined, and given the lack of 

change in dopamine content in substantia nigra of humans exposed to manganese, the relevance of the 

animal studies to central nervous system disorder is questionable. 

Smargiassi et al. (1995) evaluated platelet monoamine oxidase (MAO) and serum dopamine 

β-hydroxylase (DBH) activities in 11 men occupationally exposed to manganese via inhalation in a 

ferroalloy plant. Exposed workers, in general, had lower MAO activities, but similar DBH activities, in 

comparison to 15 nonexposed control males. However, a positive dose-effect relationship was observed 

in the exposed group between a Cumulative Exposure Index (CEI) and DBH activity (r2

=0.40, p<0.05). 

The CEI took into account the average annual respirable or total manganese concentrations in dust, the 

ventilation characteristic of each working area, the number of years that each worker spent in a given 

area, and all of the areas that a worker had been during his job history. The authors proposed that DBH, 

which is an expression of catecholamine release, might be increasing dose-dependently in response to 

reduced turnover of MAO. The authors cautioned however, that while the data appear interesting, they 

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should be investigated in a larger study population, with careful analysis of possible confounding factors 

(Smargiassi et al. 1995). 

Reduced urinary excretion of 17-ketosteroids (perhaps as a consequence of decreased testosterone 

production) has been noted in many patients with neurological signs of manganism (Rodier 1955), but it 

has not been determined whether this change is detectable prior to the occurrence of neurological effects. 

Although the urinary excretion of manganese is generally not related to oral manganese intake, Davis and 

Greger (1992) have suggested that the concentration of manganese in serum, combined with lymphocyte 

manganese-dependent superoxide dismutase activity, may be helpful in assessing low and moderate levels 

of manganese exposure. Manganese superoxide dismutase is activated by manganese, thus it is sensitive 

to the overall manganese balance. Therefore, increased manganese concentrations will affect an 

increased manganese superoxide dismutase level. There is no clear link between activity of superoxide 

dismutase and the harmful effects of manganese. Therefore, the potential usefulness of this technique as a 

biomarker of effect requires further evaluation. 

The Clara cell protein CC16 is a potential biomarker for pulmonary effects from exposure to MMT 

(Bernard and Hermans 1997; Halatek et al. 1998). Damage of Clara cells by MMT causes a significant 

reduction in the levels of this protein in the BALF, but does not affect its level in serum. The protein can 

be quantified in serum or urine as well. However, no dose-response studies on the potential biomarker 

have been performed. Further, the protein has only been studied following intraperitoneal administration 

of MMT. It is unknown if CC16 levels will change following other exposure pathways. 

For more information on biomarkers for renal and hepatic effects of chemicals see ATSDR/CDC 

Subcommittee Report on Biological Indicators of Organ Damage (Agency for Toxic Substances and 

Disease Registry 1990) and for information on biomarkers for neurological effects see OTA (1990). 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

There is clear evidence from studies in animals that the gastrointestinal absorption (and hence the 

toxicity) of manganese is inversely related to dietary iron concentrations. That is, high levels of nonheme 

iron lead to decreased manganese absorption and toxicity, and low levels of iron lead to increased 

manganese absorption and toxicity (Chandra and Tandon 1973; Davis et al. 1992a, 1992b; Diez-Ewald 

et al. 1968; Rehnberg et al. 1982). Conversely, high levels of dietary manganese lead to decreased iron 

absorption (Davis et al. 1992b; Diez-Ewald et al. 1968; Garcia et al. 2006, 2007; Li et al. 2006; 

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Rossander-Hulten et al. 1991; Thomson et al. 1971). Short-term effects of this sort are believed to be the 

result of kinetic competition between iron and manganese for a limited number of binding sites on 

intestinal transport enzymes (Thomson et al. 1971), while longer-term effects of iron deficiency or excess 

are thought to be due to adaptive changes in the level of intestinal transport capacity (Cotzias 1958). The 

studies reporting competition between iron and manganese in absorption clearly indicate the impact an 

iron-poor diet will have on manganese uptake in the human (Chandra and Tandon 1973; Davis et al. 

1992a, 1992b; Diez-Ewald et al. 1968; Mena et al. 1969; Rehnberg et al. 1982; Thomson et al. 1971). 

Further, competition between manganese and iron at the blood-brain barrier has been reported (Aschner 

and Aschner 1990), indicating that excesses of either metal will affect the brain distribution of the other. 

Johnson and Korynta (1992) found that, in rats, dietary copper can also decrease manganese absorption 

and increase manganese turnover; dietary ascorbate supplementation had minimal effects on manganese 

absorption. However, there is insufficient information to determine the significance of these observations 

for health effects in humans exposed to copper and manganese by the oral route. 

Mn(II) pretreatment reduces Cd(II)-induced lethality (Goering and Klaassen 1985). Cadmium has been 

noted to have an inhibitory effect on manganese uptake (Gruden and Matausic 1989). In addition, 

manganese appears to be capable of increasing the synthesis of the metal-binding protein metallothionine 

(Waalkes and Klaassen 1985). Data from a study by Goering and Klaassen (1985) suggest that 

manganese pretreatment increases the amount of Cd+2 bound to metallothionine, thereby decreasing 

hepatotoxicity due to unbound Cd+2. The significance of these observations for health effects in humans 

exposed to cadmium and manganese by the oral or inhalation routes is not clear. 

High dietary intakes of phosphorus (Wedekind et al. 1991) and calcium (Wilgus and Patton 1939) were 

shown to depress manganese utilization in chicks. Low levels of calcium and iron may act synergistically 

to affect manganese toxicity by increasing absorption, but it is not known whether ensuring iron plus 

calcium sufficiency will reduce the toxic effects of manganese once it has been absorbed (Cawte et al. 

1989). Thus, the importance of these observations to humans exposed to manganese by the oral or 

inhalation routes is not clear. 

Ethanol has been suspected of increasing the susceptibility of humans to manganese toxicity (e.g., Rodier 

1955), but evidence to support this is limited. Singh et al. (1979) and Shukla et al. (1976) reported that 

concomitant exposure of rats to ethanol and manganese (as manganese chloride in drinking water) led to 

higher levels of manganese in the brain and liver than if manganese were given alone; the higher levels 

were accompanied by increased effects as judged by various serum or tissue enzyme levels (Shukla et al. 

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1978). Although the authors referred to these effects as "synergistic," the data suggest that the effects 

were more likely additive. Based on the report in humans and evidence in animals, the effects of 

manganese on humans may be enhanced by the consumption of ethanol, but additional investigation is 

needed. 

There is some evidence from a study in animals that chronic administration of drugs such as 

chlorpromazine (an antipsychotic) results in increased levels of manganese in the brain, including the 

caudate nucleus (Weiner et al. 1977). Chronic chlorpromazine treatment sometimes results in tardive 

dyskinesia, and manganese deposition in the brain might contribute to this condition. It has not been 

determined whether excess manganese exposure increases the risk of chlorpromazine-induced dyskinesia. 

Intramuscular injection of animals with metallic nickel or nickel disulfide (Ni3S2) normally leads to a high 

incidence of injection-site sarcomas, but this increased incidence is reduced when the nickel is injected 

along with manganese dust (Sunderman et al. 1976). The mechanism of this effect is not clear, but 

natural killer cell activity normally undergoes a large decrease following nickel injection, and this is 

prevented by the manganese (Judde et al. 1987). However, the significance that these observations have 

for human health effects resulting from exposure to nickel and/or manganese by the oral or inhalation 

routes is not clear. 

One study found that allopurinol, when administered orally to rats, antagonized the oxidative effects of 

manganese in the striatum and brainstem (Desole et al. 1994). The authors suggest that allopurinol, a 

xanthine oxidase inhibitor, may exert its protective effect by inhibiting both dopamine oxidative 

metabolism and xanthine oxidase-mediated production of reactive oxygen species. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to manganese than will most 

persons exposed to the same level of manganese in the environment. Reasons may include genetic 

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters result in reduced detoxification or excretion of manganese, or compromised function of 

organs affected by manganese. Populations who are at greater risk due to their unusually high exposure 

to manganese are discussed in Section 6.7, Populations with Potentially High Exposures. 

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A number of researchers have observed that there is a wide range in individual susceptibility to the 

neurological effects of inhaled manganese dusts (Rodier 1955; Schuler et al. 1957; Smyth et al. 1973; 

Tanaka and Lieben 1969). For example, Rodier (1955) reported that the majority of manganism cases in 

miners occurred after 1–2 years of exposure to the metal, with only six cases observed occurring with 1– 

3 months exposure. Schuler et al. (1957) showed that in his group of miners, the average time for 

manifestation of manganism was 8 years, 2 months, with a minimum exposure of 9 months required for 

symptoms to present. However, the reason for this variable susceptibility is not clear. One likely factor is 

a difference in work activities and level of exertion. Another is that rates of manganese absorption and/or 

excretion can vary widely among individuals (Saric et al. 1977a). These toxicokinetic variations may be 

due to differences in dietary levels of iron and differences in transferrin saturation (Chandra and Tandon 

1973; Davis et al. 1992a, 1992b; Mena et al. 1969; Thomson et al. 1971), to differences in dietary levels 

of other metals (Chowdhury and Chandra 1987; Gruden and Matausic 1989) or of calcium (Cawte et al. 

1989), or to different levels of alcohol ingestion (Schafer et al. 1974). Another factor that might be 

relevant is dietary protein intake: low-level protein intake appears to increase the effect of manganese on 

brain neurotransmitter levels in exposed animals (Ali et al. 1983a, 1983b, 1985). However, a genetic 

basis for the wide difference in susceptibility cannot be ruled out. 

One group that has received special attention as a potentially susceptible population is the very young. 

This is mainly because a number of studies indicate that neonates retain a much higher percentage of 

ingested or injected manganese than adults, both in animals (Keen et al. 1986; Kostial et al. 1978; 

Rehnberg et al. 1980) and in humans (Zlotkin and Buchanan 1986). The basis for high manganese 

retention in neonates is not certain, but is presumably a consequence of increased absorption (Mena et al. 

1974; Rehnberg et al. 1980) and/or decreased excretion (Kostial et al. 1978; Miller et al. 1975; Rehnberg 

et al. 1981), possibly because maternal milk is low in manganese (Ballatori et al. 1987). Regardless of the 

mechanism, the result of the high retention is increased levels of manganese in the tissue of exposed 

neonatal animals (Miller et al. 1975; Rehnberg et al. 1980, 1981), especially in the brain (Kontur and 

Fechter 1985, 1988; Kostial et al. 1978; Kristensson et al. 1986; Miller et al. 1975; Rehnberg et al. 1981). 

This increase has caused several researchers to express concern over possible toxic effects in human 

infants exposed to manganese in formula (Collipp et al. 1983; Keen et al. 1986; Zlotkin and Buchanan 

1986). At least one recent report indicates that an infant’s rate of absorption of manganese from infant 

formulas, cow’s milk, and breast milk is similar (Lönnerdal et al. 1994), resulting mainly from recent 

modifications to formulas to optimize the bioavailability of several essential minerals. There is some 

limited evidence that prenatal or neonatal exposure of animals to elevated levels of manganese can lead to 

neurological changes in the newborn (Ali et al. 1983a; Chandra and Shukla 1978; Deskin et al. 1980, 

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1981; Dorman et al. 2000; Kristensson et al. 1986); other studies have either not observed any 

neurochemical or neurophysiological effects in young animals exposed to excess manganese or the effects 

have been transient (Kontur and Fechter 1988; Kostial et al. 1978; Pappas et al. 1997). Currently, there is 

only one report that indicates that neonatal animals showed adverse neurological effects at a dose of 

manganese that had no effect on adults (Dorman et al. 2000). Brain concentrations of manganese were 

elevated in the neonates, but not in the adult animals given comparable doses of manganese for similar 

durations. The concern is that the young may be more susceptible due to increased absorption and/or 

retention and the potential toxicity from higher circulating levels of the metal. A few studies have 

reported increased blood and brain levels of the metal, either because of an inability to clear manganese 

due to chronic liver disease (Devenyi et al. 1994) or to an excess in parenteral nutrition (Kafritsa et al. 

1998; Ono et al. 1995). However, observable neurological signs associated with manganese toxicity were 

only reported in the case of chronic liver disease (Devenyi et al. 1994). Although data suggest that 

children, particularly infants, are potentially more susceptible to the toxic effects of manganese, available 

evidence indicates that individual susceptibility varies greatly. Current information is not sufficient to 

quantitatively assess how susceptibility in children might differ from adults. 

Elderly people might also be somewhat more susceptible to manganese neurotoxicity than the general 

population. Neurological effects were observed in older persons consuming manganese levels similar to 

levels found in U.S. surface water and groundwater (Deverel and Millard 1988; EPA 1984; Kondakis et 

al. 1989). The neurological effects observed in a group of families exposed to manganese in their 

drinking water were reportedly more severe among the older persons, whereas there was little effect in the 

youngest (Kawamura et al. 1941). Further, occupational studies indicate that older workers represent the 

largest numbers of manganese poisoning cases (Rodier 1955; Tanaka and Lieben 1969). More recent 

occupational (Crump and Rousseau 1999; Gibbs et al. 1999) and environmental (Mergler et al. 1999) 

manganese exposure studies indicate that increasing age was a factor in poorer performance on certain 

neurobehavioral tests. For example, Beuter et al. (1999) and Mergler et al. (1999) reported that 

performance on tests that required regular, rapid, and precise pointing movements was significantly 

decreased in exposed individuals, especially in those 50 years of age and over with high blood manganese 

levels. These reports suggest that older persons may have a greater susceptibility to adverse effects from 

inhaled or ingested manganese. One factor that could contribute to this increased susceptibility is a loss 

of neuronal cells due to aging or to accumulated neurological damage from other environmental 

neurotoxicants (Silbergeld 1982). Homeostatic mechanisms might become less effective in aged 

populations, which leads to higher tissue levels of manganese following exposure (Silbergeld 1982). 

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Mena et al. (1969) noted that the oral absorption of manganese was increased in individuals with irondeficiency anemia. Altered nutritional status might be another predisposing factor. The inverse relationship of manganese absorption and iron-status has also been reported in animal models (Davis et al. 1992a, 

1992b). It has been suggested that anemic persons may be more susceptible to the toxic effects of 

manganese because of enhanced absorption of iron and manganese through similar uptake mechanisms 

(Cotzias et al. 1968). Baldwin et al. (1999) reported an inverse relationship between serum iron and 

blood manganese levels in individuals environmentally exposed to airborne manganese. 

Another group of potential concern is people with liver disease. This is because the main route of 

manganese excretion is via hepatobiliary transport (see Section 3.4.4), so individuals with impaired 

biliary secretion capacity would be expected to have a diminished ability to handle manganese excesses. 

In support of this hypothesis, Hambidge et al. (1989) reported that in a group of infants and children 

receiving parenteral nutrition, children with liver disease had higher average plasma concentrations of 

manganese than children without liver disease. Devenyi et al. (1994) also observed increased blood 

manganese concentrations, abnormal MRI scans indicative of increased manganese in the brain, and 

dystonia similar to that of patients with manganism, in an 8-year-old girl suffering from cholestatic liver 

disease. Hauser et al. (1994) reported increased blood and brain manganese in two patients with chronic 

liver disease and one with cirrhosis of the liver and a portacaval shunt. All three exhibited some form of 

neuropathy, including postural tremor of the upper extremities and a general lack of alertness, along with 

failure to concentrate and follow simple commands. In a later study, Hauser et al. (1996) did not observe 

movement disorders, but did observe the increased blood manganese concentrations and abnormal MRI 

scans in a group of adults with failing livers. Other studies have shown the link between increased 

deposition of manganese in the blood and/or the brains of humans with cirrhosis of the liver or chronic 

liver disease (Pomier-Layrargues et al. 1998; Rose et al. 1999; Spahr et al. 1996). 

Patients on parenteral nutrition may be at risk for increased exposure to manganese. Forbes and Forbes 

(1997) observed that 31 of 32 adults treated with total parenteral nutrition (TPN) due to intestinal failure 

had increased manganese concentrations in their blood. Nagatomo et al. (1999) observed elevated blood 

manganese levels and hyperintense signals in the basal ganglia upon T1-weighted MRI in two elderly 

patients receiving TPN. Both patients exhibited severe symptoms associated with manganese exposure 

(masked facies, marked rigidity, hypokinesia). When manganese supplementation in the TPN was 

reduced, the blood and brain levels returned to normal. 

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Children receiving parenteral nutrition have also been shown to have increased blood manganese 

concentrations with accompanying hyperintense signals in the globus pallidus as observed by MRI (Fell 

et al. 1996; Kafritsa et al. 1998; Ono et al. 1995). Fell et al. (1996) studied a group of 57 children 

receiving parenteral nutrition, 11 of whom had a combination of hypermanganesemia and cholestasis. 

Four of these 11 patients died; the 7 survivors had whole blood manganese concentrations ranging from 

34–101 μg/L. Four months after reduction or removal of manganese from the supplementation, the blood 

concentration of manganese decreased by a median of 35 μg/L. Two of the seven survivors had 

movement disorders, one of whom survived to have a MRI scan. The scan revealed bilateral 

symmetrically increased signal intensity in the globus pallidus and subthalamic nuclei. These signals 

were also observed in five other children—one from the original group exhibiting cholestasis with 

hypermanganesemia and five more given parenteral nutrition chronically with no liver disease. These 

results indicate that the cholestatic condition is not necessary for manganese to accumulate in the brain. 

A supporting study is provided by Ono et al. (1995) who observed increased blood manganese 

concentrations and hyperintense signals on MRI in the brain of a 5-year-old child on chronic parenteral 

nutrition due to a gastrointestinal failure. Five months after the manganese was removed from the 

parenteral solution, blood manganese levels returned to normal, and the brain MRI scans were almost 

completely free of abnormal signals. Further, the authors reported no neurological effects from exposure 

to manganese. Kafritsa et al. (1998) reported results similar to those of Ono et al. (1995). In the latter 

study, two siblings, one 9 years old and the other 2 years old, had been administered TPN chronically 

since the ages of 4 and 1 month(s), respectively. While elevated blood and brain manganese levels were 

reported (via laboratory analyses and MRI), no adverse neurological or developmental effects were 

observed. Once the manganese supplementation was reduced, the MRI signals abated, and the blood 

manganese levels returned to a normal range. 

Although human interindividual variability is great concerning the ability to tolerate excess amounts of 

manganese in the body, these data indicate that, in general, children and the elderly may be more 

susceptible than young and middle-aged adults due to differential toxicokinetics and potential adverse 

effects superimposed on normal decline in fine motor function with age. 

With respect to the respiratory effects of inhaled manganese (e.g., bronchitis, pneumonitis), people with 

lung disease or people who have exposure to other lung irritants may be especially susceptible. This is 

supported by the finding that the inhalation of manganese dusts by manganese alloy workers caused an 

increased incidence of respiratory symptoms (e.g., wheezing, bronchitis) in smokers, but not in 

nonsmokers (Saric and Lucic-Palaic 1977b). 

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3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to manganese. However, because some of the treatments discussed may be experimental and 

unproven, this section should not be used as a guide for treatment of exposures to manganese. When 

specific exposures have occurred, poison control centers and medical toxicologists should be consulted 

for medical advice. The following texts provide specific information about treatment following exposures 

to manganese. 

Leikin JB, Paloucek JB. 2002. Leikin and Paloucek's poisoning and toxicology handbook. Hudson, OH: 

Lexi-Comp, Inc., 773-774. 

Schonwald S. 2004. Manganese. In: Dart RC, eds. Medical toxicology. 3rd ed. Philadelphia, PA: 

Lippicott Williams & Wilkins, 1433-1434. 

WHO. 1999. Concise international chemical assessment document 12. Manganese and its compounds. 

Geneva: United Nations Environment Programme. International Labour Organisation. World Health 

Organization. http://whqlibdoc.who.int/publications/1999/924153012X.pdf. August 04, 2008. 

3.11.1 Reducing Peak Absorption Following Exposure 

There is substantial evidence to indicate that an interaction between iron and manganese occurs during 

intestinal absorption (Chandra and Tandon 1973; Diez-Ewald et al. 1968; Keen and Zidenberg-Cher 

1990; Mena et al. 1969; Rehnberg et al. 1982). Cawte et al. (1989) cite low levels of iron and calcium as 

"synergistic factors" that impact on the toxic effects associated with manganese exposures. In a dietary 

study investigating the effects of copper, iron, and ascorbate on manganese absorption in rats, these 

substances were all found to influence manganese absorption, depending in part on their relative 

concentrations (Johnson and Korynta 1992). 

Evidence from these reports suggests that it may be possible to reduce the uptake of manganese and 

thereby circumvent the potential for toxic effects caused by current and future exposure to excess 

manganese through specific dietary supplementation. For example, sufficient iron or calcium stores, as 

opposed to a deficiency in these or other minerals, may reduce manganese absorption, and thus reduce 

potential toxicity. It is not known whether ensuring iron and calcium sufficiency will reduce the toxic 

effects of manganese once it has been absorbed into the body because information on critical levels of 

manganese at target sites is not available. No consistent clinical data are available documenting benefit 

from ipecac or dilution after ingestion of metallic, inorganic, or organic manganese (Schonwald 2004). 

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3.11.2 Reducing Body Burden 

Inhaled manganese is readily absorbed by the lungs, although some may be retained there. Larger 

particles of dust containing manganese may be transported by mucociliary transport from the throat to the 

gut (Drown et al. 1986). Manganese in the gut may be directly absorbed either by a simple diffusion 

process (Bell et al. 1989) or by a high-affinity, low-capacity, active-transport mechanism (Garcia-Aranda 

et al. 1983). Once in the plasma, manganese is reportedly transported by transferrin; however, 

information on the mechanism of uptake in extrahepatic tissues is limited (Keen and Zidenberg-Cher 

1990). 

In severe cases of manganese poisoning, chelation therapy may be recommended in order to reduce the 

body burden of manganese and to help alleviate symptoms. Chelation therapy with agents such as 

ethylenediaminetetraacetic acid (EDTA) may alleviate some of the neurological signs of manganism, but 

in cases where it has been used, not all patients have shown improvement, and some of the improvements 

have not always been permanent (Cook et al. 1974; Schonwald 2004). Nagatomo et al. (1999) recently 

reported the use of Ca-EDTA treatment to reduce the body burden of two elderly patients with increased 

blood and brain levels of manganese. These patients exhibited masked faces, hypokinesia, and rigidity 

that are among the clinical signs of manganese poisoning. The potential use of calcium disodium 

ethylenediaminetetracetate (CaNa2 EDTA) for the management of heavy metal poisoning was 

investigated in dogs by Ibim et al. (1992). CaNa2 EDTA-treated dogs (without excess manganese 

exposure) were found to have decreased manganese levels in their hair. It is possible that the decrease 

was partially associated with mobilization and redistribution of this element from storage as well as from 

soft tissues. The authors, however, cautioned that the use of CaNa2 EDTA could adversely affect the 

metabolism of manganese. 

In an attempt to treat seven welders with manganism, a solution of 20% CaNa2 EDTA was administered 

intravenously at the dose of 1.0 g daily for 3 days followed by a pause for 4 days. The therapy continued 

for 2–4 courses of this treatment, depending upon the improvement of symptoms. The symptoms, as well 

as blood manganese concentrations and urinary manganese concentrations, were monitored before and 

after each course of treatment. EDTA treatment resulted in increased manganese excretion in urine and 

decreased manganese concentrations in the blood; however, the patients did not show significant 

improvement in their symptoms (Crossgrove and Zheng 2004). A lack of improvement after EDTA 

chelation has also been observed in an additional case study of an adult worker (Jiang et al. 2006). It is 

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postulated that four carboxyl groups in the EDTA structure, which are essential to its chelating property, 

render the molecule poorly lipophilic, thus preventing it from effectively crossing the blood-brain barrier. 

Thus, EDTA appears to successfully chelate and remove the extracellular manganese ions in the blood, 

but with limited access to brain parenchyma, it cannot effectively chelate and remove manganese ions 

from the brain. Because EDTA cannot significantly remove manganese from damaged neurons, it 

appears to be of very limited therapeutic value for more advanced cases of manganism. 

Cyclohexylene-aminotetraacetic acid (CDTA) and dimercaptol-1-propanesulphonic acid sodium salt 

(DTPA) were shown to decrease tissue manganese content in rats following inhalation exposure, but it is 

unknown whether the effects of manganese were alleviated (Wieczorek and Oberdörster 1989a, 1989b). 

The use of the anti-tuberculosis drug para-aminosalicylic acid (PAS) to treat manganism has been 

reported (Jiang et al. 2006). The patient in this case study had palpitations, hand tremor, lower limb 

myalgia, hypermyotonia, and a distinct festinating gait. She received 6 g PAS per day through an 

intravenous drip infusion for 4 days and rest for 3 days. Fifteen courses of this treatment were 

administered to the patient. At the end of PAS treatment, the patient’s symptoms were reportedly 

significantly alleviated, and handwriting recovered to normal. A reexamination at 17 years after PAS 

therapy found a general normal presentation in clinical, neurologic, brain MRI, and handwriting 

examinations. Her gait improved, and although it did not improve to an entirely normal status, it could be 

described as passable. A literature survey of more than 90 cases using PAS (Jiang et al. 2006) indicates a 

significant therapeutic benefit. 

A study in monkeys reported a long half-life of manganese in the brain following inhalation exposure 

(Newland et al. 1987). Given that neurotoxicity is of concern with manganese exposure, knowledge of 

the mechanisms behind this longer half-life in the brain may be central to the development of mitigation 

methods. Newland et al. (1987) reported that this long half-life reflected both redistribution of 

manganese from other body depots and a slow rate of clearance from the brain. A later study reported 

that elevated levels in the brain persisted after inhalation exposure (due to redistribution), whereas for 

subcutaneous exposure, levels declined when administration was stopped (Newland et al. 1989). The 

authors observed that the accumulation of manganese in the brain was preferential in specific regions, but 

was unrelated to the route of exposure (Newland et al. 1989). They also reported that there are no known 

mechanisms or "complexing agents" that have been shown to remove manganese from the brain. 

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Few data are available regarding the reversibility of the neurological injury produced by prolonged excess 

manganese exposure. The effects are thought to be largely irreversible, and treatment for manganese 

intoxication is mainly supportive (Schonwald 2004). However, some evidence indicates that recovery 

may occur when exposure ceases (Smyth et al. 1973). Anti-Parkinsonian drugs, such as levo-dopa, have 

been shown to reverse some of the neuromuscular signs of manganism (Ejima et al. 1992; Rosenstock et 

al. 1971), but these drugs can produce a variety of side effects, and reports have indicated that they are not 

effective in improving the symptoms of neurotoxicity in manganism patients (Calne et al. 1994; Chu et al. 

1995; Cook et al. 1974; Haddad et al. 1998; Huang et al. 1989; Schonwald 2004). Para-aminosalicylic 

acid was used successfully to treat two patients who exhibited neurological signs of manganese 

poisoning; one person made an almost complete recovery and the other was significantly improved. The 

mechanism for this treatment is unknown (Shuqin et al. 1992). Parenti et al. (1988) has proposed the use 

of antioxidants such as vitamin E, but the effectiveness of this treatment has not been further evaluated. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

The oxidation state of manganese may influence both its retention in the body (see Section 3.4.3) and its 

toxicity (see Section 3.5). Therefore, it is possible that interference with the oxidation of manganese 

could be a method for preventing manganese cellular uptake and toxicity. Regarding retention, one study 

suggests that clearance is much more rapid for divalent manganese than for trivalent manganese (Gibbons 

et al. 1976). Regarding neurotoxicity,Mn(III) appears to be more efficient in enhancing the oxidation of 

catechols than either Mn(II) or Mn(IV) (Archibald and Tyree 1987). Thus, it is plausible that reducing 

the formation of Mn(III) could possibly both enhance elimination and prevent neurotoxicity, but no 

studies were located that evaluate this theory. 

Ceruloplasmin is involved in the oxidation of iron and has also been involved in the oxidation of divalent 

manganese ion to the trivalent state (Gibbons et al. 1976). Selective inhibition of this oxidative function 

may be a method of mitigating the toxic effects of exposure to manganese. However, inhibition of the 

oxidation of manganese might also result in adverse effects on transport and cellular uptake of other 

essential metals, especially iron. Furthermore, it is not completely clear how the oxidation state of 

manganese is related to its normal function in neural cells or how this role is altered in manganese 

toxicity. Both Mn(II) and Mn(III) have been reported as components of metalloenzymes (Keen and 

Zidenberg-Cher 1990; Leach and Lilburn 1978; Utter 1976). 

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Manganese has been shown to catalyze the oxidation of dopamine in vitro; Cawte et al. (1989) reported 

that the toxicity induced by manganese resulted from the depletion of dopamine and the production of 

dopamine quinone and hydrogen peroxide through this mechanism. Antioxidants were tested for their 

ability to inhibit the dopamine oxidation induced by manganese, and it was found that ascorbic acid and 

thiamine completely inhibited dopamine oxidation both in the presence and absence of manganese. The 

report did not include data on background oxidation levels nor on the extent of dopamine oxidation in the 

absence of manganese. Results from treatment with antioxidants were viewed as evidence for their use in 

mitigating the adverse effects of manganese. However, because dopamine oxidation was inhibited to 

some degree in the absence of manganese, these data could alternately be interpreted as suggesting a more 

complex mechanism than the direct action of manganese for inducing dopamine oxidation and subsequent 

cell toxicity. Further investigation of the inhibition of manganese oxidation as a possible mitigation 

method should be preceded by additional studies to elucidate the role of manganese in its various 

oxidation states in normal neuronal cell metabolism and to determine whether oxidative stress is a 

primary mechanism for neurotoxicity mediated by manganese exposure. 

3.12 ADEQUACY OF THE DATABASE 

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of manganese is available. Where adequate information is not 

available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the 

initiation of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of manganese. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.12.1 Existing Information on Health Effects of Manganese 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

inorganic manganese are summarized in Figure 3-10. The purpose of this figure is to illustrate the 

existing information concerning the health effects of manganese. Each dot in the figure indicates that one 

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or more studies provide information associated with that particular effect. The dot does not necessarily 

imply anything about the quality of the study or studies, nor should missing information in this figure be 

interpreted as a “data need”. A data need, as defined in ATSDR’s Decision Guide for Identifying 

Substance-Specific Data Needs Related to Toxicological Profiles (Agency for Toxic Substances and 

Disease Registry 1989), is substance-specific information necessary to conduct comprehensive public 

health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific 

information missing from the scientific literature. 

As the upper part of Figure 3-10 reveals, studies in humans exposed to inorganic manganese have focused 

mainly on intermediate and chronic inhalation exposure and the resulting neurological effects. There are 

several reports of humans exposed by ingestion and these too have focused on neurological effects. 

Reproductive effects have been studied in men exposed to manganese by inhalation, but other effects 

have generally not been formally investigated. 

Inorganic manganese toxicity has been investigated in numerous animal studies, both by the oral and the 

inhalation routes. These studies have included most end points of potential concern. The dermal route 

for inorganic manganese has not been investigated, but there is no evidence that this exposure pathway is 

a human health concern. Dermal contact to MMT is expected to occur mainly in occupational settings, 

and no human dermal contact with mangafodipir is expected to occur. In addition, organic compounds 

are degraded to some extent in the environment. Thus, dermal effects from organic manganese 

compounds are not expected to be of great concern for the general population or to persons near 

hazardous waste sites. 

3.12.2 Identification of Data Needs 

Presented below is a brief review of available information and a discussion of research needs. Although 

data are lacking, dermal studies to inorganic manganese are not discussed since there is no evidence that 

this exposure pathway is a human health concern. 

Acute-Duration Exposure. Studies in animals and humans indicate that inorganic manganese 

compounds have very low acute toxicity by any route of exposure. An exception is potassium 

permanganate, which is an oxidant that can cause severe corrosion of skin or mucosa at the point of 

contact (Southwood et al. 1987). Acute inhalation exposure to high concentrations of manganese dusts 

(manganese dioxide, manganese tetroxide) can cause an inflammatory response in the lung, which can 

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Figure 3-10. Existing Information on Health Effects of Inorganic Manganese 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Animal 

Inhalation 

Oral 

Dermal 

Existing Studies 

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lead to impaired lung function (Maigetter et al. 1976; Shiotsuka 1984). However, this response is 

characteristic of nearly all inhalable particulate matter (EPA 1985d) and is not dependent on the 

manganese content of the particle. Large oral doses of highly concentrated solutions of manganese salts 

given by gavage can cause death in animals (Holbrook et al. 1975; Kostial et al. 1978; Smyth et al. 1969), 

but oral exposures via food or water have not been found to cause significant acute toxicity (Gianutsos 

and Murray 1982; NTP 1987a, 1987b). Since the acute database is incomplete and studies demonstrating 

a dose-response are not available, an acute MRL was not derived. In order to derive acute MRL values, 

further studies would be helpful to define the threshold for adverse effects following acute exposure to 

manganese. However, any MRL derived for the oral route would have to take into consideration that 

manganese is an essential nutrient. 

Acute-duration exposure studies in animals exposed to MMT via inhalation or via a dermal pathway are 

lacking. The dermal pathway is very important, because MMT in gasoline that may be spilled on the skin 

could penetrate and become absorbed. Although the photolability of the compound is an important 

obstacle for any animal study, carefully planned and executed analyses of the toxicity of this compound to 

animal models through these exposure pathways are needed. 

The likelihood for exposure to mangafodipir is small and clinical trials in humans have shown a great 

tolerance for a controlled exposure to the compound. Toxicity studies in several different animal species 

have been performed, including reproductive and developmental studies (and more specifically, 

teratogenic analysis). Although behavioral data in the young who have been exposed during gestation are 

relatively limited, human gestational exposure to this compound is not believed to be very likely. Reports 

of neurological effects have been limited to complaints of headaches in clinical trials. Further evaluation 

of these effects relative to the distribution of manganese to the brain during clinical use is warranted. 

Mangafodipir is administered intravenously, which bypasses homeostatic control of the compound. 

Although animal studies indicate that a single, clinical dose does not cause accumulation of manganese in 

the brain for longer than 2 weeks (Gallez et al. 1997), human studies have not monitored central nervous 

system distribution of manganese following mangafodipir injection for longer than half an hour (Lim et 

al. 1991). In addition, given the neurotoxic effects of excess manganese, evaluation of patients treated 

with mangafodipir for neurological sequelae are needed. 

Intermediate-Duration Exposure. Intermediate-duration inhalation exposure of humans to 

manganese compounds can lead to central nervous system effects (Rodier 1955). However, reliable 

estimates of intermediate-duration NOAELs or LOAELs for neurotoxicity in humans are not available. 

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Intermediate-duration inhalation studies in animals have yielded NOAEL and LOAEL values for 

biochemical and neurobehavioral effects (EPA 1977; Morganti et al. 1985; Ulrich et al. 1979a, 1979b), 

but the range of exposure levels associated with these effects is too wide (an order of magnitude) to define 

a threshold. Although neurological effects were observed in animals, symptoms characteristic of 

manganese toxicity (e.g., ataxia, tremor, etc.) are not typically observed in rodent species (with the 

exception of one study in which ataxia was seen only transiently) (Kristensson et al. 1986). Although 

other rodent studies indicated decreases in motor activity (Gray and Laskey 1980; Komura and Sakamoto 

1991), increased activity and aggression (Chandra 1983; Shukakidze et al. 2003), delayed reflexes (Ali et 

al. 1983a), or deficits in learning (Shukakidze et al. 2003; Vezér et al. 2005, 2007) the effects are not 

consistent and are observed over a wide dose range. For these reasons, it is concluded that these data are 

not sufficient to derive an intermediate-duration inhalation MRL. Epidemiological studies in 

occupationally exposed human populations that help define the intermediate-duration exposure levels that 

are associated with neurological effects would be valuable. 

Intermediate-duration oral exposure of humans to manganese has been reported to cause neurotoxicity in 

two cases (Holzgraefe et al. 1986; Kawamura et al. 1941), but the data for quantitating exposure levels are 

too limited to define the threshold or to judge whether these effects were due entirely to manganese 

exposure. An epidemiological investigation of people who have ingested high levels of manganese may 

provide valuable information on the health risk of intermediate-duration oral exposure and may provide 

sufficient dose-response data from which to derive an MRL. Additional oral studies in animals including 

rodents may be valuable in revealing cellular and molecular mechanisms of manganese neurotoxicity; 

studies on nonhuman primates would probably be the most helpful in estimating a MRL because they 

appear to be the most suitable animal model for manganese-induced neurological effects comparable to 

effects observed in humans. However, any MRL derived for the oral route would have to take into 

consideration that manganese is an essential nutrient and account for manganese intake from daily dietary 

sources. 

Intermediate-duration studies of inhalation and oral exposure to MMT in humans and animals are lacking. 

Animal studies of this duration evaluating systemic toxicity from exposure to MMT and typical 

environmental concentrations of its combustion products would be helpful to determine body burdens that 

might be anticipated for the general population in areas that use this compound. Further, these studies 

would be helpful in determining mechanisms of toxicity and expected adverse effects in exposed 

populations. 

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Due to the nature of mangafodipir administration, which typically occurs only once in a subject, no 

intermediate-duration studies in humans have been identified for this compound. Although there are a 

few intermediate-duration studies in animals (Grant et al. 1997a; Larsen and Grant 1997; Treinen et al. 

1995), they have focused primarily on reproductive and developmental effects. Studies of the potential 

neurological effects of exposure to this compound are lacking, although the reason for this may be due to 

the lack of evidence that the compound distributes in the central nervous system. As discussed 

previously, the exposure to mangafodipir is expected to be very limited due to the compound’s clinical 

use. There are no identified data needs for this compound. 

Chronic-Duration Exposure and Cancer. As discussed in Sections 2.3 and 3.2.1.4, and 

Appendix A, a number of epidemiological studies have reported psychological or neurological effects of 

exposure to low levels of manganese in the workplace (Bast-Pettersen et al. 2004; Beuter et al. 1999; 

Blond and Netterstrom 2007; Blond et al. 2007; Bouchard et al. 2003, 2005, 2007a, 2007b; Chia et al. 

1993a, 1995; Crump and Rousseau 1999; Deschamps et al. 2001; Gibbs et al. 1999; Iregren 1990; 

Lucchini et al. 1995, 1999; Mergler et al. 1994; Myers et al. 2003a, 2003b; Roels et al. 1987a, 1992, 

1999; Wennberg et al. 1991) or in environmental media close to manganese-emitting industries (Lucchini 

et al. 2007; Mergler et al. 1999; Rodríguez-Agudelo et al. 2006). Some of these studies have found 

statistically significant differences between exposed and non-exposed groups or significant associations 

between exposure indices and neurological effects (Bast-Pettersen et al. 2004; Chia et al. 1993a; Iregren 

1990; Lucchini et al. 1995, 1999; Mergler et al. 1994; Roels et al. 1987a, 1992; Wennberg et al. 1991), 

whereas others have not found significant associations (Deschamps et al. 2001; Gibbs et al. 1999; Myers 

et al. 2003a, 2003b; Young et al. 2005). Table A-3 in Appendix A summarizes results from these studies. 

Additional studies involving follow-up evaluation of previously exposed occupational cohorts may be 

useful to provide information on threshold levels that are correlated with observed preclinical effects. 

Additional studies of populations living close to manganese-emitting industries may be useful to better 

describe neurotoxicological potentials of low-level exposure to air-borne manganese. 

In early animal studies, intermediate or chronic inhalation exposure of monkeys and rats to manganese 

dusts did not produce neurological signs similar to those seen in humans (Bird et al. 1984; EPA 1983c; 

Ulrich et al. 1979a, 1979b). For example, Ulrich et al. (1979a) reported that monkeys continually 

exposed for 9 months to aerosols of manganese dioxide at concentrations as high as 1.1 mg 

manganese/m3 showed no obvious clinical signs of neurotoxicity, no histopathological changes in brain 

tissues, and no evidence for limb (leg) tremor or electromyographic effects on flexor and extensor 

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muscles in the arm. However, in a chronic study with Rhesus monkeys, decreased levels of dopamine 

were found in several regions of the brain (caudate and globus pallidus) (Bird et al. 1984). Behavioral 

tests detected signs of neurological effects in mice (increased open-field activity and decreased maternal 

pup retrieval latency), although these are only seen at relatively high exposure levels (60–70 mg 

manganese/m3

) (Lown et al. 1984; Morganti et al. 1985). 

Other animal intermediate-duration studies provide evidence for associations between decreased neuronal 

cell counts in the globus pallidus and neurobehavioral changes (increased locomotor activity) in rats 

exposed by inhalation for 13 weeks to a mixture of manganese phosphate/sulfate (at 1.05 mg 

manganese/m3

) or manganese sulfate alone (at concentration between 0.009 and 0.9 mg manganese/m3), 

but not to manganese phosphate alone at concentrations up to 1.1 mg manganese/m3 (Normandin et al. 

2002; Salehi et al. 2003, 2006; Tapin et al. 2006). Other 13-week rat inhalation exposure studies reported 

increased brain manganese concentrations and increased locomotor activity after exposure to 3.75 mg 

manganese/m3 as metallic manganese (St-Pierre et al. 2001) and increased brain manganese 

concentrations with no increases in olfactory bulb, cerebellar, or striatal concentrations of glial fibrillary 

acidic protein (GFAP) after exposure to 0.5 mg manganese/m3 as manganese sulfate or 0.1 mg 

manganese/m3 as manganese phosphate (Dorman et al. 2004b). Other animal studies have examined the 

influence of inhalation exposure to manganese sulfate on biochemical end points associated with 

oxidative stress or inflammation in the brain of rats (Erikson et al. 2005, 2006; HaMai et al. 2006; Taylor 

et al. 2006) and monkeys (Erikson et al. 2007). The results from these studies indicate that acute- or 

intermediate-duration inhalation exposure to manganese sulfate concentrations ranging from about 0.1 to 

1 mg manganese/m3 can differentially affect brain biochemical markers of neurotoxicity, but 

understanding of the neurotoxic mechanism of manganese is inadequate to confidently define any one of 

the observed changes as biologically adverse. 

Chronic inhalation studies in animal models (Bird et al. 1984; EPA 1977; Newland et al. 1989; Olanow et 

al. 1996) indicate that while non-human primates are very sensitive to the neurological effects of 

manganese at very low doses (depending on exposure route), rodent models do not exhibit the same 

neurological symptoms as humans and monkeys despite the administration of high doses through 

inhalation, oral, and intravenous exposure routes. Although there is an apparent difference in 

susceptibility, neurological effects have been observed in rodents treated with manganese. Additional 

studies in animals could be valuable to increase our understanding of the mechanism of manganeseinduced disease and the basis for the differences between humans and animals. 

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Some data on neurological or other health effects in humans from repeated or chronic oral intake of 

manganese exist (Bouchard et al. 2007c; Cawte et al. 1987; He et al. 1994; Holzgraefe et al. 1986; 

Kawamura et al. 1941; Kilburn 1987; Kondakis et al. 1989; Vieregge et al. 1995; Wasserman et al. 2006; 

Wright et al. 2006; Zhang et al. 1995). The majority of these studies are limited by uncertainties in the 

exposure routes, total exposure levels, duration of exposure, or the influence of other confounding factors; 

none of these studies adequately assessed daily dietary manganese intake. Five studies (Bouchard et al. 

2007c; He et al. 1994; Sahni et al. 2007; Wasserman et al. 2006; Zhang et al. 1995) indicate 

concentrations of manganese in drinking water that may be associated with preclinical neurological 

effects in children, but the studies have several limitations. 

As discussed in Section 2.3, no oral MRLs were derived for acute-, intermediate-, or chronic-duration oral 

exposure to manganese, even though the limited human data and extensive animal data clearly identify 

neurobehavioral changes as the most sensitive effect from intermediate- and chronic-duration oral 

exposure to excess inorganic manganese. However, inconsistencies in the dose-response relationship 

information across studies evaluating different neurological end points under different experimental 

conditions in different species, as well as a lack of information concerning all intakes of manganese (e.g., 

dietary intakes plus administered doses), make it difficult to derive intermediate- or chronic-duration 

MRLs using standard MRL derivation methodology from the animal studies. An interim guidance value 

of 0.16 mg manganese/kg/day is recommended for ATSDR public health assessments. The interim 

guidance value is based on the Tolerable Upper Intake Level for adults of 11 mg manganese/day 

established by the U.S. Food and Nutrition Board/Institute of Medicine (FNB/IOM 2001) based on a 

NOAEL for Western diets. The interim guidance value is necessary because of the prevalence of 

manganese at hazardous waste sites and the fact that manganese is an essential nutrient. 

Additional chronic oral studies, especially epidemiological studies in populations exposed to high levels 

of either inorganic and organic manganese in the environment, particularly the combustion products of 

MMT in areas of high traffic density, would be valuable for evaluating the potential for adverse effects 

from oral exposure to excess manganese from the environment in addition to that ingested through dietary 

intake. 

No studies or anecdotal reports were located that described cancer associated with exposure of humans to 

inorganic manganese. Chronic oral exposure of rats and mice to high doses of manganese sulfate has 

provided equivocal evidence of carcinogenic potential (NTP 1993); however, the lack of evidence for the 

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carcinogenic potential of manganese in humans and the equivocal evidence in animals suggest that the 

potential for cancer may be low. Further animal studies are not needed at this time. 

MMT has not been found to induce tumor formation in rodents (Witschi et al. 1981) and additional 

studies measuring this end point would be useful to corroborate the limited database. Though no studies 

of carcinogenesis involving mangafodipir exposure were identified, there are no data needs regarding this 

end point with this compound. 

Genotoxicity. One study was located regarding the genotoxic effects of inorganic manganese in 

humans. An increase in chromosomal aberrations was observed in welders exposed to manganese; 

however, the welders were also exposed to nickel (known to cause chromosomal aberrations) and iron, so 

the observed increase could not be attributed solely to manganese (Elias et al. 1989). Some in vivo 

studies in fruit flies and rats have been negative (Dikshith and Chandra 1978; Rasmuson 1985; Valencia 

et al. 1985), but manganese has been found to be clastogenic in mice (Joardar and Sharma 1990). In vitro 

studies in bacteria, yeast, and cultured mammalian cells have yielded mixed, but mainly positive, results 

(Casto et al. 1979; De Méo et al. 1991; Joardar and Sharma 1990; Kanematsu et al. 1980; Nishioka 1975; 

NTP 1993; Oberly et al. 1982; Orgel and Orgel 1965; Singh 1984; Ulitzur and Barak 1988; Wong and 

Goeddel 1988; Zakour and Glickman 1984). Additional studies, especially in cultured mammalian cells, 

heritable cell types, or in lymphocytes from exposed humans, would be valuable in clarifying the 

genotoxic potential of manganese. As for organic manganese, no genotoxicity studies were located 

regarding MMT and studies measuring this end point are needed. Genotoxicity studies for mangafodipir 

have shown negative effects (Grant et al. 1997a). 

Reproductive Toxicity. Men who are exposed to manganese dust in workplace air report decreased 

libido and impotency (Emara et al. 1971; Mena et al. 1967; Rodier 1955), and may suffer from sexual 

dysfunction (Jiang et al. 1996b) and decreased sperm and semen quality (Wu et al. 1996). In addition, 

studies in animals indicate that manganese can cause direct damage to the testes (Chandra et al. 1973; 

Seth et al. 1973). While the Jiang et al. (1996b) study suggests testicular damage in occupationally 

exposed men, additional epidemiological studies involving these subjects or other exposed groups to 

more fully evaluate reproductive function would be valuable. Results from such studies may provide 

definitive exposure-response data on reproductive function (e.g., impotence, libido, and number of 

children). 

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Additional studies in animals are needed to determine whether the testes are damaged directly from 

exposure to manganese. Information on adverse reproductive effects in women is not available. Data 

from studies in female animals indicate that manganese can cause post-implantation loss when 

administered through both oral and subcutaneous exposure routes in female mice and rats (Colomina et al. 

1996; Sánchez et al. 1993; Szakmáry et al. 1995; Treinen et al. 1995). To establish more clearly whether 

or not this is a human health concern, two types of studies would be valuable. First, single-generation 

reproductive studies of female animals exposed by the inhalation route could be done. Then, if strong 

evidence for concern is found in animals from these studies, epidemiological studies that included women 

and men exposed in the workplace would be valuable to assess the effects of manganese on reproductive 

function. 

Developmental Toxicity. There is a growing body of human data on potential developmental effects 

of excess manganese, although these studies are generally confined to studies of neurodevelopmental 

effects as observed in children. The incidences of stillbirths and malformations have been studied in an 

Australian aboriginal population living on an island where environmental levels of manganese are high 

(Kilburn 1987), but small population size and lack of data from a suitable control group preclude 

determining whether reported incidence of developmental abnormalities is higher than average. Hafeman 

et al. (2007) reported high mortality among infants <1 year of age in a Bangladesh population where the 

drinking water supplied by certain local wells contained high levels of manganese. Two studies 

investigated neurobehavioral and school performances (He et al. 1994; Zhang et al. 1995) of children 

exposed to excess levels of manganese in water and food. However, these studies did not report data on 

either lengths of exposure to the metal or on excess manganese intake compared to control areas. More 

recent investigations include epidemiological studies that have detected altered behavioral and cognitive 

performance among children exposed to excess levels of manganese in their local drinking water 

(Bouchard et al. 2007c; Wasserman et al. 2006). These results suggest the neurotoxic potential of 

excessive manganese exposure to children, but these studies have uncertainties that preclude the 

establishment of causal relationships between the observed effects and manganese exposure. The studies 

are limited in their ability to address several important concerns, such as whether manganese alone is 

responsible for the observed effects and the contribution of dietary manganese levels as well as inhalation 

exposure levels and small sample sizes. Studies evaluating developmental effects with clear analysis of 

exposure levels and duration are needed to estimate dose-response relationships of manganese toxicity in 

children. 

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Several developmental studies have been performed in animals, but they are mainly limited to rodent 

species and have measured limited developmental end points. One study in pregnant mice that inhaled 

manganese resulted in decreased pup weight and a transient increase in activity (Lown et al. 1984). Other 

studies have indicated that oral exposure to manganese adversely affects reproductive development in 

male mice (Gray and Laskey 1980) and rats (Laskey et al. 1982, 1985). A single study on rats involving 

oral exposure indicated that manganese caused a transient decrease in pup weight and increased activity 

(Pappas et al. 1997). Another study involving gavage dosing reported skeletal abnormalities in unborn 

pups, but these effects were resolved in pups allowed to grow to 100 days of age (Szakmáry et al. 1995). 

Neurobehavioral effects have been shown in neonates given excess manganese orally from PND 1 to 21 

(Dorman et al. 2000; Reichel et al. 2006; Tran et al. 2002a). Several studies have shown neurochemical 

changes in offspring of dams exposed to increased manganese concentrations (Lai et al. 1991; Garcia et 

al. 2006, 2007) or in neonatal animals dosed with excess manganese (Chandra and Shukla 1978; Deskin 

et al. 1980, 1981; Dorman et al. 2000). Also of interest is the possibility that developmental manganese 

exposure may influence the timing of puberty; such results have been observed in studies of both male 

and female rats (Lee et al. 2006; Pine et al. 2005). Studies conducted in infant Rhesus monkeys found 

that soy-based infant formulas (which contain higher manganese levels than cow’s milk) and a soy-based 

infant formula supplemented with manganese produced behavioral changes that may be comparable to 

those implicated in attention deficit-hyperactivity disorders (Golub et al. 2005). 

Other studies indicate that injected manganese is more toxic to a developing fetus than inhaled or ingested 

manganese. Manganese injected subcutaneously or intravenously during the gestation period causes 

serious effects on skeletal development and ossification, but studies to date using this exposure pathway 

have not measured neurological deficits in pups or young rodents. The relevance to humans of results 

from these injection studies is unclear. 

The monkey is increasingly regarded as a more appropriate model for neurological end points; however, 

monkey studies are extremely expensive and will be limited for this reason. Evaluation of appropriate 

end points in rodent assays by the oral and inhalation route are needed so that these models can be used to 

increase the body of knowledge of the developmental toxicity of manganese. Further, the one 

developmental study involving inhalation exposure (Lown et al. 1984) had many complications; 

additional studies involving neurobehavioral effects in animals following gestational and postnatal 

exposure to airborne manganese are necessary. A few developmental studies have involved sectioning 

fetuses to detect internal malformations (Blazak et al. 1996; Grant et al. 1997a; Szakmáry et al. 1995; 

Treinen et al. 1995). However, these studies have primarily administered the manganese intravenously, 

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MANGANESE 312 

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except for Szakmáry et al. (1995). Additional teratogenesis studies that assess bone malformations 

following inhalation and oral exposures using a wide range of doses are needed given that manganese 

overexposure affects the developing skeletal system (Blazak et al. 1996; Grant et al. 1997a; Szakmáry et 

al. 1995; Treinen et al. 1995). In order to improve the accuracy of the development of an oral MRI for 

manganese, additional developmental neurotoxicology studies using a functional observational battery 

design and using a wide range of well-established measures in rodents and primates would be useful 

(Moser 2000). 

Immunotoxicity. Studies in animals indicate that injection or consumption of manganese compounds 

can cause significant changes in the functioning of several cell types of the immune system (NTP 1993; 

Rogers et al. 1983; Smialowicz et al. 1985, 1987). However, it is not known whether these changes are 

associated with significant impairment of immune system function. Further studies are needed to 

determine whether these effects also occur after inhalation exposure in animals or humans. If so, a 

battery of immune function tests would be valuable in determining if observed changes result in a 

significant impairment of immune system function. 

Neurotoxicity. Studies in humans exposed to high levels of manganese dust in the workplace provide 

clear evidence that the chief health effect of concern following manganese exposure is injury to the 

central nervous system (Emara et al. 1971; Mena et al. 1967; Rodier 1955; Schuler et al. 1957; Smyth 

et al. 1973). Quantitative data on exposure levels for chronic durations are sufficient to identify a 

LOAEL for preclinical neurological effects (Iregren 1990; Roels et al. 1987a, 1992), and some of these 

data have been used to estimate a NOAEL using benchmark dose analysis (Iregren 1990; Roels et al. 

1992). These NOAEL estimates are comparable to a NOAEL for early neurological effects recently 

reported by Gibbs et al. (1999). Thus, no additional epidemiological studies to characterize effects in 

workers exposed to manganese via inhalation appear necessary at this time. Two recent studies 

investigated longitudinally whether manganese-induced preclinical effects in workers previously 

evaluated were reversible (Crump and Rousseau 1999; Roels et al. 1999). Improved performance was 

observed only in workers exposed to the lowest levels of manganese and effects in others neither 

improved nor worsened. High variability in the results of neurobehavioral testing from year-to-year was a 

limitation in the interpretation of results in one of these studies (Crump and Rousseau 1999). Also, the 

two studies reported conflicting findings on the effect aging the in workers may have had on their 

performance in certain tests. Additional follow-up studies are needed to further evaluate the reversibility 

of manganese-induced effects and define threshold exposure levels above which manganese-induced 

neurological effects are irreversible. 

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Studies of environmental exposure to airborne manganese report a correlation between high levels of the 

metal and increased blood manganese levels and subtle neurological effects, particularly in those over 

50 years old (Baldwin et al. 1999; Mergler et al. 1999). These studies are also the first to study 

manganese exposures and potential adverse effects in women. More studies are needed that include 

analyses of both sexes and assess the relationship between environmental sources of excess manganese, 

altered manganese body burden, and the potential for adverse effects. 

The evidence for neurotoxicity in humans following oral exposure to manganese is inconclusive due to 

several limitations in the majority of these reports (Bouchard et al. 2007c; Holzgraefe et al. 1986; 

Kawamura et al. 1941; Kilburn 1987; Kondakis et al. 1989; Wasserman et al. 2006). One report in 

Japanese adults (Iwami et al. 1994) showed the link between eating food with concentrations of 

manganese on the high end of the normal range of a typical Western diet (5.79 mg manganese ingested 

per day) and low intake concentrations of magnesium associated with an increased incidence of motor 

neuron disease. Four studies in children (Bouchard et al. 2007c; He et al. 1994; Wasserman et al. 2006; 

Zhang et al. 1995) indicated that those who ingested drinking water and/or who ate food with increased 

concentrations of manganese (≥0.241 mg/L) for at least 3 years had measurable deficits in performance 

on certain tests. In addition, the children exposed to manganese performed more poorly in school 

compared to non-exposed control students (who drank water with manganese concentrations no higher 

than 0.04 mg/L), as measured in mastery of Chinese, performance in mathematics, and overall grade 

average (Zhang et al. 1995). These studies show that both adults and children show adverse neurological 

effects from oral exposure to excess manganese. There are no existing studies showing adverse 

neurological effects in children as a result of inhalation exposure to the airborne metal, either from 

locations near work sites or near hazardous waste sites. 

There currently exists only one series of studies of potential neurotoxic effects of inhaled environmental 

manganese (Baldwin et al. 1999; Beuter et al. 1999; Mergler et al. 1999). These exposures most likely 

resulted from a point source, but the possible contribution of airborne manganese from MMT-gasoline 

exhaust cannot be excluded. These studies lend support to the possibility that the elderly may be a 

population susceptible to the neurotoxic effects of excess manganese exposure. Studies are currently 

needed to further investigate the potential for neurological effects in people, including children, who may 

have ingested excess amounts of excess manganese from sources in the environment. Clearly defined 

information on exposure levels and regular dietary intakes should also be captured. Further studies are 

needed to determine whether manganese from MMT and/or its unique combustion products contribute to 

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airborne manganese concentrations that can be associated with adverse effects (e.g., respiratory or 

neurological effects). 

Studies in rodents and nonhuman primates indicate that oral intake of high doses of manganese can lead 

to biochemical and behavioral changes indicative of nervous system effects (Bonilla and Prasad 1984; 

Chandra 1983; Gupta et al. 1980; Kristensson et al. 1986; Lai et al. 1984; Nachtman et al. 1986), and this 

is supported by intravenous studies in monkeys (Newland and Weiss 1992). Rodents do not appear to be 

as susceptible to manganese neurotoxicity as humans; however, a study by Newland and Weiss (1992) 

indicates that Cebus monkeys would be a reasonable animal model. Further studies in animals may help 

determine the basis for the apparent differences in route and species susceptibility. 

Additional studies in animals concerning the cellular and biochemical basis of manganese neurotoxicity, 

including a more detailed analysis of precisely which neuronal cell types are damaged and why, are 

needed. For example, Carl et al. (1993) have performed initial studies investigating the relationship 

between manganese and the major Mn(II) enzymes (arginase and glutamine synthetase) in epileptic and 

induced seizures. Further studies may prove helpful in elucidating mechanism(s) of toxic action and 

could potentially lead to developing methods for mitigating adverse effects induced by manganese. 

Epidemiological and Human Dosimetry Studies. As already noted, there are numerous 

epidemiological studies of workers exposed to manganese dusts in air, and the clinical signs and 

symptoms of the resulting disease are well established. However, these studies have only involved males 

and have only involved the inhalation route of exposure. Additional epidemiological studies on 

populations exposed to manganese dust in the workplace or local environments (e.g., such as near 

foundries, populations exposed to manganese emissions from MMT-burning automobiles, particularly 

those living in areas of high-traffic density, and populations exposed to above-average oral intakes [either 

through water and/or food]) may help to strengthen conclusions on dose-response relationships and noeffect exposure levels. This would be helpful in evaluating potential risks to people who may be exposed 

to above-average manganese levels near hazardous waste sites. 

Biomarkers of Exposure and Effect. 

Exposure. Studies in humans have shown that it is difficult to estimate past exposure to manganese by 

analysis of manganese levels in blood, urine, feces, or tissues (Roels et al. 1987b; Smyth et al. 1973; 

Valentin and Schiele 1983; Yamada et al. 1986). This is the result of several factors: (1) manganese is a 

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MANGANESE 315 

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normal component of the diet and is present in all human tissues and fluids, so above average exposure 

must be detected as an increase over a variable baseline; (2) manganese is rapidly cleared from the blood 

and is excreted mainly in the feces, with very little in the urine; and (3) manganese absorption and 

excretion rates are subject to homeostatic regulation, so above average exposures may result in only small 

changes in fluid or tissue levels. Probably the most relevant indicator of current exposure is manganese 

concentrations in tissues, but at present, this can only be measured in autopsy or biopsy samples. Studies 

on new, noninvasive methods capable of measuring manganese levels in vivo, either in the whole body or 

in specific organs (e.g., brain), would be very helpful in identifying persons with above average exposure. 

Dorman et al. (2006b) evaluated the use of the pallidal index (PI—ratio of hyperintensities in the globus 

pallidus and the adjacent subcortical frontal white matter) and the T1 relaxation rate (R1) from MRI to 

reflect manganese concentrations determined by analytical chemistry in brain regions and concluded that 

R1 can be used to estimate regional brain manganese concentrations and be used as a reliable biomarker 

of occupational manganese exposure. 

Effect. The principal biological markers of toxic effects from manganese exposure are changes in the 

levels of various neurotransmitters and related enzymes and receptors in the basal ganglia (Bird et al. 

1984; Bonilla and Prasad 1984; Eriksson et al. 1987a, 1987b). Noninvasive methods to detect preclinical 

changes in these biomarkers or in the functioning of the basal ganglia need to be developed to help 

identify individuals in whom neurological effects might result. Research to determine the correlation 

between urinary excretion levels of neurotransmitters, neurotransmitter metabolites, and/or 

17-ketosteroids (Bernheimer et al. 1973; Rodier 1955; Siqueira and Moraes 1989) and the probability or 

severity of neurological injury in exposed people is also needed. Measurements of MnSOD as a 

biomarker of effect may also be helpful (Greger 1999), but there is a lack of information concerning the 

relationship of this enzyme to manganese toxicity. 

Research in the use of Clara cell protein CC16 may be useful in identifying populations at risk from 

exposure to MMT; however, the majority of exposure to this compound is expected to arise from 

inhalation and ingestion of its combustion products. Therefore, increased use of MMT in gasolines 

necessitates the development of biomarkers of exposure to inorganic manganese compounds, as discussed 

previously. 

Absorption, Distribution, Metabolism, and Excretion. The toxicokinetics of manganese 

absorption, distribution, and excretion have been studied in both humans and animals. The oral 

absorption rate is about 3–5% in humans (Davidsson et al. 1988, 1989a; Mena et al. 1969), but the rate 

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may vary depending on age and dietary iron and manganese intake levels (Chandra and Tandon 1973; 

Diez-Ewald et al. 1968; Rehnberg et al. 1982; Thomson et al. 1971). Information is needed on the 

relative proportion of manganese that is absorbed via the gut following mucociliary transport of particles 

from the lung to the stomach. The oral absorption rate may depend on the chemical form of manganese 

ingested, but data on this are sparse. Data on the differences in uptake as a function of chemical species 

(manganese dioxide, manganese tetroxide) and particle size would also be valuable in assessing human 

health risk from different types of manganese dusts. Absorption of manganese deposited in the lung is 

expected to be higher for soluble forms of manganese compared with relatively insoluble forms of 

manganese (Aschner et al. 2005; Roels et al. 1997). Results consistent with nasal uptake of manganese 

and transport to the brain along neuronal tracts have been obtained in several animal studies (Brenneman 

et al. 2000; Dorman et al. 2001a, 2002a; Elder et al. 2006; Fechter et al. 2002; Henriksson et al. 1999; 

Lewis et al. 2005; Normandin et al. 2004; Tjälve and Henriksson 1999; Tjälve et al. 1996; Vitarella et al. 

2000). Following nasal instillation of solutions of manganese chloride or sonicated suspensions of 

ultrafine insoluble manganese oxide particles to rats, similar manganese concentrations were found in the 

brain olfactory bulb (Elder et al. 2006). These results suggest that ultrafine particles can be distributed 

from the nasal mucosa to the brain olfactory bulb. Absorption of manganese deposited in the lung or 

nasal mucosa of rats is expected to be influenced by iron status, with enhanced absorption under irondeficient conditions and diminished absorption under iron-excess conditions (Thompson et al. 2006, 

2007). 

Manganese appears to be distributed to all tissues, including the brain (Aschner et al. 2005, 2007; 

Kristensson et al. 1986; Rehnberg et al. 1980, 1981, 1982). Inhaled manganese appears to be distributed 

more extensively to the brain than ingested manganese and there are differences in distribution between 

different forms of manganese (manganese chloride compared with manganese dioxide or manganese 

phosphate) (Dorman et al. 2001a, 2004b; Roels et al. 1997). Addtional research would be useful in 

understanding how particle size and solubility of manganese forms influence distribution of manganese to 

and within the brain. In addition, the metabolism of manganese (specifically, the degree and the rate of 

oxidation state interconversions) has not been thoroughly investigated. Data on this topic are needed to 

understand the mechanism of manganese toxicity and would help in evaluating the relative toxicity of 

different manganese compounds. Excretion of manganese is primarily through the feces (Drown et al. 

1986; Klaassen 1974; Mena et al. 1969); because the rate of excretion is an important determinant of 

manganese levels in the body, further studies would be valuable on the biochemical and physiological 

mechanisms that regulate manganese excretion. 

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MANGANESE 317 

3. HEALTH EFFECTS 

Additional studies would be useful to more fully elucidate the pharmacokinetic mechanisms responsible 

for uptake, distribution, and excretion in humans and animals, including studies to determine the 

following: control rates and processes for uptake of ingested manganese by the intestines and liver, 

including uptake rates of protein-bound forms by the liver; oxidation rates of manganese in the blood and 

tissues; relative speciation of Mn(II vs. III) in blood transport mechanisms into the central nervous 

system, including transfer rates; competition between manganese and iron in terms of transport processes; 

and distribution following long-term exposures to assess potential storage depots. 

Andersen et al. (1999) suggested that an approach to setting acceptable exposure levels for an essential, 

but neurotoxic, nutrient such as manganese could be based on predicting exposure levels by any route that 

would increase brain manganese concentrations to a small fraction (e.g., 10–25%) of the variation 

observed in the general human population. Reliable and validated multiple-route PBTK models for 

multiple species, including humans, are needed to take this approach to setting acceptable exposure 

levels. Efforts to develop such models in rats have been recently described (Leavens et al. 2007; Nong et 

al. 2008; Teeguarden et al. 2007a, 2007b, 2007c). Continued development of these models and extension 

of them to nonhuman primates and humans would be needed to establish MRLs for manganese by this 

alternative approach. 

Data on the pharmacokinetics of mangafodipir are sufficient for environmental assessment purposes. 

Additional studies concerning absorption, distribution, metabolism, and excretion of MMT, via 

inhalation, ingestion, and dermal exposures, would be very helpful. 

Comparative Toxicokinetics. Several papers have reviewed the fairly extensive literature showing 

differences in the expression of manganese neurotoxicity in humans, nonhuman primates, and rodents 

(Aschner et al. 2005; Gwiazda et al. 2007; Newland et al. 1999). Aschner et al. (2005) concluded that 

manganese-exposed monkeys show overlapping effects to those observed in patients with manganism 

(e.g., retention of manganese in the basal ganglia and loss of dopamergic neurons), but similar changes in 

regional brain manganese concentrations, neurochemical concentrations, and neuropathological effects 

have been observed less consistently in rodents. Likewise, Gwiazda et al. (2007) concluded from their 

analysis of estimated internal cumulative doses associated with neurobehavioral, histological, and 

neurochemical changes in manganese-exposed animals that the range of adverse internal cumulative 

doses extended more than 2 orders of magnitude above the lowest estimated doses associated with subtle 

neurological deficits in manganese-exposed workers. The reasons for these differences are poorly 

understood, but may be due to interspecies differences in toxicokinetics or toxicodynamics (i.e., 

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MANGANESE 318 

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differences in tissue sensitivities). Research to further develop PBTK models in rats that have been 

recently described (Leavens et al. 2007; Nong et al. 2008; Teeguarden et al. 2007a, 2007b, 2007c) and 

extend them to nonhuman primates and humans may be useful to increase understanding of interspecies 

differences in manganese neurotoxicity. 

Methods for Reducing Toxic Effects. In general, the methods which provide the greatest 

likelihood of reducing toxic effects are the same as those aimed at reducing body burden (see section 

3.11.2). The recommended methods for the mitigation of manganese toxicity (manganism) are mainly 

supportive (Schonwald 2004). Administration of anti-Parkinson drugs, such as levo-dopa, is of little use 

(Calne et al. 1994; Chu et al. 1995; Cook et al. 1974; Schonwald 2004; Huang et al. 1989; Leikin and 

Paloucek 2002). Chelation therapy with agents such as ethylenediaminetretraacetic acid (EDTA) has 

reportedly been effective in reducing some of the symptoms (Schonwald 2004; Haddad and Winchester 

1990), but was not effective in all cases (Crossgrove and Zheng 2004; Jiang et al. 2006). Studies on the 

efficacy of newly developed methods to reduce the toxic effects of manganese are needed. The available 

data indicate that para-aminosalicylate has been successfully used to treat neurological symptoms of 

manganese poisoning in several patients (Shuqin et al. 1992; Jiang et al. 2006). The use of the 

antioxidant vitamin E has also been proposed to mitigate manganese-induced effects (Parenti et al. 1988). 

Additional studies on the efficacy of these treatments are needed. Further evaluation for the mitigation of 

effects from excess exposure to manganese is also needed. 

Methods for reducing toxic effects have not been identified for MMT. 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 

Children have been identified as a potentially susceptible population because of their high absorption 

and/or retention of manganese as compared to adults. Although some available studies indicate that tissue 

concentrations of human fetuses are comparable to adults, animal studies indicate that neonates retain 

higher tissue concentrations than adult animals. Researchers hypothesize that this increased retention of 

manganese may lead to neurotoxicity. Existing data indicate that the adverse neurological effects of 

manganese overexposure from intravenous and oral sources are qualitatively similar in children and 

adults. One study has reported that neonates are more susceptible to the effects of oral exposure to excess 

manganese than adults (Dorman et al. 2000). Additional quantitative information on the levels of 

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MANGANESE 319 

3. HEALTH EFFECTS 

manganese that result in adverse effects in children as compared to adults for inhalation, oral, and 

intravenous exposures are needed. Further, analysis of existing data from effects observed in the clinical 

setting might be helpful. 

There are inadequate data on the pharmacokinetics of manganese in children. Although two studies 

provided typical serum manganese levels in differing ages of healthy children (Alarcón et al. 1996; 

Rükgauer et al. 1997), no studies have provided any data on the distribution of manganese in infants or 

adolescents. Studies in animals, particularly nonhuman primates, are needed to clearly elucidate the 

pharmacokinetic handling of manganese in neonates and the young (absorption, metabolism, distribution, 

elimination). There are no PBPK models for children, embryos, fetuses and pregnant women, infants and 

lactating women, or adolescents. Such models would be very informative if they could assist in the 

identification of depots for manganese storage under conditions of excess exposure, as well as the 

nutritional needs of these age groups for the compound. One study was available that would provide 

information on the concentrations of manganese that might be found in the developing fetus of a highlyexposed mother (Jarvinen and Ahlström 1975). Further studies of this nature, especially those that 

measure neurological end points in live offspring following excess exposure, are needed. Similarly, data 

are needed to determine whether increased amounts of manganese might be present in the breast milk of a 

mother with significantly elevated blood or tissue manganese concentrations. 

There are likely to be multiple mechanisms of manganese toxicity and most of these have probably been 

elucidated. However, there is a deficiency in our knowledge of how these mechanisms act singly or in 

combination to explain the different functional deficits observed in children versus adults. There are 

inadequate data to determine whether metabolism of manganese is different in children than in adults. 

Manganese is necessary for normal functioning of certain enzymes. However, there are no definitive data 

to indicate that children might need more manganese than adults for normal body processes. A few 

studies suggest that children may have a higher need for manganese than adults, based on the increased 

retention of manganese in the brains of certain neonatal animals, but this hypothesis has not been proven. 

Additional studies are necessary to determine the nutritional requirements of children for manganese, 

especially in infants for which FNB/IOM has not provided any guidelines. 

Studies indicate that children exposed to increased concentrations of inorganic manganese, either via the 

diet, due to inability to clear the compound from the body or through parenteral nutrition, develop 

neurological dysfunction similar to that of adults (Devenyi et al. 1994; Fell et al. 1996; He et al. 1994; 

Zhang et al. 1995). Other data exist that indicate that children may not be as susceptible as adults to the 

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MANGANESE 320 

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adverse neurological effects of inorganic manganese (Kawamura et al. 1941), but the limitations in this 

report make predictions about susceptibility inconclusive. Additional animal studies comparing the 

potential for inorganic manganese to induce neurological effects in different age groups are needed to 

help understand the susceptibility of the young compared to adults. 

The mechanism of action of inorganic manganese toxicity has not been identified. Studies in humans 

indicate that children and adults with increased manganese deposition in the globus pallidus and other 

basal regions suffer neuromuscular deficits. It has been suggested that manganese accelerates the 

autoxidation of catecholamines and contributes to oxidative stress in these affected regions of the brain. 

Further research is needed to more completely elucidate the mechanism of inorganic manganese toxicity. 

There are no dependable biomarkers of exposure or effect that are consistently used in a clinical setting. 

However, MRI scans have been used in both adults and children to determine whether manganese is 

accumulating in certain brain regions. More data are needed to determine the sensitivity and specificity 

of this method. 

Available data do not indicate that there are any interactions of manganese with other compounds that 

occur only in children. Interactions with compounds in adults are expected to also occur in children. 

Data concerning the significance of any interactions of manganese with other compounds are needed. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

3.12.3 Ongoing Studies 

Ongoing studies pertaining to manganese have been identified and are shown in Table 3-20. 

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MANGANESE 321 

3. HEALTH EFFECTS 

Table 3-20. Ongoing Studies on Manganese 

Investigator Affiliation Research description Sponsor 

Aschner, Judy L 

Aschner, Michael 

Berkowitz, Bruce A 

Brain, Joseph D 

Culotta, Valeria C 

Dees, WL 

Dietrich, Kim 

Erikson, Keith M 

Glasfeld, Arthur 

Graziano, Joseph H, 

Grazi 

Guilarte, Tomas R 

Gunter, Thomas E 

Hu, Howard, MD 

Kanthasamy, 

Anumantha 

Gounder, G 

Klimis-Zacas, D 

Klimis-Zacas, D 

Klimis-Zacas, D 

Vanderbilt 

University 

Vanderbilt 

University 

Wayne State 

University 

Harvard 

University 

Johns Hopkins 

University 

Texas A&M 

University 

University of 

Cincinnati 

University of 

North Carolina 

Greensboro 

Reed College 

Columbia 

University 

Johns Hopkins 

University 

University of 

Rochester 

Brigham and 

Women's 

Hospital 

Iowa State 

University 

University of 

Maine 

University of 

Maine 

University Of 

Maine 

Brain manganese deposition in 

high risk neonates 

Mechanisms of manganese 

neurotoxicity 

Manganese-enhanced MRI 

studies of retinal 

neovascularization 

Manganese, iron, cadmium, and 

lead transport from the 

environment to critical organs 

Intracellular pathways of 

manganese trafficking 

Actions of manganese on 

neuroendocrine development 

Early lead exposure, ADHD, and 

persistent criminality: Role of 

genes and environment 

Neurotoxicology of dietary 

iron/manganese interactions 

Mechanism and specificity in 

manganese homeostasis 

Research description: Health 

effects and geochemistry of 

arsenic and manganese 

Molecular and behavioral effects 

of low level Mn exposure 

Mitochondrial role in manganese 

toxicity 

Gene-metal interactions and 

Parkinson's disease 

Mechanisms of manganese 

neurotoxicity 

Manganese, arterial functional 

properties, and metabolism as 

related to cardiovascular disease 

Manganese, arterial functional 

properties, and proteoglycanlipoprotein interactions 

Manganese, proteoglycanlipoprotein interactions, and 

arterial wall functional properties 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Eye Institute 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of General 

Medical Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

Department of Agriculture 

Hatch 

Department of Agriculture 

Hatch 

Department of Agriculture NRI 

Competitive 

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MANGANESE 

3. HEALTH EFFECTS 

322 

Investigator 

Table 3-20. Ongoing Studies on Manganese 

Affiliation Research description Sponsor 

Korrick, Susan A Brigham and 

Women's 

Hospital 

Liu, Bin University of 

Florida 

Miller, Gary W Emory 

University 

Nass, Richard Vanderbilt 

Michael University 

Oberley, Larry W University of 

Iowa 

Pecoraro, Vincent L University of 

Michigan at 

Ann Arbor 

Rao, Rajini Johns Hopkins 

University 

Shine, James P Harvard 

University 

Smith, Donald R University of 

California 

Santa Cruz 

Srinivasan, Chandra	 California State 

University 

Fullerton 

Tjalkens, Ronald B	 Colorado State 

University-Fort 

Collins 

Weisskopf, Marc G	 Harvard 

University 

Wessling-Resnick,	 Harvard 

Marianne	 University 

Williams, Michael T	 Children's 

Hospital 

Medical 

Center, 

Cincinnati 

Wright, Robert O,	 Brigham and 

MD	 Women's 

Hospital 

Zheng, Wei	 Purdue 

University 

West Lafayette 

Metal and organochlorines 

exposure: Impact on adolescent 

behavior and cognition 

Combined dopaminergic 

neurotoxicity of manganese and 

LPS 

Neurotoxicity of nanomaterials: 

Evaluation of subcellular redox 

state 

Molecular genetics of manganese 

induced dopamine neuron toxicity 

Oxidative stress and metabolism 

research cluster 

Structural models for multinuclear 

manganese enzymes 

Secretory pathway calcium and 

manganese pumps 

Exposure assessment of children 

and metals in mining waste 

Role of manganese in 

neurodegenerative disease 

Superoxide dismutases and ionic 

manganese in aging 

Manganese and basal ganglia 

dysfunction: Role of NO 

Metal neurotoxicity 

Influence of iron status on the 

neurotoxicity of inhaled 

manganese 

Effect of lead, manganese, and 

stress during development 

Metal mixtures and 

neurodevelopment 

Choroid plexus as a target in 

metal-induced neurotoxicity 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of General 

Medical Sciences 

National Institute of General 

Medical Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute on Aging 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

National Institute of 

Environmental Health Sciences 

Source: FEDRIP 2008 

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MANGANESE 323 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Table 4-1 lists common synonyms, trade names, and other relevant information regarding the chemical 

identity of manganese and several of its most important compounds. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Information regarding the physical and chemical properties of manganese is located in Table 4-2. 

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MANGANESE 324 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Manganese and Compoundsa 

Characteristic Information 

Chemical name 

Synonym(s) 

Registered trade name(s) 

Chemical formula 

Chemical structure 

Manganese 

Elemental 

manganeseb; 

collodial 

manganeseb

; 

cutavalb 

Cutavalb; Manganb 

Mn 

Mn(II) chloride 

Manganese chlorideb; 

manganese dichloride 

No data 

MnCl2 

Cl 

Manganese sulfate 

Manganese sulfate 

Sorba-spray manganeseb 

MnSO4 

Mn Mn

2+ 

Mn

2+ 

Cl O 

Identification numbers: 

CAS registry 

NIOSH RTECS 

7439-96-5 

009275000b 

7773-01-5 

009625000b 

7785-87-7 

OP1050000b 

EPA hazardous waste No data No data No data 

OHM/TADS 

DOT/UN/NA/IMDG shipping 

HSDB 

No data 

No data 

00550b 

No data 

No data 

02154b 

No data 

No data 

02187b 

NCI No data No data No data 

O 

S 

O 

O 

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MANGANESE	 325 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Manganese and Compoundsa 

Characteristic	 Information 

Mn 

O 

Mn 

O 

Mn 

O 

O 

Chemical name	 Manganese (II, III) Manganese dioxide Potassium permanganate 

oxide 

Synonym(s)	 Manganese Manganese peroxide; Permanganic acid; 

tetroxide; mangano- manganese binoxide; potassium salt; chameleon 

manganic oxidec manganese black; mineralc 

battery manganese 

Registered trade name(s) No data No data No data 

Chemical formula Mn3O4 MnO2 KMnO4 

Chemical structure 

O 

O Mn O K+ O Mn O 

O 

Identification numbers: 

CAS registry 1317-35-7 1313-13-9 7722-64-7 

NIOSH RTECS OP0900000b No data SD6475000b 

EPA hazardous waste No data No data No data 

OHM/TADS No data No data No data 

DOT/UN/NA/IMDG shipping No data No data UN1490b, IMDG 5.1b 

HSDB No data No data 01218b 

NCI No data No data No data 

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MANGANESE	 326 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Manganese and Compoundsa 

Characteristic	 Information 

Chemical name Mn(II) carbonate Mangafodipir	 Methylcyclopentadienyl 

manganese tricarbonyl 

(MMT) 

Synonym(s)	 Carbonic acid; Mangafodipir trisodiumd; MMT; manganese, 

manganese (2+) MnDPDPd tricarbonyl ([1,2,3,4,5-eta]-1­

salt; manganous methyl-2,4-cyclopentadiencarbonateb

; 1yl)-; methylcymantrene; 

natural tricarbonyl (2­

rhodochrositeb methylcyclopentadientyl) b manganese

Registered trade name(s) No data Teslascand; Win 59010d	 AK-33X; Antiknock-33; CI-2; 

Combustion Improver-2b 

Chemical formula MnCO3 C22H24MnN4O14P2H3Na3	 C9H7MnO3 

Chemical structure 

O 

No data O O Mn

O O Mn++ 

O 

Identification numbers: 

CAS registry 598-62-9 140678-14-4 12108-13-3 

NIOSH RTECS No data OO9163250 48184 

EPA hazardous waste No data No data No data 

OHM/TADS No data No data No data 

DOT/UN/NA/IMDG shipping No data No data No data 

HSDB 00790b No data 2014 

NCI No data No data No data 

a

All information obtained from Sax and Lewis 1987, except where noted.

b

HSDB 2008 

c

O’Neil et al. 2006 

d

RTECS 2007 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMDG = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for 

Occupational Safety and Health; OHM/TADS = Oil and Hazardous Material Technical Assistance Data System; 

RTECS = Registry of Toxic Effects of Chemical Substances 

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MANGANESE 327 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Manganese and Compoundsa 

Property Manganese Mn(II) chloride Manganese sulfate 

Molecular weight 

Color 

54.94b 

Steel-grayb 

125.85b 

Pink 

151.00b 

Pale rose-red 

Physical state Solid Solid Solid 

Melting point 

Boiling point 

Density at 20 °C 

1,244 °Cc 

2,095 °Cb 

7.26 g/cm3 b at 20 °C 

650 °C 

1,412 °Cb 

2.325 g/cm3 at 25 °C b 

700 °C 

850 °C (decomposes) 

3.25 g/cm3 d 

Odor No data No data Odorless 

Odor threshold: 

Water No data No data No data 

Air No data No data No data 

Solubility: 

Water at 20 °C Decomposes No data No data 

Acids Reacts with diluted mineral No data No data 

acids with evolution of 

hydrogen and formation of 

divalent manganous saltsb 

Organic solvents No data Soluble in alcohol, 

insoluble in ether 

Soluble in alcohol, 

insoluble in ether 

Partition coefficients: 

Log Kow No data No data Not applicable 

Log Koc No data No data Not applicable 

Vapor pressure at 20 °C 1 Pa at 955 °Cc 1,000 Pa at 760 °Cc No data 

Henry's law constant at 25 °C No data Not applicable Not applicable 

Autoignition temperature No data Noncombustible No data 

Flashpoint No data No data No data 

Flammability limits Flammable and 

moderately explosive in 

dust form when exposed to 

flamed 

No data No data 

Conversion factors Not applicable Not applicable Not applicable 

Explosive limits 

Reactivity 

Mixture of aluminum and 

manganese dust may 

explode in air. Mixtures 

with ammonium nitrate 

may explode when heatedd 

No data 

Hydrogend; when heated 

above 200 °C in presence 

of nitrogen, forms nitrode; 

violent reaction with NO2 

and oxidants; 

incandescent reaction with 

No data 

No data 

No data 

phosphorous, nitryl 

fluoride, nitric acidd 

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MANGANESE 328 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Manganese and Compoundsa 

Manganese (II, III) Potassium 

Property oxide Manganese dioxide permanganate 

Molecular weight 228.81b 86.94b 158.03b 

Color Brownish-blackb Black Purple 

Physical state Solid Solid Solid 

Melting point 1,564 °C Loses oxygen at 535 °Cd <240 °C (decomposes) 

Boiling point No data No data No data 

Density at 20 °C No data 5.0 g/cm3 d 2.703 g/cm3 

Odor No data No data Odorless 

Odor threshold: 

Water No data No data No data 

Air No data No data No data 

Solubility: 

Water at 20 °C Insoluble Insoluble No data 

Acids Soluble in hydrochloric Soluble in hydrochloric Soluble in sulfuric acid 

acid acid 

Organic solvents No data No data Soluble in acetone 

Partition coefficients: 

Log Kow Not applicable No data No data 

Log Koc Not applicable No data No data 

Vapor pressure at 20 °C No data No data No data 

Henry's law constant at 25 °C Not applicable No data No data 

Autoignition temperature No data No data No data 

Flashpoint No data No data No data 

Flammability limits No data No data No data 

Conversion factors Not applicable Not applicable Not applicable 

Explosive limits No data No data No data 

Reactivity No data No data Spontaneously 

flammable on contact 

with ethylene glycol 

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MANGANESE 329 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Manganese and Compoundsa 

Property Mn(II) carbonate 

Mangafodipir 

trisodium 

Methylcyclopentadienyl 

manganese tricarbonyl (MMT)f 

Molecular weight 114.95 757.4e 218.1 

Color Pinkc No data Yellow to dark orange 

Physical state hexagonal, crystalsc Liquid (solution for Liquid, solid below 2 °C 

infusion) 

Melting point Decomposes No data 1.5 °Cd 

Boiling point No data No data 232 °C 

Density at 20 °C 3.70 g/cm3 c 1.537 g/cm3 b 1.39 g/cm3 

Odor No data No data Faint, pleasant 

Odor threshold: 

Water No data No data No data 

Air No data No data No data 

Solubility: 

Water at 20 °C Insoluble 459.6 g/Lb Insoluble 

Acids Soluble in dilute acidc No data No data 

Organic solvents No data 23 g/L (methanol); Readily soluble in hydrocarbons 

0.8 g/L (ethanol); and the usual organic solvents 

0.6 g/L (acetone); 

1.1 g/L (chloroform)b 

including hexane, alcohols, 

ethers, acetone, ethylene glycol, 

lubricating oils, gasoline and 

diesel fuelb 

Partition coefficients: 

Log Kow No data -5.62b No data 

Log Koc No data No data No data 

Vapor pressure at 20 °C No data No data Ranges from 8 mm Hg at 100 °C 

to 360.6 mm Hg at 200 °Cb 

Henry's law constant at 25 °C No data No data No data 

Autoignition temperature No data No data No data 

Flashpoint No data No data 110 °C 

Flammability limits No data No data No data 

Conversion factors Not applicable No data No data 

Explosive limits No data No data No data 

Reactivity No data No data Light (decomposes) 

a

All information obtained from Sax and Lewis 1987, except where noted.

b

O’Neil et al. 2006 c

Lide 2000 d

Lewis 2000 

e

RTECS 2007 

f

Data for MMT from NIOSH 2005 unless otherwise noted 

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4. CHEMICAL AND PHYSICAL INFORMATION 

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MANGANESE 331 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 PRODUCTION 

Tables 5-1 and 5-2 list the facilities in each state that manufacture or process manganese, the intended 

use, and the range of maximum amounts of manganese that are stored on site. The data listed in 

Tables 5-1 and 5-2 are derived from the Toxics Release Inventory (TRI06 2008). Only certain types of 

facilities were required to report. Therefore, this is not an exhaustive list. 

Manganese is an abundant element comprising about 0.1% of the earth's crust (Graedel 1978). It does not 

occur naturally as a base metal, but is a component of over 100 minerals, including various sulfides, 

oxides, carbonates, silicates, phosphates, and borates (NAS 1973). The most commonly occurring 

manganese-bearing minerals include pyrolusite (manganese dioxide), rhodocrosite (manganese 

carbonate), and rhodanate (manganese silicate) (EPA 1984; NAS 1973; Windholz et al. 1983). 

Most manganese ore is smelted in electric furnaces to produce ferromanganese, a manganese-iron alloy 

widely used in the production of steel (EPA 1984; NAS 1973). Approximately 2 tons of manganese ore 

are required to make 1 ton of ferromanganese (NAS 1973). Production of manganese metal is achieved 

by aluminum reduction of low iron-content manganese ore, and electrolytically from sulfate or chloride 

solution (Lewis 2001). Manganese with <0.1% metallic impurities can be produced electrolytically from 

a manganese sulfate solution (EPA 1984; Lewis 2001). 

Manganese compounds are produced either from manganese ores or from manganese metal. For 

example, manganese chloride is produced by the reaction of hydrochloric acid with manganese oxide 

(Pisarczyk 2005). Manganese carbonate and manganese sulfate are produced by dissolving manganese 

carbonate ore (rhodochrosite) or Mn(II) oxide in sulfuric acid (Pisarczyk 2005). Potassium permanganate 

may be manufactured by the one-step electrolytic conversion of ferromanganese to permanganate, or by a 

two-step process involving the thermal oxidation of manganese(IV) dioxide of a naturally occurring ore 

into potassium manganate(VI), followed by electrolytic oxidation to permanganate (Pisarczyk 2005). 

Most manganese is mined in open pit or shallow underground mines (EPA 1984; NAS 1973). Manganese 

ores were previously mined in the United States, but no appreciable quantity has been mined in the United 

States since 1978 (USGS 2007). The only mine production of manganese in the United States consisted 

of small amounts of manganiferous material having a natural manganese content of <5%. This type of 

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MANGANESE 332 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Manganese 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AK 4 0 99,999 1, 5, 12, 13, 14 

AL 93 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AR 61 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

AZ 36 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CA 108 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CO 37 100 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 

CT 25 0 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13 

DE 5 100 999,999 1, 3, 4, 5, 8, 10 

FL 45 100 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

GA 62 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14 

HI 5 100 99,999 2, 3, 4, 7, 8, 12 

IA 94 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ID 11 1,000 9,999,999 1, 3, 4, 5, 7, 8, 12, 13 

IL 169 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

IN 171 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KS 49 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KY 96 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

LA 53 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MA 36 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 14 

MD 36 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

ME 21 0 999,999 1, 2, 3, 5, 6, 8, 11, 12, 13 

MI 157 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MN 56 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MO 76 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MS 37 0 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14 

MT 9 10,000 999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12 

NC 91 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ND 16 100 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12 

NE 43 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14 

NH 14 0 49,999,999 1, 5, 7, 8, 11, 12, 13 

NJ 65 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

NM 5 1,000 9,999,999 6, 8, 11, 12 

NV 32 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NY 98 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 

OH 221 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OK 72 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

OR 57 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

PA 212 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

PR 11 100 999,999 2, 3, 4, 7, 8, 11, 12 

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MANGANESE 333 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Manganese 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

RI 12 0 999,999 2, 3, 4, 8, 9, 11, 12 

SC 62 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

SD 29 0 49,999,999 1, 2, 3, 5, 7, 8, 9, 11, 12, 13, 14 

TN 99 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

TX 141 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 60 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

VA 58 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

VT 4 0 999,999 2, 4, 7, 11, 12 

WA 59 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

WI 132 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WV 44 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WY 11 0 999,999 1, 2, 3, 5, 8, 9, 11, 12, 13, 14 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical processing aid 

2. Import 7. Reactant 12. Manufacturing aid 

3. Onsite use/processing 8. Formulation component 13. Ancillary/other uses 

4. Sale/distribution 9. Article component 14. Process impurity 

5. Byproduct 10. Repackaging 

Source: TRI06 2008 (Data are from 2006) 

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MANGANESE 334 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-2. Facilities that Produce, Process, or Use Manganese Compounds 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AK 12 0 49,999,999 1, 2, 3, 5, 7, 8, 11, 12, 13, 14 

AL 141 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AR 68 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

AZ 55 100 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

CA 100 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CO 52 100 499,999,999 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CT 30 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

DC 2 1,000 99,999 12 

DE 32 0 9,999,999 1, 2, 3, 5, 7, 8, 9, 10, 11, 12, 13, 14 

FL 88 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

GA 93 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

HI 6 100 999,999 1, 5, 7, 9, 10 

IA 90 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ID 25 0 49,999,999 1, 5, 6, 7, 8, 10, 11, 12, 13 

IL 186 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

IN 150 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KS 68 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KY 85 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

LA 58 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MA 28 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13 

MD 69 100 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ME 18 0 9,999,999 1, 5, 6, 8, 13, 14 

MI 159 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MN 59 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MO 79 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MS 66 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MT 23 100 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14 

NC 116 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ND 21 1,000 9,999,999 1, 3, 5, 7, 8, 9, 10, 11, 12, 13, 14 

NE 49 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

NH 10 0 99,999 1, 2, 3, 5, 7, 8, 9 

NJ 86 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NM 29 100 10,000,000,000 1, 3, 4, 5, 7, 9, 12, 13, 14 

NV 33 1,000 499,999,999 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14 

NY 113 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OH 253 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OK 49 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OR 48 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

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MANGANESE 335 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-2. Facilities that Produce, Process, or Use Manganese Compounds 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

PA 243 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

PR 18 0 999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12 

RI 5 10,000 999,999 8, 11 

SC 91 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

SD 12 100 9,999,999 1, 5, 6, 7, 8, 9, 11, 12, 13, 14 

TN 122 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

TX 181 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 71 100 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

VA 64 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

VT 3 1,000 99,999 1, 5, 7, 8 

WA 72 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WI 96 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WV 60 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WY 24 0 999,999 1, 3, 4, 5, 7, 9, 12, 13, 14 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical processing aid 

2. Import 7. Reactant 12. Manufacturing aid 

3. On-site use/processing 8. Formulation component 13. Ancillary/other uses 

4. Sale/distribution 9. Article component 14. Process impurity 

5. Byproduct 10. Repackaging 

Source:TRI06 2008 (Data are from 2006) 

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MANGANESE 336 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

material was produced in South Carolina for use in coloring brick (USGS 2007). Essentially all 

manganese ore used in manganese production in the United States is now imported (USGS 2007). 

Currently, there are 3,200 facilities in the United States that indicate that they produce, process, or use 

manganese (TRI06 2008). These facilities are scattered across the United States, with the largest numbers 

in Ohio (221), Pennsylvania (212), and Indiana (171). Over 3,700 facilities are involved in the 

distribution or use of manganese or manganese compounds (TRI06 2008). Tables 5-1 and 5-2 list the 

number of facilities in each state, the ranges of the maximum amounts stored at each facility, and the uses 

of the material (TRI06 2008). 

The organomanganese compound methylcyclopentadienyl manganese tricarbonyl (MMT) is produced in 

either of the following ways: via the reaction of manganous chloride, cyclopentadiene, and carbon 

monoxide in the presence of manganese carbonyl and an element of group II or IIIA, or via the reaction of 

methylcyclopentadiene with manganese carbonyl (EPA 1984; Sax and Lewis 1987). According to data 

submitted to the EPA by the American Chemistry Council Petroleum Additives Panel, MMT is 

manufactured by adding methylcyclopentadienyl dimer to a dispersion of sodium metal in diethylene 

glycol dimethyl ether under a nitrogen environment (EPA 2006b). Keeping the mixture at elevated 

temperature yields sodium-methylcyclopentadienyl, which is an intermediate in the reaction process. 

Manganese chloride is added to the stirred mixture containing the sodium methylcyclopentadienyl 

intermediate. The reaction eventually yields bis(methylcyclopentadienyl)manganese as a second 

intermediate of the reaction process. The reaction vessel is then pressurized with carbon monoxide, 

which results in the formation of MMT, which is separated from the reaction mixture via vacuum 

distillation (EPA 2006b). 

No production data from facilities that manufacture or process MMT were found. According to data from 

the 2007 Directory of Chemical Producers, only one company located in Orangeburg, South Carolina 

produces MMT in the United States (SRI 2007). 

Mn(II) dipyridoxyl diphosphate (MnDPDP), or mangafodipir trisodium, is classified as a drug or 

therapeutic agent, and no production data were found for it. 

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MANGANESE 337 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.2 IMPORT/EXPORT 

The United States does not produce manganese and is 100% import reliant (USGS 2007). Import and 

export data for manganese are provided in Table 5-3. Demand for manganese metal comes primarily 

from the aluminum and steel industry (USGS 2007). Manganese consumption in 2007 was about 13% 

lower than that of 2006, owing to constant demand by the domestic steel industry and reduction of 

producer and consumer stocks. From January through August of 2007, domestic steel production was 

1.4% lower than that for the same period in 2006 (USGS 2008). The United States imports the bulk of its 

manganese ore from Gabon, 65%; South Africa, 19%; Australia, 7%; Ghana, 2%; and other nations, 7% 

(USGS 2007). Ferromanganese is imported from South Africa, 51%; China, 14%; Mexico, 6%; Republic 

of Korea, 5%; and other nations, 24% (USGS 2007). 

There were no data located regarding the import or export of MMT or mangafodipir. 

5.3 USE 

Metallic manganese (ferromanganese) is used principally in steel production to improve hardness, 

stiffness, and strength. It is used in carbon steel, stainless steel, high-temperature steel, and tool steel, 

along with cast iron and superalloys (EPA 1984; NAS 1973). According to data obtained from the 

U.S. Geological Society (USGS), manganese ore was consumed primarily by eight firms with plants 

principally in the east and midwest United States (USGS 2008). The majority of ore consumed was 

associated with steel production, directly in pig iron manufacture and indirectly through upgrading ore to 

ferroalloys. Additional quantities of ore were used for nonmetallurgical purposes such as production of 

dry cell batteries, in plant fertilizers and animal feed, and as a brick colorant. Manganese ferroalloys were 

produced at two smelters, although one operated sporadically throughout the year (USGS 2008). 

Construction, machinery, and transportation end uses accounted for approximately 24, 10, and 10%, 

respectively, of manganese demand (USGS 2008). Most of the rest went to a variety of other iron and 

steel applications. The value of domestic consumption, estimated from foreign trade data, was about 

$730 million (USGS 2008). 

Manganese compounds have a variety of uses. Manganese dioxide is commonly used in production of 

dry-cell batteries, matches, fireworks, porcelain and glass-bonding materials, amethyst glass, and as the 

starting material for production of other manganese compounds (EPA 1984; NAS 1973; Venugopal and 

Luckey 1978). Manganese chloride is used as a precursor for other manganese compounds, as a catalyst 

in the chlorination of organic compounds, in animal feed to supply essential trace minerals, and in 

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MANGANESE 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

338 

Table 5-3. Manganese Import/Export Data for 2003–2007 

Imports for consumptiona 

Manganese ore 

Ferromanganese 

Silicomanganese 

Exportsa 

Manganese ore 

Ferromanganese 

2003 

347 

238 

267 

18 

11 

2004 

451 

429 

422 

123 

9 

2005 

656 

255 

327 

13 

14 

2006 

572 

358 

400 

2 

22 

2007 

610 

322 

390 

2 

33 

a

Data in thousand metric tons gross weight 

Source: USGS 2008 

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MANGANESE 339 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

dry-cell batteries (EPA 1984). Manganese sulfate is used primarily as a component of fertilizer (60% of 

total consumption) and as a livestock supplement (30% of total consumption); it is also used in some 

glazes, varnishes, ceramics, and fungicides (EPA 1984; Windholz et al. 1983). Potassium 

permanganate’s oxidizing power allows it to be used as a disinfectant; an antialgal agent; for metal 

cleaning, tanning, and bleaching; and as a water purification agent (Lewis 2001). Another common 

source of manganese is found in the street drug “Bazooka”. It is a cocaine-based drug contaminated with 

manganese-carbonate from free-base preparation methods (Ensing 1985). 

MMT is a fuel additive developed in the 1950s to increase the octane level of gasoline and thus improve 

the antiknock properties of the fuel (Davis 1998; EPA 1984; Lynam et al. 1990; NAS 1973). MMT was 

introduced into Canada in 1976 and its use increased so substantially that it completely replaced tetraethyl 

lead in gasoline in that country in 1990 (Zayed et al. 1999a). The major refiners in Canada have 

voluntarily stopped using MMT, out of concern that its use may harm on-board diagnostic equipment 

(OBD), which monitors the performance of emissions control devices in the vehicle (ICCT 2004). As a 

result, as much as 95% of Canadian gasoline is now MMT-free (ICCT 2004). MMT was used as an 

additive in leaded gasoline in the United States; however, EPA banned its use in unleaded gasoline in 

1977 (EPA 1978, 1979a, 1981). In 1995, the ban on MMT use in unleaded gasoline was lifted, and a 

court decision ordered EPA to register the product for use as a fuel additive (EPA 1995a). Recent data 

suggest that MMT is currently used only sparsely in the developed world including the United States, 

although exact quantities are not known (ICCT 2004). Historical data suggest that approximately 

70 million pounds of MMT were sold for use in leaded gasoline in the United States between 1976 and 

1990 (Veysseyre et al. 1998). 

Mangafodipir trisodium (MnDPDP) is used as both a liver- and pancreas-specific contrast agent for 

magnetic resonance imaging (MRI); it improves lesion detection in MRI of these organs by selectively 

enhancing the normal parenchyma, but not lesions, so that the contrast between tumorous and normal 

tissue is increased (Federle et al. 2000). 

5.4 DISPOSAL 

Manganese is listed as a toxic substance under Section 313 of the Emergency Planning and Community 

Right to Know Act (EPCRA) under Title III of the Superfund Amendments and Reauthorization Act 

(SARA) (EPA 1998). Disposal of wastes containing manganese is controlled by a number of federal 

regulations (see Chapter 8). 

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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Disposal of waste manganese into water requires a discharge permit from the EPA (see Chapter 8), but 

disposal of solid wastes such as manganese metal or manganese compounds is not regulated under current 

federal law. There are incomplete federal records of this disposal because most, but not all, solid 

manganese wastes are disposed of by being deposited on land or by being trucked to off-site disposal 

facilities (TRI06 2008). The total amount of waste manganese disposed of in this way in 2006 was in 

excess of 200 million pounds (TRI06 2008) (see Tables 6-1 and 6-2). 

Manganese and other metals are commonly recycled for future use. In 1998, 218,000 metric tons of 

manganese were estimated to have been recycled from old scrap, of which 96% was from iron and steel 

scrap (USGS 2001). In 2007, the USGS reported that manganese was recycled incidentally as a minor 

constituent of ferrous and nonferrous scrap; however, scrap recovery specifically for manganese was 

negligible (USGS 2008). No quantitative statistics were provided regarding the amount recovered from 

steel slag. 

No information on disposal of MMT was located. 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Manganese has been identified in at least 869 of the 1,699 hazardous waste sites that have been proposed 

for inclusion on the EPA National Priorities List (NPL) (HazDat 2008). However, the number of sites 

evaluated for manganese is not known. The frequency of these sites can be seen in Figure 6-1. Of these 

sites, 861 are located within the United States, 5 are located in the Commonwealth of Puerto Rico, 2 are 

located in the Virgin Islands, and 1 is located in Guam (not shown). 

Manganese is ubiquitous in the environment, and human exposure arises from both natural and 

anthropogenic activities. It occurs naturally in more than 100 minerals with background levels in soil 

ranging from 40 to 900 mg/kg, with an estimated mean background concentration of 330 mg/kg 

(Barceloux 1999). Manganese is released to the environment from industrial emissions, fossil fuel 

combustion, and erosion of manganese-containing soils. Volcanic eruptions can also contribute to levels 

of manganese in air. Almost 80% of industrial emissions of manganese are attributable to iron and steel 

production facilities (EPA 2003a). Power plant and coke oven emissions contribute about 20% (EPA 

2003a). Manganese may also be released to the environment through the use of MMT as a gasoline 

additive. Thus, all humans are exposed to manganese, and manganese is a normal component of the 

human body. 

Background levels of manganese in the atmosphere vary widely depending on the proximity of point 

sources, such as ferroalloy production facilities, coke ovens, and power plants. The estimated average 

background concentration of manganese in urban areas is approximately 40 ng/m3

, based on 

measurements obtained in 102 U.S. cities (EPA 2003a; WHO 2004b). Concentrations near source 

dominated areas were reported to range from 220 to 300 ng/m3 (WHO 2004b) and rural/remote levels are 

typically under 10 ng/m3 (Sweet et al. 1993). Manganese occurs naturally in surface water and 

groundwater. A median dissolved manganese concentration of 24 μg/L in samples from 286 U.S. rivers 

and streams was reported (Smith et al. 1987). Natural concentrations of manganese in seawater 

reportedly range from 0.4 to 10 μg/L (EPA 1984). 

The general population is exposed to manganese primarily through food intake. The World Health 

Organization (WHO) estimates that adults consume between 0.7 and 10.9 mg of manganese per day in the 

diet, with higher intakes for vegetarians who may consume a larger proportion of manganese-rich nuts, 

grains, and legumes in their diet as compared to non-vegetarians in the general population (WHO 2004b). 

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MANGANESE 342

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with Manganese Contamination

Frequency of 

NPL Sites

1-5 

6-11 

12-17 

20-27 

32-40 Derived from HazDat 2008 49-61 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Manganese intake from drinking water is substantially lower than intake from food. Using a median 

drinking-water level of 10 μg/L and an assumption that the average adult drinks 2 L of water/day, an 

average intake of approximately 0.020 mg/day was estimated (WHO 2004b). Exposure to manganese 

from air is considered negligible as compared to intake from diet; however, persons in certain occupations 

may be exposed to much higher levels than the general public (see Section 6.7). 

Manganese adsorbed to particulate matter in air can be classified by the size of the particles. Air 

concentrations can be reported as total suspended particulate matter (TSP), respirable particulates, and 

fine particulates. In this document, manganese adsorbed to particulate matter <10 microns in 

aerodynamic diameter is referred to as PM10. The EPA has further divided these tiny particles into "fine" 

particles of ≤2.5 microns (PM2.5) and "coarse" particles of between 2.5 and 10 microns. 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ 10 or more full-time 

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI 

chemical in a calendar year (EPA 2005). 

According to the Toxics Release Inventory (TRI), in 2006, a total of 27,094,361 pounds (12,290 metric 

tons) of manganese was released to the environment from 2,040 large processing facilities (TRI06 2008). 

An additional 199,804,760 pounds (90,630 metric tons) of manganese compounds were released from 

1,748 facilities. Tables 6-1, and 6-2 list the amount of manganese and manganese related compounds, 

respectively, that were released from all of the facilities that manufacture or process manganese to each 

medium within each state in 2006 (TRI06 2008). The TRI data should be used with caution because only 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
 

Use Manganesea
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek off-site 

AK 1 440 0 0 43,596 0 440 43,596 44,036 

AL 46 14,003 2,594 0 311,137 138 39,354 288,519 327,873 

AR 28 14,187 202 0 40,397 11,970 14,345 52,410 66,756 

AZ 23 1,249 86 0 988,345 5 989,128 557 989,685 

CA 52 5,905 446 0 266,849 508 190,728 82,980 273,708 

CO 13 673 61 0 14,367 0 686 14,415 15,101 

CT 9 6 7 0 550 76 6 633 639 

DE 1 0 0 0 14 0 0 14 14 

FL 28 1,387 304 0 19,193 10 1,390 19,504 20,894 

GA 43 3,256 2,559 0 47,464 10 3,618 49,671 53,289 

HI 1 0 0 3 33 0 3 33 36 

IA 75 26,407 3,501 0 87,121 387,890 52,459 452,460 504,919 

ID 2 206 0 0 1,159,780 0 1,159,986 0 1,159,986 

IL 113 16,708 3,288 723 725,350 2,914 17,866 731,117 748,983 

IN 142 31,353 5,835 0 487,103 23,334 32,009 515,617 547,626 

KS 28 7,838 290 0 1,045,331 159,947 1,013,666 199,740 1,213,406 

KY 57 8,743 1,431 0 93,655 16,068 10,660 109,238 119,898 

LA 35 11,553 7,316 0 64,028 8,095 17,306 73,686 90,993 

MA 16 453 108 0 8,497 737 465 9,329 9,795 

MD 12 148 57 0 759 6 148 822 970 

ME 5 15 68 0 81 420 20 564 584 

MI 101 13,587 3,774 0 418,116 6,311 42,212 399,577 441,789 

MN 43 4,752 184 0 86,817 394 4,757 87,390 92,148 

MO 59 10,907 1,718 0 20,096 10,164 21,102 21,783 42,885 

MS 30 4,955 345 0 67,256 0 8,037 64,518 72,555 

MT 3 0 0 0 78,546 0 78,546 0 78,546 

NC 58 2,225 140 0 30,064 2,830 2,250 33,009 35,260 

ND 7 1,592 7 0 531 0 1,600 530 2,130 

NE 17 1,723 307 0 49,079 635 1,770 49,974 51,744 

NH 6 87 17,300 0 6,245 0 17,387 6,245 23,632 

NJ 10 583 29 0 11,324 0 600 11,336 11,936 

NM 1 500 0 0 1,699 0 2,199 0 2,199 

NV 11 135 0 0 94,028 0 94,163 0 94,163 

NY 43 5,555 8,766 0 320,476 1,182 7,932 328,047 335,979 

OH 166 39,047 120,301 2 11,591,066 2,463,430 10,515,399 3,698,447 14,213,846 

OK 77 4,384 325 0 62,595 0 10,352 56,952 67,304 

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MANGANESE 345 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
 

Use Manganesea
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek off-site 

OR 14 349 0 0 528 0 349 528 877 

PA 152 43,170 11,360 0 1,000,943 59,278 375,255 739,495 1,114,751 

PR 4 2 0 0 0 16 2 16 18 

RI 2 0 0 0 0 0 0 0 0 

SC 48 6,328 536 0 85,146 29,788 46,481 75,318 121,799 

SD 19 8,727 5 0 26,330 0 16,460 18,602 35,062 

TN 62 49,422 1,924 0 348,780 3,943 99,022 305,047 404,069 

TX 121 53,231 22,104 5 171,602 624 155,306 92,260 247,566 

UT 17 2,559 13 0 747,419 0 738,680 11,311 749,992 

VA 29 2,033 608 0 161,608 22,211 2,356 184,105 186,461 

WA 26 5,729 42,723 0 139,920 539 51,480 137,431 188,911 

WI 171 20,115 8,948 0 2,137,917 12,870 58,935 2,120,915 2,179,850 

WV 8 26 1 0 38,324 14 24,026 14,338 38,364 

WY 5 193 0 0 71,139 5 71,332 5 71,337 

Total 2,040 426,449 269,573 733 23,171,244 3,226,362 15,992,276 11,102,084 27,094,361 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number. b

Data in TRI are maximum amounts released by each facility. 

c

Post office state abbreviations are used. d

Number of reporting facilities.

e

The sum of fugitive and point source releases are included in releases to air by a given facility. 

f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal 

and metal compounds). 

g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills. i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for 

disposal, unknown j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

k

Total amount of chemical transferred off-site, including to POTWs. 

RF = reporting facilities; UI = underground injection 

Source: TRI06 2008 (Data are from 2006) 

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MANGANESE 346 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Releases to the Environment from Facilities that Produce, Process, or
 

Use Manganese Compoundsa
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek off-site 

AK 5 25,328 750 0 845,025 6,280 871,103 6,280 877,383 

AL 68 178,265 875,746 0 5,663,753 2,104,302 5,163,681 3,658,386 8,822,066 

AR 50 19,489 441,421 0 1,480,122 989,320 1,844,948 1,085,404 2,930,352 

AZ 14 4,047 410,010 0 1,971,519 28,019 2,113,096 300,499 2,413,595 

CA 37 7,828 1,059 0 200,104 193 124,029 85,154 209,183 

CO 24 5,126 11,022 0 2,246,268 9,100 714,772 1,556,744 2,271,516 

CT 10 4,362 1,883 0 60,665 7,840 5,865 68,885 74,750 

DC 3 0 4,347 0 6,000 0 10,347 0 10,347 

DE 11 4,334 39,657 0 4,092,502 28,305 116,524 4,048,274 4,164,798 

FL 37 18,745 202,776 0 3,397,056 33,456 3,360,138 291,895 3,652,032 

GA 61 47,377 773,805 0 2,836,912 7,944 3,330,409 335,629 3,666,038 

HI 1 38 0 0 26,872 0 38 26,872 26,910 

IA 42 41,786 22,496 0 840,340 364,964 227,129 1,042,457 1,269,586 

ID 12 841 190,590 0 14,737,870 130 14,679,285 250,146 14,929,431 

IL 84 96,010 35,152 0 9,033,549 259,391 5,687,449 3,736,654 9,424,103 

IN 79 192,010 93,426 1,900 18,418,915 1,671,366 7,130,422 13,247,195 20,377,618 

KS 28 13,257 652 250 244,236 250 220,445 38,200 258,645 

KY 47 68,576 147,644 0 1,528,078 119,954 1,660,270 203,982 1,864,252 

LA 29 20,544 387,475 0 6,371,936 1,408 6,476,794 304,569 6,781,363 

MA 17 1,436 1,331 0 100,634 32,790 61,732 74,459 136,191 

MD 26 21,618 90,703 25,571 2,166,200 125,137 2,233,047 196,182 2,429,229 

ME 10 2,117 331,758 0 677,049 18,587 792,798 236,713 1,029,511 

MI 67 81,060 99,058 2,000 2,612,249 43,241 1,138,887 1,698,721 2,837,608 

MN 31 14,598 256,905 0 1,587,019 23,337 1,591,056 290,802 1,881,858 

MO 46 13,796 51,704 0 708,194 3,865 418,616 358,943 777,558 

MS 33 15,064 288,780 8,506,700 9,204,141 6,158 17,937,765 83,078 18,020,843 

MT 9 9,747 29,912 0 1,981,375 46,473 1,849,854 217,652 2,067,506 

NC 63 19,836 213,027 0 2,011,149 1,177,640 1,796,233 1,625,420 3,421,652 

ND 9 15,474 16,333 0 2,480,954 15,612 1,479,091 1,049,282 2,528,373 

NE 22 21,131 500 0 153,009 612,303 161,275 625,668 786,943 

NH 1 134 0 0 4,770 0 4,034 870 4,904 

NJ 15 3,032 10,005 0 472,763 13,484 31,191 468,093 499,284 

NM 6 3,916 1,300 0 828,935 0 834,151 0 834,151 

NV 10 12,998 3,611 0 10,169,735 0 9,260,544 925,800 10,186,344 

NY 26 4,650 81,183 0 584,743 26,423 261,995 435,004 697,000 

OH 138 430,169 642,313 30,514 11,063,512 597,498 6,580,637 6,183,369 12,764,006 

OK 32 11,618 48,634 0 750,631 508,644 531,270 788,257 1,319,527 

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Table 6-2. Releases to the Environment from Facilities that Produce, Process, or
 

Use Manganese Compoundsa
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek off-site 

OR 23 8,314 144,618 0 2,142,046 323,198 2,004,367 613,809 2,618,176 

PA 134 72,526 184,992 0 10,063,261 340,932 5,031,291 5,630,420 10,661,710 

PR 6 8,490 401 0 282 0 8,886 287 9,173 

RI 1 103 31 0 169 0 134 169 303 

SC 44 27,819 378,152 0 6,760,363 6,148 2,292,815 4,879,668 7,172,483 

SD 7 38 0 0 27,700 0 22,038 5,700 27,738 

TN 53 50,882 293,774 0 16,727,879 38,873 16,041,491 1,069,917 17,111,408 

TX 104 66,756 185,907 0 6,283,703 94,244 6,150,141 480,469 6,630,610 

UT 20 6,687 761 0 1,271,573 13 1,264,871 14,163 1,279,034 

VA 35 19,359 183,002 0 1,522,896 4,563 729,421 1,000,399 1,729,820 

VT 1 0 0 0 0 0 0 0 0 

WA 25 3,227 187,304 0 814,927 16,167 808,095 213,530 1,021,626 

WI 60 23,609 116,184 0 2,533,313 95,152 364,876 2,403,382 2,768,258 

WV 26 133,302 13,412 0 1,700,100 24,034 1,325,047 545,801 1,870,848 

WY 6 8,493 1,327 0 647,297 0 617,518 39,599 657,117 

199,804,76 

Total 1,748 1,859,959 7,496,834 8,566,935 172,054,292 9,826,740 137,361,909 62,442,851 0 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number. b

Data in TRI are maximum amounts released by each facility. 

c

Post office state abbreviations are used. 

d

Number of reporting facilities.

e

The sum of fugitive and point source releases are included in releases to air by a given facility. 

f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal 

and metal compounds). 

g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills. i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for disposal, 

unknown 

j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

k

Total amount of chemical transferred off-site, including to POTWs. 

RF = reporting facilities; UI = underground injection 

Source: TRI06 2008 (Data are from 2006) 

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MANGANESE 348 

6. POTENTIAL FOR HUMAN EXPOSURE 

certain types of facilities are required to report. This is not an exhaustive list. Also, because these data 

reflect past releases, they may not be representative of current releases at these facilities. 

Manganese may also be emitted to the environment through the use of gasoline that contains MMT; 

however, no data on the amount of MMT that is currently being used in gasoline in the United States were 

located. No data for releases of mangafodipir to the environment were found. Because mangafodipir is a 

compound used exclusively in a clinical environmental, it is not expected to be released to the 

environment and will not be discussed in subsequent sections concerning fate and transport. 

6.2.1 Air 

Estimated releases of 426,449 pounds (193 metric tons) of manganese to the atmosphere from 

2,040 domestic manufacturing and processing facilities in 2006, accounted for about 1.6% of the 

estimated total environmental releases from facilities required to report to the TRI (TRI06 2008). 

Estimated releases of 1,859,959 pounds (844 metric tons) of manganese compounds to the atmosphere 

from 1,748 domestic manufacturing and processing facilities in 2006, accounted for about 1% of the 

estimated total environmental releases from facilities required to report to the TRI (TRI06 2008). These 

releases are summarized in Tables 6-1 and 6-2. 

According to data from the National Pollutant Release Inventory (NPRI) maintained by Environment 

Canada, approximately 273.9 metric tons of manganese were released to air in Canada in 2003 from 

various industrial sources (Health Canada 2008). The major industrial sources for manganese emissions 

in Canada were attributed to an iron-ore mine located in Labrador, iron- and steel-related industries, 

pulp/paper/newsprint mills, fossil fuel electric power generation, and the manufacturing of heating and 

commercial refrigeration equipment. 

Manganese has been identified in air samples collected at 31 of the 869 NPL hazardous waste sites where 

it was detected in some environmental media (HazDat 2008). 

The main sources of manganese release to the air are industrial emissions, combustion of fossil fuels, and 

reentrainment of manganese-containing soils (EPA 1983c, 1984, 1985c, 1985d, 1987a; Lioy 1983). The 

principal sources of industrial emissions are ferroalloy production and iron and steel foundries, and the 

principal sources of combustion emissions are power plants and coke ovens (EPA 1983c, 1985c, 1985d). 

Atmospheric emissions of manganese and other trace metals from these industrial sources have declined 

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6. POTENTIAL FOR HUMAN EXPOSURE 

over the last 2 decades due to the use of advanced pollution control devices and increased government 

regulations regarding these emissions (EPA 1984, 1985d). 

Windblown erosion of dusts and soils is also an important atmospheric source of manganese. Wallace 

and Slonecker (1997) estimated that the background contribution of windblown soil to fine particulate 

atmospheric manganese levels was 1–2 ng/m3 in the United States and Canada. Volcanic eruptions may 

also release manganese to the atmosphere (Schroeder et al. 1987). 

MMT is a manganese-containing compound used to enhance the octane rating in gasoline. MMT was 

used as an additive in leaded gasoline until the phase-out of leaded gas in the United States in 1995. It 

was also used in unleaded gasoline for a short period of time in the late 1970’s, but was banned as an 

additive in unleaded gasoline by EPA in 1977 (EPA 1978, 1979a, 1981). In 1995, the ban on MMT use 

in unleaded gasoline was lifted, and a court decision ordered EPA to register the product for use as a fuel 

additive, although testing for health effects continues (EPA 1995a). Analysis of manganese levels in the 

air indicates that vehicular emissions from MMT containing fuels contributed an average of 13 ng 

manganese/m3 in southern California, while vehicular emissions were only responsible for about 3 ng/m3 

in central and northern California (Davis et al. 1988). A survey of ambient air concentrations of fine 

(PM2.5) manganese in rural sites in U.S. national parks and in urban sites in California indicated that from 

1988 to 1993, ambient concentrations of manganese ranged from 1 ng/m3 in rural sites to 3 ng/m3 in urban 

sites (Wallace and Slonecker 1997). Part of the increase in fine manganese during this period was 

considered to be the result of the use of MMT in leaded gasoline. It was estimated that automobile 

emissions from leaded gasoline were responsible for 37% of the fine manganese levels in California in 

1992. In 1994, automobile emissions were estimated to contribute 12% of the fine manganese levels in 

the atmosphere, as the use of leaded gasoline declined. It has been estimated that if MMT were used in 

all gasoline, urban air manganese levels would be increased by about 50 ng/m3 (Cooper 1984; Ter Haar 

et al. 1975). Other authors have estimated that the increase in atmospheric manganese levels would be 

<20 ng/m3 (Lynam et al. 1994). 

In Canada, where the use of MMT containing gasoline has been extensive, a 10% per year increase in 

manganese emission rates from MMT in gasoline since 1981 was estimated (Loranger and Zayed 1994). 

A positive correlation between atmospheric manganese concentration and traffic density has been 

observed (Loranger and Zayed 1997a; Loranger et al. 1994a). The principal emission product of MMT 

combustion is a fine particulate matter (0.1–0.4 μm diameter) consisting of manganese oxide (Egyed and 

Wood 1996; Ter Haar et al. 1975), manganese phosphate, and some manganese sulfate (Lynam et al. 

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1999). The finding of soluble manganese (<0.4 μm) in snow samples obtained close to a highway in 

Montreal, Canada suggested a possible contamination from mobile sources (Loranger and Zayed 1997a; 

Loranger et al. 1995). However, it has been difficult to assess the exact contribution of mobile sources to 

overall contamination from natural and industrial sources because of the physico-chemical characteristics 

of manganese particulate, environmental factors affecting its dispersion, and the difficulties in 

distinguishing between mobile sources of manganese and background manganese levels (Loranger and 

Zayed 1997a; Veysseyre et al. 1998). 

Despite the estimated 10% per year increase in manganese emission rates from the use of MMT in 

gasoline in Canada, atmospheric manganese concentrations in Montreal have remained fairly constant 

between 1981 and 1990, and have decreased markedly in 1991 and 1992 (Loranger and Zayed 1994). 

The decline in manganese concentration after 1990 may have been due to a shutdown in 1991 of a 

ferromanganese plant located near Montreal. Air concentrations are in general below the EPA reference 

concentration (RfC) of 0.05 μg/m3 for respirable manganese. However, in 1998, it was observed that 

some atmospheric concentrations in specific microenvironments with important traffic density were 

higher than the RfC (Zayed et al. 1999a). 

6.2.2 Water 

Estimated releases of 269,573 pounds (122 metric tons) of manganese to water from 2,040 domestic 

manufacturing and processing facilities in 2006, accounted for about 1% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI06 2008). Estimated releases of 

7,496,834 pounds (3,401 metric tons) of manganese compounds to water from 1,748 domestic 

manufacturing and processing facilities in 2006, accounted for about 4% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI06 2008). These releases are 

summarized in Tables 6-1 and 6-2. 

Manganese has been identified in surface water and groundwater samples collected at 392 and 692, 

respectively, of the 869 NPL hazardous waste sites where it was detected in some environmental media 

(HazDat 2008). 

Based on comparison to typical background levels of manganese in surface water or groundwater (see 

Section 6.4.2), it seems likely that some waste sites where manganese is detected contain only natural 

levels. Although ambient manganese levels are about 200 μg/L in a number of cases, high levels (in 

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excess of 1,000 μg/L) have been detected indicating that manganese wastes may lead to significant 

contamination of water at some sites. For example, at one site in Ohio where "heavy metals" had been 

disposed, manganese concentrations up to 1,900 μg/L were found in on-site wells (Cooper and Istok 

1988). Levels in water at two NPL sites in Missouri ranged from 0.009 to 3.7 μg/L (MDNR 1990). No 

information is available on the method used to determine these values, so it is not clear whether the data 

refer to total or dissolved manganese. 

6.2.3 Soil 

Estimated releases of 23,171,244 pounds (10,510 metric tons) of manganese to soil from 2,040 domestic 

manufacturing and processing facilities in 2006, accounted for about 86% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI06 2008). Estimated releases of 

172,054,292 pounds (78,043 metric tons) of manganese compounds to the soil from 1,748 domestic 

manufacturing and processing facilities in 2006, accounted for about 86% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI06 2008). An additional 

8,566,935 pounds (3,886 metric tons) were injected underground. These releases are summarized in 

Tables 6-1 and 6-2. 

Manganese deposition to soils from the use of MMT in gasoline was estimated for two sites in Toronto, 

Canada (Bhuie et al. 2005). Accounting for variables such as annual average daily traffic (AADT) 

density, fuel consumption, distance traveled by automobiles, and a manganese content of 10 mg/L of 

gasoline, the annual average manganese contribution to soils from MMT emissions were calculated as 

5.73 and 2.47 mg/kg at two sites (Bhuie et al. 2005). These concentrations were considered insignificant 

when compared to natural background manganese levels (541 and 557 mg/kg ) in soil for these areas. 

Manganese has been identified in soil and sediment, samples collected at 355 and 257, respectively, of the 

869 NPL hazardous waste sites where it was detected in some environmental media (HazDat 2008). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

Manganese compounds have negligible vapor pressures (see Table 4-2), but may exist in air as suspended 

particulate matter derived from industrial emissions or the erosion of soils. Manganese-containing 

particles are mainly removed from the atmosphere by gravitational settling, with large particles tending to 

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fall out faster than small particles (EPA 1984). The half-life of airborne particles is usually on the order 

of days, depending on the size of the particle and atmospheric conditions (Nriagu 1979). Some removal 

by washout mechanisms such as rain may also occur, although it is of minor significance in comparison 

to dry deposition (EPA 1984; Turner et al. 1985). 

In a study completed by Evans (1989), there were two mechanisms involved in explaining the retention of 

manganese and other metals in the environment by soil. First, through cation exchange reactions, 

manganese ions and the charged surface of soil particles form manganese oxides, hydroxides, and 

oxyhydroxides, which in turn form absorption sites for other metals. Secondly, manganese can be 

adsorbed to other oxides, hydroxides, and oxyhydroxides through ligand exchange reactions. When the 

soil solution becomes saturated, these manganese oxides, hydroxides, and oxyhydroxides can precipitate 

into a new mineral phase and act as a new surface to which other substances can absorb (Evans 1989). 

The behavior of heavy metals in the combustion gases of urban waste incinerators was studied by 

Fernandez et al. (1992). Manganese was detected inside gaseous fly ash particles in the form of oxides 

and chlorides. When these soluble oxides and chlorides reach environmental media, they can leach out 

and become mobile (Fernandez et al. 1992). 

The transport of manganese in air is largely determined by its particle size. About 80% of the manganese 

in suspended particulate matter is associated with particles having a mass median aerodynamic diameter 

(MMAD) of <5 μm (WHO 1981). The compound’s small particle size (approximately 80% with a 

MMAD <5 μm and approximately 50% with an MMAD <2 μm) favors widespread airborne distribution 

and is within the respirable range (WHO 1981). 

The transport and partitioning of manganese in water is controlled by the solubility of the specific 

chemical form present, which in turn is determined by pH, Eh (oxidation-reduction potential), and the 

characteristics of the available anions. The metal may exist in water in any of four oxidation states; 

however, Mn(II) predominates in most waters (pH 4–7), but may become oxidized under alkaline 

conditions at pH >8 (EPA 1984). The principal anion associated with Mn(II) in water is usually 

carbonate (CO3

–2), and the concentration of manganese is limited by the relatively low solubility 

(65 mg/L) of manganese carbonate (Schaanning et al. 1988). Under oxidizing conditions, the solubility of 

Mn(II) may be controlled by manganese oxide equilibria (Ponnamperuma et al. 1969), with manganese 

being converted to the Mn(II) or Mn(IV) oxidation states (Rai et al. 1986). In extremely reduced water, 

the fate of manganese tends to be controlled by formation of a poorly soluble sulfide (EPA 1984). 

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Manganese is often transported in rivers as suspended sediments. It has been reported that most of the 

manganese in a South American river came from industrial sources and was bound to suspended particles 

in the water (Malm et al. 1988). 

In an aquifer studied in France, manganese was shown to originate from within the aquifer itself (Jaudon 

et al. 1989). In the presence of decreased dissolved oxygen in the groundwater, Mn(IV) has been shown 

to be reduced both chemically and bacterially into the Mn(II) form (Jaudon et al. 1989). This oxidation 

state is water soluble and easily released into the groundwater. 

Manganese in water may be significantly bioconcentrated at lower trophic levels. A bioconcentration 

factor (BCF) relates the concentration of a chemical in plant and animal tissues to the concentration of the 

chemical in the water in which they live. Folsom et al. (1963) estimated that the BCFs of manganese 

were 2,500–6,300 for phytoplankton, 300–5,500 for marine algae, 800–830 for intertidal mussels, and 

35–930 for coastal fish. Similarly, Thompson et al. (1972) estimated that the BCFs of manganese were 

10,000–20,000 for marine and freshwater plants, 10,000–40,000 for invertebrates, and 100–600 for fish. 

In general, these data indicate that lower organisms such as algae have larger BCFs than higher 

organisms. In order to protect consumers from the risk of manganese bioaccumulation in marine 

mollusks, EPA has set a criterion for manganese at 0.1 mg/L for marine waters (EPA 1993b). 

The tendency of soluble manganese compounds to adsorb to soils and is dependent upon the cation 

exchange capacity and the organic composition of the soil (Curtin et al. 1980; Hemstock and Low 1953; 

Kabata-Pendias and Pendias 1984; McBride 1979; Schnitzer 1969). Baes and Sharp (1983) noted that 

soil adsorption constants (the ratio of the concentration in soil to the concentration in water) for Mn(II) 

span five orders of magnitude, ranging from 0.2 to 10,000 mL/g, increasing as a function of the organic 

content and the ion exchange capacity of the soil; thus, adsorption may be highly variable. In some cases, 

adsorption of manganese to soils may not be a readily reversible process. At low concentrations, 

manganese may be "fixed" by clays and will not be released into solution readily (Reddy and Perkins 

1976). At higher concentrations, manganese may be desorbed by ion exchange mechanisms with other 

ions in solution (Rai et al. 1986). For example, the discharge of waste water effluent into estuarine 

environments resulted in the mobilization of manganese from the bottom sediments (Helz et al. 1975; 

Paulson et al. 1984). The metals in the effluent may have been preferentially adsorbed resulting in the 

release of manganese. 

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6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Very little information is available on atmospheric reactions of manganese (EPA 1984). Manganese can 

react with sulfur dioxide and nitrogen dioxide, but the occurrence of such reactions in the atmosphere has 

not been demonstrated. 

MMT undergoes photolysis rapidly by sunlight in the atmosphere or in aqueous solutions with a very 

short half-life (i.e., <2 minutes) (Ter Haar et al. 1975; Garrison et al. 1995). The photodegradation 

products tentatively identified in aqueous photolysis experiments were methylcyclopentadiene, 

cyclopentadiene, carbon monoxide, manganese carbonyl, and trimanganese tetroxide (Garrison et al. 

1995). Undegraded MMT is not likely to be released directly to the atmosphere in significant quantities 

from it intended use as a gasoline additive. Spectroscopic studies of the tailpipe emissions of 

MMT-containing gasoline indicated that the manganese in MMT is converted to a mixture of solid 

manganese oxides, sulfates, and phosphates. The manganese containing particulates were determined to 

be Mn3O4, MnSO4·H2O and a divalent manganese phosphate, Mn5(PO4)[PO3(OH)]2·4H2O (Mölders et al. 

2001; Ressler et al. 2000). 

6.3.2.2 Water 

Manganese in water may undergo oxidation at high pH or Eh (see Section 6.3.1) and is also subject to 

microbial activity. For example, Mn(II) in a lake was oxidized during the summer months, but this was 

inhibited by a microbial poison, indicating that the oxidation was mediated by bacteria (Johnston and 

Kipphut 1988). The microbial metabolism of manganese is presumed to be a function of pH, 

temperature, and other factors, but no data were located on this. 

The rate of MMT degradation in natural aquifer and sediment systems was determined to be very slow 

under anaerobic conditions (Garrison et al. 1995). Calculated half-lives ranged from approximately 0.2 to 

1.5 years at 25 °C. However, MMT photolyzed rapidly in purified, distilled water exposed to sunlight. 

The disappearance of MMT followed first-order kinetics, with a calculated half-life of 0.93 minutes. 

Reaction products included methylcyclopentadiene, cyclopentadiene, carbon monoxide, and a manganese 

carbonyl that readily oxidized to trimanganese tetroxide. 

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6.3.2.3 Sediment and Soil 

The oxidation state of manganese in soils and sediments may be altered by microbial activity. Geering 

et al. (1969) observed that Mn(II) in suspensions of silt or clay loams from several areas of the United 

States was oxidized by microorganisms, leading to the precipitation of manganese minerals. Other 

studies (Francis 1985) have shown that bacteria and microflora can increase the mobility of manganese in 

coal-waste solids by increasing dissolution of manganese in subsurface environments. 

MMT was found to be stable in a stream bottom sediment under anaerobic conditions. Photodegradation 

of MMT is not likely to occur in sediments, and it may equilibrate between the sediment, sediment 

porewater, and water column manganese (Garrison et al. 1995). 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to manganese depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. Concentrations of 

manganese in unpolluted atmospheres and in pristine surface waters are often so low as to be near the 

limits of current analytical methods. In reviewing data on manganese levels monitored or estimated in the 

environment, it should also be noted that the amount of chemical identified analytically is not necessarily 

equivalent to the amount that is bioavailable. The analytical methods available for monitoring manganese 

in a variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

Table 6-3 summarizes historic manganese air level data collected over a period of nearly 30 years from 

numerous urban, nonurban, and source-dominated areas of the United States. Direct comparisons of data 

from different time periods are complicated because of changes in sample collection and analytical 

methodology. However, it is clear that manganese levels tend to be higher in source-dominated and urban 

areas than in nonurban areas. These data also indicate that concentrations in all areas have tended to 

decrease over the past three decades (EPA 1984; Kleinman et al. 1980). This decrease came as the result 

of the installation of emission controls in the metals industry (EPA 1984, 1985d). A concurrent decrease 

in total suspended particulates (TSP) was observed in most areas. Ambient air levels of manganese (PM10 

and PM2.5) in Canadian locations monitored from the late 1980s through the early 2000s were reported to 

have a 13–77% reduction over that time period (Health Canada 2008). Annual averages of manganese in 

urban and rural areas without significant manganese pollution are in the range of 10–70 ng/m3 (0.01– 

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Table 6-3. Average Levels of Manganese in Ambient Aira 

Concentration (ng/m3) 

Sampling location 1953–1957 1965–1967 1982 

Nonurban 60 12 5 

Urban 110 73 33 

Source dominated No data 250–8,300 130–140 

a

Adapted from EPA 1984 

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0.07 μg/m3) (WHO 1997). The daily intake of manganese in the air by the general population in areas 

without manganese emitting industries was estimated to be <2 μg/day (WHO 1981). In areas with major 

foundry facilities, intake may rise to 4–6 μg/day, and in areas associated with ferro- or silicomanganese 

industries, it may be as high as 10 μg, with 24-hour peak values exceeding 200 μg/day (WHO 1981). 

Data compiled for 2006 under the EPA Urban Air Toxics Monitoring Program, studied ambient air levels 

of manganese and several other metals at 20 urban locations across the United States. Manganese (PM10) 

was detected in 415 samples of urban air at levels ranging from 0.24 to 89.10 ng/m3 (EPA 2007b). The 

arithmetic mean, geometric mean, and median concentrations were 10.13, 6.68, and 6.29 ng/m3

, 

respectively. Manganese levels ranged from 0.85 to 614.00 ng/m3 in 114 samples of total suspended 

particulates (TSP) at these 20 urban locations. The arithmetic mean, geometric mean, and median 

concentrations of manganese in TSP were 47.89, 22.39, and 23.98 ng/m3

, respectively. 

During 1988–1993, ambient concentration of fine (PM2.5) manganese ranged from 1 ng/m3 (0.001 μg/m3

) 

in rural sites in U.S. National Parks to 3 ng/m3 (0.003 μg/m3

) in urban sites in California (Wallace and 

Slonecker 1997). There is concern in Canada regarding the combustion of MMT as an important source 

of manganese contamination in the urban environment, especially in areas of high traffic density. For 

instance, Loranger and Zayed (1997a) reported significantly higher levels of both respirable and total 

manganese levels at a high traffic density site (24 and 50 ng/m3

, respectively) in Montreal in contrast to a 

low traffic density site (15 and 27 ng/m3

, respectively). Temporal variation of respirable and total 

manganese was similar for both sites, and atmospheric manganese concentrations reflected a positive 

relationship with the traffic density. However, as discussed in Section 6.2.1, it has been difficult to assess 

the exact contribution of the combustion of MMT by vehicles to manganese levels in the environment. 

In Montreal, Canada, ambient atmospheric concentrations of MMT, and respirable and total manganese, 

were measured in five microenvironments including a gas station, an underground car park, downtown 

Montreal, near an expressway, and near an oil refinery (Zayed et al. 1999a). The overall mean 

concentrations of respirable manganese, total manganese, and MMT measured for all the 

microenvironments were 36, 103, and 5 ng/m3

, respectively (0.036, 0.103, and 0.005 μg/m3); however, 

the mean respirable manganese concentration 53 ng/m3 (0.053 μg/m3

) near the expressway was greater 

than the EPA Reference Concentration (RfC) of 0.05 μg/m3

. 

The Canadian National Air Pollution Surveillance (NAPS) Program reported that average fine (PM2.5) 

manganese levels from 2003 to 2005 in cities with industrial sources (Windsor and Hamilton) were 9– 

15 ng/m3 (Health Canada 2008). In Vancouver, Winnipeg, Montreal, Quebec, Toronto, and Edmonton, 

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the average levels were 4–14 ng/m3. In Saskatoon, Ottawa, Victoria, St. John, and background sites, 

levels were <5 ng/m3

. NAPS also reported manganese PM10 levels were: 20–60 ng/m3 in Hamilton and 

Windsor; 8–25 ng/m3 in Montreal, Toronto, Edmonton, Winnipeg, Quebec, Calgary, Vancouver, and 

Victoria; and generally <10 ng/m3 in Saskatoon, Ottawa, St. John, Yellowknife, and background sites 

(Health Canada 2008). 

Studies were conducted in Indianapolis, Indiana and Toronto, Canada to assess levels of PM2.5 and PM10 

manganese in indoor, outdoor, and personal air samples (Pellizzari et al. 1999, 2001). The levels 

observed in Toronto, where MMT had been used in gasoline for over 20 years, were approximately 

2 times greater in indoor and outdoor air than in Indianapolis, where MMT was not being used as a 

gasoline additive. The monitoring data from these studies are summarized in Table 6-4. 

6.4.2 Water 

Many factors, both environmental (e.g., the presence of high or low levels of other inorganics in drinking 

water) and biological or host-related (e.g., age, nutritional status, and alcohol consumption) can 

significantly influence the uptake of manganese by an individual (EPA 1993b). The determination of a 

single concentration of manganese in drinking water, then, must be recognized as a process that is limited 

in its ability to reflect the variable nature of manganese toxicity (EPA 1993b). 

Concentrations of manganese in surface water are usually reported as dissolved manganese. Although 

total manganese may be a better indicator, since manganese adsorbed to suspended solids may exceed 

dissolved manganese in many systems, the bioavailability of manganese in this form has not been 

established (EPA 1984; NAS 1977). In a 1962–1967 survey of U.S. surface waters, dissolved manganese 

was detected in 51% of 1,577 samples, at a mean concentration of 59 μg/L. Individual values ranged 

from 0.3 to 3,230 μg/L. Mean concentrations for 15 different drainage basins in the United States ranged 

from 2.3 μg/L in the western Great Lakes to 232 μg/L in the Ohio River drainage basin (Kopp and Kroner 

1967). A later (1974–1981) survey of U.S. river waters reported a median dissolved manganese 

concentration of 24 μg/L in samples from 286 locations, with values ranging from <11 μg/L (25th 

percentile) to >51 μg/L (75th percentile) (Smith et al. 1987). Analyzing data available from the USGS 

National Water Quality Assessment (NAWQA) database, the EPA reported that the median concentration 

of manganese was 16 μg/L for surface water and 5 μg/L for groundwater from 20 watersheds and 

16 drainage basins in the United States (EPA 2003a). The results of this analysis for all sites are 

reproduced in Table 6-5. Reported mean groundwater concentrations of manganese were 20 and 90 μg/L 

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Table 6-4. Levels of PM2.5 and PM10 in Indoor and Outdoor Air in Toronto, Canada 

and Indianapolis, Indiana 

Median concentration 90th concentration 

Location Number (ng/m3) (ng/m3) 

PM10 Manganese 

Toronto (indoor) 203 6.7 14 

Indianapolis (indoor) 59 3.9 8.7 

Toronto (outdoor) 203 17 28 

Indianapolis (outdoor) 59 8.8 14 

PM2.5 Manganese 

Toronto (indoor) 187 4.7 9.9 

Indianapolis (indoor) 58 2.2 4.6 

Toronto (outdoor) 185 8.6 16 

Indianapolis (outdoor) 57 3.2 5.8 

Sources: Pellizzari et al. 1999, 2001 

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Table 6-5. Manganese Detections and Concentrations in Surface Water and
 

Groundwater in the United States
 

Detection frequency 

Above the minimal Above the health reference 

reporting level (1 μg./L) levela (300 μg/L) Concentration (μg/L) 

Samples Sites Samples Sites Median 99th 

Surface water 

Urban 99.1% 99.6% 4.6% 13.0% 36 700 

Mixed 92.4% 98.5% 1.3% 6.4% 12 400 

Agricultural 96.3% 97.2% 3.7% 12.3% 19 700 

Forest/rangeland 90.9% 96.4% 5.0% 6.6% 11 800 

All sites 94.0% 96.9% 3.0% 10.2% 16 700 

Groundwater 

Urban 74.7% 85.3% 17.2% 21.0% 15 5,600 

Mixed 56.9% 62.9% 8.9% 9.0% 2 1,300 

Agricultural 61.4% 64.0% 11.9% 12.8% 4 1,600 

Forest/rangeland 75.3% 81.3% 10.9% 13.8% 12 2,900 

All sites 64.1% 70.1% 12.8% 13.8% 5 2,900 

a

The Health Reference Level (HRL) is based on the dietary reference dose (RfD) and application of a modifying 

factor (MF) of 3 for drinking water, and on an allocation of an assumed 20% relative source contribution from water 

ingestion as opposed to total manganese exposure. 

Source: EPA 2003a 

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in an analysis of California shallow groundwater from two geologic zones (Deverel and Millard 1988). 

Values up to 1,300 and 9,600 μg/L have been reported in neutral and acidic groundwater, respectively 

(EPA 1984). Manganese levels of 9,500–18,600 μg/L have been reported in four private wells in 

Connecticut (CDHS 1990). Natural concentrations of manganese in seawater reportedly range from 

0.4 to 10 μg/L (EPA 1984). 

A 1962 survey of public drinking water supplies in 100 large U.S. cities reported that 97% contained 

<100 μg/L of manganese (USGS 1964). Similarly, a 1969 survey of 969 systems reported that 91% 

contained <50 μg/L, with a mean concentration of 22 μg/L (U.S. DHEW 1970). Several other studies 

reported similar manganese concentrations, with mean values ranging from 4 to 32 μg/L (EPA 1984; 

NAS 1980a; WHO 1981). The EPA analyzed drinking water statistics from Alabama, California, Illinois, 

New Jersey, and Oregon for occurrence and concentration data for manganese in public water supplies. 

The data used contained >37,000 analytical results from about 4,000 public water supplies from 1993 to 

1997, although some prior monitoring data were also employed in the analysis. The median manganese 

level for all detections was 10 μg/L and the 99th percentile of the detections was 720 μg/L (EPA 2003a). 

6.4.3 Sediment and Soil 

Manganese comprises about 0.1% of the earth's crust (Graedel 1978; NAS 1973), and manganese occurs 

naturally in virtually all soils. Average natural ("background") levels of manganese in soils range from 

around 40 to 900 mg/kg, with an estimated mean background concentration of 330 mg/kg (Barceloux 

1999; Cooper 1984; Eckel and Langley 1988; EPA 1985c; Rope et al. 1988; Schroeder et al. 1987). The 

maximum value reported was 7,000 mg/kg (Eckel and Langley 1988). Using data from 20 watersheds 

and 16 drainage basins in the United States, manganese was detected at 100% of the National WaterQuality Assessment Program (NAWQA) stream bed sediment sampling sites. The median and 99th 

percentile concentrations in bed sediments were reported as 1.1 mg/kg (dry weight) and 9.4 mg/kg (dry 

weight), respectively (EPA 2003a). Manganese levels as high as 1,900 mg/kg were detected in sediment 

samples obtained from the Tar Creek Superfund site (a site heavily contaminated with mining wastes) in 

Ottawa County, Oklahoma (Wright et al. 2006). 

Accumulation of manganese in soil usually occurs in the subsoil and not on the soil surface; 60–90% of 

manganese is found in the sand fraction of the soil (WHO 1981). A preliminary survey was conducted in 

Utah to provide an initial field measurement of the contamination by manganese oxides from exhaust in 

roadside soil and plant species due to the addition of MMT to motor vehicle fuels. Soil (0–5 cm) 

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manganese concentrations were strongly correlated with distance from roadways with moderate and 

moderately high traffic volumes (Lytle et al. 1994). In addition, exchangeable manganese was found to 

be significantly higher in an organic soil located at stations with a high traffic density comparing to 

another one with a low traffic density (Brault et al. 1994). The average soil manganese concentration 

measured at 1 meter from a moderate to moderately-high traffic volume roadside was 3,046 μg/g dry 

weight. At 15m, the average soil manganese concentration decreased to 254 μg/g dry weight. 

6.4.4 Other Environmental Media 

Manganese is a natural component of most foods. A summary of mean manganese concentrations in 

foods analyzed by the Food and Drug Administration (FDA) Total Diet Study (TDS) 1991–1996 is 

summarized in Table 6-6. TDS sampling is conducted 4 times annually, once in each of the major 

geographical regions of the country (west, north central, south, and northeast). Each round of sampling is 

referred to as an individual market basket survey and for each market basket survey, samples of 

260 selected food and beverages were obtained from three cities within the region. The mean and median 

concentration of manganese in all foods were 2.4 and 1.0 mg/kg, respectively (Capar and Cunningham 

2000). The TDS results concluded that detectable levels of manganese were present in roughly 75% of all 

foods, although approximately 24% of these detections were below the quantification limits used in the 

study (Capar and Cunningham 2000). The highest manganese level was observed in a sample of 

shredded wheat cereal (44.4 mg/kg). The five foods with the highest mean manganese levels were oat 

ring cereal (33.8 mg/kg), raisin bran cereal (28.8 mg/kg), shredded wheat cereal (25.0 mg/kg), mixed nuts 

(23.2 mg/kg), and granola cereal (20.1 mg/kg). These levels are similar to levels found in previous 

market basket surveys (Pennington et al. 1986). Tea and leafy green vegetables were the major dietary 

sources of manganese for young women taking part in a dietary study in Wisconsin (Davis et al. 1992a). 

Bioaccumulation of manganese by plants was examined using oats (Avena nova) and beans (Phaseolus 

vularis) (Brault et al. 1994). These plants were grown in sandy and organic soil at a control site 

(greenhouse) and at two outdoor sites near <20,000 and 132,000 vehicles/day respectively. The highest 

manganese accumulation was found in the fruits and stems of oats grown in the organic and sandy soils at 

the station with the highest traffic density. Lönnerdal (1997) reported that infant formulas contain 30– 

75 ppb (0.03–0.075 ppm) manganese, as compared to concentrations of 3–10 ppb (0.003–0.01 ppm) in 

breast milk and 30 ppb (0.03 ppm) in cow's milk. 

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Table 6-6. Mean Concentrations of Manganese for FDA’s Total Diet Study Market
 

Baskets 1991 through 1997a
 

Food product Range (mg/kg) 

Milk and cheese Not detected–<2 

Eggs <1 

Meat, poultry, and fish Not detected–3.7 

Legumes and nuts 3.4–23.2 

Grain products <1–33.8 

Fruit <1–10.0 

Vegetables <1–5.9 

Mixed dishes and meals <1–3.4 

Desserts Not detected–4.9 

Snacks 3.4–9.3 

Condiments and sweeteners Not detected–4.1 

Fats and dressings Not detected–<1 

Beverages Not detected–2.9 

Infant and junior foods Not detected–7.5 

a

A < symbol indicates that manganese was detected, but at a level lower than the limit of quantification. 

Source: Capar and Cunningham 2000 

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During a 1992 survey conducted by Canada’s Department of Fisheries and Oceans, concentrations of 

manganese were detected in the muscle samples of bluefin tuna (Thunnus thynnus) (Hellou et al. 1992). 

Concentrations of manganese in 14 samples of fish muscle ranged from 0.16 to 0.31 μg manganese/g dry 

weight, with a mean of 0.22 μg/g. Although the analysis was administered with a high accuracy of 94% 

using inductively coupled plasma-mass spectrometry (ICP-MS), the sample population was small. 

In the field survey conducted by Lytle et al. (1994), terrestrial and aquatic plant samples were collected 

along motorways and local urban roadways throughout Utah during 1992 and 1993. Manganese was 

detected in the plant samples, with manganese concentrations ranging from 30.2 to 13,680 μg/g dry 

weight. Manganese was detected in plants found nearest to the motorway. Loranger et al. (1994b) 

evaluated the use of the pigeon as a monitor for manganese contamination from motor vehicles in urban 

and rural areas of Canada, a country in which MMT has been used to replace lead in gasoline. 

Manganese concentrations were similar in the two groups of pigeons for all tissues except the liver and 

feces; urban pigeons had about 35% more manganese than rural ones. Loranger et al. (1994b) suggested 

that although pigeon feces and liver may be good biomarkers of manganese contamination, it is premature 

to associate the excess manganese with the combustion of MMT. Toxicokinetic studies of manganese in 

both male and female rats suggested that MMT-derived manganese administered in oral doses resulted in 

higher and more prolonged plasma concentration versus time profiles than inorganic (MnCl2) complexes, 

leading to the conclusion that MMT-derived manganese was likely to accumulate following repeated 

exposures (Zheng et al. 2000). 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Since manganese is ubiquitous in the environment, the general population is exposed to manganese from 

both natural and anthropogenic sources. The manganese concentration in blood of healthy adults is 

reported to range from 4 to 15 μg/L with an average value of about 9 μg/L (Barceloux 1999). Typical 

daily human exposure levels to manganese from water, air, and food are summarized in Table 6-7 (EPA 

1984). As the table illustrates, the most significant exposure for the general population is from food, with 

an average ingestion rate of 3,800 μg/day (EPA 1984). Other estimates of daily intake for adults range 

from 2,000 to 8,800 μg (EPA 1984; NAS 1977; Patterson et al. 1984; Pennington et al. 1986; WHO 

1984a) and 700–10,900 μg/day (WHO 2004b). Even though gastrointestinal absorption of manganese is 

low (3–5%), oral exposure is the primary source of absorbed manganese. 

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Table 6-7. Summary of Typical Human Exposure to Manganesea 

Exposure medium 

Parameter Water Air Food 

Typical concentration in medium 4 μg/L 0.023 μg/m3 1.28 μg/calories 

Assumed daily intake of medium by 70-kg adult 2 L 20 m3 3,000 calories 

Estimated average daily intake by 70-kg adult 8 μg 0.46 μgb 3,800 μg 

Assumed absorption fraction 0.03c 1c 0.03d 

Approximate absorbed dose 0.24 μg 0.46 μg 114 μg 

a

Adapted from EPA 1984

b

Assumes 100% deposition in the lungs 

c

No data; assumed value

d

Vitarella et al. 2000 

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Manganese intake among individuals varies greatly, depending upon dietary habits. For example, an 

average cup of tea may contain 0.4–1.3 mg of manganese (Pennington et al. 1986; Schroeder et al. 1966). 

Thus, an individual consuming three cups of tea per day might receive up to 4 mg/day from this source 

alone, increasing the average intake from all dietary sources. 

As part of the Third National Health and Nutrition Examination Survey (NHANES) conducted by the 

Centers of Disease Control and Prevention (CDC), manganese was detected at quantifiable levels in urine 

samples from 73% of 496 participants of the monitoring study (Paschal et al. 1998). The mean urinary 

manganese concentration in these 496 individuals (aged 6–88 years of age) was 1.19 μg/L (Paschal et al. 

1998). 

The EPA Reference Dose (RfD)/RfC workgroup in June 1990 set an RfD for manganese in food of 

0.14 mg manganese/kg/day, equivalent to about 10 mg/day for a 70-kg man based on chronic manganese 

uptake (EPA 1993b). The Food and Nutrition Board of the National Research Council (NRC) estimated 

the adequate and safe intake of manganese for adults at 2–5 mg/day (NAS 1980b). This level was chosen 

because it includes an "extra margin of safety" of 5 mg/day below the level of 10 mg/day, which the NRC 

considered to be safe for occasional intake (IRIS 2008). 

In the workplace, exposure to manganese is most likely to occur by inhalation of manganese fumes or 

manganese-containing dusts. This is a concern mainly in the ferromanganese, iron and steel, dry-cell 

battery, and welding industries (WHO 1986). Exposure may also occur during manganese mining and 

ore processing; however, the most recent data indicate that only a very small amount of manganese is still 

mined in the United States (USGS 2007). Excluding insignificant quantities of similar low-grade 

manganiferous ore, the United States has not mined significant amounts of manganese since 1978 and 

now relies on imports to fill its needs (USGS 2007). In 1980, it was estimated that in the United States 

about 300 workers were exposed to pure manganese and about 630,000 workers were exposed to other 

forms of manganese (NOES 1989). Concentrations as large as 1.5–450 mg manganese/m3 have been 

reported in U.S. manganese mines (EPA 1984), 0.30–20 mg manganese/m3 in ferroalloy production 

facilities (Saric et al. 1977), and 3–18 mg manganese/m3 in a dry-cell battery facility (Emara et al. 1971). 

Steel-manufacturing facilities are significant employers in the United States. There is a potential for 

manganese exposure to workers in these facilities. Airborne manganese levels in a metal-producing plant 

in the United States were reported as 0.066 mg/m3

(mean), 0.051 mg/m3(median) as respirable dust, and 

0.18 mg/m3 in total dust (Gibbs et al. 1999). Exposure levels should not exceed the Occupational Safety 

and Health Administration (OSHA) time-weighted average Permissible Exposure Limit (PEL) of 1 mg 

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total manganese/m3 (see Table 8-1). Average airborne manganese levels during welding operations of 

two factories located in China were 0.24 and 2.21 mg/m3 (Wang et al. 2008). Manganese levels in 

workplace air at a smelting facility in China ranged from 0.30 to 2.9 mg/m3 in the furnace smelting area 

and from about 0.2 to 0.8 mg/m3 in a power control room (Jiang et al. 2007). The workplace air at this 

facility contained mainly MnO (20%) and SiO2 (22%), in addition to other trace metals including 

Fe2O3 (4%), CaO (4.5%), MgO (4%), and Al2O3 (5%). Thus, for workers in industries using manganese, 

the major route of exposure may be inhalation from workplace air rather than from ingestion of food. 

Occupational exposure to manganese resulting from the combustion of MMT in Montreal, Canada has 

been studied. Sierra et al. (1995) conducted a study of Montreal automotive workers (garage mechanics) 

and nonautomotive workers (control group). Exposure to manganese was measured for 5 consecutive 

working days. In addition, their environmental exposure (at home) was measured on 2 days of the same 

week. Air sampling was performed by portable pumps; for sampling at homes, workers were asked to 

wear the pumps as much as possible. At the workplace, the mechanics were exposed to manganese 

concentrations ranging from 0.010 to 6.673 μg/m3 (mean of 0.45 μg/m3

), while nonautomotive workers 

were exposed to manganese concentrations ranging from 0.011 to 1.862 μg/m3 (mean of 0.04 μg/m3

). 

The average manganese concentrations in the indoor air of the homes were 0.012 μg/m3 for the mechanics 

and were 0.008 μg/m3 for the nonautomotive workers (Sierra et al. 1995). Based on measurements of 

manganese particle size distributions, Sierra et al. (1995) estimated that <10% of the manganese exposure 

of the garage mechanics was due to MMT; however, the exact contribution of MMT could not be 

determined. 

A similar study conducted in Montreal by these investigators, but involving taxi drivers and garage 

mechanics revealed that garage mechanics at work were exposed to an average of 0.250 μg/m3 and taxi 

drivers to 0.024 μg/m3 (Zayed et al. 1994). In another study, exposure of office workers and taxi drivers 

to both respirable and total manganese was evaluated (Zayed et al. 1996). Manganese concentrations 

measured for the office workers ranged from 0.001 to 0.034 μg/m3 (respirable manganese) and from 

0.002 to 0.044 μg/m3 (total manganese). For the taxi drivers, the manganese concentrations ranged from 

0.007 to 0.032 μg/m3 (respirable manganese) and from 0.008 to 0.073 μg/m3 (total manganese). Zayed et 

al. (1996) concluded that the higher exposure to atmospheric manganese in the outdoor urban 

environment may be at least partly due to the use of MMT in cars. Nevertheless, these investigators 

indicated that the exposures of taxi drivers to manganese were well below existing exposure and health 

guidelines. 

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6. POTENTIAL FOR HUMAN EXPOSURE 

In order to assess the potential health risks from MMT combustion, Loranger and Zayed (1995) 

conducted a multi-media assessment (i.e., food, water, and ambient air) of manganese exposure in 

two groups of workers (garage mechanics and blue-collar workers) potentially exposed to different levels 

of manganese from MMT. Garage mechanics were exposed to higher air manganese concentrations 

(0.42 μg/m3

) than blue-collar workers (0.04 μg/m3). However, for the garage workers, exposure to 

atmospheric manganese represented only approximately 4% of the total absorbed dose, while ingestion of 

food represented 95.7% of the total multi-media dose. For the blue collar workers, atmospheric 

manganese contributed only 0.3% to the total absorbed dose, whereas ingestion of food represented 

99.2% of the total multi-media dose. These results were consistent with values of multi-media doses 

predicted by GADUS, an environmental fate/exposure model (Loranger and Zayed 1997b). Based on 

governmental standards or criteria for occupational and environmental exposures, Loranger and Zayed 

(1995) concluded that the manganese levels in food and air may not cause any problems for these 

workers. 

Based on an analysis of data obtained from a large, continuous personal exposure study in Toronto, 

Canada, a city with widespread use of MMT, it was determined that the general population was exposed 

to low concentrations (median concentration was 0.008 μg/m3

) of PM2.5 manganese in personal air 

samples (Lynam et al. 1999; Pellizzari et al. 1999). A similar study, which collected 925 personal 

exposure samples for residents of Toronto, also concluded that MMT was not a significant source of 

PM2.5 manganese inhalation exposure for the general population (Crump 2000). However, personal 

exposure levels of fine manganese in Toronto were nearly 3 times greater when compared to data 

obtained from Indianapolis, Indiana where MMT was not being used as a gasoline additive. The median 

concentration of PM2.5 manganese in personal exposure samples from Indianapolis was 0.0028 μg/m3 

(Pellizzari et al. 2001). These data are summarized in Table 6-8. Certain activities such as time spent in 

subways, metal working, and smoking were associated with higher personal manganese exposure. 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

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Table 6-8. Levels of PM2.5 in Personal Air Samples Collected in Toronto, Canada 

and Indianapolis, Indiana 

Median concentration 90th concentration 

Location Number (μg/m3) (μg/m3) 

PM2.5 Manganese in personal air 

Toronto 272 0.008 0.016 

Indianapolis 240 0.0028 0.006 

Source: Pellizzari et al. 1999, 2001 

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The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

Children would be exposed to manganese in the same manner as adults. The main source of exposure of 

children to manganese is through food. Infants and young toddlers who are formula-fed may receive 

higher daily intakes of manganese than breast-fed infants because of the increased levels of the element in 

infant formulas as compared to breast milk (Collipp et al. 1983; Cook 1997; Dorner et al. 1989; Keen et 

al. 1986; Lönnerdal et al. 1983, 1994). For example, a study of 2,339 breast milk samples obtained from 

nursing mothers in Germany had a mean manganese level of 6.2 μg/L, while two different brands of 

formula had levels of 77 and 99 μg/L (Dorner et al. 1989). It was concluded that the mean daily 

manganese intake of formula-fed infants was approximately 13 times greater than that of breast-fed 

infants. 

Manganese concentrations in blood serum of children of different ages are provided in Section 3.4.2. The 

data indicate that manganese concentrations decrease slightly from the time the infant is 5 days of age 

until he or she is 12 months of age (Alarcón et al. 1996; Rükgauer et al. 1997). Manganese 

concentrations increase after this time, and they have been measured as an average of 1.4±1.25 μg/L in 

children aged 1 month to 18 years (Rükgauer et al. 1997). 

Children are exposed in utero because manganese in maternal blood crosses the placenta to satisfy the 

fetus’s need for manganese. The compound has been measured in cord blood plasma of premature and 

full-term infants and their mothers (Wilson et al. 1991). Full-term babies had higher (but not statistically 

significantly different) blood concentrations of manganese than premature babies, and pregnant women 

had higher blood concentrations than nonpregnant women. The average manganese concentration in the 

cord blood of full term babies was 5.5 μg/L, as compared to 5.0 μg/L for preterm babies (Wilson et al. 

1991). No correlations were observed between maternal and infant concentrations of manganese. 

Manganese in breast milk has been found to range from 3.4 to 10 μg/L (Arnaud and Favier 1995; Collipp 

et al. 1983) depending on the maturity of the milk. The Food and Nutrition Board of the NRC based the 

recommended manganese intake of infants on the analyses of pooled human milk samples. As discussed 

above, manganese intakes of infants fed some formulas appear high, but no signs of toxicity have been 

observed (Dorner et al. 1989; Lönnerdal et al. 1983). Differences in weight-adjusted intake are likely to 

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be caused by the type of diet that infants and small children receive. It is unknown whether nursing 

mothers exposed to higher-than-average concentrations of manganese would excrete increased 

concentrations of the metal in their breast milk. 

Young children often eat dirt (exhibiting what is called soil pica, the ingestion of a material unfit for food) 

and exhibit frequent hand-to-mouth activity; they can be exposed to manganese through this unique 

pathway if the soils contain the metal. Current estimates indicate that soil pica may be more prevalent in 

the general population than previously thought and that most children periodically ingest soil to varying 

degrees; this may be a potential health concern (EPA 1986d; Stanek and Calabrese 1995). The predicted 

oral average daily intake of manganese for children from soils in the vicinity of a municipal solid waste 

incinerator was estimated to range from approximately 0.0021 to 0.0032 mg/kg/day (Mari et al. 2007). 

However, no information was found concerning the bioavailability of manganese from soil and, therefore, 

determining the actual risk posed to children from this exposure pathway is difficult. This behavior 

should not pose an increased risk of exposure to manganese in most residential situations where the 

manganese levels are in the normal or background range. If the soils are from a hazardous waste site that 

contains high concentrations of manganese, then increased exposure to the compound may occur. 

Manganese levels in hair samples of 32 children residing near a hazardous waste site (former mining 

facility) in Northeast Oklahoma ranged from 89.1 to 2,145.3 ppb (471.5 ppb mean) (Wright et al. 2006). 

The authors found that in school-aged children, higher manganese and arsenic levels in hair samples were 

associated with significantly lower scores on a standardized test, as well as on tests of verbal learning and 

memory. 

Children who suffer from cholestatic liver disease or who have gastrointestinal disorders that mandate 

they be given parenteral nutrition may be at increased risk from overexposure to manganese. Increased 

manganese concentrations in blood and brain, and symptoms of neuromotor dysfunction were observed in 

an 8-year-old girl with cholestatic liver failure (Devenyi et al. 1994). Children with or without chronic 

liver disease and a 5-year-old boy who had gastrointestinal disorders, all of whom were administered 

parenteral nutrition, had abnormal MRI scans indicative of manganese accumulation (Fell et al. 1996; 

Ono et al. 1995) accompanied by motor disorders (Fell et al. 1996). 

Because manganese is a trace element that is essential for normal human health and is predominantly 

obtained from food, it is unlikely that toxic amounts of manganese will be absorbed from food. However, 

diets vary and some are higher in manganese than others (diets high in grains and tea, for instance). One 

case study suggested that a 59-year-old man developed manganism-like symptoms from abusing vitamins 

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6. POTENTIAL FOR HUMAN EXPOSURE 

and minerals. This man had very high manganese concentrations in blood, urine, feces, hair, and brain 

(Banta and Markesbery 1977). Both manganese and iron are bound by transferrin and these elements 

compete for the binding protein in the body. Therefore, diets that are low in iron allow transferrin to bind 

more manganese. For this reason, it is important to provide children with a balanced diet to maintain 

optimal iron and manganese stores in the body. Studies show that adults absorb only 3–5% of manganese 

ingested from the diet (Davidsson et al. 1988, 1989a; Mena et al. 1969); infants have increased absorption 

relative to adults (Dorner et al. 1989). Neonatal animals also exhibit increased absorption relative to older 

animals (Ballatori et al. 1987; Miller et al. 1975; Rehnberg et al. 1981). 

Children may be exposed to organic manganese compounds through a variety of routes. They may be 

exposed to MMT combustion products via inhalation of these products in air, or ingestion of them after 

deposition on the soil. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

As discussed in Section 6.5, workers in industries using or producing manganese are mostly likely to have 

higher exposures to manganese, primarily by inhalation of manganese dusts in workplace air as compared 

to the general population. In a year-long investigation of personal exposure to manganese fine particulate 

matter (PM2.5) for residents of Toronto, Canada, it was determined that workers in the metal industry had 

the highest personal exposures as compared to other groups. The mean concentration of manganese PM2.5 

in personal samples for 39 workers engaged in welding, soldering, or other metal working practices was 

105 ng/m3

, which was more than 10 times greater than the mean concentration (10 ng/m3 ) for 886 nonmetal workers (Crump 2000). Smokers and those nearby second-hand smoke were also shown to be 

exposed to higher levels of fine particulate matter manganese as compared to nonsmokers. The mean 

concentration of PM2.5 manganese in 702 personal air samples of nonsmokers in Toronto, Canada was 

10 ng/m3

, while the mean concentration calculated from 223 personal samples obtained from smokers 

was 27 ng/m3 (Crump 2000). 

Average airborne manganese levels (total dust) in the breathing zone of two factories located in China 

were 0.24 and 2.21 mg/m3 (Wang et al. 2008). The greatest levels were observed during welding 

operations in enclosed spaces. The workers at these two factories had higher measurable manganese 

levels in their saliva (3.47±1.42 and 5.55±2.31 μg/L), as compared to a control group of nonoccupationally exposed individuals (3.04±1.40 μg/L). 

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Workers in three manganese alloy production plants located in Norway were found to have slightly higher 

manganese blood and urine levels when compared to a group of non-occupationally exposed individuals. 

The arithmetic mean manganese level in the blood of workers at these plants was 189 nmol/L (10.3 μg/L) 

versus 166 nmol/L (9.1 μg/L) for the reference group (Ellingsen et al. 2003c). The urinary arithmetic 

mean concentrations were 3.9 nmol/mmol creatinine for the occupationally exposed workers and 

0.9 nmol/mmol creatinine for the reference group (Ellingsen et al. 2003c). The arithmetic mean inhalable 

and respirable concentrations of manganese in the air of these production plants were 0.769 and 

0.064 mg/m3

, respectively (Ellingsen et al. 2003c). Section 3.2.1.4 summarizes other studies that 

compared noted health effects with urinary and blood manganese levels of occupationally exposed 

individuals and reference populations. It has been demonstrated that levels in the blood and urine may 

not be adequate biomarkers for high level manganese exposure since free manganese usually does not 

accumulate within the circulatory system (Josephs et al. 2005). 

Populations living in the vicinity of ferromanganese or iron and steel manufacturing facilities, coal-fired 

power plants, or hazardous waste sites may also be exposed to elevated manganese particulate matter in 

air or water, although this exposure is likely to be much lower than in the workplace. Populations living 

in regions of natural manganese ore deposits may be exposed to above-average levels in soil, water, or air. 

People ingesting large amounts of foods high in manganese also have a potential for higher-than-usual 

exposure. Included in this group would be vegetarians, who ingest a larger proportion of grains, legumes, 

and nuts in their diets than the average U.S. population, and heavy tea drinkers. While the intake of 

manganese from vegetarians may exceed the estimates of daily dietary intake, the bioavailability of 

manganese from vegetable sources is substantially decreased by dietary components such as fiber and 

phytates (EPA 1993b). In addition to the population with these dietary habits, individuals with iron 

deficiency show increased rates of manganese absorption (Mena et al. 1969, 1974); iron deficiency leads 

to increased brain manganese concentrations in experimental animals (Aschner and Aschner 1990). 

Manganese is eliminated from the body primarily through the bile. Interruption of the manufacture or 

flow of bile can impair the body’s ability to clear manganese. Several studies have shown that adults and 

children (Devenyi et al. 1994; Fell et al. 1996; Hauser et al. 1994, 1996; Pomier-Layrargues et al. 1998; 

Rose et al. 1999; Spahr et al. 1996), as well as experimental animals (Rose et al. 1999), with cholestatic 

liver disorders have increased manganese levels in their blood and brain and are at risk from potentially 

increased exposure to manganese due to their decreased homeostatic control of the compound. 

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In addition to oral diets, people on partial and total parenteral nutrition may be exposed to increased 

amounts of manganese. Forbes and Forbes (1997) found that of 32 patients receiving home parenteral 

nutrition due to digestive problems, 31 had elevated serum manganese levels (0.5–2.4 mg/L). It is unclear 

whether these levels reflected steady-state conditions due to the time the samples were taken. However, 

these levels are much higher than other studies involving patients on TPN; thus, it is unlikely that these 

levels represent steady-state conditions. Further, the normal range reported by these authors (0.275– 

0.825 mg/L) is elevated compared to other studies, suggesting the possibility that the blood samples were 

contaminated with exogenous manganese. The authors observed no clinical evidence of toxicity in the 

patients. Fourteen of the patients suffered iron deficiency anemia; because low iron concentrations are 

associated with increased manganese uptake, the anemia may have exacerbated the increased blood 

manganese concentrations. Increased blood manganese levels and MRI scans indicative of increased 

manganese in brains have been reported in children fed entirely on parenteral nutrition (Fell et al. 1996; 

Ono et al. 1995). Only in the Fell et al. (1996) study were neurotoxic effects reported. Whole-blood 

manganese in the children from this study ranged from 9.9 to 110 μg/L. Devenyi et al. (1994) found 

hyperintense signals in the brain of an 8-year-old child who had cholestatic liver disease and exhibited 

dystonia and other motor dysfunctions. Nagatomo et al. (1999) reported that two elderly patients who had 

been administered TPN for 3–4 months exhibited clinical signs of manganism (including masked facies, 

marked rigidity, hypokinesia) with associated elevated blood manganese levels and hyperintense signals 

on MRI, localized to the basal ganglia, especially the globus pallidus. Signs of manganism abated upon 

levodopa treatment and the administration of Ca-EDTA; the high intensity signals on MRI abated when 

manganese supplementation ceased. In addition to patients on parenteral nutrition, uremic patients on 

hemodialysis have been found to have increased manganese levels due to increased concentrations of 

manganese in the dialysis solution (Lin et al. 1996). These studies indicate that while increased levels of 

manganese in blood and brain are often associated with TPN administration, adverse neurological effects 

are not always reported. Nagatomo et al. (1999) found increased serum concentrations of manganese and 

brain abnormalities in two patients who showed Parkinsonism with psychiatric symptoms after 3– 

4 months of total parenteral nutrition. Discontinuation of manganese supplementation in the parenteral 

diet, coupled with levodopa treatment, gradually improved both the symptoms and brain abnormalities in 

the patients. 

In comparison to other groups within the general population, persons living close to high density traffic 

areas, automotive workers, gas station attendants, and taxi drivers may be exposed to higher 

concentrations of manganese arising from the combustion of MMT. Levels of respirable manganese, in 

both indoor and outdoor air near an expressway with high traffic density were shown to be greater than 

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corresponding air samples obtained from a rural location in Montreal, Canada (Bolte et al. 2004). The 

average concentration of respirable manganese (defined in this study as <5 μm diameter) in outdoor air 

from the urban location of Montreal was 0.025 μg/m3

, which is 5 times greater than the average of 

0.005 μg/m3 found in the rural location. The average indoor respirable manganese concentration was also 

greater for the urban area (0.017 μg/m3

) as compared to the rural area (0.007 μg/m3). However, 

differences in exposure levels did not lead to significantly greater levels of manganese in blood for 

residents of these areas. The mean manganese concentration in blood samples obtained from female 

residents in the urban location (8.4 μg/L) was only slightly greater than the average level observed for 

females living in the rural location (7.8 μg/L). 

It is possible that medical workers may be exposed to higher concentrations of mangafodipir than the 

general population, although exposure routes other than intravenous are not expected to pose a significant 

risk. 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of manganese is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of manganese. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The fundamental physical and chemical properties of 

manganese and manganese compounds are known (see Table 4-2), and additional research does not 

appear necessary. 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2006, became available in March of 2008. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

Information is available on U.S. import, export and production of manganese ore and related materials 

(USGS 2007, 2008). It is clear that most manganese is used in steel production. Information regarding 

the import, export, and use of MMT in U.S. fuels is a data need. 

Data from the TRI database provide valuable information on the amounts of manganese released to 

different environmental media (e.g., air, soil, and water) each year, although details on the chemical form 

and physical state of the waste materials are not included. These disposal practices are not regulated 

under current federal law. TRI data may not be complete estimates of total release. Also, because these 

data reflect past releases, they may not be representative of current releases at these facilities. 

Environmental Fate. The partitioning of manganese between water and soil can be fairly well 

predicted using thermodynamic equilibrium concepts, if soil-specific information is available (Baes and 

Sharp 1983; Rai et al. 1986). The fate of manganese particles released into the air is determined by the 

particle size, and the direction and distance of particle transport at a site can be predicted from 

meteorological data and particle size data (EPA 1984; Nriagu 1979). Transport of manganese in water is 

determined mainly by the solubility of the manganese compounds present, although suspended particles 

may also be transported in flowing waters (EPA 1984; Schaanning et al. 1988). 

The primary transformations that manganese undergoes in the environment are oxidation/reduction 

reactions (EPA 1984; Rai et al. 1986). Reactions of manganese with airborne oxidants have not been 

studied. Information on the rate and extent of such reactions would be helpful in understanding the fate 

of atmospheric releases. The transformation of manganese in water or soil is dependent mainly on Eh, 

pH, and available counter ions (EPA 1984). In some soils, manganese may also be oxidized by bacteria 

(Geering et al. 1969; Johnston and Kipphut 1988). More work is needed on the environmental factors, 

such as soil composition and pH, which may determine the form in which manganese will appear and thus 

impact manganese availability and absorption. 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Modeling has also provided interesting insight into the contribution of the combustion of MMT to 

atmospheric manganese (Loranger et al. 1995). According to the model estimations, the contribution of 

direct emissions from motor vehicles to the atmospheric background manganese (as measured from 

sampling stations) would be about 50% at <25 m and <8% at 250 m. These results are confirmed with an 

in situ study using snow as the environmental indicator where the average deposition rates of manganese 

for the top and bottom layers ranged from 0.01 to 0.21 mg/m2

/day (Loranger et al. 1996). The average 

concentrations of manganese decreased with distance from the road. However, it was impossible to 

distinguish between directly-emitted manganese from automobiles, manganese enriched road dust, and 

the naturally-occurring manganese in crustal materials. No study to date has provided the complete 

answer to this question and this constitutes one of the major remaining data needs regarding the 

environmental significance of manganese from MMT and the resulting potential for exposure. 

Bioavailability from Environmental Media. Manganese is known to be absorbed following 

inhalation or oral exposure (Mena et al. 1969; Pollack et al. 1965; Zheng et al. 2000), but dermal exposure 

is not considered to be significant. The uptake of manganese from air, food, milk, and water has been 

studied (Davidsson et al. 1988, 1989a). However, absorption from soil has not been investigated. In 

view of the potential for tight binding of manganese to some soil types, studies on this subject would be 

valuable in evaluating risk to humans, especially children who may ingest contaminated soils near 

hazardous waste sites. Additional information would also be valuable on the relative bioavailability of 

different manganese compounds across various environmental media. 

Food Chain Bioaccumulation. It has been established that while lower organisms (e.g., plankton, 

aquatic plants, and some fish) can significantly bioconcentrate manganese, higher organisms (including 

humans) tend to maintain manganese homeostasis (EPA 1984; Folsom et al. 1963; Thompson et al. 

1972). This indicates that the potential for biomagnification of manganese from lower trophic levels to 

higher ones is low, and it does not appear that additional research in this area is essential at this time. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of manganese 

in contaminated media at hazardous waste sites are needed so that the information obtained on levels of 

manganese in the environment can be used in combination with the known body burden of manganese to 

assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste 

sites. 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Manganese levels have been monitored in all environmental media, including air, water, soil, and food 

(Capar and Cunningham 2000; EPA 1984; NAS 1980a; Pennington et al. 1986). Estimates are available 

for the average human intake levels of manganese from water, air, and food (EPA 1984; WHO 2004b). 

More specific data on levels in the environment around those particular sites where manganese is believed 

to have been dumped would be helpful in determining the extent of exposure levels around such waste 

sites. In particular, data on the concentration of manganese in the air around hazardous waste sites would 

be valuable in assessing the potential significance of this exposure pathway. 

Exposure Levels in Humans. This information is necessary for assessing the need to conduct 

health studies on these populations. Manganese is a normal component of human tissues and fluids 

(Sumino et al. 1975; Tipton and Cook 1963). Increased average levels of manganese have been detected 

in blood and urine of populations exposed to high concentrations of manganese in the workplace (Roels 

et al. 1987b). Manganese has been measured in hair samples of children residing near a hazardous waste 

site (Wright et al. 2006); however, the absence of data on levels of manganese in the hair of U.S. children 

in the general population makes it difficult to draw conclusions about whether the exposures of the 

children at this site are unusually high. Surveys of manganese levels in the blood or urine of populations 

living near waste sites could be useful in identifying groups with above-average levels of manganese 

exposure. More information is also needed to determine whether iron-deficient populations have a higher 

manganese body burden. Manganese and iron have many physico/chemical similarities and there is a 

possibility of competition between these elements. Increased manganese concentrations have been shown 

to inhibit the metabolic function of the iron-dependent enzyme, aconitase (Zheng et al. 1998). Iron 

deficiency is the single most prevalent nutritional deficiency in the world, and so the potential health risk 

associated with iron deficiencies exacerbating the brain manganese burden may represent a crucial issue 

of exposure and susceptibility, and has yet to be evaluated. Air concentrations in areas with high traffic 

density are sometimes higher than the guide level (Zayed et al. 1999a); therefore, some individuals could 

be at risk. Research focusing on the environmental level of exposure of certain groups of the population, 

such as those living near a major highway, is needed. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Children are exposed daily to manganese. The compound is an essential 

trace element vital for the body to function properly and body burden studies are available (Alarcón et al. 

1996; Rükgauer et al. 1997). Although the primary pathway for exposure is the diet, studies involving 

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6. POTENTIAL FOR HUMAN EXPOSURE 

exposures to airborne manganese (e.g., in dust that may be present at a nearby hazardous waste site or 

manganese-processing plant) would aid in understanding other pathways that may contribute significantly 

to children’s total body burden of manganese 

Soil ingestion is likely the only unique exposure pathway for children. Additional studies concerning 

bioavailability of manganese from soil would provide important information concerning the proportion of 

the total daily manganese intake that could originate from ingested soils. 

Although infants differ in their weight-adjusted intake of manganese, it is unknown whether older 

children differ in this parameter. Studies concerning this end point would be very valuable. 

Studies involving inhalation or ingestion exposure to MMT in the young are very few (Komura and 

Sakamoto 1992b, 1994). Although these studies indicate that MMT had very little measurable effect on 

development, only one dose level was used. Although analytical data indicate that environmental MMT 

is unlikely to persist (Lynam et al. 1999), it is unknown what typical body burdens of manganese might 

be in children following long-term exposure to MMT combustion products. Additional studies measuring 

these end points in the young would be helpful. 

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data 

Needs: Children’s Susceptibility. 

Exposure Registries. No exposure registries for manganese were located. This substance is not 

currently one of the compounds for which a sub-registry has been established in the National Exposure 

Registry. The substance will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates 

the epidemiological research needed to assess adverse health outcomes that may be related to exposure to 

this substance. 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2008) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Researchers at the University of Delaware (D.M. Di Toro, principal investigator) are conducting research 

to develop models for predicting the toxicity and mobilization of individual metals (including manganese) 

and metal mixtures in sediments. These predictions are critical in evaluating the risk associated with 

contaminated sediments at Superfund sites. 

Thomas R. Guilarte and co-workers at Johns Hopkins University are studying the behavioral and 

neuropathological changes that occur as a result of chronic exposure to low levels of manganese. The 

findings from the proposed studies will be used to aid in understanding the mechanism(s) of chronic, lowlevel manganese neurotoxicity. Moreover, these data will identify sensitive markers for the early 

detection of manganese neurotoxicity that can be used in vivo in humans. 

Wei Zheng and co-workers at Purdue University are studying the biomarkers for early diagnosis of 

manganese toxicity among Chinese smelting workers. They plan to combine exposure indices and 

biological effects into one parameter for quick clinical assessment of manganese toxicity. They are also 

conducting clinical trials to investigate the efficacy of para-aminosalicylic acid in treatment of severe 

manganism. Advanced MRI and MRS techniques along with molecular biotechnology have been used in 

these studies. 

Donald Smith and co-workers at the University of California, Santa Cruz are studying the effect that early 

manganese exposure in neonatal rats has on neurobehavioral and neurocognitive deficits and comparing 

these data with epidemiological studies in children. 

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MANGANESE 381 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring manganese, its metabolites, and other biomarkers of exposure and effect to 

manganese. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is 

to identify well-established methods that are used as the standard methods of analysis. Many of the 

analytical methods used for environmental samples are the methods approved by federal agencies and 

organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other 

methods presented in this chapter are those that are approved by groups such as the Association of 

Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). 

Additionally, analytical methods are included that modify previously used methods to obtain lower 

detection limits and/or to improve accuracy and precision. 

The most common analytical procedures for measuring manganese levels in biological and environmental 

samples use the methods of atomic absorption spectroscopy (AAS) and atomic emission spectroscopy 

(AES). In AAS analysis, the sample is aspirated into a flame or in a graphite furnace (GFAAS) until the 

element atomizes (Tsalev 1983). The ground-state atomic vapor absorbs monochromatic radiation from a 

source and a photoelectric detector measures the intensity of radiation absorbed at 279.5 nm (Tsalev 

1983). Furnace atomic absorption analysis is often used for very low analyte levels and for the analysis 

of solid samples or slurries (Baruthio et al. 1988). Inductively coupled plasma-atomic emission 

spectrometry (ICP-AES) analysis is frequently employed for multianalyte analyses that include 

manganese. Neutron activation analysis is also a very effective method for determining manganese 

concentrations in different samples (Rose et al. 1999). This technique uses no reagents and a minimum of 

sample handling; thus, potential contamination with exogenous sources of manganese can be avoided. In 

addition, the technique has a low detection limit in biological tissues (4 ng/g) and high precision. Further, 

the technique can be used for environmental samples as well as biological samples. Other methods for 

measuring manganese include spectrophotometry, mass spectrometry, neutron activation analysis, and 

x-ray fluorimetry. 

It is important to note that none of these methods distinguish between different oxidation states of 

manganese or between different manganese compounds. Thus, monitoring data on manganese are nearly 

always available only as total manganese present. 

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7. ANALYTICAL METHODS 

Levels of organometallic species in environmental and toxicological samples are typically in ppb 

concentrations, ng/mL in solution, or ng/g in solids (Walton et al. 1991). Therefore, methods of 

determination must be both selective and sensitive, achieved usually by coupling liquid or gas 

chromatography (GC) with detection via electrochemical, mass spectrometry, and atomic spectrometry 

detectors. A number of analytical methods for quantifying MMT in gasoline have been described, 

including simple determination of total elemental manganese by atomic absorption and gas 

chromatography followed by flame-ionization detection (FID). These methods usually measure MMT by 

detecting the metallic portion of the compound and reporting detection of MMT as manganese. 

X-ray absorption near edge structure (XANES) and x-ray absorption fine structure (XAFS) spectroscopy 

have been used for the analysis of manganese-containing particulates emitted from automobile exhaust 

containing MMT (Mölders et al. 2001; Ressler et al. 2000). These methods are particularly useful in 

determining the chemical speciation and valence state of manganese or other metal complexes attached to 

particulate matter. 

7.1 BIOLOGICAL MATERIALS 

Normally, determination of manganese in biological materials requires digestion of the organic matrix 

prior to analysis. For tissue samples or feces (detection limits ranging from 0.2 to <1 μg/g), this is usually 

done by treatment with an oxidizing acid mixture such as 3:1:1 (v/v/v) nitric:perchloric:sulfuric acid 

mixture (Kneip and Crable 1988a). Fluid samples such as blood, saliva, or urine may be digested in the 

same way (blood, detection limits=1 μg/100 g, 10 μg/L), or manganese can be extracted by an ion 

exchange resin (urine, detection limit=0.5–2 μg/L) or by chelating agents such as cupferon in 

methylisobutylketone (urine, detection limit=<1 μg/L). A method for directly measuring concentrations 

of trace elements in hair that does not require digestion prior to analysis has been developed (Stupar and 

Dolinsek 1996). While the authors used their technique to determine chromium, lead, and cadmium 

levels in hair, it is assumed that their slurry sampling or direct solid sampling technique might also work 

for manganese determination. Table 7-1 summarizes some of the methods used for sample preparation 

and analysis of manganese in biological materials. It is important to note that special care is needed to 

avoid contamination of biological materials with exogenous manganese, especially for samples with low 

levels of manganese (Tsalev 1983; Versieck et al. 1988). 

GC-FID may be used to determine levels of MMT in biological tissues and fluids with a detection limit of 

1–2 ppm and percent recovery of 93.5–102.7% (Hanzlik et al. 1979). 

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7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Manganese in Biological
 

Materialsa
 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Urine Extraction into AAS (furnace <1 μg/Lb No data Baselt 1988 

methylisobutyl-ketone as technique) 

the cupferon chelate 

Urine Extract with resin, ash resin ICP-AES <1 μg/Lb 100±10 NIOSH 1984d 

Blood Acid digestion ICP-AES 1 μg/dL 98±2.1 Kneip and 

Craple 1988a 

Blood Digestion in oxidizing acid ICP-AES 1 μg/100 g 98±2.1 NIOSH 1984c 

Tissue Digestion in oxidizing acid ICP-AES 0.2 μg/g 98±2.1 NIOSH 1984c 

Tissue Acid digestion ICP-AES 0.2 μg/g 104±5.6 Kneip and 

Craple 1988a 

Feces Dry at 110 °C, ash at AAS (furnace <1 μg/g 102±7 Friedman et al. 

550 °C, dissolve in nitric technique) 1987 

acid 

Hair Digestion in concentrated Flameless <0.2 μg/g No data Collipp et al. 

nitric:perchloric acid (3:1) AAS 1983 

mixture 

Hair (a) slurry sample 

introduction technique (hair 

ETAAS 

(furnace 

No data No data Stupar and 

Dolinsek 1996c 

powder added to twice technique) 

distilled water to measure 

bulk hair trace elements, or 

(b) direct introduction of 

hair segments to measure 

longitudinal gradients 

Methods for determination of MnDPDP 

Human Mix heparinized blood Mixed-bed 0.8–2.3 μM 85–115 Toft et al. 1997a 

plasma samples of patients resin HPLC­ (manganese 

receiving MnDPDP via anion compounds) 

injection with solid exchange 0.1–0.8 μM (zinc 

trisodium phosphate and reverse- compounds) of 

dodecahydrate pH phase 50 μL injection 

10.0±0.2; ultrafiltrate volume 

a

Magnetic resonance imaging (MRI) has been useful in determining brain accumulation of manganese, but is not a 

quantitative method; therefore, it is not listed as an entry in this table. b

Estimated from sensitivity and linearity data 

c

Methods were used to determine levels of chromium, lead, and cadmium in hair. Manganese concentrations in hair 

were evaluated for some, but not all, of the samples and tested one, but not both, new methods. However, it is 

assumed that both techniques will work for the trace element manganese. 

AAS = atomic absorption spectroscopy; HPLC = high performance liquid chromatography; ICP-AES = inductively 

coupled-plasma atomic emission spectroscopy; MnDPDP = mangafodipir; NIOSH = National Institute for 

Occupational Safety and Health 

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Walton et al. (1991) have described high performance liquid chromatography (HPLC) coupled with laserexcited atomic fluorescence spectrometry (LEAFS) to detect various species of MMT. The detection 

limit for this GC-LEAFS method ranged from 8 to 20 pg of manganese for the various organomanganese 

species; the detection limit for determining manganese in MMT was 0.4 ng/mL. This limit of detection 

was several orders of magnitude better than those for HPLC with ultraviolet (UV) detection or 

HPLC-atomic fluorescence spectrometry (AFC) (Walton et al. 1991), but was worse than detection by 

GC-FID (DuPuis and Hill 1979). Walton et al. (1991) used their method to determine manganese species 

present in rat urine after rats had been administered MMT prepared in propylene glycol via subcutaneous 

injection. 

Table 7-1 summarizes some common methods for the determination of manganese in various types of 

biological materials. 

7.2 ENVIRONMENTAL SAMPLES 

Manganese in air exists as particulate matter, so sampling is done by drawing air through a filter in order 

to collect the suspended particles. A variety of filter types (e.g., glass fibers and cellulose acetate) and 

sampling devices (e.g., low volume, high volume, and dichotomous) are available, depending on the 

particle sizes of concern and the concentration range of interest. In some cases, material on the filter may 

be analyzed directly (e.g., by x-ray fluorescence), or the filter may be digested by ashing in acid prior to 

analysis. In general, sensitivity is dependent on the volume of air drawn through the filter prior to 

analysis, and typically, detection limits are 1–2 μg/sample. 

Several analytical methods from the EPA Office of Solid Waste publication SW-846, entitled Test 

Methods for Evaluating Solid Waste, Physical/Chemical Methods are applicable for analyzing manganese 

in water, soil, and wastes. In addition, the EPA Emission Measurement Center (EMS) and Office of 

Water (OW) have standardized methods for the measurement of manganese and other metals in 

environmental media. Several of these methods, including the analytical instrumentation and detection 

limits, are summarized in Table 7-2. 

Water may either be analyzed directly, or, if the concentration of manganese is low, a concentration step 

(e.g., evaporation, extraction, and binding to a resin) may be employed (detection limits ranging from 

0.005–50 μg/L). In all cases, acid is added to the sample to prevent precipitation of manganese. 

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7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Manganese in Environmental
 

Samples
 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection limit 

Percent 

recovery Reference 

Air Collect sample on MCE 

or PVC filter, followed 

by nitric/perchloric acid 

ashing 

Method 7300 

(ICP-AES) 

0.2 mg/m3 94.7–101 

(MCE) 

99.3–101.9 

(PVC) 

NIOSH 2003a 

Air Collect sample on MCE 

filter, followed by hot 

block/HCl/HNO3 

digestion 

Method 7303 

(ICP-AES) 

1.2 mg/m3 No data NIOSH 2003b 

Air Collect sample on MCE 

or PVC filter, followed 

by aqua regia ashing 

Method 7301 

(ICP-AES) 

0.2 mg/m3 91.2–103.5 

(MCE) 

77.4–93.4 

(PVC) 

NIOSH 2003c 

Water Acidify with nitric acid AAS (furnace 

technique) 

0.2 μg/L No data EPA 1983b 

Water Acidify with nitric acid AAS (flame) 

AAS (furnace) 

ICP-AES 

2 μg/L 

0.01 μg/L 

1 μg/L 

No data 

No data 

No data 

Taylor 1982 

Water Acidify with nitric acid Method 311 

(AAS) 

<10 μg/L No data APHA 1998a 

Water Filter and acidify filtrate 

with HNO3 and analyze 

Method 3113A 

(AAS furnace 

technique) 

0.2 μg/L No data APHA 1998b 

Water Digest sample with 

HNO3/HCl and analyze 

Method 3120B 

(ICP-AES) 

2 μg/L No data APHA 1998c 

Water Acidify with nitric acid AAS (direct 

aspiration) 

10 μg/L 100±2a EPA 1983a 

Water Acid digest and analyze Method 3125A 

(ICP-MS) 

0.002 μg/L 91.81–110 APHA 1998d 

Water Preconcentration 

manganese-containing 

solution and 

3,3’5,5’-tetramethylbenzidine (TMB) onto 

filter paper; add oxidant 

KIO4 to catalyze 

oxidation; measure 

Catalytic 

kinetic method 

of analysis 

0.005 μg/L No data Beklemishev et 

al. 1997 

absorbance 

Water, 

waste water, 

sludge, and 

soils 

For dissolved 

constituents: filter, 

acidify filtrate, and 

analyze; for samples 

containing solids: 

digestion with HNO3/HCl 

prior to analysis 

Method 200.8 

(ICP-MS) 

0.01–0.04 μg/L 

(liquids); 

0.05 mg/kg 

(solids) 

95.8–96.9 

(water); 

95.2–103.6 

(wastes) 

EPA 1994b 

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Table 7-2. Analytical Methods for Determining Manganese in Environmental
 

Samples
 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Water and Acid digestion AAS 10 μg/L 100±2 EPA 1986c 

wastes 

Water, For dissolved Method 6010C 0.93 μg/L No data EPA 2007a 

solids, constituents: filter, (ICP-AES) 

sediment, acidify filtrate, and 

analyze; for samples 

containing solids: 

digestion with HNO3/HCl 

prior to analysis 

Foods Digest wet or dry foods AAS (flame) AAS (flame): No data Tinggi et al. 

with HNO3–H2SO4 AAS (furnace) 0.15 mg/kg 1997 

mixture (12:2 mL) AAS (furnace): 

1.10 μg/kg 

Foods Digestion with nitric, ICP-AES 0.2 mg/kg 96.2–97 Capar and 

sulfuric, perchloric acid Cunningham 

solution 2000 

Methods for MMT determination 

Air Draw known volume of GC-ECD 0.001 mg/m3 (in No data Gaind et al. 

air through XAD-2 10-L sample); 1992 

sampling tubes for 0.02 ng from a 

10–60 minutes 2.0 μL injection 

of a 0.01 μg/mL 

MMT solution 

Gasoline Dilute gasoline in Capillary 62 pg/s No data Ombaba and 

acetone (1:10) GC-ACP Barry 1994 

detector 

Gasoline Dilute with hexane GC-ECD No data No data Gaind et al. 

(1:99); direct injection 1992 

Gasoline Inject sample GC-MED 0.25 pg/s No data Quimby et al. 

1978 

Gasoline Inject sample GC-FPD 0.6 ppm No data Aue et al. 1990 

a

Percent recovery at manganese concentration >80 μg/L; at lower concentrations (10–20 μg/L), percent recoveries 

were >120%. 

AAS = atomic absorption spectrometry; ACP = alternating current plasma; AES = atomic emission spectroscopy; 

APDC = ammonium pyrrolidine dithiocarbamate; APHA = American Public Health Association; ECD = electroncapture detection; EPA = Environmental Protection Agency; FPD = flame photometric detection; GC = gas 

chromatography; ICP = inductivity coupled plasma; MCE = mixed cellulose ester; MED = microwave emission 

detector; MS = mass spectrometry; NIOSH = National Institute for Occupational Safety and Health; PVC = polyvinyl 

chloride; XRF = x-ray fluorescence 

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Beklemishev et al. (1997) measured the concentrations of manganese in tap and river water. Their 

analytical method relies on an indicator reaction that is catalyzed by Mn(II) (the oxidation of 

3,3',5,5'-tetramethylbenzidine [TMB] by potassium periodate [KIO4]) and is carried out on the surface of 

a paper-based sorbent. The advantages of this novel technique are that it has a much lower detection limit 

(0.005 μg/L) than do established methods and is transportable, allowing it to be used for rapid tests in the 

field (i.e., spot tests and similar procedures). 

Determination of manganese levels in soils, sludges, or other solid wastes requires an acid extraction/ 

digestion step prior to analysis. The details vary with the specific characteristics of the sample, but 

usually treatment will involve heating in nitric acid, oxidation with hydrogen peroxide, and filtration 

and/or centrifugation to remove insoluble matter. 

Manganese levels in foods have been determined in order to define more clearly human dietary 

requirements or levels of absorption of manganese from the diet (Tinggi et al. 1997). Atomic absorption 

spectrometry has been the most widely used analytical technique to determine manganese levels in a 

broad range of foods, as well as other environmental and biological samples (Tinggi et al. 1997). Tinggi 

et al. (1997) contributed a wet digestion technique using a 12:2 (v/v) nitric:sulfuric acid mixture for their 

determination, and for food samples with low levels of manganese, they found that the more sensitive 

graphite furnace atomic absorption analysis was required. Because manganese is often found at very low 

levels in many foods, its measurement requires methods with similarly low detection limits; these 

researchers identified detection limits of 0.15 mg/kg (ppm) and 1.10 μg/kg (ppb) for flame and graphite 

furnace atomic absorption spectrometry, respectively (Tinggi et al. 1997). Neutron activation analysis is 

an effective technique for measuring manganese in environmental samples; it provides a low detection 

limit and high precision (Kennedy 1990). 

A number of analytical methods for quantifying MMT in gasoline have been described including simple 

determination of total elemental manganese by atomic absorption (Smith and Palmby 1959) and gas 

chromatography followed by FID (DuPuis and Hill 1979). The former has measured manganese 

concentrations from 0.1 to 4 g/gallon of gasoline after dilution of the sample with isooctane to minimize 

the effects of differences in base stock composition and is accurate to about 3% of the amount of 

manganese present. The latter has an absolute detection limit of 1.7x10-14 g/sample (0.017 pg/s) and 

could easily measure 6 mg/gallon of manganese in a gasoline sample; it is one of the most sensitive 

approaches. Aue et al. (1990) described a method in which MMT is detected in gasolines by gas 

chromatography coupled with flame photometric detection (FPD); the chemiluminescence of manganese 

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is measured to determine MMT levels in a method that uses simple, inexpensive, and commercially 

available instrumentation. MMT levels can be determined down to 0.6 ppm (w/w) in gasoline (Aue et al. 

1990). In another method showing excellent performance, Quimby et al. (1978) used GC followed by 

atmospheric pressure helium microwave detection system (or microwave emission detector [MED]); this 

method has a high degree of selectivity (1.9x106

) and a detection limit of 0.25 pg/s at a wavelength of 

257.6 nm. 

GC followed by electron-capture detection (ECD) (Gaind et al. 1992) or alternating current plasma (ACP) 

emission detection (Ombaba and Barry 1994) (detection limit: 62 pg as manganese) has also been 

described for determination of MMT in gasoline. GC followed by ACP emission detection has been 

described for detecting MMT in air samples; airborne MMT concentrations as low as 0.001 mg/m3 can be 

measured (Ombaba and Barry 1994). 

Table 7-2 summarizes some common methods for the determination of manganese in various types of 

environmental media. 

7.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of manganese is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of manganese. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

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MANGANESE 389 

7. ANALYTICAL METHODS 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect 

Exposure. Sensitive and selective methods are available for the detection and quantitative measurement 

of manganese in blood, urine, hair, feces, and tissues (Baselt 1988; Collipp et al. 1983; Friedman et al. 

1987; Kneip and Crable 1988a; NIOSH 1984c, 1984d). Since levels in biological samples are generally 

rather low, sample contamination with exogenous manganese can sometimes occur (Tsalev 1983; 

Versieck et al. 1988). Development of standard methods for limiting this problem would be useful. 

Measurement of average manganese concentrations in these materials has proved useful in comparing 

groups of occupationally exposed people to nonexposed people (Roels et al. 1987b), but has not been 

especially valuable in evaluating human exposure in individuals (Rehnberg et al. 1982). This is due to the 

inherent variability in intake levels and toxicokinetics of manganese in humans, rather than a limitation in 

the analytical methods for manganese. Smith et al. (2007) have discussed the limitations of using blood 

and urine levels of manganese as biomarkers of exposure and have suggested further investigation of 

using manganese levels in teeth and hair as exposure biomarkers. The use of tooth enamel as a potential 

biomarker has been explored by Ericson et al. (2007). Josephs et al. (2005) have also discussed the 

limitations of using manganese levels in serum or urine as a direct measure of exposure since free 

manganese does not accumulate in the circulatory system. Magnetic resonance imaging (MRI) in 

conjunction with analysis of manganese in whole blood (MnB), plasma (MnP), or red blood cells has 

been used in the diagnosis of manganism in humans (Jiang et al. 2007). Development of additional 

noninvasive methods for measuring whole-body or tissue-specific manganese burdens would be valuable 

in estimating human exposure levels, but would be limited by the same considerations of individual 

variability that limit existing methods. 

There is a need to evaluate the accuracy and reproducibility of analytical measures of manganese in 

biological media, so that analytical variability is not inappropriately incorporated into natural biological 

variability in reported data, as may now be the case. 

Effect. No reliable biomarkers of manganese effect are known. Biochemical changes such as altered 

blood or urinary levels of steroids, neurotransmitters, or their metabolites are plausible biomarkers of 

exposure, but this possibility has not been thoroughly investigated. Although methods exist for the 

analysis of these biochemicals, further work to improve the analyses does not seem warranted unless the 

utility of this approach is established. 

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MANGANESE 390 

7. ANALYTICAL METHODS 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. All humans are exposed to manganese, primarily through food (EPA 1984). Near a hazardous 

waste site that contains manganese or a factory that uses manganese, humans could receive above-average 

exposure by inhalation of air or ingestion of water, soil, or food. Methods exist for the analysis of 

manganese in air (NIOSH 2003a, 2003b, 2003c), water (APHA 1998a, 1998b, 1998c, 1998d; EPA 1994b, 

2007a), and soils and sediment (EPA 2007a). Methods are also available to analyze manganese in food 

(Capar and Cunningham 2000; Tinggi et al. 1997). 

7.3.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2008) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs pertinent to the analysis of manganese 

in biological or environmental samples. Donald Smith and co-workers at the University of California, 

Santa Cruz are studying the role of manganese in neurodegenrative disease using particle induced x-ray 

emission (PIXE) analyses of in situ brain regional manganese levels of rodents(FEDRIP 2008). Carmen 

Enid Martinez and co-workers at Pennsylvania State University are studying the elemental distribution in 

soil particles using novel techniques that include synchrotron-based microprobe- x-ray fluorescence 

(XRF) and x-ray diffraction (XRD) in addition to scanning electron microscopy coupled to energy or 

wavelength dispersive x-ray analysis (SEM/E-W-DS). Metal solubility measurements are to be studied 

by inductively coupled plasma emission spectroscopy (ICP), anodic/cathodic stripping voltammetry 

(A/C-SV), and ion-selective electrodes (ISE). 

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MANGANESE	 391 

8. REGULATIONS, ADVISORIES, AND GUIDELINES
 

MRLs are substance-specific estimates, which are intended to serve as screening levels, are used by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. 

An MRL of 3x10-4 mg manganese/m3 (0.3 μg manganese/m3

) in respirable dust has been derived for 

chronic inhalation exposure to manganese. As discussed in Appendix A, dichotomous models in the EPA 

Benchmark Dose software were fit to the incidence data for abnormal eye-hand coordination scores in 

battery workers exposed to respirable manganese (Roels et al. 1992). The model with the lowest AIC was 

selected as the best fitting model, and the BMCL10 from this model, 142 μg respirable manganese/m3

, was 

selected as the point of departure for the chronic inhalation MRL. The MRL of 0.3 μg respirable 

manganese/m3 was derived by adjusting the point of departure to a continuous exposure basis (142 x 5/7 x 

8/24) and dividing by an uncertainty factor of 100: 

•	 10 for uncertainty about human variability including possibly enhanced susceptibility of the 

elderly, infants, and children; individuals with chronic liver disease or diminished hepatobiliary 

function; and females and individuals with iron deficiency; and 

•	 10 for limitations/uncertainties in the database including the lack of epidemiological data for 

humans chronically exposed to soluble forms of manganese and the concern that the general 

population may be exposed to more soluble forms of manganese than most of the manganeseexposed workers in the principal and supporting studies and the uncertainty that a factor of 10 for 

human variability will provide enough protection for manganese effects on brain development in 

children. In addition, data on developmental toxicity for this route and duration of exposure are 

lacking. There is limited information on reproductive effects in females (one study in rat dams) 

and reported effects on male reproductive organs have not been clearly associated with decreased 

reproductive function. Though it is clear that the neurological system is the target organ for 

effects from chronic-duration inhalation exposure to manganese, data are lacking to fully 

characterize the potential risk for all organ systems from chronic inhalation exposure. 

No oral MRLs were derived for acute-, intermediate-, or chronic-duration oral exposure to manganese, 

but an interim guidance value of 0.16 mg manganese/kg/day, based on the Tolerable Upper Intake Level 

for adults of 11 mg manganese/day (established by the U.S. Food and Nutrition Board/Institute of 

Medicine [FNB/IOM 2001]) is recommended to be used for ATSDR public health assessments of oral 

exposure to inorganic forms of manganese. The interim guidance value is necessary because of the 

prevalence of manganese at hazardous waste sites and the fact that manganese is an essential nutrient. It 

is recommended to be used until more information on actual intake levels across environmental media can 

be obtained. 

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MANGANESE 392 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

The EPA derived a chronic inhalation RfC of 5x10-5 mg/m3 for respirable manganese (IRIS 2008). This 

value is based on the LOAEL of 0.15 mg/m3 from a study of battery workers exposed to manganese 

dioxide (Roels et al. 1992). EPA verified this assessment in 1993. The LOAEL was calculated by 

dividing the geometric mean concentration of the lifetime-integrated respirable dust concentration for the 

exposed workers by the average duration of employment in the facility. EPA calculated the RfC by 

adjusting for continuous exposure and dividing by an uncertainty factor of 1,000 (10 for use of a LOAEL, 

10 to protect sensitive individuals, and 10 for database limitations reflecting both the less-than-chronic 

periods of exposure and the lack of developmental data, as well as potential, but unquantified, differences 

in the toxicity of different forms of manganese). The estimated breathing rate in the exposed workers was 

assumed to be 10 m3

/workday. 

The EPA (IRIS 2008) derived an oral reference dose (RfD) value of 0.14 mg/kg/day manganese from all 

oral exposures. As of August 2008, this value was last updated in May 1996. The agency suggested 

using a modifying factor of 1 if the manganese is ingested in food and a modifying factor of 3 if the 

element is ingested in water or soil. The RfD was developed using a previous determination of the upper 

range of total dietary intake of 10 mg/day. The modifying factor of 1 was based on composite data on 

chronic human NOAELs from the World Health Organization (WHO 1973) (0.11–0.13 mg/kg/day), the 

National Academy of Sciences/National Research Council (1989) “safe and adequate level” (0.04– 

0.07 mg/kg/day), and a study by Freedland-Graves et al. (1994) concerning nutritional requirements for 

manganese. The FNB/IOM (2001) re-established an Adequate Intake (AI) value for manganese for men 

and women at 2.3 and 1.8 mg manganese/day, respectively (for 70-kg individuals, this would result in 

exposures of 0.033 and 0.026 mg manganese/kg/day, respectively). A Tolerable Upper Intake Level (UL) 

of 11 mg/day was also set by the FNB/IOM (2001) for adults based on a NOAEL for Western diets 

(approximately 0.16 mg manganese/kg/day assuming a 70-kg body weight). 

The international and national regulations, advisories, and guidelines regarding manganese in air, water, 

and other media are summarized in Table 8-1. 

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MANGANESE 393 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Manganese 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification No data IARC 2008 

WHO Air quality guidelines 

Manganesea 0.15 μg/m3 

WHO 2000a 

Drinking water quality guidelines 

Manganeseb 0.4 mg/L 

WHO 2004a 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA) 

Manganese 

MMTc 

0.2 mg/m3 

0.2 mg/m3 

ACGIH 2007 

TLV basis (critical effects) 

Manganese Central nervous system 

impairment 

MMT Central nervous system 

impairment, lung, liver, 

and kidney damage 

EPA Second list of AEGL priority chemicals 

for guideline development 

EPA 2008a 

Manganese Yes 

MMT Yes 

NIOSH Category of pesticides NIOSH 1992 

Potassium permanganate Group 1 pesticide 

REL (10-hour TWA) 

Manganese 

Manganese (II,III) oxided 

MMTe 

1 mg/m3 

Not established 

0.2 mg/m3 

NIOSH 2005 

STEL (15-minute TWA) 

Manganese 3 mg/m3 

IDLH 

Manganese 500 mg/m3 

Target organs 

Manganese Respiratory system, 

central nervous system, 

blood, and kidneys 

Manganese (II,III) oxide Respiratory system, 

central nervous system, 

blood, and kidneys 

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MANGANESE	 394 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Manganese 

Agency Description	 Information Reference 

NATIONAL (cont.) 

NIOSH Target organs (cont.) 

MMT 

OSHA	 PEL (8-hour TWA) for general industry 

(ceiling limit) 

Manganese (compounds and fume) 

PEL (8-hour TWA) for shipyard industry 

(ceiling limit) 

Manganese (compounds and fume) 

PEL (8-hour TWA) for construction 

industry (ceiling limit) 

Manganese (compounds and fume) 

b. Water 

EPA Designated as hazardous substances in 

accordance with Section 311(b)(2)(A) of 

the Clean Water Act 

Potassium permanganate 

Drinking water contaminant candidate 

list 

Manganese 

Drinking water standards and health 

advisories 

Manganese 

1-Day health advisory for a 10-kg 

child 

10-Day health advisory for a 10-kg 

child 

DWEL 

Lifetime 

National recommended water quality 

criteria 

Manganesef 

Human health for consumption of 

water + organism 

Human health for consumption of 

organism only 

National secondary drinking water 

standards 

Manganeseg 

Reportable quantities of hazardous 

substances designated pursuant to 

Section 311 of the Clean Water Act 

Potassium permanganate 

Eyes, central nervous 

system, liver, and 

kidneys 

5 mg/m3 

5 mg/m3 

5 mg/m3 

Yes 

Yes 

1 mg/L 

1 mg/L 

1.6 mg/L 

0.3 mg/L 

0.05 mg/L 

0.1 mg/L 

0.05 mg/L 

100 pounds 

OSHA 2007c 

29 CFR 1910.1000, 

Table Z-2 

OSHA 2007a 

29 CFR 1915.1000 

OSHA 2007b 

29 CFR 1926.55, 

Appendix A 

EPA 2008b 

40 CFR 116.4 

EPA 1998 

EPA 2006a 

EPA 2006c 

EPA 2003b 

EPA 2008d 

40 CFR 117.3 

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MANGANESE 395 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Manganese 

Agency Description Information Reference 

NATIONAL (cont.) 

c. Food 

EPA Inert ingredients permitted for use in EPA 2008e 

nonfood use pesticide products 

Mn(II) carbonate Yes 

Manganese dioxide Yes 

Manganese sulfate Yes 

Potassium permanganate Yes 

FDA Bottled drinking water FDA 2007a 

Manganese 0.05 mg/L 21 CFR 165.110 

EAFUSh FDA 2008 

Potassium permanganate Yes 

Indirect food additives: adhesives and FDA 2007b 

components of coatings 21 CFR 175.105 

Potassium permanganate Yes 

d. Other 

ACGIH Carcinogenicity classification ACGIH 2007 

Manganese No data 

MMT No data 

DEA Records and reports of listed chemicals DEA 2007 

Potassium permanganate List II chemical 21 CFR 1310.02 

EPA Carcinogenicity classification IRIS 2008 

Manganese Group Di 

RfC 

Manganese 5x10-5 mg/m3 

RfD 

Manganese 0.14 mg/kg/day 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous EPA 2008c 

substance 40 CFR 302.4 

Manganesej Yes 

Potassium permanganatek Yes 

Reportable quantity 

Manganese Nonel 

Potassium permanganate 100 pounds 

Effective date of toxic chemical EPA 2008g 

release reporting 40 CFR 372.65 

Manganese 01/01/1987 

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MANGANESE 396 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Manganese 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA Superfund, emergency planning, and 

community right-to-know 

Extremely Hazardous Substances EPA 2008f 

MMT 40 CFR 355, 

Reportable quantity 100 pounds Appendix A 

Threshold planning quantity 100 pounds 

NTP Carcinogenicity classification No data NTP 2005 

a

TWA based on effects other than cancer or odor/annoyance using an averaging time of 1 year.

b

Concentrations of the substance at or below the health-based guideline value may affect the appearance, taste, or 

odor of the water, resulting in consumer complaints. c

Skin designation refers to the potential significant contribution to the overall exposure by the cutaneous route, 

including mucous membranes and the eyes, by contact with vapors, liquids, and solids. d

NIOSH has not established a REL for magnesium oxide fume under the “Proposed Rule on Air Contaminants" 

(29 CFR 1910, Docket No. H-020) in which NIOSH questioned whether the OSHA PEL for magnesium oxide fume 

(1 mg/m3

) was adequate enough to protect workers from potential health hazards (NIOSH 2005). e

Skin designation indicates the potential for dermal absorption; skin exposure should be prevented as necessary 

through the use of good work practices, gloves, coveralls, goggles, and other appropriate equipment. f

The human health criteria are based on carcinogenicity of 10-6 risk. This criterion for manganese is not based on 

toxic effects, but rather is intended to minimize objectionable qualities such as laundry stains and objectionable 

tastes in beverages. 

g

National Secondary Drinking Water Standards are non-enforceable guidelines regulating contaminants that may 

cause cosmetic effects (such as skin or tooth discoloration) or aesthetic effects (such as taste, odor, or color) in 

drinking water. h

The EAFUS list of substances contains ingredients added directly to food that FDA has either approved as food 

additives or listed or affirmed as GRAS. i

Group D: not classifiable as to human carcinogenicity. 

j

Designated CERCLA hazardous substance pursuant to Section 112 of the Clean Air Act. k

Designated CERCLA hazardous substance pursuant to Section 311(b)(2) of the Clean Water Act. 

l

No reportable quantity is being assigned to the generic or broad class. 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels; 

CERCLA = Comprehensive Environmental Response, Compensation, and Liability Act; CFR = Code of Federal 

Regulations; DEA = Drug Enforcement Administration; DWEL = drinking water equivalent level; EAFUS = Everything 

Added to Food in the United States; EPA = Environmental Protection Agency; FDA = Food and Drug Administration; 

GRAS = Generally Recognized As Safe; IARC = International Agency for Research on Cancer; IDLH = immediately 

dangerous to life or health; IRIS = Integrated Risk Information System; MMT = methylcyclopentadienyl manganese 

tricarbonyl; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; 

OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; REL = recommended 

exposure limit; RfC = inhalation reference concentration; RfD = oral reference dose; STEL = short-term expsoure 

limit; TLV = threshold limit values; TWA = time-weighted average; WHO = World Health Organization 

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_______________________ 

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10. GLOSSARY 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 

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MANGANESE 486 

10. GLOSSARY 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 

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MANGANESE 487 

10. GLOSSARY 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 

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MANGANESE 488 

10. GLOSSARY 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 

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MANGANESE 489 

10. GLOSSARY 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

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MANGANESE 490 

10. GLOSSARY 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 

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MANGANESE A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

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MANGANESE A-2 

APPENDIX A 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-32, Atlanta, Georgia 30333. 

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MANGANESE A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Manganese 

CAS Number: 7439-96-5 

Date: August 8, 2008 

Profile Status: Draft 3, Pre-Public 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 

Species: Human 

Minimal Risk Level: 0.0003 mg respirable manganese/m3 (0.3 μg/m3

) 

Reference: Roels HA, Ghyselen P, Buchet JP, et al. 1992. Assessment of the permissible exposure level 

to manganese in workers exposed to manganese dioxide dust. Br J Ind Med 49:25-34. 

Experimental design: Neurological effects of manganese exposure were evaluated in 92 male workers in 

a dry alkaline battery factory. The control group was 101 age- and area-matched workers not 

occupationally exposed to manganese but with similar work schedules and workloads. Workers were 

exposed for an average duration of 5.3 years (range 0.2–17.7 years) to average (geometric mean) 

concentrations of 0.215 and 0.948 mg manganese/m3 in respirable and total dust, respectively. The 

authors noted that the work processes had not changed significantly in the last 15 years, indicating that 

past exposures should be comparable to those measured in the study. Neurological function was 

measured using an audioverbal short term memory test, a simple visual reaction time test using a 

chronoscope, and three manual tests of hand steadiness, coordination, and dexterity. This report provided 

good documentation of individual exposure data and characterization of the population studied. 

Effects noted in study and corresponding doses: Manganese-exposed workers performed significantly 

worse than the controls on the neurobehavioral tests, with particular differences in simple reaction time, 

eye-hand coordination, and hand steadiness. Dr. Harry Roels provided the data on the manganeseexposed group evaluated in this study. These data included individual exposure levels and whether the 

individual had an abnormal performance in the neurobehavioral tests (scores below the 5th percentile 

score of the control group). Percent precision score in the eye-hand coordination test was the most 

sensitive end point among the end points showing statistically significantly elevated incidences of 

abnormal scores and was selected as the basis of the MRL. Average exposure concentration for each 

worker was calculated by dividing the individual lifetime integrated respirable concentration (LIRD; 

calculated by Dr. Roels from occupational histories and measurements of workplace air manganese 

concentrations) by the individual’s total number of years working in the factory. Individuals were 

grouped into eight exposed groups and the control group, and the average of the range in each group was 

used in benchmark modeling of the incidence data for number of workers with abnormal percent 

precision eye-hand coordination scores (Table A-1). 

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MANGANESE A-4 

APPENDIX A 

Table A-1. Incidence Data for Abnormal Eye-Hand Coordination Scores in 

Workers Exposed to Respirable Manganesea
 

Range of Average Number of 

manganese manganese workers with 

(respirable) (respirable) abnormal eyeexposure exposure hand 

concentrationsc concentration coordination Total number 

Groupb (μg/m3) (μg/m3) scored of workers 

1 Control 0 5 101 

2 1.0–99 33 1 7 

3 100–174 160 3 11 

4 175–199 179 3 28 

5 200–249 208 3 22 

6 250–299 280 1 6 

7 300–399 307 2 3 

8 400–499 451 4 9 

9 >500 (523–650) 564 4 6 

a

Based on individual exposure and dichotomized response data collected by Roels et al. (1992).

b

Individuals were sorted into 9 groups, based on manganese exposure, for use in benchmark dose modeling c

For each individual, the time-weighted average exposure concentration (respirable manganese) was calculated by 

dividing the individual lifetime integrated respirable concentrations (LIRD) by the individual’s respective total number 

of years exposed.

d

An abnormal eye-hand coordination score was defined by Roels as a score below the 5th percentile score in the 

control group for percent precision (52.4) in the eye-hand coordination test. 

Available dichotomous models in the EPA Benchmark Dose Software (version 1.4.1c) were fit to the 

incidence data for abnormal eye-hand coordination scores in workers exposed to respirable manganese 

(Roels et al. 1992, Table A-1). Results from the modeling are shown in Table A-2, including: (1) the 

BMC10 and the 95% lower confidence limit (BMCL10) calculated as an estimate of the concentration 

associated with a 10% extra risk for an abnormal score; (2) BMC05 and BMCL05 values; (3) the p-value 

for the chi-square goodness of fit statistic (adequate fit, p > 0.1); and (4) Akaike’s Information Criteria 

(AIC) [lower AIC indicates better fit when comparing models, EPA (2000)]. Based on the chi-square and 

AIC measures of fit, all of the models provided adequate and comparable fits to the data (the quantal 

linear and Weibull models had the same parameter values The model with the lowest AIC, the logistic 

model, was selected as the best fitting model (Table A-2), and the BMCL10 from the logistic model, 

142 μg/m3

, was selected as the point of departure for the chronic inhalation MRL. Figure A-1 plots 

predicted risks for abnormal scores from the logistic model and observed incidence values calculated 

from data in Table A-1. 

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MANGANESE A-5 

APPENDIX A 

Table A-2. Modeling Results for Incidences of Abnormal Eye-Hand Coordination 

Scores in Workers Exposed to Respirable Manganese
 

BMC10 BMCL10 BMC05 BMCL05 

Model (μg/m3) (μg/m3) (μg/m3) (μg/m3) x2 p-value AIC 

Gammaa 183.82 87.00 132.27 42.36 0.42 135.47 

Logistic 179.80 142.61 109.29 84.14 0.58 133.15 

Log-logisticb 185.53 91.70 134.25 43.83 0.42 135.48 

Multi-stagec 110.67 73.28 53.88 35.67 0.42 135.33 

Probit 166.66 131.67 98.75 76.14 0.59 133.19 

Log-probitb 187.21 122.99 143.17 85.52 0.39 135.63 

Quantal linear 181.91 88.19 125.38 42.93 0.43 135.37 

Weibulla 181.91 88.19 125.38 42.93 0.43 135.37 

a

Restrict power ≥1 b

Slope restricted to >1 

c

Restrict betas ≥0; lowest degree polynomial with an adequate fit is reported; degree of polynomial=1 

Source: Roels et al. 1992 

Figure A-1. Predicted (Logistic Model) and Observed Incidence of Abnormal EyeHand Coordination Scores in Workers Exposed to Respirable Manganese (Roels 

et al. 1992)* 

Logistic Model with 0.95 Confidence Level 

Fraction Affected 

1 

0.8 

0.6 

0.4 

0.2 

0 

BMDL BMD 

Logistic 

0 100 200 300 400 500 

dose 

09:27 06/13 2008 

*BMD=BMC, BMDL=BMCL; BMDs and BMDLs indicated are associated with a 10% extra risk change from the 

control, and are in units of μg/m3

. 

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MANGANESE A-6 

APPENDIX A 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] Other BMCL10 

Uncertainty and modifying factors used in MRL derivation: 

[ ] 10 for the use of a LOAEL 

[ ] 10 for extrapolation from animals to humans 

[X]	 10 for human variability including possibly enhanced susceptibility of the elderly, infants, and 

children; individuals with chronic liver disease or parenteral nutrition; and females and 

individuals with iron deficiency. 

[X] 10 for limitations/uncertainties in the database including the lack of epidemiological data for 

humans chronically exposed to soluble forms of manganese and the concern that the general 

population may be exposed to more soluble forms of manganese than most of the manganeseexposed workers in the principal and supporting studies and the uncertainty that a factor of 10 for 

human variability will provide enough protection for manganese effects on brain development in 

children. In addition, data on developmental toxicity for this route and duration of exposure are 

lacking. There is limited information on reproductive effects in females (one study in rat dams) 

and reported effects on male reproductive organs have not been clearly associated with decreased 

reproductive function. Though it is clear that the neurological system is the target organ for 

effects from chronic-duration inhalation exposure to manganese, data are lacking to fully 

characterize the potential risk for all organ systems from chronic inhalation exposure. 

Was a conversion used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

Not applicable. 

Was a conversion used from intermittent to continuous exposure? 

[X]	 5/7 to account for intermittent exposure (5 days/week) 

[X]	 8/24 to account for intermittent exposure (8 hours/day) 

MRL = 0.1426 mg manganese/m3 x 5d/7d x 8h/24h x 1/100 = 0.0003 mg manganese/m3 = 0.3 μg 

manganese/m3

. 

Other additional studies or pertinent information that lend support to this MRL: An alternative approach 

to selecting a point of departure (averaging BMCL10 values across all models in Table A-2) arrived at a 

similar point of departure of 105 μg respirable manganese/m3

, which would yield an identical MRL value. 

Neurological effects from repeated inhalation exposure to manganese are well recognized as effects of 

high concern based on case reports and epidemiological studies of groups of occupationally exposed 

people and results from animal inhalation studies. A number of epidemiological studies have used 

batteries of neurobehavioral tests of neuromotor, cognition, and mood states to study the psychological or 

neurological effects of exposure to low levels of manganese in the workplace (Bast-Pettersen et al. 2004; 

Beuter et al. 1999; Blond and Netterstrom 2007; Blond et al. 2007; Bouchard et al. 2003, 2005, 2007a, 

2007b; Chia et al. 1993a, 1995; Crump and Rousseau 1999; Deschamps et al. 2001; Gibbs et al. 1999; 

Iregren 1990; Lucchini et al. 1995, 1999; Mergler et al. 1994; Myers et al. 2003a, 2003b; Roels et al. 

1987a, 1992, 1999; Wennberg et al. 1991) or in environmental media close to manganese-emitting 

industries (Lucchini et al. 2007; Mergler et al. 1999; Rodríguez-Agudelo et al. 2006). Some of these 

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MANGANESE A-7 

APPENDIX A 

studies have found statistically significant differences between exposed and non-exposed groups or 

significant associations between exposure indices and neurological effects (Bast-Pettersen et al. 2004; 

Chia et al. 1993a; Iregren 1990; Lucchini et al. 1995, 1999; Mergler et al. 1994; Roels et al. 1987a, 1992; 

Wennberg et al. 1991), whereas others have not found significant associations (Deschamps et al. 2001; 

Gibbs et al. 1999; Myers et al. 2003a, 2003b; Young et al. 2005). Table A-3 summarizes results from 

these studies. Comparison of the effect levels in these studies provides support for selection of the Roels 

et al. (1992) as the basis of the MRL; the advantage of the Roels et al. (1992) study is that individual 

worker data were available to support a benchmark dose analysis. 

Table A-3. Epidemiological Studies of Neurological End Points in Workers
 

Exposed to Low Levels of Manganese in Workplace Air
 

Estimated 

exposure 

(mg Number Number 

Reference 

Place of 

work 

manganese/ 

m3)

a 

Years 

workedb 

of 

exposed 

of 

control Effects 

Chia et al. 

1993a 

Roels et al. 

1987a 

Roels et al. 

1992, 1999 

Iregren 

1990; 

Wennberg et 

al. 1991 

Lucchini et 

al. 1995 

Lucchini et 

al. 1999 

Mergler et al. 

1994 

Gibbs et al. 

1999 

Deschamps 

et al. 2001 

Myers et al. 

2003a 

Mn ore 

process 

Mn salt and 

oxide plant 

Dry alkaline 

battery plant 

Mn foundry 

Mn alloy 

plant 

Mn alloy 

plant 

Mn alloy 

plant 

Mn process 

plant 

Enamels 

production 

plant 

Mn mines 

1.59 

0.97 

0.948 

(0.215) 

0.14 

0.149 

0.097 

(0.038) 

0.23 

(0.04) 

0.18 

(0.051) 

2.05 

(0.035) 

0.21 

7.4 

7.1 

5.3 

9.9 

13 

11.5 

16.7 

12.7 

19.7 

10.8 

17 

141 

92 

30 

58 

61 

115 

75 

134 

489 

17 

104 

37 

60 

None 

87 

115 

75 

137 

None 

↓ finger tapping, digit symbol, 

pursuit aiming 

↓ reaction time, short-term 

memory, eye-hand 

coordination, hand steadiness 

↓ reaction time, short-term 

memory, eye-hand 

coordination, hand steadiness 

↓ finger tapping, reaction time 

↓ finger tapping, short-term 

memory with increasing 

exposure indices 

↓ hand movements, finger 

tapping, short-term memory 

↓ rapid hand movements, 

cognitive flexibility; ↑ indices for 

tension, anger, fatigue, 

confusion 

No effects on neuromotor tests 

or self-reported symptoms 

No effects on self-reported 

symptoms or several cognitive 

tests; no neuromotor tests 

given. 

No associations between 

indices of exposure and 

outcomes from tests of 

neuromotor and cognitive 

functions or self-reported 

symptoms 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

MANGANESE A-8 

APPENDIX A 

Table A-3. Epidemiological Studies of Neurological End Points in Workers
 

Exposed to Low Levels of Manganese in Workplace Air
 

Estimated 

exposure 

(mg Number Number 

Place of manganese/ Years of of 

3

)

a Reference work m workedb exposed control Effects 

Myers et al. Mn smelter 0.85 18.2 509 67 Neurobehavioral test batteries 

2003b; (0.58) showed significant effects in 

Young et al. only a few of the many end 

2005 points evaluated 

Bast- Mn alloy 0.753 20.2 100 100 ↑ scores for hand tremor, but no 

Pettersen et plant (0.049) effect on other neuromotor or 

al. 2004 cognitive tests or symptoms 

Blond and Steel works 0.07 24 60–92 14–19 ↓ fast hand and finger 

Netterstrom movement, but no effects on 

2007; Blond slow movements, reaction time, 

et al. 2007 or cognitive end points 

a

Mean, median, or midpoint of reported ranges of manganese concentration in total dust. Values for respirable dust
 

are noted in parentheses when they were available.

b

Mean, median, or midpoint of reported ranges of years employed at the facility.
 

The neurological effects associated with prolonged low-level manganese exposure generally have been 

subtle changes including deficits in tests of neuromotor or cognitive functions and altered mood states; 

they have been referred to by various authors as preclinical or subclinical neurological effects. 

Manganese air concentrations associated with these effects in chronically exposed workers range from 

about 0.07 to 1.59 mg manganese/m3 (manganese in total or inhalable dust measurements; values for 

manganese in respirable dust are noted in parentheses in Table A-3). For several of these work 

environments, values of concentrations of manganese in respirable dust (generally particulate diameters 

<10 μm) represented <20–80% of the total dust values. 

Several benchmark analyses of results from other epidemiological data for neurobehavioral deficits in 

manganese-exposed workers provide support for the MRL. 

Dr. Anders Iregren provided ATSDR with individual worker data on total dust manganese exposure and 

performance on neurobehavioral tests for the occupational cohort that participated in his study (Iregren 

1990; Wennberg et al. 1991). A benchmark analysis was also performed with these data under contract 

with ATSDR (Clewell and Crump 1999) and the BMCL10 value derived from this evaluation was 

0.071 mg manganese/m3 based upon the reported observation that the respirable fraction ranged upwards 

to 80% of the total dust measured. This BMCL10 value is similar to that estimated for the Roels et al. 

(1992) study (0.105 mg manganese/m3

), thus giving support to the value obtained for the current MRL 

study. 

Clewell et al. (2003) conducted benchmark analyses on data from three neuromotor tests in the Roels et 

al. (1992) study (visual reaction time, eye-hand coordination, and hand steadiness) and from five 

neuromotor tests in the Gibbs et al. (1999) study (hole 6 of the hand steadiness test, percent precision of 

the eye-hand coordination test, reaction time in the complex reaction test, RMS amplitude in the steady 

test, and tap time). Exposure measures in these analyses were recent measures of manganese 

concentrations in respirable dust. BMCL10 values were 0.257, 0.099, and 0.202 mg manganese/m3 for the 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MANGANESE A-9 

APPENDIX A 

visual reaction time, eye-hand coordination, and hand steadiness data from the Roels et al. (1992) study. 

BMCL10 values from the analyses of outcomes from the Gibbs et al. (1999) study ranged from 0.09 to 

0.27 mg manganese/m3 (averaging the BMCLs within end points across different benchmark dose models 

applied to the data). Clewell et al. (2003) did not have individual worker data from the Iregren (1990) or 

Mergler et al. (1994), but, based on some assumptions about exposures (e.g., all exposed workers were 

exposed to average concentrations for the facilities and respirable manganese concentrations were 

calculated for the Iregren workers based on an assumption that 50% of total dust manganese was 

respirable), they calculated BMCL10 values for six end points from the Mergler et al. (1994) study and the 

simple reaction time end point in the Iregren (1990) study. BMCL10 values ranged from 0.1 to 0.3 mg 

manganese/m3 from the Mergler et al. (1994) study end points to 0.1 mg manganese/m3 for the reaction 

time end point in the Iregren (1990) study. 

Health Canada (2008) recently prepared a draft document in which benchmark dose analyses were 

conducted on data for neurobehavioral end points from the study of Mn alloy workers by Lucchini et al. 

(1999). Using the average manganese concentrations in respirable dust over the 5-year period before 

testing as the dose metric, dose-response data for six tests of fine motor control, two aspects of memory 

tests, and one test of mental arithmetic were fit to linear models, which were used to calculate BMCL05 

values ranging from about 0.019 to 0.0588 mg manganese/m3

. After adjustment to convert from 

occupational exposure (5 days/week, 8 hours/24 hours) to continuous exposure, adjusted BMCL05 values 

were divided by a total uncertainty factor of 100 to arrive at prospective reference concentrations. The 

uncertainty factor was comprised of a factor of 10 to account for interindividual variability in response to 

manganese to protect possibly enhanced susceptibility of the elderly, infants and children, individuals 

with asymptomatic pre-parkinsonism, individuals with chronic liver disease or parenteral nutrition, and 

females and individuals with iron deficiency and a second factor of 10 to account for limitations/ 

uncertainties in the database including: (1) the general population may be exposed to more soluble forms 

of manganese than most of the manganese-exposed workers; (2) the lack of extensive studies of the effect 

of prenatal exposure to manganese; and (3) the potential effects that manganese exposure early in life may 

have on health outcomes later in life. The prospective reference concentrations ranged from about 0.05 to 

0.08 μg manganese/m3

. 

The 2000 ATSDR Toxicological Profile for Manganese derived a chronic MRL for inorganic manganese 

of 0.00004 mg manganese/m3 (manganese in respirable dust), based on a BMCL10 of 0.074 mg 

manganese/m3 (manganese in respirable dust) for abnormal performance in tests of hand steadiness, eyehand coordination, or reaction time in the same study of 92 male workers in a dry alkaline battery plant 

(Roels et al. 1992) used in the current assessment. The MRL was derived by adjustment of the BMCL10 

to a continuous exposure basis and division by an uncertainty factor of 500 (10 for human variability, 

10 for database deficiencies and limitations, and a modifying factor of 5 for potentially increased 

susceptibility in children based on differential kinetics in the young). 

The current assessment does not use a modifying factor of 5 for potentially increased susceptibility in 

children based on differential kinetics in the young, because recent studies in lactating rats and their 

offspring exposed to manganese by the oral or inhalation routes suggest that the human variability factor 

of 10 provides sufficient protection for the differential kinetics in children and adults. For example, in 

neonatal rats orally exposed to 25 or 50 mg manganese/kg/day manganese chloride from postnatal day 1 

through 21, manganese concentrations in various brain regions were about 2-fold higher than brain 

manganese concentrations in adult rats exposed to the same oral dose levels for 21 days (Dorman et al. 

2000). Similarly, 18-day-old neonatal rats exposed from birth to aerosols of manganese sulfate at 1 mg 

manganese/m3

, 6 hours/day showed a 2.6-fold increase in striatum manganese concentrations, compared 

with controls, while lactating adults exposed to the same aerosol concentration showed a 1.7-fold increase 

compared with controls (Dorman et al. 2005a). 

***DRAFT FOR PUBLIC COMMENT*** 
MANGANESE A-10 

APPENDIX A 

Agency Contact (Chemical Manager): Malcolm Williams, DVM, Ph.D. 

***DRAFT FOR PUBLIC COMMENT*** 
MANGANESE A-11 

APPENDIX A 

This page is intentionally blank. 

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MANGANESE B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1.	 What effects are known to occur in humans? 

2.	 What effects observed in animals are likely to be of concern to humans? 

3.	 What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

MANGANESE B-2 

APPENDIX B 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

MANGANESE B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1)	 Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2)	 Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3)	 Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4)	 Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5)	 Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6)	 Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7)	 System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8)	 NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

 

 

 

MANGANESE B-4 

APPENDIX B 

(9)	 LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10)	 Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11)	 CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12)	 Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13)	 Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14)	 Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)	 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in 

mg/kg/day. 

(16)	 NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17)	 CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

MANGANESE B-5 

APPENDIX B 

(18)	 Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19)	 Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 

***DRAFT FOR PUBLIC COMMENT*** 
SAMPLE

***DRAFT FOR PUBLIC COMMENT*** 

1 → Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

LOAEL (effect) Exposure 

Key to frequency/ NOAEL Less serious Serious (ppm) figurea Species duration System (ppm) (ppm) Re

2 3 4 

→ INTERMEDIATE EXPOSURE 

5 6 7 8 9 10 

→ Systemic ↓ ↓ ↓ ↓ ↓ ↓

18 Rat 13 wk Resp 3b 10 (hyperplasia) 

→ 5 d/wk Nit

6 hr/d 

CHRONIC EXPOSURE 

Cancer 11 

↓

38 Rat 18 mo 20 (CEL, multiple Wo

5 d/wk organs) 7 hr/d 

39 Rat 89–104 wk 10 (CEL, lung tumors, NT

5 d/wk nasal tumors) 6 hr/d 

40 Mouse 79–103 wk 10 (CEL, lung tumors, NT

5 d/wk hemangiosarcomas) 6 hr/d 

12 → a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent ex

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 
***DRAFT FOR PUBLIC COMMENT*** 
MANGANESE B-8 

APPENDIX B 

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***DRAFT FOR PUBLIC COMMENT*** 
MANGANESE C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD/C benchmark dose or benchmark concentration 

BMDX dose that produces a X% change in response rate of an adverse effect 

BMDLX 95% lower confidence limit on the BMDX 

BMDS Benchmark Dose Software 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

MANGANESE C-2 

APPENDIX C 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMDG North America/Intergovernmental Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

MANGANESE C-3 

APPENDIX C 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

MANGANESE C-4 

APPENDIX C 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 

***DRAFT FOR PUBLIC COMMENT*** 
 

MANGANESE C-5 

APPENDIX C 

> greater than 

≥ greater than or equal to 

= equal to 

< less than 

≤ less than or equal to 

% percent 

α alpha 

β beta 

γ gamma 

δ delta 

μm micrometer 

μg microgram 

q1

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 

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MANGANESE C-6 

APPENDIX C 

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MANGANESE D-1 

APPENDIX D. INDEX
 

absorbed dose.................................................................................................................... 283, 287, 365, 368
 

acetylcholine .............................................................................................................................................175
 

acetylcholinesterase .................................................................................................................. 170, 175, 277
 

active transport.......................................................................................................................... 214, 236, 259
 

adrenal gland..................................................................................................................................... 139, 184
 

adsorbed............................................................................................................................ 343, 352, 353, 358
 

adsorption..................................................................................................................................................353
 

alanine aminotransferase................................................................................................................... 156, 187
 

ambient air .......................................................................................................................... 11, 349, 357, 368
 

anaerobic........................................................................................................................................... 354, 355
 

anemia....................................................................................................................................... 205, 295, 374
 

bioaccumulation........................................................................................................................................353
 

bioavailability ..................................................................... 38, 204, 206, 286, 293, 358, 371, 373, 377, 379
 

bioconcentration factor .............................................................................................................................353
 

biomarker .................................. 205, 282, 283, 285, 286, 287, 288, 290, 315, 320, 364, 373, 380, 381, 389
 

blood cell count........................................................................................................................... 27, 136, 142
 

body weight effects............................................................................................. 64, 140, 141, 182, 188, 189
 

breast milk......................................................................... 165, 204, 206, 210, 233, 281, 293, 319, 362, 370
 

cancer.............................................................................................................. 5, 15, 184, 225, 272, 308, 395
 

carcinogenic .............................................................................................. 15, 19, 39, 91, 179, 180, 183, 308
 

carcinogenicity.............................................................................................................................. 15, 34, 395
 

cardiovascular ........................................................................... 27, 28, 61, 62, 134, 135, 180, 185, 186, 321
 

cardiovascular effects...................................................................................... 27, 61, 62, 134, 180, 185, 186
 

chromosomal aberrations.......................................................................................... 194, 197, 199, 210, 309
 

clearance ......................40, 199, 200, 220, 229, 236, 242, 248, 249, 250, 253, 254, 255, 265, 285, 299, 300
 

cognitive function ................................................................................................... 24, 70, 81, 152, 173, 265
 

death.......................................................... 39, 58, 61, 92, 132, 133, 138, 143, 153, 154, 166, 180, 185, 304
 

deoxyribonucleic acid (see DNA).............................................................................................................196
 

dermal effects.............................................................................................................. 64, 140, 181, 188, 302
 

developmental effects ..................... 17, 18, 91, 170, 171, 174, 179, 183, 192, 278, 279, 296, 306, 310, 318
 

developmental neurotoxicity.....................................................................................................................175
 

DNA (see deoxyribonucleic acid)............................................................................................. 194, 196, 283
 

dopamine........................................ 27, 28, 86, 156, 158, 160, 161, 163, 164, 170, 173, 174, 175, 176, 177, 

229, 260, 262, 265, 267, 277, 279, 285, 289, 292, 301, 307, 322
 

elimination half-time......................................................................................................................... 235, 236
 

elimination rate ................................................................................................................................. 248, 256
 

endocrine............................................................................................... 63, 64, 139, 140, 181, 188, 269, 270
 

endocrine effects ........................................................................................... 63, 64, 139, 140, 181, 188, 270
 

erythema....................................................................................................................................................181
 

fetal tissue ................................................................................................................................. 207, 218, 276
 

fetus........................................................................................... 178, 209, 218, 271, 277, 281, 311, 319, 370
 

follicle stimulating hormone (see FSH)...................................................................................................... 63
 

FSH (see follicle stimulating hormone)...................................................................... 63, 166, 167, 172, 270
 

gastrointestinal effects ................................................................................................ 62, 135, 136, 181, 186
 

general population.................................................................. 12, 23, 25, 209, 279, 282, 294, 302, 305, 341, 

357, 364, 368, 371, 372, 374, 375, 378, 391 

genotoxic............................................................................................................................. 39, 197, 199, 309 

genotoxicity....................................................................................................................................... 197, 309 

groundwater .................................................................................................. 3, 294, 341, 350, 353, 358, 361 

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MANGANESE D-2 

APPENDIX D 

growth retardation.....................................................................................................................................166
 

half-life........................................................................................................ 58, 203, 227, 283, 299, 352, 354
 

hematological effects .................................................................................................. 62, 136, 137, 181, 186
 

hepatic effects ............................................................................................... 62, 63, 137, 138, 181, 187, 290
 

hydroxyl radical ........................................................................................................................................265
 

immune system ........................................................................................................................... 65, 142, 312
 

immunological .............................................................................................................. 39, 65, 142, 182, 189
 

immunological effects......................................................................................................................... 65, 142
 

Kow ............................................................................................................................................ 327, 328, 329
 

LD50............................................................................................................................. 58, 132, 133, 180, 184
 

lymphatic ..................................................................................................................................................203
 

lymphoreticular................................................................................................................... 65, 142, 182, 189
 

magnetic resonance imaging (see MRI)................................................................................ 2, 7, 12, 39, 339
 

menstrual...................................................................................................................................................270
 

metabolic effects ........................................................................................................... 64, 65, 142, 182, 189
 

micronuclei ....................................................................................................................................... 197, 199
 

milk ................14, 28, 150, 173, 178, 179, 204, 206, 209, 210, 214, 233, 280, 281, 293, 311, 362, 370, 377
 

minimal risk level (see MRL).....................................................................................................................19
 

MRI (see magnetic resonance imaging)............... 7, 12, 39, 66, 68, 150, 152, 153, 183, 213, 220, 224, 226, 

228, 259, 268, 273, 282, 286, 288, 295, 296, 299, 312, 

315, 320, 321, 339, 371, 374, 380, 383, 389
 

MRL (see minimal risk level)................. 19, 22, 23, 24, 26, 28, 31, 32, 34, 35, 40, 304, 305, 308, 317, 391
 

mucociliary ................................................................................................. 68, 199, 200, 248, 257, 298, 316
 

musculoskeletal effects ....................................................................................................... 63, 137, 181, 187
 

neonatal.............................................................. 27, 28, 29, 31, 87, 153, 172, 174, 175, 176, 177, 218, 222, 

233, 263, 275, 276, 277, 280, 293, 311, 319, 380
 

neoplastic ....................................................................................................................................................39
 

neurobehavioral........................ 16, 21, 22, 23, 24, 25, 26, 27, 28, 29, 31, 34, 70, 73, 75, 76, 77, 78, 79, 80, 

81, 82, 84, 86, 147, 163, 170, 266, 267, 268, 270, 274, 281, 

286, 288, 294, 305, 307, 308, 310, 311, 312, 317, 380
 

neurochemical..................................... 27, 160, 174, 176, 260, 264, 267, 268, 276, 277, 281, 294, 311, 317
 

neurodevelopmental............................................................................................................................ 27, 310
 

neurological effects........ 14, 15, 16, 17, 19, 21, 23, 33, 38, 66, 69, 70, 73, 78, 82, 84, 86, 88, 91, 143, 144, 

146, 148, 155, 164, 177, 182, 189, 190, 212, 272, 273, 275, 278, 282, 287, 288, 

290, 293, 294, 296, 302, 304, 305, 306, 307, 308, 312, 313, 315, 318, 320, 374
 

neurophysiological....................................................................................................................................294
 

neurotoxicity .................. 16, 21, 33, 68, 86, 88, 90, 156, 162, 174, 178, 190, 213, 217, 228, 235, 260, 261, 

262, 263, 265, 266, 267, 268, 269, 273, 274, 275, 277, 294, 299, 300, 

301, 304, 305, 306, 307, 313, 314, 317, 318, 321, 322, 380
 

neurotransmitter ........................................................................................................ 164, 179, 260, 293, 315
 

norepinephrine .................................................................................................................. 164, 170, 174, 277
 

nuclear.......................................................................................................................................................139
 

ocular effects....................................................................................................................... 64, 140, 182, 188
 

odds ratio............................................................................................................................................... 71, 85
 

oxidative phosphorylation.........................................................................................................................264
 

partition coefficients ......................................................................................................................... 242, 250
 

PBTK (see physiologically based pharmacokinetic) ........................................................ 239, 269, 317, 318
 

pharmacodynamic.....................................................................................................................................237
 

pharmacokinetic........................................................ 202, 237, 238, 240, 250, 256, 271, 280, 282, 317, 319
 

photolysis..................................................................................................................................................354
 

physiologically based pharmacokinetic (see PBTK) ................................................................................239
 

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MANGANESE D-3 

APPENDIX D 

placenta ............................................................................................................................. 218, 276, 281, 370
 

rate constant ...................................................................................... 242, 247, 248, 250, 251, 253, 254, 255
 

renal effects................................................................................................................. 63, 138, 139, 181, 188
 

reproductive effects............................................... 17, 19, 23, 30, 88, 90, 139, 165, 169, 183, 191, 310, 391
 

respiratory effects...................................................................... 17, 20, 59, 61, 133, 180, 185, 272, 288, 296
 

retention ......................................................................... 14, 62, 81, 147, 203, 204, 206, 222, 227, 229, 233, 

235, 280, 282, 293, 300, 317, 318, 319, 352
 

sequestered................................................................................................................................................259
 

solubility ............................................................................................................. 38, 257, 316, 352, 376, 390
 

spermatogonia...........................................................................................................................................197
 

systemic effects............................................................................................................. 27, 59, 133, 180, 185
 

T3.......................................................................................................................................................... 41, 93
 

T4..............................................................................................................................................................195
 

thyroid............................................................................................................................................... 139, 179
 

toxicokinetic........................................................ 37, 190, 224, 230, 236, 268, 282, 293, 296, 315, 317, 389
 

tremors .................................................................................................................... 14, 16, 87, 143, 151, 182
 

tumors ................................................................................................................. 39, 184, 186, 187, 225, 280
 

vapor pressure ...........................................................................................................................................351
 

weanling.................................................................................... 134, 159, 166, 167, 171, 172, 201, 222, 278
 

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