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This report contains the collective views of an international group of experts and does notnecessarily represent the decisions or the stated policy of the United Nations EnvironmentProgramme, the International Labour Organisation, or the World Health Organization.

Concise International Chemical Assessment Document 12

MANGANESE AND ITS COMPOUNDS

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

Please note that the layout and pagination of this pdf file are not identical to the printed

CICAD

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

World Health OrganizationGeneva, 1999

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The International Programme on Chemical Safety (IPCS), established in 1980, is a joint ventureof the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO),and the World Health Organization (WHO). The overall objectives of the IPCS are to establish thescientific basis for assessment of the risk to human health and the environment from exposure tochemicals, through international peer review processes, as a prerequisite for the promotion of chemical

safety, and to provide technical assistance in strengthening national capacities for the sound managementof chemicals.

The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) wasestablished in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO,the United Nations Industrial Development Organization, the United Nations Institute for Training andResearch, and the Organisation for Economic Co-operation and Development (ParticipatingOrganizations), following recommendations made by the 1992 UN Conference on Environment andDevelopment to strengthen cooperation and increase coordination in the field of chemical safety. The

purpose of the IOMC is to promote coordination of the policies and activities pursued by the ParticipatingOrganizations, jointly or separately, to achieve the sound management of chemicals in relation to humanhealth and the environment.

WHO Library Cataloguing-in-Publication Data

Manganese and its compounds.

(Concise international chemical assessment document ; 12)

1.Manganese adverse effects 2.Manganese toxicity3.Environmental exposure 4.Maximum permissible exposure levelI.International Programme on Chemical Safety II.Series

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

The World Health Organization welcomes requests for permission to reproduce or translate itspublications, in part or in full. Applications and enquiries should be addressed to the Office of Publications,World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information onany changes made to the text, plans for new editions, and reprints and translations already available.

World Health Organization 1999

Publications of the World Health Organization enjoy copyright protection in accordance with the

provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.The designations employed and the presentation of the material in this publication do not imply the

expression of any opinion whatsoever on the part of the Secretariat of the World Health Organizationconcerning the legal status of any country, territory, city, or area or of its authorities, or concerning thedelimitation of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers products does not imply that they areendorsed or recommended by the World Health Organization in preference to others of a similar naturethat are not mentioned. Errors and omissions excepted, the names of proprietary products aredistinguished by initial capital letters.

The Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Germany,provided financial support for the printing of this publication.

Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10

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TABLE OF CONTENTS

FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

3. ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION . . . . . . . . . . . . . . . . . 8

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96.2 Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS ANDHUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

8. EFFECTS ON LABORATORY MAMMALS ANDIN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . 13

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.2 Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.3 Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.4 Long-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

8.4.1 Subchronic exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.4.2 Chronic exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

8.5 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148.6 Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158.7 Immunological and neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

9. EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

9.1 Case reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189.2 Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

10. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

10.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2110.1.1 Hazard identification and doseresponse assessment . . . . . . . . . . . . . . . . . . . . . . . . . . 2110.1.2 Criteria for setting guidance values for manganese . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2210.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

11. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

12. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

12.1 Human health hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2312.2 Advice to physicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2312.3 Health surveillance programme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

13. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

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INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

APPENDIX 1 SOURCE DOCUMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

APPENDIX 2 CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

APPENDIX 3 CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

APPENDIX 4 ADDITIONAL APPROACHES FOR GUIDANCE VALUE DEVELOPMENT . . . . . . . . . 36

RSUM DORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

RESUMEN DE ORIENTACIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

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Manganese and its compounds

1

FOREWORD

Concise International Chemical Assessment

Documents (CICADs) are the latest in a family ofpublications from the In ternational Programme onChemical Safety (IPCS) a cooperative programme ofthe World Health Organization (WHO), the InternationalLabour Organisation (ILO), and the United NationsEnvironment Programme (UNEP). CICADs join theEnvironmental Health Criteria documents (EHCs) asauthoritative documents on the risk assessment of

chemicals.

CICADs are concise documents that providesummaries of the relevant scientific information

concerning the potential effects of chemicals uponhuman health and/or the environment. They are basedon selected national or regional evaluation documents oron existing EHCs. Before acceptance for publication asCICADs by IPCS, these documents undergo extensivepeer review by internat ionally se lected experts to ensuretheir completeness, accuracy in the way in which theoriginal data are represented, and the validity of theconclusions drawn.

The primary objective of CICADs is

characterization of hazard and doseresponse fromexposure to a chemical. CICADs are not a summary of all

available data on a particular chemical; rather, theyinclude only that information considered critical forcharacterization of the risk posed by the chemical. Thecritical studies are, however, presented in sufficientdetail to support the conclusions drawn. For additionalinformation, the reader should consult the identifiedsource documents upon which the CICAD has beenba se d.

Risks to human health and the environme nt willvary considerably depending upon the type and ex tentof exposure. Responsible authorities are strongly

encouraged to characterize risk on t he basis of locallymeasured or predicted exposure scenarios. To assist thereader, examples of exposure estimation and riskcharacterization are provided in CICADs, wheneverposs ible . These examples cannot be cons idered asrepresenting all possible exposure situations, but areprovided as guidance only. The reader is referred to EHC1701 for advice on the derivation of health-basedguidance values.

While every effort is made to ensure that CICADs

represent the current status of knowledge, newinformation is being developed constantly. Unlessotherwise stated, CICADs are based on a search of the

scientific literature to the date shown in the executiv esummary. In the event that a reader becomes aware ofnew information that would change the conclusionsdrawn in a CICAD, the reader is requested to co ntactIPCS to inform it of the new information.

Procedures

The flow chart shows the procedures followed toproduce a CICAD. These procedures a re designed totake advantage of the expertise that exists around theworld expertise that is required to produc e the high-quality evaluations of toxicological, exposure, and otherdata that are necessary for assessing risks to humanhealth and/or the environment.

The first draft is based on an existing nation al,regional, or international review. Authors of the firstdraft are usually, but not necessarily, from the institutionthat developed the original review. A standard outline

has been developed to encourage consistency in form.The first draft undergoes primary review by IPCS toensure that it meets the specified criteria for CICADs.

The second stage involves international peer

review by scientists known for their particular expertiseand by scientists selected from an international rostercompiled by IPCS through recommendations from IPCSnational Contact Points and from IPCS ParticipatingInstitutions. Adequate time is allowed for the selectedexperts to undertake a thorough review. Authors arerequired to take reviewers comments into account and

revise their draft, if necessary. The resulting secon d draftis submitted to a Final Review Board together with thereviewers comments.

The CICAD Final Review Board has several

important functions:

to ensure that ea ch CICAD has be en subj ec ted toan appropriate and thorough peer review;

to verify that the peer reviewers comments havebe en addres sed appropr ia te ly ;

to prov ide guidanc e to those responsible for thepreparat ion of CICADs on how to resolve any

remaining issues if, in the opinion of the Board, theauthor has not adequately addressed all commentsof the reviewers; and

to approve CICADs as international assessments.

Board members serve in their personal capacity, not asrepresentatives of any organization, government, orindustry. They are selected because of their expertise inhuman and environmental toxicology or because of their

1

International Programme on Chemical Safety (1994)Assessinghuman health risks of chemicals: derivationof guidance values for health-based exposure limits.

Geneva, World Health Organization (Environmental HealthCriteria 170).

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2

SE L E C T ION OF HIGH QUAL IT YNA TI ON AL /R EG IO NA L

ASSESSMENT DOCUMENT(S)

CICAD PREPARATION FLOW CHART

FIRST DRAFT

PREPARED

REVIEW BY IPCS CONTACT POINTS/SPECIALIZED EXPERTS

FINAL REVIEW BOARD 2

FINAL DRAFT 3

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

SELECTION OF PRIORITY CHEMICAL

1 Taking into account the comments from reviewers.2 The second draft of documents is submitted to the Final Review Board together with the reviewers comments.3 Includes any revisions requested by the Final Review Board.

REVIEW OF COMMENTS (PRODUCER/RESPONSIBLE OFFICER),PREPARATION

OF SECOND DRAFT 1

PRIMARY REVIEW BY IPCS(REVISIONS AS NECESSARY)

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experience in the regulation of chemicals. Boards arechosen according to the range of expert ise required for ameeting and the need for balanced geographicrepresentation.

Board members, authors, reviewers, consultants,

and advisers who participate in the prep aration of aCICAD are required to declare any real or potentialconflict of interest in relation to the subjects underdiscussion at any stage of the process. Representativesof nongovernmental organizations may be invited to

observe the proceedings of the Final Review Board.Observers may participate in Board discussions only atthe invitation of the Chairperson, and they may notparticipate in the fin al decision-making process.

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1. EXECUTIVE SUMMARY

This CICAD on manganese and its compounds

was based principally on the report entitled Toxicologi-cal profile for manganese (update), draft for public

comment, prepared by the Agency for Toxic Substancesand Disease Registry, US Department of Health andHuman Services (ATSDR, 1996). Information containedin the Hazardous Substances Data Bank, developed andmaintained by the National Library of Medicine, USDepartment of Health and Human Services, was also

used (HSDB, 1998). Data identified as of November 1998were considered in these source documents. Additionaldata came from other references, such as assessmentsprepared by the US Environmental Protection Agency

(EPA) and the World Health Organization (WHO), aswell as a variety of reports in the literature. The sourcedocuments used to develop this CICAD do not coverthe effects of manganese on the ecological environment.No othe r sou rces (doc umen ts deve lope d by a na tionalorganization and subject to rigorous scientific review) onthis topic were identified. Therefore, this CICADaddresses environmental levels as a source of humanexposure only. No attempt has been made in this

document to assess effects on organisms in the environ-ment. Information on the availability of the source docu-ments is presented in Appendix 1. Information on thepeer review of this CICAD is pre sen ted in Appendix 2.

This CICAD was approved as an international assess-ment at a meeting of the Final Review Board, held inBerlin, Germany, on 2628 November 1997. Participantsat the Final Review Board meeting are presentedin Appendix 3. The International Chemical Safety Card(ICSC 0174) for manganese, produced by the Interna-tional Programme on Chemical Safety (IPCS, 1993), hasalso been reproduced in this document.

Manganese (Mn) is a naturally occurring elementthat is found in rock, soil, water, and food. Thus, allhumans are exposed to manganese, and it is a normal

component of the human body. Food is usually the mostimportant route of exposure for humans. Estimated Safeand Adequate Daily Intakes of 15 mg manganese havebeen es tabl ished for children 1 year of age and o lderthrough to adults; these levels generally parallelamounts of the compound delivered via the diet.

Manganese is released to air mainly as particulat ematter, and the fate and transport of the particles depend

on their size and density and on wind speed and direc-tion. Some manganese compounds are readily solub le inwater, so significant exposures can also occur by inges-

tion of contaminated drinking-water. Manganese in sur-face water can oxidize or adsorb to sediment particlesand settle to the bottom. Manganese in soil can migrateas particulate matter to air or water, or soluble manga-nese compounds can be leached from the soil.

Above-average exposures to manganese are most

likely to occur in people who work at or live near afactory or other site where significant amounts of man-ganese dust are released into the air. In some regions,

the general population can be exposed to manganesereleased into air by the combustion of unleaded gasolinecontaining the organomanganese compound methyl-cyclopentadienyl manganese tricarbonyl (MMT) as anantiknock ingredient. Some people can be exposed toexcess manganese in drinking-water for example,when manganese from batteries or pesticides leaches

into well-water. Children can be exposed to excessmanganese in soils through hand-to-mouth behaviour.

In humans, manganese is an essential nutrient thatplays a role in bone mineralization, protein and energ ymetabolism, metabolic regulation, cellular protection fromdamaging free radical species, and the formationof glycosaminoglycans. However, exposure to high lev-els via inhalation or ingestion can cause adverse healtheffects. Given comparable doses, more manganesereaches the brain following inhalation than followingingestion, and most health effects are associated withchronic inhalation exposure. Little is known about the

relative toxicity of different manganese compounds.However, available evidence indicates that variousmanganese compounds can induce neurological effects;these effects have been observed following chronic(365 days or more) inhalation exposures in humans and

intermediate (15364 days) and chronic oral exposures inanimals.

In general, the available data indicate that expo-

sure to excess manganese for 14 days or less (acuteduration) or up to a year (intermediate duration ) has aneffect on the respiratory system and the nervous system,

with little to no effect on other organ systems. Acuteinhalation exposure to high concentrations of manga-nese dusts (specifically manganese dioxide [MnO2] andmanganese tetroxide [Mn3O4]) can cause an inflamma-tory response in the lung, which, over time, can result in

impaired lung function. Lung toxicity is manifested as anincreased susceptibility to infections such as bronchitisand can result in manganic pneumonia. Pneumonia hasalso been observed following acute inhalation exposuresto particulates containing other metals. Thus, this effectmight be characteristic of inhalable particulate matter andmight not depend solely on the manganese content ofthe particle.

There are a few reports suggesting that interme di-

ate inhalation exposure to manganese compounds pro-duces effects on the central nervous system, but reliableestimates of exposure levels are not available. Inhalationstudies in animals resulted in biochemical, respiratory,and neurobehavioural effects. However, a threshold forthese effects has not been identified, because the expo-

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sure levels associated with these effects range over anorder of magnitude.

In chronic inhalation exposure to manganese, the

main organ systems affected are the lungs, nervoussystem, and reproductive system, although effects onother organ systems have also been observed. A recur-ring manganic pneumonia and acute respiratory effectshave been associated with chronic inhalation exposuresto manganese. Effects on the nervous system includeneurological and neuropsychiatric symptoms that can

culminate in a Parkinsonism-like disease known asmanganism; evidence suggests that laboratory animals,especially rodents, are not as sensitive as humans, andpossibly other primates, to the neurological effec ts ofinhalation exposure to manganese. Reproductive effectsof chronic inhalation exposure to manganese includedecreased libido, impotence, and decreased fertility inmen; information is not available on reproductive effectsin women. Studies in animals indicate that mangan esecan cause direct damage to the testes and late resorp-tions. Data from animal studies on the effects of inhale dmanganese on the immunological system and the devel-oping fetus are too limited to make firm conclusions on

the significance of these effects for humans.

Information on the carcinogenic potential of man-

ganese is limited, and the results are difficult to interpretwith certainty. In rats, chronic oral studies with manga-

nese sulfate (MnSO4) showed a small increase in theincidence of pancreatic tumours in males and a smallincrease in pituitary adenomas in females. In otherstudies with manganese sulfate, no evidence for cancerwas noted in rats and a marginally increased incidence ofthyroid gland follicular cell adenomas was observed inmice. The results ofin vitro studies show that at least

some chemical forms of manganese have mutagenicpotent ial. However, as the resul ts of in vivo studies inmammals are inconsistent, no overall conclu sion can bemade about the possible genotoxic hazard to humansfrom exposure to manganese compounds.

Large oral doses of concentrated manganese saltsgiven by gavage can cause death in animals, but oralexposures via food or water have not been found tocause significant toxicity over acute or short-term expo-sures. Similarly, parenteral administration of manganesesalts can cause developmental toxicity, but effects werenot found with oral exposure. Intermediate-duration oral

exposure of humans to manganese has been reported tocause neurotoxicity in two cases, but the data are toolimited to define the threshold or to judge if these effectswere due entirely to the manganese exposure. Some dataon neurological or other healt h effects in humans fromchronic oral intake of manganese exist, but these studiesare limited by uncertainties in the exposure routes andtotal exposure level s as well as by the existence of otherconfounding factors. The studies in humans and animals

do not provide sufficient information to determine doselevels or effects of concern following chronic oral expo-sure. Thus, the available evidence for adverse effectsassociated with chronic ingestion of excess manganese

is suggestive but inconclusive.

The dermal route does not appear to be of signi-

ficant concern and has not been investigated to anyextent. Available information is limited to reports on thecorrosive effects of potassium permanganate (KMnO4)and case reports of effects from dermal absorption of

organic manganese compounds such as MMT.

From these data, it is clear that adverse neurologi-cal and respiratory effects from manganese exposure canoccur in occupational settings. Limited evidence alsosuggests that adverse neurological effects can beassociated with ingestion of excess manganese inenvironmental settings. As a result of predisposingfactors, certain individuals might be more susceptib le toadverse effects from exposure to excess manganese.These might include people with lung disease, peoplewho are exposed to other lung irritants, neonates, olderpeople, individuals with iron deficiency, or people with

liver disease.

There are several approaches to the development

of a guidance value for manganese in a ir. A recentlydeveloped guidance value of 0.15 :g manganese/m3 is

highlighted here as one possible example; some add i-tional approaches are also presented.

2. IDENTITY AND PHYSICAL/CHEMICALPROPERTIES

Table 1 lists common synonyms and other relevantinformation on the chemical identity and properties ofmanganese and several of its most important com-

pounds . Manganese is a natural ly occurr ing e lement thatis found in rock, soil, water, and food. Manganese canexist in a number of oxidation states. Mangan ese and itscompounds can exist as solids in the soil and as solutesor small particles in water. Most manganese salts arereadily soluble in water, with only the phosphate and thecarbonate having low solubilities. The manganese oxides(manganese dioxide and manganese tetroxide) are poorlysoluble in water. Manganese can also be present in smalldust-like particles in the air. Additional

physical/chemical properties are presented in the Inter-national Chemical Safety Card (ICSC 0174) reproduced in

this document.

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

ManganeseManganous chloride

Manganesesulfate

Manganese(II,III) oxide

Manganesedioxide

Potassiumpermanganate

Methylcyclo-pentadienyl-manganesetricarbonylb

Manganeseethylene-bis-d ithiocarbamate Mancozebc

S ynonym s E lement almanganese;colloidalmanganese;cutavald

Manganesechlorided;manganesedichloride

Manganoussulfate;sulfuric acidmanganese

Trimanganesetetroxide;mangano-manganicoxidee;manganesetetroxide

Manganeseperoxide;manganesebinoxide;manganese black;batterymanganese

Permanganicacid, potassiumsalte; chameleonmineral

MMT f; methyl-cymantrene;Antiknock-33;manganesetricarbonyl methyl-cyclopentadienyl

Trimangol 80;manebg;ethylene-bis[dithiocarbamic acid],manganous salt;Dithane

Dithane M-45;manganeseethylenebis(dithiocarba-mate)(polymeric);Manzate; Man-zeb; Zimaneb

Chemicalformula

Mn MnCl 2 MnSO4 Mn3O4 MnO 2 KMnO4 C9H7MnO 3 C4H6MnN2S4 C4H6MnN2S4AC4H6N2S4Zn

CASNumber

7439-96-5 7773-01-5 7785-87-7 1317-35-7 1313-13-9 7722-64-7 12108-13-3 12427-38-2 12427-38-2

Molecularweight

54.94e 125.85e 151.00e 228.81h 86.94e 158.04e 218.10 265.31 541.03

Colour Grey-whiteh Pinkh Pale rose-red

Blackh Black Purple Dark orange-redi Yellow-brown Gr eyish- yellow

Physicalstate

Solid Solid Solid Solid Solid Solid Liquid i Powder Powder

Meltingpoint

1244 Ch 650 C 700 C 1564 C 535 Ch

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3. ANALYTICAL METHODS

Atomic absorption spectrophotometric analysis is

the most widely used method for determining manganesein biological materials and environmental samples.Fluorimetric, colorimetric, neutron activation analysis,and plasma atomic emission techniques are also recom-mended for measuring manganese in such samples.Most of these methods require wet digestion, derivati-zation, and/or extraction before detection. In most cases,distinguishing between different oxidation states of

manganese is impossible, so total manganese is mea-sured.

The detection limits of these methods range from

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and waste treatment plants; and as a preservative forfresh flowers and fruits (HSDB, 1998).

The main sources of manganese releases to the air

are industrial emissions, combustion of fossil fuels, andre-entrainment of manganese-containing soils (Lioy,1983; US EPA, 1983, 1984, 1985a, 1985b). Manganese canalso be released to the air during other anthropogenicprocesses, such as welding and fungic ide app lica tion(Ferraz et al., 1988; MAK, 1994; Ruijten et al., 1994). Totalemissions to air from anthropogenic sources in the USA

were estimated to be 16 400 t in 1978, with about 80%(13 200 t) from industrial facilities and 20% (3200 t) fromfossil fuel combustion (US EPA, 1983). Air emissions byUS industrial sources reported for 1987 totalled 1200 t(TRI87, 1989). In 1991, air emissions from facilities in theUSA ranged from 0 to 74 t, with several US statesreporting no emissions (TRI91, 1993). Air erosion ofdusts and soils is also an important atmospheric sourceof manganese, but no quantitative estimates ofmanganese release to air from this source were identified(US EPA, 1984). Volcanic eruptions can also releasemanganese to the atmosphere (Schroeder et al., 1987).

In some countries, combustion of gasoline con-

taining MMT contributes approximately 8% to levels ofmanganese tetroxide in urban air (Loranger & Zayed,1995). MMT was used as a gasoline additive in the USAfor a number of years, resulting in manganese emissions.

Analysis of manganese levels in the air indicated thatvehicular emissions contributed an average of 13 ngmanganese/m3 in southern California, whereas vehicularemissions were only about 3 ng/m3 in central andnorthern California (Davis et al., 1988). A ban on MMTuse as a fuel additive was impose d for a period of time,then lifted by the US EPA in 1995.

In Canada, MMT use as a fuel additive hasgradually increased since 1976. Manganese emissionsfrom gasoline combustion rose sharply from 1976through the early 1980s, reaching an estimated 200.2 t by

1985 (Jacques, 1984). In 1990, lead was completelyreplaced by MMT in gasoline in Canada (Loranger &Zayed, 1994). MMT use peaked in 1989 at over 400 t,which was more than twice the usage in 1983 and 1.5times the usage in 1986. MMT use declined to about300 t by 1992, owing to reductions in its concentration ingasoline. However, ambient monitoring data formanganese in Canadian cities without industrial sources

for the 19891992 period did not reflect this peak inMMT use. Air manganese levels (PM 2.5, or particulatematter with an aerodynamic diameter less than or equalto 2.5 :m) remained constant at 0.110.013 :g/m3 forsmall cities and 0.0200.025 :g/m3 for large cities (HealthCanada, 1994; Egyed & Wood, 1996). Manganeseemission levels can vary depending on the concen-tration of MMT in gasoline and gasoline usage patterns.

One study reported a correlation between atmosphericmanganese concentrations in 1990 air samples and trafficdensity in Montreal (Loranger et al., 1994). However, alater study by these investigators reported that

atmospheric manganese concentrations in Montrealdecreased in 1991 and 1992 despite an estimated 100%increase in manganese emission rates from MMT ingasoline (Loranger & Zayed, 1994). Another studysuggested that the high manganese levels in Montrealwere, in part, due to the presence o f a silico- and ferro-manganese facility that ceased operation in 1991 (Egyed

& Wood, 1996).

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

Land disposal of manganese-containing wastes is

the principal source of manganese releases to soil. In1991, reported industrial releases to land in the USAranged from 0 to 1000 t. More than 50% of the totalenvironmental release of manganese (3753 t) was to land

(TRI91, 1993).

5. ENVIRONMENTAL TRANSPORT,DISTRIBUTION, AND TRANSFORMATION

Elemental manganese and inorganic manganese

compounds have negligible vapour pressures but canexist in air as suspended particulate matter derived fromindustrial emissions or the erosion of soils. Manganese-

containing particles are removed from the atmospheremainly by gravitational settling or by rain (US EPA,1984).

Soil particulate matter containing manganese canbe transpor ted in air . The fate and t ransport of manga-nese in air are largely determined by the size and densityof the particle and wind speed and direction. An esti-mated 80% of the manganese in suspended particulatematter is associated with particle s with a Mass Median

Equivalent Diameter (MMED) of

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ferromanganese and dry-cell battery plants, whereaslarge particles tend to predominate near mining opera-tions [WHO, 1999].) Based on these data, manganesessmall particle size is within the respirable range, and

widespread airborne distribution would be expected(WHO, 1981). Very little information is available onatmospheric reactions of manganese (US EPA, 1984).Although manganese can react with sulfur dioxide andnitrogen dioxide, the occurrence of such reactions in theatmosphere has not been demonstrated.

The transport and partitioning of manganese inwater are controlled by the solubility of the specificmanganese compound present. In most waters (pH 47),Mn(II) predominates and is associated principally withcarbonate, which has relatively low solubility (US EPA,1984; Schaanning et al., 1988). The solubility of Mn(II)can be controlled by manganese oxide equilibria(Ponnamperuma et al., 1969), with manganese beingconverted to other oxidation states (Rai et al., 1986). Inextremely reduced water, the fate of manganese tends tobe controlled by the formation of the poorly solublesulfide (US EPA, 1984). In groundwater with low oxygenlevels, Mn(IV) can be reduced both chemically and

bacterially to the Mn(I I) oxidation sta te (Jaudon et al .,1989). MMT has been found to be persistent in naturalaquatic and soil environments in the absence ofsunlight, with a tendency to sorb to soil and sedimentpar ticles (Garrison et a l., 1995). In the presence of l ight,

photodegradation of MMT is rapid, with identif iedproducts including a manganese carbonyl tha t readi lyoxidizes to manganese tetroxide (Garrison et al., 1995).

Manganese is often transported in rivers adsorbed

to suspended sediments. Most of the manganese fromindustrial sources found in a South American river was

bound to suspended particles (Malm et al ., 1988). Thetendency of soluble manganese compou nds to adsorb tosoils and sediments can be highly variable, dependingmainly on the cation exchange capacity and the organiccomposition of the soil (Hemstock & Low, 1953;

Schnitzer, 1969; McBride, 1979; Curtin et al., 1980; Baes& Sharp, 1983; Kabata-Pendias & Pendias, 1984). Theoxidation state of manganese in soils and sediments canbe altered by microbial activity (Geering et al ., 1969;Francis, 1985).

Manganese in water can be significantly biocon-centrated at lower trophic levels. Bioconcentration fac-

tors (BCFs) of 10 00020 000 for marine and freshwaterplants , 25006300 for phytoplankton, 3005500 formarine algae, 800830 for intertidal mussels, and 35930for fish have been estimated (Folsom et al., 1963;Thompson et al., 1972). The high reported BCFsprobably reflect the essentiality of manganese for a widevariety of organisms; specific uptake mechanisms existfor essential elements.

6. ENVIRONMENTAL LEVELS ANDHUMAN EXPOSURE

6.1 Environmental levels

Concentrations of manganese in seawater report-

edly range from 0.4 to 10 :g/litre (US EPA, 1984). In theNorth Sea , the northeas t Atlantic Ocean, the Engl ishChannel, and the Indian Ocean, manganese content wasreported to range from 0.03 to 4.0 :g/litre. Levels foundin coastal waters of the Irish Sea and in the North Sea offthe coast of the United Kingdom ranged from 0.2 to 25.5

:g/litre (Alessio & Lucchini, 1996). In a number of cases,higher levels in water (in excess of 1000 :g/litre) havebeen de tect ed at US ha za rdous was te si te s, sugges ting

that, in some instances, wastes from industrial sourcescan lead to significant contamination of water (ATSDR,1996).

In a 19741981 survey of 286 US river watersamples, concentrations of dissolved manganese rangedfrom less than 11:g/litre (25th percentile) to more than51 :g/litre (75th percentile) (Smith et al., 1987), with amedian of 24 :g/litre. Mean groundwater concentrationswere 20 and 90 :g/litre from two geological zones in

California (Deverel & Millard, 1988). The surface watersof Welsh rivers were reported to contain from 0.8 to 28:g manganese/litre. Concentrations of manganeseranged from 1 to 530 :g/litre in 37 rivers in the UnitedKingdom and in the Rhine and the Maas and theirtributaries (Alessio & Lucchini, 1996).

Concentrations of manganese in surface water are

usually reported as dissolved manganese. Total manga-nese might be a better indicator, because manganeseadsorbed to suspended solids can exceed dissolvedmanganese in many systems, and the bioavailability of

manganese in this form has not been established (NAS,1977; US EPA, 1984).

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

According to a National Research Council ofCanada report (Stokes et al., 1988), manganese conce n-trations in air tend to be lowest in remote locations

(about 0.514 ng/m3 on average), higher in rural areas (40ng/m3 on average), and still higher in urban areas (about

65166 ng/m3

on average) (see Table 2). Similarconcentrations have been reported elsewhere, leading tothe conclusion that annual manganese concentrations

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Table 2: Average levels of manganese in air.

a) Atmospheric air (worldwide)a:

Type of location

Average

concentration(ng/m3) Range (ng/m3)

Remote

Continental 3.4

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

Parameter

Exposure medium

Water Air Food

Typical

concentration in

medium

4 :g/litre 0.023

:g/m 31.28

:g/calorie

Assumed daily

intake of medium

by 70-kg adult

2 litres 20 m3 3000

calories

Estimated

average daily

intake by 70-kg

adult

8 :g 0.46 :gb 3800 :g

Assumed

absorption

fraction

0.03c 1c 0.03d

Approximate

absorbed dose

0.24 :g 0.46 :g 114 :g

a Adapted from US EPA (1984); b Assumes 100% deposition in

the lungs; c No data; assumed value; d Davidsson et al. (1988).

persons consume more or less than the est imated dailyintakes noted above (NAS, 1980; Pennington et al., 1986;

Davis et al., 1992). Indeed, estimates of daily intake foradults in the USA range from 2.0 to 8.8 mg (NAS, 1977;Patterson et al., 1984; US EPA, 1984; WHO, 1984;Pennington et al., 1986).

Although gastrointestinal absorption of manga-

nese is only 35% (Mena et al., 1969; Davidsson et al.,1988) (see section 7), food is not only the largest sourceof manganese exposure in the general population, butalso the primary source of absorbed manganese(Table 3). The bioavailability of manganese fromvegetable sources is substantially decreased by dietary

components such as fibre and ph ytates (US EPA, 1993).Individuals with iron deficiency exhibit increased rates ofmanganese absorption (Mena et al., 1969, 1974).

In 1962, the public drinking-water supplies in 100large cities in the USA were surveyed, an d 97% con-tained less than 100 :g manganese/litre (Durfor &

Becker, 1964). A 1969 survey of 969 systems reportedthat 91% contained less than 50 :g/litre, with a meanconcentration of 22 :g/litre (ATSDR, 1996). In theFederal Republic of Germany, mean concentrations ofmanganese in drinking-water were reported to range from1 to 63 :g/litre (Alessio & Lucchini, 1996).

Certain groups are more highly exposed to manga-

nese than the general population. Infants given preparedinfant foods and formulas, for example, may be morehighly exposed to manganese than adults in the generalpopulation. Collipp et al . (1983) reported that concen-

trations of manganese in infant formulas range from 34 to1000 :g/litre, compared with concentrations of10 :g/litre in human milk and 30 :g/litre in cows milk;Lavi et al. (1989) found an even lower concentration of

Table 4: Manganese concentrations in selected foods.a

Type of food

Range of meanconcentrations

(ppm; ::g/g ormg/litre)

Nuts and nut products 18.2146.83

Grains and grain products 0.4240.70

Legumes 2.246.73

Fruits 0.2010.38

Fruit juices and drinks 0.0511.47

Vegetables and vegetable

products

0.426.64

Desserts 0.047.98

Infant foods 0.174.83

Meat, poultry, fish, and eggs 0.103.99

Mixed dishes 0.692.98

Condiments, fats, and sweeteners 0.041.45

Beverages (including tea) 0.002.09

Soups 0.190.65

Milk and milk products 0.020.49

a Adapted from Pennington et al. (1986).

manganese in market milk (16 2 :g/litre), suggestingthat the difference between formula and milk could beeven greater in some regions. Because of the high man-ganese levels in prepared infant foods and formulas,some infants might ingest more than the ESADDI for

their age group (Pennington et al., 1986; NRC, 1989).

In addition, people living in the vicinity of ferro-manganese or iron and steel manufacturing facilities,coal-fired power plants, or hazardous waste sites can beexposed to elevated manganese particulate matter in air,although this exposure is likely to be much lower thanin the workplace. Loranger & Zayed (1997) estimated

average exposure doses of respirable manganese andtotal manganese in an urban site (botanical gardens) inMontreal, Canada, to be 0.005 and 0.008 :g/kg bodyweight per day (0.35 and 0.56 :g/day for a 70-kg person),

respectively. Similarly, the daily intake of manganese inthe air by the general US population was estimated to beless than 2 :g (WHO, 1981). According to a study byPellizari et al. (1992) and subsequent analyses by the USEPA (1994a, 1994b), measurements of personal exposurelevels in an urban area in the USA (Riverside, California)in 1990 indicated that about half the population had 24-hpersonal exposures to PM 10 (particulate matter with an

aerodynamic diameter less than or equal t o 10 :m)manganese above 0.035 :g/ m3 (0.7 :g/day, assuming aventilation rate of 20 m3/day), while the highest 1% ofthe population had exposures above 0.223 :g/ m3 (4.46:g/day). By contrast, intak es in areas of the USA withferro- or silicomanganese industries were as high as 10:g/day, with 24-h peak values exceeding 100 :g/day(WHO, 1981).

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People living in regions of natural manganese ore

deposits or where manganese-containing materials (e.g.,pest ic ides , bat te ries) a re used or di sposed of ca n a lso beexposed to elevated levels of mangane se in soil or water.

For example, Kawamura et al. (1941) reported on sixJapanese families exposed to high leve ls (at least14 mg/litre) of manganese in their drinking-water; thecontamination was believed to result from manganesethat leached from batteries buried near the well. Childrenare especially likely to receive elevated doses frommanganese-containing soils because they have a higher

intake of soil (mainly through hand-to-mouth contact)than adults (Calabrese et al., 1989). Organomanganesecompounds such as MMT can be absorbed through theskin (Tanaka, 1994).

In the workplace, exposure to manganese is mostlikely to occur by inhalation of mangan ese fumes ormanganese-containing dusts. These dusts can containvarious manganese oxides as well as manganese in theoxides of other elements, such as potassium permanga-nate, manganese ferric oxide (MnFe2O4), and manganesesilicate (MnSiO 3) (Pflaumbaum et al., 1990). Exposure is aconcern mainly in the ferromanganese, iron and steel,

dry-cell battery, and welding industries (WHO, 1986).Exposure can also occur during manganese mining andore processing, and dermal exposure and inhalation canoccur during the application of manganese-containingfungicides.

Manganese air concentrations of 1.5450 mg/m3

have been reported in US manganese mines (US EPA,1984), 0.3020 mg/m3 in ferroalloy production facilities(Saric et al., 1977), 0.025 mg/m3 in German foundries(Coenen et al., 1989), 14 mg/m3 during welding withelectrodes (Sjgren et al., 1990), up to 14 mg/m3 during

welding with welding wire (Pflaumbaum et al., 1990), and318 mg/m3 in a dry-cell battery facility (Emara et al.,1971). Many of the more recent studies on occupationalexposures to manganese have recorded averageexposure levels of 1 mg manganese/m3 or less in the

workplace (Roels et al., 1987, 1992; Mergler et al., 1994;Lucchini et al., 1995). Thus, for workers in industriesusing manganese, the major route of exposure might beinhalation from workplace air rather than ingestion offood.

7. COMPARATIVE KINETICS ANDMETABOLISM IN LABORATORY ANIMALS

AND HUMANS

Manganese absorption occurs primarily from the

gastrointestinal tract after ingestion and from the alveo-lar lining after inhalation of manganese-containin g dust

or fumes. Several studies in animals indicate that keydeterminants of absorption are the absorption pathwayand the specific compound in which manganese ispresent (Smith e t al ., 1995; Roels et al ., 1997). Roels et al.

(1997) studied manganese levels in the blood and braintissue of rats exposed to repeated doses of manganesechloride or manganese dioxide administered by oralgavage, intraperitoneal injection, or intratrachealinstillation. Manganese chloride was readily absorbedafter administration by each of these routes and distrib-uted in brain tissue to varying degrees. Manganese

dioxide, on the other hand, was significantly absorbedand distributed in the brain to varying degrees whenadministered by intraperitoneal injection and intra-tracheal instillation, but not when administered orally.Higher levels of manganese in tissue were found afteradministering manganese chloride by intratrachealinstillation compared with manganese dioxide. Theauthors concluded that the route of exposure might be acritical determinant of how absorbed manganese isdistributed in the brain. In addition, when manganesedioxide was administered by either intratracheal instil-lation or oral gavage, manganese levels in the blood roseand fell more slowly than when manganese chlorid e was

given, indicating a marked difference in the absorptionkinetics of these two manganese compounds. The find-ing that the body handles manganese dioxide moreslowly than manganese chloride suggests that manga-nese dioxide might remain in the body longer, contrib-

uting longer to body burden, albeit at much lower levels.Whether this is true and whether this indicates greatertoxicological risk in cases of prolonged low-level expo-sure to manganese dioxide are unclear.

A second study also found that route of exposure

affects absorption of manganese. Tjlve et al. (1996)

found that intranasal instillation of mangane se (Mn2+) inrats resulted in initial uptake of manganese in the olfac-tory bulbs of the brain, whereas intraperitoneal adminis-tration resulted in low uptake in the olfactory bulbs. Theauthors suggested that olfactory neurons might serve as

a pathway for manganese uptake and distribution to thebrain (bypassing the bloodbrain barrier) during intra-nasal exposure.

Another key determinant of absorption appears tobe die tary i ron intake, with low iron levels leading toincreased manganese absorption (Mena et al., 1969). Inaddition, several studies in animals indicate that gastro-

intestinal absorption of manganese might vary with age(Rehnberg et al., 1980, 1981).

The amount of manganese absorbed acro ss the

gastrointestinal tract in humans varies, but typicallyaverages about 35% (Mena et al., 1969; Davidssonet al., 1988). Particles that are deposited in the lowerairways are probably absorbed, whereas particles depos-

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ited in the upper airways are generally swallowed viamucociliary clearance; thus, they can be absorbed fromthe gastrointestinal tract as well.

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

Limited data suggest that manganese can undergochanges in oxidation state within the body. Support forthis hypothesis comes from the observation that theoxidation state of the manganese ion in several enzyme sappears to be Mn(III) (Utter, 1976; Leach & Lilburn,1978), whereas most manganese intake from the environ-ment is as Mn(II) or Mn(IV). The rate and ex tent ofmanganese reduction/oxidation reactions might beimportant determinants of manganese retention in thebody .

8. EFFECTS ON LABORATORYMAMMALS AND IN VITRO TEST SYSTEMS

8.1 Single exposure

Lung inflammation has been reported following

single inhalation exposures to 2.843 mg/m3 for manga-nese dioxide or manganese tetroxide particulates inrodent species (Bergstrom, 1977; Adkins et al., 1980;Shiotsuka, 1984). It is important to note that an inflam-matory response of this type is not unique to manga-nese-containing particles, but is characteristic of nearly

all inhalable particulate matter (US EPA, 1985b). Thus, itmight not be manganese alone that causes the inflam-matory response from single exposures, but possibly the

par ticulate matter i tself.

Following single oral exposures, LD 50s ranged from275 to 804 mg/kg body weight per day for mangan esechloride in different rat strains (Holbrook et al., 1975;Kostial et al., 1989; Singh & Junnarkar, 1991). ReportedLD50s from single exposures to manganese sulfate andmanganese acetate in rats were 782 and 1082 mg/kg bodyweight per day, respectively (Smyth et al., 1969; Singh &Junnarkar, 1991).

8.2 Irritation and sensitization

Little information is available on the irritant and

contact sensitivity properties of manganese compounds.

Manganese salts failed to induce lymph node cell prolif-eration in the murine local lymph node assay, a predic-tive test for the detection of contact allergens (Ikarashiet al., 1992). The manganese-containing fungicide maneb

has been reported to be a sensitizer in animal tests, butlittle information exists on whether this effect occurs inhumans (Thomas et al., 1990). Contact sensitization inhumans has been reported in one study (see section 9.2).

8.3 Short-term exposure

Results from studies of short-term exposures inexperimental animals indicate tha t the lungs and nervoussystem are the major target organs following the inhala-tion of manganese compounds. For example, Maigetteret al. (1976) found increased susceptibility to pneumoniain mice exposed via inhalation to 69 mg manganese/m3 asmanganese dioxide for 3 h/day for 14 da ys. Effects onthe nervous system associated with short-term exposureto manganese compounds are presented in section 8.7.

8.4 Long-term exposure

8.4.1 Subchronic exposure

Results from studies of subchronic exposures inexperimental animals also indicate that the lungs andnervous system are the major target organs following theinhalation of manganese compounds. Signs of lung

inflammation have been reported in rhesus monkeysexposed via inhalation to 0.7 mg manganese/m3 asmanganese dioxide for 22 h/day over 10 months (Suzukiet al., 1978). Effects on the nervous system associatedwith subchronic exposure to manganese compounds arepresented in section 8.7.

Systemic effects reported following subchronic

oral exposures to manganese compounds includechanges in blood cell counts (leukocytes, erythrocytes,neutrophils), reduced liver weight, and decreased bodyweight (Gray & Laskey, 1980; Komura & Sakamoto, 1991;

NTP, 1993) . In mice fed 284 mg manganese/kg bodyweight per day for 100 days, for example, red blood cellcount was decreased by manganese acetate andmanganese chloride; white blood cell count wasdecreased by manganese acetate, manganese chloride,and manganese dioxide; and haematocrit was decreasedby mangan ese c arbonate (MnCO3) (Komura &Sakamoto, 1991).

8.4.2 Chronic exposure and carcinogenicity

Available data from animal studies involving oral

exposure to manganese as well as from epidemiologicalstudies involving inhalation exposure to manganesesuggest that similar chronic toxicities (i.e., neurologicaleffects) occur regardless of the valence state of the

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inorganic manganese compounds (e.g., manganesedioxide, manganese tetroxide). In experimental animals,the nervous system is the major organ affected followinglong-term oral and inhalation exposure to manganese.

These data are described in more detail in section 8.7.Few chronic inhalation exposure studies in animals areavailable, and these studies reported effects in thenervous system. Significant effects in other organ sys-tems following long-term exposure to manganese havenot been reported. Available data from animal studiessuggest that it is unlikely that other significant effects

result from long-term oral exposure to manganese (NTP,1993).

Information on the carcinogenic potential of man-ganese is limited, and the results are difficult to interpretwith certainty. For example, male rats exposed to up to331 mg manganese/kg body weight per day (as manga-nese sulfate) for 2 years had an increased incidence ofpancreati c ce ll adenomas (3/50, 4/51, and 2/51 in the low,mid, and high dose groups); this type of tumour wasnoted in only one female in the mid dose group. Theinvestigators indicated that these lesions, although lowin incidence, were a concern and attributed to

manganese treatment because pancreatic cell hyper-plas ia was observed in all treatment groups, al thoughneither hyperplasia nor adenomas were observed incontrols of either sex (Hejtmancik et al., 1987a). On theother hand, a small increase in the incidence of pituitary

adenomas was noted in female mice at 905 mg manga-nese/kg body weight per day (as manganese sulfate),but not in males at 722 mg manganese/kg body weightper day . The incidence was cons idered equivoca lbe ca use l es ions ha d b ee n obser ve d in p reviou s s tudiesas well as in historical controls (Hejtmancik et al., 1987b).In a 2-year study, no evidence of cancer was noted in

male and female F344 rats given 20200 and 23232 mgmanganese sulfate/kg body weight per day, respectively,via feed (NTP, 1993). A marginally increased incidence ofthyroid gland follicular cell adenomas was observed inmale and female B6C3F1 mice given 52585 and 65731

mg manganese sulfate/kg body weight per day,respectively, in the feed for 2 years (NTP, 1993). Intra-peritoneal injection of mice wi th manga nese sulf ate(20 weeks) led to an increased incidence of lung tumours(Stoner et al., 1976), but intramuscular injection of ratsand mice with manganese or manganese dio xide did notresult in tumours (Furst, 1978). Firm conclusions on thecarcinogenic potential of manganese cannot be made

based on the equivoca l carcinogenici ty da ta reported forrodents and the paucity of evidence from other species.

8.5 Genotoxicity and related end-points

Manganese sulfate was not mutagenic to

Salmonella typhimurium strains TA97, TA98, TA100,TA1535, or TA1537 in either the presence or absence ofS9 from Aroclor 1254-induced liver from rats or Syrian

hamsters in studies performed at two different labora-tories (Mortelmans et al., 1986), but it was reportedelsewhere to be genotoxic to strain TA97 (Pagano &Zeiger, 1992). Manganese chloride was not mutagenic in

S. typhimurium strains TA98, TA100, and TA1535, but itwas mutagenic in TA1537, and conflicting results wereobtained for TA102 (Wong, 1988; De Mo et al., 1991). Afungal gene conversion/reverse mutation assay inSaccharomyces cerevisiae strain D7 indicated thatmanganese sulfate was mutagenic (Singh, 1984).

Manganese chloride produced gene mutations invitro in a mouse lymphoma assay (Oberly et al., 1982). Italso caused DNA damage in human lymphocytes whentested in vitro using the single-cell gel assay techniquein the absence of metabolic activation, but it caused noDNA damage when S9 was present (De Mo et al., 1991).The results of an in vitro assay using Chinese hamsterovary (CHO) cells showed that manganese sulfateinduced sister chromatid exchange in both the presenceand absence of S9 from Aroclor 1254-induced rat liver(Galloway et al., 1987). In a separate assay, manganesesulfate also induced chromosomal aberrations in CHOcells in the absence of S9 but not in its presence

(Galloway et al., 1987). In contrast, manganese chloridewas not clastogenic when tested in vitro in the absenceof metabolic activation using FM3A cells (Umeda &Nishimura, 1979), although i t did cause chromosomalaberrations in the root tips ofVicia faba (Glass, 1955,

1956). Potassium permanganate caused chromosomalaberrations in FM3A cells (Umeda & Nishimura, 1979)but no t in a primary cultu re of cells f rom Syrian hamsterembryos (Tsuda & Kato, 1977) when teste d in theabsence of metabolic activation. Magnesium chloridecaused cell transformation in Syrian hamster embryocells (Casto et al., 1979).

Manganese chloride did not produce somatic

mutations inDrosophila melanogasterfruit flies(Rasmuson, 1985). Manganese sulfate did not inducesex-linked recessive lethal mutations in the germ cells of

maleD. melanogaster(Valencia et al., 1985).

In vivo assays in mice showed that oral d oses ofmanganese sulfate or potassium permanganate causedmicronuclei and chromosomal aberrations in bonemarrow (Joardar & Sharma, 1990). In contrast, oral dosesof manganese chloride did not cause chromosomalaberrations in the bone marrow or spermatogonia of rats

(Dikshith & Chandra, 1978).

The results ofin vitro studies show that at least

some chemical forms of manganese have mutagenicpotential. However, as the resul ts of in vivo studies inmammals are inconsistent, no overall conclusion ca n bemade about the possible genotoxic hazard to humansfrom exposure to manganese compounds.

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8.6 Reproductive and developmental

toxicity

Considerable information is available on the

reproductive and developmental effects of manganese inanimals. Mice exposed subcutaneously to 0, 2, 4, 8, or 16mg manganese chloride tetrahydrate/kg body weight perday on gestation days 615 showed no treatment-relatedeffects on the number of total implants, earlyresorptions, dead fetuses, or sex ratio. However, asignificant increase in the numbe r of late resorptions wasfound in the 4, 8, and 16 mg/kg body weight per day

groups. Significant maternal toxicity was associated withthe 8 and 16 mg/kg body weight per day groups(Snchez et al., 1993). A single intratracheal dose of160 mg manganese/kg (as manganese dioxide) in rabbits

caused slow degenerative changes in the seminiferoustubules and led to sterility (Seth et al., 1973; Chandra etal., 1975). Abnormal sperm morphology was observed inmice treated with 23198 mg manganese/kg body weightpe r day as po tass iu m permang anat e o r man gane sesulfate by gavage in water for u p to 3 weeks (Joardar &Sharma, 1990). No gross or histopathological lesions ororgan weight changes were observed in the reproductiveorgans of rodents exposed to 1300 mg manganese/kg

body weight per day for 14 days or fed up to 1950 mgmanganese/kg body weigh t per day for 13 weeks (NTP,1993). From the available evidence, no firm conclusionson effects in male reproductive organs can be made, andreproductive performance was not evaluated in many ofthese studies.

A slight decrease in pregnancy rate was observed

in female rats exposed to 130 mg manganese/kg bodyweight per day as manganese tetroxide in the diet for90100 days before breeding (Laskey et al., 1982). Femalereproductive parameters such as litter size, ovulations,

resorptions, or fetal weights were not affected in ratsconsuming excess manganese as manganese tetroxide infeed or water (Laskey et al., 1982; Kontur & Fechter,1985), except at concentrations so high (1240 mg/kg

body weight per day) that water in take by the dams wasseverely reduced. In mice, inhalation exposure of femalesto 85 mg manganese/m3 (as manganese dioxide) for 16weeks prior to conception and 17 days after conceptionled to a decrease in average pup weight at birth anddecreased activity levels (Lown et al., 1984). Webster &Valois (1987) found that intraperitoneal injection ofpregnant mice with 12.5 mg manganese/kg body weight(as manganese sulfate) on days 810 of gestation

resulted in exencephaly and embryolethality. Finally,manganese chloride administered by gavage at doses of0, 25, 50, or 75 mg/kg body weight per day caused major

dose-dependent abnormalities in the fetuses whenadministered to gestating rats for the duration ofgestation, but did not cause major abnormalities in the

fetuses when administered to pregnant rabbits duringthe period of organogenesis (Szakmry et al., 1995).

In a rat teratology study, intravenous injection of

20 :mol manganese chloride/kg body weight (1.1 mgmanganese/kg body weight) on days 617 of pregnanc yinduced mild skeletal malformations in the fetuses; theno-observed-adverse-effect level (NOAEL) was 0.28 mgmanganese/kg body weight (Treinen et al., 1995). Similareffects were observed in another study (Grant & Ege,1995) when administration was by injection, but not

when manganese was administered by gavage at400 :mol manganese chloride/kg body weight (22 mgmanganese/kg body weight). These results suggest thatparenteral administration has a much greater potential fordevelopmental toxicity than oral exposure.

In rabbits exposed to manganese by intratrachealinstillation, a single dose of 160 mg manganese/kg bodyweight (as manganese dioxide) resulted in a slow degen-eration of the seminiferous tubules over a period of18 months. This was associated with loss of spermato-genesis and complete infertility (Seth et al., 1973;Chandra et al., 1975). Similar degenerative changes in

testes have been observed in rats and mice followingintraperitoneal injection of manganese sulfate (Singhet al., 1974; Chandra et al., 1975) and in rabbits followingintravenous injection of manganese chloride (Imam &Chandra, 1975).

8.7 Immunological and neurological

effects

As with exposure to other airborne particulate

matter, an increased susceptibility to infection has beenobserved in mice and guinea-pigs exposed to manganese

via inhalation for a short period (Maigetter et al., 1976;Adkins et al., 1980). Altered blood levels of leukocytes,lymphocytes, and neutrophils have been observed inrats and mice that ingested manganese in the feed forshort-term (33 mg/kg body weight per day for 14 days) or

subchronic (284 mg/kg body weight per day for100 days) durations (Komura & Sakamoto, 1991; NTP,1993). However, it is unknown if these changes areassociated with any significant impairment of theimmune system.

No evidence of neurological effects was seen inrhesus monkeys (0.011.1 mg manganese tetroxide/m3) or

macaque monkeys (2040 mg manganese chloride/m3)exposed to manganese via inhalation over subchronicand chronic periods (Ulrich et al., 1979). However,intravenous administration of 540 mg manganese/kg (asmanganese chloride) to cebus monkeys did result inmovement tremors accompanied by increasedmanganese in the globus pallidus and substantia nigraregions of the brain (Newland & Weiss, 1992).

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Decreased levels of dopamine were found in severalregions of the brain (caudate and globus pallidus) inrhesus monkeys exposed to 30 mg manganese/m3 (asmanganese dioxide) via inhalation for 2 years (Bird et al.,

1984).

A decrease in pup retrieval behaviour was

observed in maternal mice exposed to 61 mg manga-nese/m3 (as manganese dioxide) via inhalation for18 weeks (Lown et al., 1984). In another study, Morgantiet al. (1985) observed moderate changes in open-field

behaviour in mice exposed to 72 mg manganese/m3 (asmanganese dioxide) for 18 weeks.

In general, effects from inhalation exposure tomanganese in experimental animals occur at levels higher(3070 mg manganese/m3) than those at which effectshave been reported in humans (0.141 mg total manga -nese dust/m3 for preclinical neurological alterations and222 mg total manganese dust/m3 for overt neurologicaldisease). This evidence suggests that laboratoryanimals, especially rode nts, might not be as sensitive ashumans, and possibly other primates, to the neurologicaleffects of inhalation exposure to manganese.

There are substantial data on neurological effects

in animals following ingestion of manganese. In onestudy, decreases in spontaneous activity, alertness,touch response, muscle tone, and respiration were

observed in mice dosed once by oral gavage with 58 mgmanganese/kg body weight (as manganese chloride)(Singh & Junnarkar, 1991). Rats developed a rigid andunsteady gait after 23 weeks of exposure to a higherlevel (150 mg/kg body weight per day) of manganesechloride (Kristensson et al., 1986).

Mice ingesting food containing manganesechloride, manganese acetate, manganese carbonate, ormanganese dioxide (284 mg/kg body weight per da y) for100 days or manganese tetroxide (137 mg/kg bodyweight per day) for 90 days showed significantly

decreased motor activity (Gray & Laskey, 1980; Komura& Sakamoto, 1991). Two of the third-generation miceexhibited staggered gait and histochemical changes afterdrinking water containing manganese chloride (10.6mg/kg body weight per day) over three generations(Ishizuka et al., 1991). Conversely, rats showed increasedactivity and aggression when exposed to 140 mgmanganese chloride/kg body weight per day in drinking-

water for 4 weeks (Chandra, 1983) and just increasedactivity when exposed to 40 mg manganese chloride/kgbody weight per day for 65 wee ks (Nachtman et al .,1986).

Numerous studies have repor ted a lterat ions in

brain neurotra nsmitter levels and funct ion, bra inhistochemistry, or neuronal enzyme function. These

neurochemical changes have been observed in rats andmice following ingestion of manganese (as manganesechloride) administered via the feed, drinking-water, orgavage (in water) at doses ranging from 1 to 2270 mg

manganese/kg body weight over intermediate exposureperiods (i.e., 14364 days) (Bonilla, 1978; Chandra &Shukla, 1978; Deskin et al., 1980; Gianutsos & Murray,1982; Chandra, 1983; Bonilla & Prasad, 1984; Ali et al.,1985; Eriksson et al., 1987; Subhash & Padmashree,1991). Similar alterations were reported after chronicexposures (>365 days) to 275 mg manganese dioxide/kg

body weight in the feed of mice (Komura & Sakamoto,1992) or 40 mg manganese chloride/kg body weight indrinking-water of rats (Lai et al., 1984).

Neurochemical alterat ions have also been reportedin rats following intraperitoneal injection of manganeseat doses ranging from 2.2 to 4.4 mg manganese chloride/kg body weight over intermediate exposure periods(Sitaramayya et al., 1974; Shukla et al., 1980; Seth et al.,1981). Decreased neurotransmitter receptor binding wasobserved in macaca monkeys following subcutaneousinjection of manganese dioxide at 38 mg/kg body weightfor 26 months (Eriksson et al., 1992). Changes in region-

specific neuronal populations were reported in ratsreceiving manganese chloride from their drinking-waterfor either 4 or 8 weeks (Sarhan et al., 1986). The actualmanganese dose administered over the total experimentalperiod was not reported by the authors . However , dai ly

intakes of at least 10.7 mg manganese/kg body weigh tare estimated based on initial average body weight andwater intake reported in the study.

Neurobiochemical changes have been detec ted in

neonate rats at doses similar to or slightly above dietarylevels (110 mg manganese/kg body weight per day for

2460 days, as manganese chloride) (Chandra & Shukla,1978; Deskin et al., 1980), which could indicate tha tyoung animals may be more susceptible to manganesethan adults. Oner & Senturk (1995) demonstrated thatmanganese induces learning deficits in rats dosed with

357 :g manganese/kg body weight for 15 or 30 days;these effects were reversible.

9. EFFECTS ON HUMANS

A requirement for manganese in huma ns was

determined based on symptoms observed in a subjectinadvertently fed a diet deficient in manga nese for3.5 months (Doisy, 1972). It has been determined that

manganese is needed for the functioning of key enzymesthat play a role in cellular protection from damaging freeradical species, maintenance of healthy skin, andsynthesis of cholesterol (Freeland-Graves et al., 1987;

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Friedman et al., 1987). Based upon case-studies in peoplewith low blood manganese and known requirements inanimals, it is thought that mangan ese may also play arole in bone mineralization, metabolism of proteins,

lipids, and carbohydrates, energy production, metabolicregulation, and nervous system functioning (Schroederet al., 1966; Freeland-Graves et al., 1987; Hurley & Keen,1987; Freeland-Graves & Llanes, 1994; Wedler, 1994).However, the link between inadequate manganesenutrition and its role in these body functions in humansrequires further investigation.

Manganism is a progressive, disabling neurolog-ical syndrome that typically begins with relatively mildsymptoms and evolves to include dull affect, altered gait,fine tremor, and sometimes psychiatric disturbances.Because some of these symptoms resemble those ofParkinsons disease, many investigators have usedterms such as Parkinsonism-like disease andmanganese-induced Parkinsonism to describe symp-toms observed with manganese poisoning. Althoughsymptoms of manganism resemble those of Parkinsonsdisease, significant differences have been noted. Interms of clinical presentation, Barbeau (1984) noted that

the hypokinesia and tremor present in patients sufferingfrom manganism differed from those seen in Parkinsonsdisease. Drawing from the literature, Calne et al. (1994)noted other features that can also distinguishmanganism from Parkinsons disease; psychiatric

disturbances early in the disease (in some cases), thecock walk (see below), a propensity to fall backwardwhen displaced, less frequent resting tremor, morefrequent dystonia, and failure to respond to dopamino-mimetics (at least in the late stages of the disease) werecharacteristic of manganism. Beuter et al. (1994) showedthat 10 manganese-exposed workers (average exposure

of 13.9 years; average blood manganese level of 1.06:g/dl) and 11 patients with Parkinsonism weresignificantly different from the controls (n = 11) infunctional asymmetries between right and left hand.Therefore, use of terms such as Parkinsonism-like

disease and manganese-induced Parkinsonism aresomewhat misleading. Nonetheless, the use of theseterms may help health providers and health surveillanceworkers recognize the effects of manganese poisoningwhen encountering it for the first time in occupational orenvironmental settings. These terms appear in the dis-cussion below when they were used b y study authors intheir reports (shown in italics). The term manganism is

used as well.

Long-term exposures to manganese in occupa-

tional settings can result in a progressive neurologicaldysfunction, which can produce a disabling syndromereferred to as manganism. Mergler & Baldwin (1997)have described this disease progression as a slowdeterioration of well-being which can be initially

detected as early neurofunctional alterations... [amongexposed groups], later on, as sub-clinica l signs inindividuals... and finally as a full blown neurologicaldisease manganism. Progression along this

continuum is thought to be a function of the dose andduration of exposure, as well as individual suscepti -bil ities. In general , the clinica l ef fec ts of high- levelinhalation exposure to manganese do not becomeapparent until exposure has occurred for several years,but some ind ividua ls begin to show signs of neurologi-cal alterations after as little as 13 months of exposure

(Rodier, 1955).

Pathological findings in manganism and Parkin-sons disease also differ. In humans with chron ic man-ganese poisoning, lesions are more diffuse, found mainlyin the pallidum, the caudate nucleu s, the putamen, andeven the cortex. In people with Parkinsons disease,lesions are found in the substantia nigra and otherpigmented areas of the brain (Barbeau, 1984). Moreover,Lewy bodies are usually not found in substantia nigra incases of manganism, but are almost always found incases of Parkinsons disease (Calne et al., 1994).Magnetic resonance imaging of the brain reveals

accumulation of manganese in cases of manganism, butlittle or no changes in people with Parkinsons disease;fluorodopa positron emission tomography scans arenormal in cases of manganism, but abnormal in peoplewith Parkinsons disease (Calne et al., 1994).

The first signs of manganism are usually subjec-

tive and non-specific, often involving generalizedfeelings of weakness, heaviness or stiffness of the legs,anorexia, muscle pain, nervousness, irritability, andheadache (Rodier, 1955; Whitlock et al., 1966; Menaet al., 1967; Tanaka & Lieben, 1969; Sjgren et al., 1996).

These signs are frequently accompanied by apathy anddullness, along with impotence and lo ss of libido;especially in the case of miners, more extrememanifestations of psychomotor excitement, such asaggressive or destructive behaviour, emotional lability,

and bizarre compulsive activities, are also associatedwith the first stages of manganism (Rodier, 1955; Schuleret al., 1957; Mena et al., 1967; Emara et al., 1971; Abdel-Hamid et al., 1990; Wennberg et al., 1991; Chu e t al.,1995).

More specific clinical signs of basal ganglia dys-function characterize the next stage and ca n include a

slow or halting speech without tone or inflect ion, a dulland emotionless facial expression, slow and clumsymovement of the limbs or altered gait, late motor deficits,and fine tremor (Rodier, 1955; Schuler et a l., 1957; Menaet al., 1967; Tanaka & Lieben, 1969; Smyth et al., 1973;Yamada et al., 1986; Ky et al., 1992; Wennberg et al.,1992; Hochberg et al., 1996; Mergler & Baldwin, 1997).

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As the disease progresses, walking becomes

difficult and a characteristic staggering gait develops,the cock walk, in which patients strut on their toes,with elbows flexed and the spine erect (Calne et al.,

1994). Muscles become hypertonic, and voluntary move-ments can be accompanied by fine tremor (Chu et al.,1995; Mergler & Baldwin, 1997). In some cases,psychologica l distu rbances (manganese mania, manga-nese psychosis) precede or accompany the final stagesof disease (Rodier, 1955; Mena et al., 1967; Cook et al.,1974; Mergler & Baldwin, 1997). Few data are available

regarding the reversibility of these effects; they arethought to be largely irreversible. Some evidence indi-cates that recovery can occur when exposure c eases(Smyth et al., 1973). Manganism has been documented inwelders and in workers exposed to high levels ofmanganese dust or fumes in mines or foundries.

The studies cited above describe overt manganismresulting from long-term inhalation exposures to 222 mgtotal manganese dust/m3 (Schuler et al., 1957; Whitlocket al., 1966; Tanaka & Lieben, 1969; Cook et al., 1974;Saric et al., 1977; Huang et al., 1989). Evidence fromrecent occupational exposure studies (described below)

suggests that early or preclinical signs of neurologicaleffects can occur in generally asymptomatic workersexposed to much lower levels of manganese (about0.141 mg total manganese dust/m3) for several years(Roels et al., 1987, 1992; Iregren, 1990; Chia et al., 1993;

Mergler et al., 1994; Lucchini et al., 1995). However, thereported values are only estimates of actual ex posurelevels. Often, time-weighted averages of workplaceexposures are reported, and doseresponserelationships cannot be determined. In addition, expo-sures are generally reported as total manganese dust orthe respirable fraction of total dust, which can be defined

differently across studies (e.g., PM 5 [particulate matterwith an aerodynamic diameter less than or equal to 5 :m]or PM 10).

9.1 Case reports

Whitlock et al. (1966) reported a case-study of twoworkers exposed to manganese-containing fumes (3.5 mgmanganese/m3 average; no data on exact compounds)from an electric arc used to cut and cleave manganesecastings. Symptoms of ataxia, weakness, and decreasedmental ability developed about 912 months followingexposure. These symptoms improved after the patients

were treated with ethylenediaminetetraacetic acid(EDTA). Rosenstock et al. (1971) reported a case of amale who developed classic symptoms of manganismafter 14 months of exposure to manganese (doseunknown) from the fumes and dust of a steel foundry.After being unable to work for 3 yea rs, the patient wastreated with 612 g levodopa/day, with the largest doseproviding improvement in facial expression, speech, andmuscle tone. Six men exposed to manganese (22 mg

manganese/m3) for an unspecified period at an orecrushing plant developed signs including somnolence,abnormal gait, slurred speech, ataxia, masklike faces, andbradykines ia. Treatment with 8 g levodopa/day did not

alleviate the neurological effects observed in theseworkers (Cook et al., 1974).

An outbreak of a disease with manganism-like

symptoms was reported in a group of six Japanesefamilies (about 25 people) exposed to high levels ofmanganese in their drinking-water (Kawamura et al.,

1941). Symptoms included a masklike face, musclerigidity and tremors, and mental disturbance. Fivepeople, al l elder ly, were severely affected (2 died) , 2 weremoderately affected, 8 were mildly affected, and 10 (allchildren or young adults) were not affected. Theseeffects were postulated to be due to the contaminationof well-water with manganese (14 mg/litre) that leachedfrom batteries buried near the well. Manganeseconcentrations decreased over time, so the original levelof manganese was probably higher than 14 mg/litre. Thiscase has been interpreted as an indication that theelderly may be more sensitive than younger people tothe toxic effects of manganese (Davis & Elias, 1996).

A man noticed weakness and impaired mental

capacity after mistakenly ingesting low doses of potas-sium permanganate (1.8 mg/kg) instead of potassiumiodide for several weeks to treat lung congestion (Holz-

graefe et al., 1986). Although exposure was stopped after4 weeks, a syndrome similar to Parkinsons diseasedeveloped after about 9 months. In another case, fivepatien ts given manganese parenteral ly for an average of6 years showed early neurological symptoms ofpoisoning, while four others, exposed for an average of 4years, did not (Mirowitz et al., 1991). In a child,

accidental ingestion of potassium permanganate(174 mg/kg) resulted in severe local corrosion of themouth, oesophagus, and stomach, but there was noevidence of systemic toxicity (Southwood et al., 1987).

There are few reports regarding dermal exposure tomanganese in humans. In most cases, manganese uptakeacross intact skin is expected to be very limited.However, effects and elevated urinary manganese levelswere observed in a man burned with a hot acid solutioncontaining 6% manganese (Laitung & Mercer, 1983).There are also reports of workers experiencing effectsfrom dermal exposure to organic manganese compounds.

Headache and paraesthesia were among the symptomsreported in workers exposed dermally to MMT after aspill (doses unknown; Tanaka, 1994). Two youngBrazilian agricultural workers developedParkinsoniansyndrome (Ferraz et al., 1988) and a 37-year-old Italianman developedParkinsonism (Meco et al., 1994) afterchronic dermal and inhalation exposure to the fungicidemaneb.

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9.2 Epidemiological studies

The lungs, nervous system, and reproductive

system are the main organs affected following inhalatio n

exposures to manganese, although other effects havealso been observed. For example, in a study of 126enamellers and 64 decorators from five factories in theceramics industry, Motolese et al. (1993) found that48 workers were sensitized to at least one substance;posi tive sens it izat ion t es t resul ts wi th manganesedioxide were found in only 2 of the workers, however.

The remainder of this section focuses on the effectsmore commonly reported in epidemiological studies lung, nervous system, and reproductive system effects.

Inhalation of particulate manganese compoundssuch as manganese dioxide and manganese tetroxideleads to an inflammatory response in human lungs.Symptoms and signs of lung irritation and injury caninclude cough, bronchitis, pneumonitis, and reductionsin lung function (Lloyd Davies, 1946; Roels et al., 1987;Abdel-Hamid et al., 1990; Akbar-Khanzadeh, 1993).

Pneumonia has been reported to result from both

acute and long-term inhalation exposure to manganesedioxide dusts (Lloyd Davies, 1946; Tanaka, 1994). Theseeffects have been noted mainly in people exposed tomanganese dust under occupational conditions,although respiratory effects have also occurred in resi-

dential populations (WHO, 1987). A higher incidence ofpneumonia and a higher rate of deaths from pneumoniacompared with the general population were observedamong residents exposed to manganese dust from aferromanganese factory as well as among the factoryworkers (WHO, 1987; Tanaka, 1994). However, athreshold level for respiratory effects has not been

established. The increased susceptibility to respiratoryinfection might be secondary to the lung irritation andinflammation caused by inhaled particulate matter ratherthan caused by the manganese alone. It is likely that theinflammatory response begins shortly after exposure and

continues for the duration of the exposure.

Although available studies are not adequate todefine the doseresponse curve or determine whetherthere is a threshold for neurotoxicity, the lowest leve l ofexposure to manganese dust at which neurologicaleffects occur was reported by Iregren (1990) andWennberg et al. (1991). These investigators compared 30

male workers exposed to manganese for 135 yearsduring employment at two Swedish foundrie s with anunexposed control group of 60 workers (matched by age,type of work, and geographical area) using eight testsfrom the Swedish Performance Evaluation System andtwo additional manual tests. The mean and median levelsof manganese in the foundry air were measured at 0.25and 0.14 mg/m3, respectively, and available dataindicated that these levels had been consistent over the

past 1718 years. The exposed workers exhibited signi-ficantly inferior performance in simple reaction time, digitspan, and finger tapping. When a secondary match wasperformed, wi th scores on verbal tests used as an

additional matching criterion (which reduced the size ofthe reference group to 30), the same te st differencesremained, although the difference was not significant forthe digit span test. Although the subjects did not exhibitthe signs of clinical manganism described above, thesechanges were indicators of manganese-induced neuro-logical effects (Iregren, 1990; Wennberg et al., 1991).

The study results reported by Iregren (1990) andWennberg et al. (1991) are supported by evidencepresented by Roels et al . (1987, 1992) and Chia et al .(1993, 1995). Roels et al. (1992) detected early neuro-logical effects in male workers at an alkaline battery plantexposed to manganese dusts (manganese dioxide).Compared with 101 male workers without industrialexposure, the 92 exposed workers showed significantlypoorer ey eha nd co ordina tion , han d s tead ines s, andvisual re

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