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ThisreportcontainsthecollectiveviewsofaninternationalgroupofexpertsanddoesnotnecessarilyrepresentthedecisionsorthestatedpolicyoftheUnitedNationsEnvironmentProgramme,theInternationalLabourOrganization,ortheWorldHealthOrganization.
ConciseInternationalChemicalAssessmentDocument27
DIPHENYLMETHANEDIISOCYANATE(MDI)
FirstdraftpreparedbyDrJ.Sekizawa,NationalInstituteofHealthSciences,Japan,incollaborationwithDrM.M.Greenberg,USEnvironmentalProtectionAgency
PublishedunderthejointsponsorshipoftheUnitedNationsEnvironmentProgramme,theInternationalLabourOrganization,andtheWorldHealthOrganization,andproducedwithintheframeworkoftheInterOrganizationProgrammefortheSoundManagementofChemicals.
WorldHealthOrganizationGeneva,2000
TheInternationalProgrammeonChemicalSafety(IPCS),establishedin1980,isajointventureoftheUnitedNationsEnvironmentProgramme(UNEP),theInternationalLabourOrganization(ILO),andtheWorldHealthOrganization(WHO).TheoverallobjectivesoftheIPCSaretoestablishthescientificbasisforassessmentoftherisktohumanhealthandtheenvironmentfromexposuretochemicals,throughinternationalpeerreviewprocesses,asaprerequisiteforthepromotionofchemicalsafety,andtoprovidetechnicalassistanceinstrengtheningnationalcapacitiesforthesoundmanagementofchemicals.
TheInterOrganizationProgrammefortheSoundManagementofChemicals(IOMC)wasestablishedin1995byUNEP,ILO,theFoodandAgricultureOrganizationoftheUnitedNations,WHO,theUnitedNationsIndustrialDevelopmentOrganization,theUnitedNationsInstituteforTrainingandResearch,andtheOrganisationforEconomicCooperationandDevelopment(ParticipatingOrganizations),followingrecommendationsmadebythe1992UNConferenceonEnvironmentandDevelopmenttostrengthencooperationandincreasecoordinationinthefieldofchemicalsafety.ThepurposeoftheIOMCistopromotecoordinationofthepoliciesandactivitiespursuedbytheParticipatingOrganizations,jointlyorseparately,toachievethesoundmanagementofchemicalsinrelationtohumanhealthandtheenvironment.
WHOLibraryCataloguinginPublicationData
Diphenylmethanediisocyanate(MDI).(Conciseinternationalchemicalassessmentdocument27)1.Isocyanatestoxicity2.Riskassessment3.Environmentalexposure4.InternationalProgrammeonChemicalSafetyII.SeriesISBN9241530278(NLMClassification:QV280)ISSN10206167
TheWorldHealthOrganizationwelcomesrequestsforpermissiontoreproduceortranslateitspublications,inpartorinfull.ApplicationsandenquiriesshouldbeaddressedtotheOfficeof
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Publications,WorldHealthOrganization,Geneva,Switzerland,whichwillbegladtoprovidethelatestinformationonanychangesmadetothetext,plansforneweditions,andreprintsandtranslationsalreadyavailable.
WorldHealthOrganization2000
PublicationsoftheWorldHealthOrganizationenjoycopyrightprotectioninaccordancewiththeprovisionsofProtocol2oftheUniversalCopyrightConvention.Allrightsreserved.
ThedesignationsemployedandthepresentationofthematerialinthispublicationdonotimplytheexpressionofanyopinionwhatsoeveronthepartoftheSecretariatoftheWorldHealthOrganizationconcerningthelegalstatusofanycountry,territory,city,orareaorofitsauthorities,orconcerningthedelimitationofitsfrontiersorboundaries.
ThementionofspecificcompaniesorofcertainmanufacturersproductsdoesnotimplythattheyareendorsedorrecommendedbytheWorldHealthOrganizationinpreferencetoothersofasimilarnaturethatarenotmentioned.Errorsandomissionsexcepted,thenamesofproprietaryproductsaredistinguishedbyinitialcapitalletters.
TheFederalMinistryfortheEnvironment,NatureConservationandNuclearSafety,Germany,providedfinancialsupportfortheprintingofthispublication.
TABLEOFCONTENTS
FOREWORD
1.EXECUTIVESUMMARY
2.IDENTITYANDPHYSICAL/CHEMICALPROPERTIES
3.ANALYTICALMETHODS
4.SOURCESOFHUMANANDENVIRONMENTALEXPOSURE
5.ENVIRONMENTALTRANSPORT,DISTRIBUTION,ANDTRANSFORMATION
5.1Water
5.2Soil
5.3Air
6.ENVIRONMENTALLEVELSANDHUMANEXPOSURE
6.1Environmentallevels
6.2Humanexposure
7.COMPARATIVEKINETICSANDMETABOLISMINLABORATORYANIMALSANDHUMANS
8.EFFECTSONLABORATORYMAMMALSANDIN
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VITROTESTSYSTEMS
8.1Singleexposure
8.2Irritationandsensitization
8.2.1Irritation
8.2.2Sensitization
8.3Shorttermexposure
8.4Longtermexposure
8.4.1Subchronicexposure
8.4.2Chronicexposureandcarcinogenicity
8.5Genotoxicityandrelatedendpoints
8.6Reproductiveanddevelopmentaltoxicity
9.EFFECTSONHUMANS
9.1Casereports
9.2Epidemiologicalstudies
9.2.1Irritationandsensitization
9.2.2Longtermexposureandcarcinogenicity
10.EFFECTSONOTHERORGANISMSINTHELABORATORYANDFIELD
10.1Aquaticenvironment
10.2Terrestrialenvironment
11.EFFECTSEVALUATION
11.1Evaluationofhealtheffects
11.1.1Hazardidentificationanddoseresponseassessment
11.1.2CriteriaforsettingtolerableintakesorguidancevaluesforMDI
11.1.3Sampleriskcharacterization
11.2Evaluationofenvironmentaleffects
12.PREVIOUSEVALUATIONSBYINTERNATIONALBODIES
REFERENCES
APPENDIX1SOURCEDOCUMENTS
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APPENDIX2CICADPEERREVIEW
APPENDIX3CICADFINALREVIEWBOARD
INTERNATIONALCHEMICALSAFETYCARD
RSUMDORIENTATION
RESUMENDEORIENTACIN
FOREWORD
ConciseInternationalChemicalAssessmentDocuments(CICADs)arethelatestinafamilyofpublicationsfromtheInternationalProgrammeonChemicalSafety(IPCS)acooperativeprogrammeoftheWorldHealthOrganization(WHO),theInternationalLabourOrganization(ILO),andtheUnitedNationsEnvironmentProgramme(UNEP).CICADsjointheEnvironmentalHealthCriteriadocuments(EHCs)asauthoritativedocumentsontheriskassessmentofchemicals.
CICADsareconcisedocumentsthatprovidesummariesoftherelevantscientificinformationconcerningthepotentialeffectsofchemicalsuponhumanhealthand/ortheenvironment.TheyarebasedonselectednationalorregionalevaluationdocumentsoronexistingEHCs.BeforeacceptanceforpublicationasCICADsbyIPCS,thesedocumentsundergoextensivepeerreviewbyinternationallyselectedexpertstoensuretheircompleteness,accuracyinthewayinwhichtheoriginaldataarerepresented,andthevalidityoftheconclusionsdrawn.
TheprimaryobjectiveofCICADsischaracterizationofhazardanddoseresponsefromexposuretoachemical.CICADsarenotasummaryofallavailabledataonaparticularchemicalrather,theyincludeonlythatinformationconsideredcriticalforcharacterizationoftheriskposedbythechemical.Thecriticalstudiesare,however,presentedinsufficientdetailtosupporttheconclusionsdrawn.Foradditionalinformation,thereadershouldconsulttheidentifiedsourcedocumentsuponwhichtheCICADhasbeenbased.
Riskstohumanhealthandtheenvironmentwillvaryconsiderablydependinguponthetypeandextentofexposure.Responsibleauthoritiesarestronglyencouragedtocharacterizeriskonthebasisoflocallymeasuredorpredictedexposurescenarios.Toassistthereader,examplesofexposureestimationandriskcharacterizationareprovidedinCICADs,wheneverpossible.Theseexamplescannotbeconsideredasrepresentingallpossibleexposuresituations,butareprovidedasguidanceonly.ThereaderisreferredtoEHC1701foradviceonthederivationofhealthbasedtolerableintakesorguidancevalues.
WhileeveryeffortismadetoensurethatCICADsrepresentthecurrentstatusofknowledge,newinformationisbeingdevelopedconstantly.Unlessotherwisestated,CICADsarebasedonasearchofthescientificliteraturetothedateshownintheexecutivesummary.IntheeventthatareaderbecomesawareofnewinformationthatwouldchangetheconclusionsdrawninaCICAD,thereaderisrequestedtocontactIPCStoinformitofthenewinformation.
Procedures
TheflowchartshowstheproceduresfollowedtoproduceaCICAD.Theseproceduresaredesignedtotakeadvantageoftheexpertisethatexistsaroundtheworldexpertisethatisrequiredtoproducethehighqualityevaluationsoftoxicological,exposure,andotherdatathatarenecessaryforassessingriskstohumanhealthand/ortheenvironment.
Thefirstdraftisbasedonanexistingnational,regional,orinternationalreview.Authorsofthefirstdraftareusually,butnotnecessarily,fromtheinstitutionthatdevelopedtheoriginalreview.A
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standardoutlinehasbeendevelopedtoencourageconsistencyinform.ThefirstdraftundergoesprimaryreviewbyIPCStoensurethatitmeetsthespecifiedcriteriaforCICADs.
ThesecondstageinvolvesinternationalpeerreviewbyscientistsknownfortheirparticularexpertiseandbyscientistsselectedfromaninternationalrostercompiledbyIPCSthroughrecommendationsfromIPCSnationalContactPointsandfromIPCSParticipatingInstitutions.Adequatetimeisallowedfortheselectedexpertstoundertakeathoroughreview.Authorsarerequiredtotakereviewerscommentsintoaccountandrevisetheirdraft,ifnecessary.TheresultingseconddraftissubmittedtoaFinalReviewBoardtogetherwiththereviewerscomments.
TheCICADFinalReviewBoardhasseveralimportantfunctions:
toensurethateachCICADhasbeensubjectedtoanappropriateandthoroughpeerreview
toverifythatthepeerreviewerscommentshavebeenaddressedappropriately
toprovideguidancetothoseresponsibleforthepreparationofCICADsonhowtoresolveanyremainingissuesif,intheopinionoftheBoard,theauthorhasnotadequatelyaddressedallcommentsofthereviewersand
toapproveCICADsasinternationalassessments.
Boardmembersserveintheirpersonalcapacity,notasrepresentativesofanyorganization,government,orindustry.Theyareselectedbecauseoftheirexpertiseinhumanandenvironmentaltoxicologyorbecauseoftheirexperienceintheregulationofchemicals.Boardsarechosenaccordingtotherangeofexpertiserequiredforameetingandtheneedforbalancedgeographicrepresentation.
Boardmembers,authors,reviewers,consultants,andadviserswhoparticipateinthepreparationofaCICADarerequiredtodeclareanyrealorpotentialconflictofinterestinrelationtothesubjectsunderdiscussionatanystageoftheprocess.RepresentativesofnongovernmentalorganizationsmaybeinvitedtoobservetheproceedingsoftheFinalReviewBoard.ObserversmayparticipateinBoarddiscussionsonlyattheinvitationoftheChairperson,andtheymaynotparticipateinthefinaldecisionmakingprocess.
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1.EXECUTIVESUMMARY
ThisCICADondiphenylmethanediisocyanate(MDI)waspreparedbytheNationalInstituteofHealthSciences,Japan,incollaborationwiththeNationalCenterforEnvironmentalAssessment,USEnvironmentalProtectionAgency(EPA).TheCICADwasbasedprincipallyonthereviewsoftheJapanSocietyforOccupationalHealth(JSOH,1994)andtheUSEPA(1998)forthetoxicologicalevaluationandtheEuropeanUnion(EU,1999)fortheenvironmentalassessment.ItshouldbenotedthattheEUdocumentisstillanunapproveddraftandthattheinformationpresentedintheenvironmentalsectionsisbasedmainlyonunpublishedstudies.TheliteratureuptoNovember1998wassearchedusingMEDLINEtoidentifyanynewinformationrelevanttotheassessment.ThepreparationandpeerreviewofthesourcedocumentsaredescribedinAppendix1.InformationonthepeerreviewofthisCICADispresentedinAppendix2.ThisCICADwasapprovedasaninternationalassessmentatameetingoftheFinalReviewBoard,heldinStockholm,Sweden,on2528May1999.
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ParticipantsattheFinalReviewBoardmeetingarelistedinAppendix3.TheInternationalChemicalSafetyCard(ICSC0298)forMDI,producedbytheInternationalProgrammeonChemicalSafety(IPCS,1993),hasalsobeenreproducedinthisdocument.
Diphenylmethanediisocyanate(MDI)isthegenericnameofaproductusedinindustrialsettings.PolymericMDI(PMDI),theprimarytechnical/commercialformofMDI,isactuallyamixturethatcontains2580%monomeric4,4MDIaswellasoligomerscontaining36ringsandotherminorisomers,suchasthe2,2isomer.TheexactcompositionofPMDIvarieswiththemanufacturer.
Monomeric4,4MDIisawhitetopaleyellowsolidatroomtemperature,withamolecularweightof250.Ithasaboilingpointof>300Cat101.3kPa,ameltingpointof3943C,andavapourpressureof
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MDAintheurineofaworkerexposedtoPMDIwas7080h,andinserum,21days.
MDIisnotacutelytoxictolaboratorymammals.AnimaldataprovideclearevidenceofskinandrespiratorysensitizationduetoMDI.Humoralaswellascellularimmunitymaybeinvolvedinthepathogenesisofhypersensitivityduetoisocyanates.SevererespiratorydistressandasignificantdecreaseinbodyweightgainwereobservedinmaleandfemaleratsexposedtoPMDIaerosolataconcentrationof13.6mg/m3for6hperday,5daysperweek,overaperiodof2weeks,withmuchlessseveresignsofrespiratorydistressandonlyslightlyreducedbodyweightgaininmaleratsat4.9mg/m3.Basedonamarginalincreaseinlungtobodyweightratioathigherdoses,itwasconcludedthat2.2mg/m3,whichwasthelowestdoselevelexamined,wasanoobservedadverseeffectlevel(NOAEL).
Ina2yearchronicinhalationtoxicity/carcinogenicitystudy,ratsthatwereexposedtoPMDIaerosolatconcentrationsof0,0.19,0.98,or6.03mg/m3showedchangesintherespiratorytract.PulmonaryadenocarcinomaobservedinonecasewasconsideredasinsufficienttoidentifyPMDIasananimalcarcinogenhowever,insitugenerationofMDA,whichisaknownanimalcarcinogenviadrinkingwater,couldberesponsiblefortheeffect.Basalcellhyperplasiaintheolfactoryepitheliumdetectedat0.98and6.03mg/m3wasjudgedanoncarcinogeniccriticalendpoint.ThenonneoplasticinformationinthisstudysuggestsaNOAELof0.19mg/m3andalowestobservedadverseeffectlevel(LOAEL)of0.98mg/m3.
BothpositiveandnegativeresultswereobtainedwhenmonomericMDIdissolvedindimethylsulfoxide(DMSO)wastestedinvitrowithSalmonellatyphimurium.However,becauseoftheknowninteractionofDMSOwithMDItoyieldMDAandpossiblyotherreactionproducts,thesepositiveresultsshouldnotbeconstruedasmeaningfulforhumanhealthriskassessment.
ExposureofgravidWistarratstomonomericMDIresultedinanincreasedincidenceofasymmetricsternebraeinfetusesat9mg/m3however,astheincreasewaswithinthelimitsofbiologicalvariability,theNOAELfordevelopmentaltoxicityinthisstudywasestimatedtobe9mg/m3.InanotherstudyinwhichratswereexposedtoPMDI,theNOAELformaternalandfetaltoxicitywasestimatedtobe4mg/m3,basedonthefindingofprematuredeathsofpregnantfemalesandstatisticallysignificantdecreasesinplacentalandfetalweightsat12mg/m3.TherehavebeennostudiesthathaveexaminedtheeffectofpolymericormonomericMDIonreproductiveparameters.
Thehealthendpointsofmostconcernareoccupationallyinducedasthma,hypersensitivitypneumonitis,andinflammatoryupperrespiratorytractdiseasesthroughinhalationofpolymericormonomericMDI.Althoughnotyetwellunderstood,humoralaswellascellularimmunologicalreactionsappeartobeinvolvedintheallergicreactions.CasereportsaswellasepidemiologicalstudieshavedescribedMDIasacauseofoccupationaldermatitis,skinsensitization,andasthma.Althoughlimitedinvariousways,acohortstudyandaretrospectivestudyshowednosignificantassociationwithcancermorbidity.Therearenodataavailablefororalexposure,butitisunlikelythathumansareexposedtoMDIbytheoralroute.
MDIdidnotshowtoxicitiestofish,aquaticinvertebrates,algae,ormicroorganismsunderanyacuteorlongtermexposuretestingconditions.However,resultsofaquatictestsarenotmeaningfulbecauseofMDIsvirtualinsolubilityinwater.Similarly,afewtestsonterrestrialorganismsdidnotshowanyeffectsunderthetestingconditions.AvailabledatashowthatthereisnoneedforconcernregardingtheeffectsofMDIonorganismsintheenvironment,althoughmoredetailedinformationregardingtheformationofMDAintheenvironmentanditseffectsonorganismsisrequiredbeforeanyfirmconclusionscanbedrawn.
2.IDENTITYANDPHYSICAL/
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CHEMICALPROPERTIES
MDIisthegenericnameofaproductusedinindustrialsettings.PMDI,theprimarytechnical/commercialformofMDI,isactuallyamixturethatcontains2580%monomeric4,4MDIaswellasoligomerscontaining36ringsandotherminorisomers,suchasthe2,2isomer.Thiscompositionrendersthematerialsemisolidandsuitableforaerosolgeneration.ThecompositionofPMDIvarieswiththemanufactureranduse.Therangeofvariationreflectsvariationsfromvarioussourcesofinformation,i.e.,fromaGermanreview(DFG,1997),USToxicologicalReview(USEPA,1998),andtheEUdraftdocument(EU,1999).Figure1giveschemicalstructuresof4,4MDIandPMDI,andTable1providesChemicalAbstractsService(CAS)registrynumbersofseveralMDIisomersandPMDI.
Table1:IsomersandpolymersofMDI.
Name CASregistrynumber
4,4MDI 101688
2,4MDI 5873541
2,2MDI 2536052
nonisomerspecificMDI 26447405
PMDI 9016879
Monomeric4,4MDIisawhitetopaleyellowsolidatroomtemperature,withamolecularweightof250.26.Ithasaboilingpointof>300Cat101.3kPa,ameltingpointof3943C(capillarymethod)or40C(differentialscanningcalorimetryorDSCmethod)(Kellyetal.,1997),andavapourpressureof
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PMDIisadarkreddishbrownviscousliquidwithanindefinitemeltingpointaround0Candavapourpressureof
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ThecomplexnatureofMDIcompositionandreactionsintheenvironmentoftenmakesinterpretationdifficult.
TheobservedorlikelyfatesofMDIinair,water,andsoilhavebeendescribedbyBrochhagen&Keller(1983)andGilbert(1988).Morerecently,comprehensivestudiesonthebehaviourofMDIintheaquaticenvironmenthavebeencarriedoutbyYakabeetal.(1994)andHeimbachetal.(1996).
5.1Water
WhenMDIisaddedtowater,itsNCOgroupsreactreadilywithOHgroupsofthewatertoformmixturesofdiisocyanatesandamines,whichthenreadilyreactwithmoreMDItoproduceinert,solid,insolublepolyurea(EU,1999).Thehydrolysisofisocyanatesinaqueoussolutionisrapidahalflifeof20shasbeenmeasuredforphenylisocyanate(Castroetal.,1985).However,thesubsequentreactionoftheformedaminewithfurtherisocyanate,toproduceaurea,isevenfaster(Hegartyetal.,1975).
Yakabeetal.(1994)studiedthefateofPMDIinwaterundertwoconditionsnamely,vigorousstirringandstaticconditions,whichsimulatetwoscenariosofaccidentalspillsofPMDI.PMDIusedinexperimentsiscomplexandcomposedof56majorconstituentshaving24aromaticrings.WhenMDIcomesintocontactwithwater,itdoesnotdispersereadily,butformsglobulesorsolidmasses,whichreactattheirsurface.Undersuchheterogeneousconditions,thedisappearanceofPMDIshowszeroorderkinetics.ProductionofwatersolubleMDAincreasesgraduallywithtime,andtheMDAreachesanearlyconstantconcentrationafter16htheamountofMDAformedislessthan0.5%ofthenominalconcentrationofPMDIinitiallyadded,andthemajorproductsofPMDIbreakdownaresolid,insolublepolyureas.ThepolyureasformedfromMDIappeartobestabletochemicalattack,aswouldbeexpectedfromitsinsolubilityandthestabilityofureas.
SupportforthechemicalstabilityofMDIisgiveninonestudyinwhichthepolyureaformedfromthereactionofPMDIwithwaterwasstirredat40Cinaqueousbuffersolutionsfor14days.Nosolubleproducts(dissolvedorganiccarbonorMDA)weredetected(Yakabeetal.,1994).
AfurtherpotentialbreakdownproductofMDIinwaterisanoligourea.Anoligoureawassynthesizedfrom4,4MDIand4,4MDAandshowntobemainlydiurea.Itwasinsolubleinwaterandfoundtobenotinherentlybiodegradable(Yakabeetal.,1994).
InthestudybyHeimbachetal.(1996),upto10gofPMDIwasaddedperlitreofwaterintoartificialoutdoorponds,simulatingaccidentalpollutionofapond.Threepondscontainedgroundwater,abovenaturallakesediment,towhichcagedrainbowtrout(Oncorhynchusmykiss)wereadded.Followingequilibration,PMDIwasaddedtopartofthesedimentoftwopondsatdosagesof1and10g/litre.Thethirdpondservedasanuntreatedcontrol.Waterchemistry,MDIandMDAconcentrations,andpopulationsanddiversityofdifferenttrophiclevelsweremonitoredover112days.TheconcentrationsofMDIandMDAweremonitoredinthethreecompartments(water,fish,andsediment)overthedurationofthestudy.NoMDIorMDAwasdetectedinthewater(detectionlimits4and10g/litre,respectively)orinthefish(detectionlimits0.5and1.4mg/kg,respectively).ThestudyprovidesevidencethatMDIaccumulationthroughtheaquaticfoodchainisextremelyunlikely,asmightbeexpectedconsideringtheverylowsolubilityandhighreactivityofMDIinaqueoussolution.
5.2Soil
MDImaycomeintocontactwithsoilafteraccidentalspillageduringtransportationorstorage.
5.3Air
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TheatmosphericconcentrationofMDIarisingfromareleaseisnaturallylowonaccountofMDIsverylowvolatility.ItisexpectedthatairborneMDIwillhavearathershorthalflifeasaconsequenceofreadydegradationtoinorganiccompoundsbyhydroxylradicalspresentinthetroposphere.
ThequestionofwhetherMDIvapouroraerosolcanhydrolyseinhumidairtoyieldMDAwasassessedinalongtermstudy(Appelmanetal.,1986)andastudyofchipboardproduction(Giersig,1989).Inthefirststudy,lowconcentrationsofMDA(notdetectedto90g/m3)wereobservedinairsamplesfromthesubchronicinhalationstudyinratsexposedtoPMDI(Appelmanetal.,1986).Detectedconcentrationswereindependentoftheconcentrationsofthetestatmosphere(0,0.2,1,and5mg/m3)thus,itwasconsideredthatthedetectionofMDAwascausedbyartefacts.Inthesecondstudy,noMDAwasdetected,althoughthePMDIconcentrationsrangedupto5mg/m3whenpolyurethaneparticleboardwasheatedupto80C(thedetectionlimitforMDAinairwas10g/m3)(Giersig,1989).Thisresulthasbeenaccountedforasfollows:MDAisformedonlyslowlyatneutralpHandreactsrapidlywithexcessMDItoyieldoligoureasandpolyureasMDIaerosolscanformashellofpolyureaonthesurfaceofthedroplets,andthisshellpreventsfurtherreactionoftheenclosedMDI(Mann,1987).
6.ENVIRONMENTALLEVELSANDHUMANEXPOSURE
6.1Environmentallevels
CommercialsynthesisofMDItakesplaceinclosedsystemswherecontactofMDIwithwateriscarefullyavoidedthroughproductionandstoragestages,sincetheNCOgroupofMDIreactsreadilywiththeOHgroupofwater(EU,1999).ThereisnoinformationaboutlevelsofvariousformsofMDIintheambientair.Wherespillageistosoilorwater,MDIhasatransientexistenceduetoitsreactionwiththewatertoproducepredominantlyinsolublepolyureas.
6.2Humanexposure
Undernormalcircumstances,exposureofthegeneralpublicislikelyonlyfromreleasestotheatmosphere.
Occupationalexposuredatafromawiderangeofapplicationsandprocessescollectedacrossindustry,measuredbyrecentstandardsandcapturingtotalinhalableMDI(i.e.,vapourandaerosol)overavarietyofexposuretimes(0.258h),areavailable(ISOPA,1998).Outof1238measurements,138(11%)wereabove0.0125mg/m3,and31(2.5%)wereabove0.05mg/m3these31measurementsweredetectedduringprocessesinrigidpolyurethanefoampreparationforroofpanelsforthermalinsulationorpreparationofcoatings,adhesives,sealants,andelastomersforsprayfloorcoating,bridgedeckingprimer,orparticleboard.SinceaccidentalexposuretoMDIinoccupationalsettingsmayresultfromincidentssuchasspillages,splithoses,andleakingdrums,theintroductionofEuropeanIsocyanateProductionAssociation(ISOPA)guidelinesfortransport,storage,handling,anduseofdiisocyanatehasreducedthepotentialofaccidentalexposuresoverthepast20years.
AnalysisconductedrevealedthattheenvironmentalMDIconcentrationwas0.05mg/m3orlessin273outof319samples,andonly2samplesexceeded0.2mg/m3.Itisreported,however,thataventilationductwasinstalledabovethemouldingmachineseveralmonthsbeforetheanalysis,andthatbeforethensamplesexceeding0.2mg/m3hadoccurredfrequently(Diller&Herbert,1982).
Sepaietal.(1995b)examinedbiologicalsamples(urineandblood)from20workers(aswellas2unexposedreferenceworkers)exposedtoMDIvapourduringthemanufactureofpolyurethane
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products,togetherwiththelevelsofMDIintheairoftheworkingenvironment.Inmostcases(17outof20),theairlevelswerebelowdetectionlimits.Thebloodandurinesampleswereanalysedforthepresenceofadductsandmetabolitesusinggaschromatographymassspectrometrymethods.TheamountofMDAreleasedafteracidhydrolysis(inhydrochloricacidat3mol/litre,at100C,for60min)wasonaverage6.5timeshigherthantheamountoffreeMDAandacetylatedMDApresentinurine.
TheOntarioMinistryofLabour,Canada,assessedthecauseofmultiplerespiratorycomplaintsamongworkersataplantthatmanufacturesautomotiveinstrumentpanelsusingpolyurethane(Lissetal.,1996).Of137samplesanalysedforMDIbetween1986and1992,129(94%)werebelowthelimitofdetection(notgiven).Oftheothereight,allbutone(withaconcentrationof60g/m3)werebelow50g/m3.Tarloetal.(1997)reportedthat40%ofmeasuredMDIconcentrationsin19841988in20companieswithcompensatedisocyanateasthmaclaimsexceeded50g/m3,whilethefigurewas27%for203companieswithnocompensatedisocyanateasthmacases.
7.COMPARATIVEKINETICSANDMETABOLISMINLABORATORY
ANIMALSANDHUMANS
AnimalinhalationstudieshaveshownthatPMDIexposure(seesection8.4.2fordetailsofparticlesizedistribution)resultsinsignificantdepositionbothinthenasalregionandinthealveolarregionofthelungs(Reuzeletal.,1994a,b).Onceabsorbed,PMDIappearstobepredominantlyconjugatedtoprotein,buttheroleofotherbiomolecules,suchasglutathione,hasnotbeeninvestigated(theroleofglutathionehasbeenshownforotherisocyanatesbyDayetal.,1997).
Inanunpublishedpharmacokineticstudy(Istin,1977),noseonlyexposureofmaleSpragueDawleyratstoanaerosol(particlesizeslessthan5m)ofradiolabelled(inthemethylenegroup)monomericMDIfor15minresultedinthedistributionofradioactivity,predominantlytothelungsandavarietyofextrarespiratorysites(principallymuscle,liver,kidneys,andthedigestivetract),after96hwhentheanimalsweresacrificed.Labellingofthedigestivetractwasconsideredtobearesultoftransferenceoflabelledmaterialfromthelungs.After4days,70%oftheabsorbeddosewaseliminated(57%faecaleliminationand13%urinaryelimination).Therewasnoattempttoidentifythenatureoftheexcretedradioactivity.Twentythreepercentoftheradioactivityadministeredwasfoundinthecarcasshowever,lessthan1%oftheradioactivitywasrecoveredfromthemajororgans.Thefateoftheother22%isnotknown.
HaemoglobinadductswerefoundafterrepeatedexposureofratstoMDIaerosolsfor17hperday,5daysperweek,over3or12monthsinaninhalationchamber(Sepaietal.,1995a).InlaboratoryanimalsexposedtoPMDI/MDI,MDAinurineandbloodformedbystrongacidhydrolysiswasusedasabiomarkerforexposure(Sepaietal.,1995a).
WhenpregnantWistarratswereexposedfor6hongestationday19toanaerosolof20mgMDI/m3(particlesizedistributionnotknown),maternalblood,amnioticfluid,fetus,andplacentaweremeasuredforMDIanddegradationproducts(asMDAafteracidhydrolysisdetailsofhydrolysisconditionsnotknown)immediatelyafterexposure(Bartschetal.,1996).ThehighestlevelofMDAordegradationproductswasdetectedinthematernalblood,followedbytheplacenta,fetus,andamnioticfluid(at66.4%,42.4%,and13.6%ofthematernalbloodlevels,respectively).
Inhumans,MDAlevelsinurineand(afterstrongacidhydrolysis)inbloodwerereportedtobecorrelatedwithexposuretoPMDI/MDI(Schuetzeetal.,1995Sepaietal.,1995bSkarping&Dalene,1995).ThehalflifeofMDAintheurineofaworkerexposedtoPMDIwas7080h,andinserum,21days(Skarpingetal.,1995).OtherreportsalsosuggestthatplasmaacidhydrolysableMDA
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maybeausefulbiomarkeroflongtermexposuretoMDI(Sepaietal.,1995bDaleneetal.,1996).InarecentstudyofworkersoccupationallyexposedtoeitherPMDI/MDIorMDA,freeMDAwasdetectedinurinepriortoacidhydrolysis(Schuetzeetal.,1995).
Sepaietal.(1995b)reportedtheformationofadductsofMDAandacetylatedMDAwithhaemoglobinoralbumininthebloodofworkersexposedtoMDI,asdescribedinsection6.2.MDAwasdetectedasahaemoglobinadductinall20subjects,atlevelsrangingfrom70to710fmol/ghaemoglobinthisincludedonecaseofhaemoglobinadductofacetylatedMDA,whichwaspresumablyformedbytheinvivohydrolysisofMDI.PlasmaMDAlevelsrangedfrom3.9to70fmol/mgplasmaproteinin20workers,andupto120fmol/mgwerefoundtobecovalentlyboundtoalbumin.MDIintheairandMDAintheplasmawereobservedinastudyofpolyurethanepipewelders(Skarpingetal.,1995Daleneetal.,1996Tinnerbergetal.,1997).ThehaemoglobinadductofacetylatedMDIwasconsideredtobeformedbyinvivohydrolysis.
8.EFFECTSONLABORATORYMAMMALSANDINVITROTESTSYSTEMS
8.1Singleexposure
OralLD50sforMDI(25%incornoil)andPMDI(undiluted)administeredtoratsinsinglegavagedoseswerereportedtobe31.6g/kgbodyweightandhigherthan10g/kgbodyweight,respectively(MobayChemical,1961Wazeter,1964a).
PMDI(liquidform0,2.5,3.9,6.0,and9.4g/kgbodyweight)wasappliedtotheabradedskinofimmobilizedalbinorabbits(2persexpergroup)whosebackswerethencoveredinrubberizedclothfor24h(Wazeter,1964b).AfterthePMDIwaswashedoff,animalswerekeptfor14daysforobservation.Transientlyslightatoniawasobservedinafewanimalsatthethreehighestdoselevels.Animalswereessentiallynormal,exceptforslightoedemaobservedatthe9.4g/kgbodyweightdose.
GuineapigsexposedtomonomericMDIaerosolatconcentrationsbetween0.6and350mg/m3(nootherdetailsavailable)for3hshowedadecreaseinrespirationrateandanincreaseintidalvolumeatlowerconcentrations,whereasaconcentrationdependentincreaseinrespirationratewasseenabove10.4mg/m3(Thorneetal.,1986).Incontrast,therespirationratewasdecreasedinadosedependentmannerinmiceexposedtoMDIaerosolconcentrationsbetween10.2and58.5mg/m3(Weyel&Schaffer,1985).
WhenratswereexposedtoPMDIaerosol(inwhichmorethan99%ofparticlesweresmallerthan5m)for4hatconcentrationsof384,418,500,or523mg/m3,animalssatquietlywithclosedeyes
duringexposure,andtheirbreathingbecamelabouredandnostrilsdilated,especiallyinthehighestconcentrationgroup(Appelman&deJong,1982).Autopsyoftheanimalsimmediatelyafterexposureshowedhaemorrageandoedemainthelungs.TheLC50inthisstudywasestimatedtobe490mg/m3.
8.2Irritationandsensitization
8.2.1Irritation
WhenPMDI(liquidform0,2.5,3.9,6.0,or9.4g/kgbodyweight)wasappliedtotheabradedskinofalbinorabbits(2persexpergroup)for24h(Wazeter,1964b),oneanimalatthehighestdoseexhibitedslightoedemaduringthefirstandseconddays.Slighterythemaobservedinitiallyatalldoselevelsdidnotlastafter7days.Nodesquamationorfissuringwasnotedwiththecompound.
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8.2.2Sensitization
ThereisclearevidenceofskinsensitizationduetoMDI.Humoralaswellascellularimmunitymaybeinvolvedinthepathogenesisofhypersensitivityduetoisocyanates.
Inamouseearswellingtest,whichindicatestheextentofcontactsensitivity,MDIatconcentrationsrangingbetween0.6and187mg/kgbodyweightwasappliedtotheshavedanddepilatedabdomensof45malemice(Thorneetal.,1987).After4days,themicewerechallengedontherightearwithacetoneandontheleftearwithacetonecontainingadoseofMDIthatwasnonirritating.Thethicknessoftheearsat24hafterchallengewascomparedwiththatimmediatelybeforechallenge.AftercalibrationoftheearswellingresponsewithMDIsensitizationdoseinlogscales,anearthicknessincreaseofmorethan0.03mmwasjudgedtobesignificant.Thechallengewithacetonedidnotproduceanyearswelling.TheresponsetoMDIchallengeindicatedadoseresponseeffectat0.637mg/kgbodyweight.Crossreactivitytotoluenediisocyanate(TDI)andotherisocyanateswasdemonstrated.
Usingearthickeningasthecriterion,transferofMDIinducedcontactsensitivitywithorwithoutTcelldeletionbymonoclonalantiThy1,2antibodywasstudied(Tanakaetal.,1987).A1%solutionofMDI(reagentgrade)inethylacetatewasappliedtoagroupof797weekoldmalemice.Thechallengesolutioninducedearswellingofdelayedonset,withitspeakat24h.PassivetransferoftheMDIinducedcontactsensitivitywasachievedbyinjectinglymphocytesfromthelymphnodesofMDIsensitizedmiceintothecaudalveinofsyngeneicmice,andtheeffectorcellswerefoundtobeTcells.
8.3Shorttermexposure
Fourgroupsof10maleand10femaleWistarratswereexposed,wholebody,toPMDIaerosolfor6hperday,5daysperweek,overaperiodof2weeks(Reuzeletal.,1994a).Theoverallmeanconcentrationswere2.2,4.9,and13.6mg/m3,respectively.Ninetyfivepercentoftheparticleshadamassmedianaerodynamicdiameter(MMAD)below5m.NoMDAandnophenylisocyanatecouldbedetectedinthetestatmospheres.Severerespiratorydistressandastatisticallysignificantdecrease(extentnotgiven)inbodyweightgainwereobservedinmaleandfemaleratsexposedto13.6mgPMDI/m37outof10malesand1outof10femalesdied.Maleratsexposedto4.9mg/m3showedmuchlessseveresignsofrespiratorydistressandonlyslightlyreducedbodyweightgaincomparedwithcontrols.Lungtobodyweightratiosweresignificantlyhigheronlyinthemidandhighconcentrationgroupsrelativetocontrols.Grosspathologicalexaminationremainedessentiallynegativenodataonhistologicalexaminationwerereported.Basedonthemarginalincreaseinlungtobodyweightratios,itwasconcludedthat2.2mgPMDI/m3,whichwasthelowestdoselevelexamined,wasaNOAEL.TheresultsshowthatthetoxicityofMDI(whichislowafteroralexposure)isclearlyhigherbytheinhalationroute,withlocaleffectstothelungafterrepeateddosing.
NoshorttermstudyonmonomericMDIandnodatafromoralordermalrouteswereavailable.
8.4Longtermexposure
8.4.1Subchronicexposure
InasubchronicstudybyReuzeletal.(1994a),SPFWistarrats(30persexperexposurelevel)wereexposed,wholebody,toPMDI(Desmodur44V20fromBayerAG,withmonomericMDI52%,isocyanatecontent30%)aerosolat0,4.1,8.4,or12.3mg/m3for6hperday,5daysperweek,for13weeks.Morethan95%oftheparticleshadanMMADoflessthan5m.Thehighestconcentrationresultedin25%mortality(15/60animals,onlyduringthefirst7weeks),growthretardation,severe
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respiratorydistress,degenerationofnasaltissues,andfocalinflammatorychangesinthelungs.Signsoflesssevererespiratorydistresswerealsoobservedinanimalsexposedto8.4mg/m3.Bodyweightsinmalesofthehighconcentrationgroupweresignificantlydepressedthroughweek13.Somebodyweightdepressionwasobservedinmalesofthemidconcentrationgroupthroughweek10.Bodyweightdepressionwasnotobservedinfemales.Therewasnotacleardoseresponsetrendinmacrophageaccumulation,althoughmacrophageswereincreasedinincidenceinalltestgroupsovercontrols.Tissuesexaminedbylightmicroscopyincludednose,larynx,trachea,lungs,liver,andkidney.Theincidenceofolfactoryatrophywasstatisticallysignificantinhighdosemales(5/10)andhighdosefemales(6/10).At4.1mg/m3,olfactoryepithelialatrophyoccurredinfrequentlyinexposedanimals.Therewasasignificantaccumulationofmacrophagesinthelungsandmediastinallymphnodesofallexposedanimalscomparedwithcontrols.Theincreaseinmacrophageaccumulationatthelevelofthealveolarseptawasrelatedtoexposure,andthedifferencebetweentreatmentgroupsandcontrolswasstatisticallysignificantinmalesexposedto4.1mg/m3andinfemalesat8.4mg/m3.
Sincethefirststudyfoundhighmortality,probablyduetotheuseofveryyounganimals,another13weekstudywasconductedatactualmeanconcentrationsof0.35,1.4,and7.2mg/m3(Reuzeletal.,1994a).Unlikethefirststudy,transientgrowthretardationandanincreasednumberofpulmonarymacrophagesweretheonlyeffectsnotedatthehighestconcentration.
Thus,thesestudiesdemonstratedclearadversepulmonaryandnasaleffectsat8.4mg/m3,andtheyarestatisticallysignificantat4.1mg/m3.
8.4.2Chronicexposureandcarcinogenicity
A2yearchronictoxicity/carcinogenicityinhalationstudywascarriedoutwithSPFWistarrats(60persexperexposurelevel)exposedwholebodytoPMDIaerosolat0,0.19,0.98,or6.03mg/m3for6hperday,5daysperweek(Reuzeletal.,1994b).Anadditionalsatellitegroupof10persexperexposurelevelwassimilarlyexposedandusedforhistopathologyat1year.NinetyfivepercentoftheparticleshadanMMADlessthan5mtheMMADandgeometricstandarddeviation(inparentheses)correspondingtotheexposurelevelswere0,0.68m(2.93),0.70m(2.46)and0.74m(2.31),respectively.
Effectsat24monthswereconfinedtotherespiratorytract.Compoundrelatedchangeswerefoundinthenasalcavity(olfactorydegenerationandbasalcellhyperplasia),thelungs(fibrosisandinterstitialpneumonitis),andthemediastinallymphnodestosomedegree,theywerealreadypresentafter1yearofexposure,asindicatedinthesatellitegroup.Olfactoryepithelialdegenerationwaselevatedsignificantlyatthehighconcentrationinbothsexes.Basalcellhyperplasiaintheolfactoryepitheliumwaselevatedsignificantlyinmalesonlyatthemidandhighconcentrations.
Noadverseeffectsonthedistributionandincidenceoftumourswerefoundwiththeexceptionoftumoursinthelungs.Solitarypulmonaryadenomas,describedasrareinthisstrain,wereobservedinmales(6/60)andfemales(2/59)exposedto6.03mg/m3comparedwithcontrols(0/120).Theadenomaswereonlyafewmillimetresinsizeandwerelocatedadjacenttoareasinwhichhaemorrhage,macrophageaccumulation,andfibroblasticreactionswereobserved.Onlyonepulmonaryadenocarcinoma(10mminsize)wasobservedinonemaleexposedtothisconcentration.
ThenasalolfactoryandlunglesionsindicateaNOAELof0.19mg/m3andaLOAELof0.98mg/m3.Compoundassociatedyellowishparticulatematerialwasfoundinalveolarluminarmacrophagesinbothsexesat0.98and6.03mg/m3.Localizedfibrosiswassignificantinmalesexposedto6.03mg/m3
andinfemalesat0.98and6.03mg/m3.Theamountofparticulatematerialaccumulatedatthelevelofthealveolarductincreasedwithtimeaswellaswithlevelofexposure.Macrophageswithyellowpigment(aformofMDIwithinthemacrophage)werealsofoundinthealveolarinterstitium,and
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accumulationofthesemacrophagesalsooccurredinthemediastinallymphnodes.Theaccumulationofmacrophagesandlocalizationoftissuedamageinthisareasuggestthatthethoraciceffectisdueprimarilytotoxicitytothemacrophage,withsecondarytissuedamage.
Achronicinhalationstudy(Hoymannetal.,1995,1997)hasalsobeenconductedwith99.5%puremonomeric4,4MDI.FemaleWistarrats(80perexposuregroup)wereexposed(wholebody)toMDIinaerosolat0.23,0.70,or2.05mg/m3(MMADabout1m)for17hperday,5daysperweek,forupto24months.Aseparategroupof20perexposurelevelwasexaminedhistopathologicallyat12months.Smallernumbersofanimalswereassessedatvarioustimepointsforlungfunctionandforexaminationofbronchioalveolarlavage(BAL)fluidforcellcountsandproteinandenzymedeterminations.Statisticallysignificantconcentrationrelatedpulmonarylesionsincluded(1)anincreaseinfocal/multifocalalveolarandbronchioalveolarhyperplasia,(2)interstitialfibrosis,and(3)anaccumulationofparticleladenandpigmentedmacrophages.Alveolarcellhyperplasia,consideredpreneoplastic,exhibitedaconcentrationresponsetrend,withtheincidencereachingsignificanceinthehighexposuregroup.Theseeffectscorrelatedwithpulmonaryfunctiondeficits(FEF25[forcedexpiratoryflowfrom25%oftheforcedvitalcapacity,orFVC]andcarbonmonoxidediffusion),particularlyinthehighexposuregroup.Allgroupsexhibitedsignificantlyincreasedrelativelungweightsatalltimeperiods(morethan60%at20months),withsignificantincreasesinhydroxyprolineinBALfluid(morethan70%at12months).IncontrasttotheresultsreportedbyReuzeletal.(1994b)forPMDI,therewasnoapparenteffectofmonomericMDIonnasaltissuesatanyexposurelevel.Inonehighdoseanimal,abronchioloalveolaradenomawasobserved.Becauseoftheconcentrationrelatedlungeffects,0.23mg/m3isconsideredaLOAEL.ThereisnoNOAELinthisstudy.
MDIreactswithwatertoproduceMDA.MDAhasalsobeenstudiedforcarcinogenicitybyoraladministration.Treatmentrelatedincreasesintheincidencesofthyroidfollicularcelladenomaandhepatocellularneoplasmswereobservedinbothmaleandfemalemicegiven150or300mgMDA/litreindrinkingwaterfor103weeks.InratsadministeredMDAinasimilarmanner,treatmentrelatedincreasesintheincidencesofthyroidfollicularcellcarcinomasandhepaticnoduleswereobservedinmales,andthyroidfollicularcelladenomasoccurredinfemales(Weisburgeretal.,1984NTP,1986).TheincidenceofthyroidtumourswasgreaterwhenMDA(1000mg/kgdietfor19weeks)wasadministeredorallyafterasingleintraperitonealinjectionof2800mgNbis(2hydroxypropyl)nitrosamine(DHPN)/kgbodyweightthanwhenDHPNwasgivenalone(Hiasaetal.,1984).TherelevanceoftheseresultstotheevaluationofthecarcinogenicresponsetoMDIanditspotentialmetaboliteisnotcertain.
8.5Genotoxicityandrelatedendpoints
WhenthemutagenicityofisomersandhomologuesofMDI(4,4MDI,2,4MDI,amixtureofmonomericMDIisomers,andPMDI)wasdeterminedintheSalmonella/microsometestusingDMSOandethyleneglycoldimethylether(EGDE)assolvents,positiveresultswereobtainedforDMSOsolutionsofallfourdiisocyanatesinthepresenceofS9mixcontaining30%S9fraction.UniformlynegativeresultswerefoundwhenthediisocyanatesweredissolvedinEGDE(Andersenetal.,1980Herbold,1980a,bWoolrich,1982Shimizuetal.,1985Zeiger,1987Herboldetal.,1998).MDIisnotstableinDMSO,therebeingmanyproductsgeneratedwithinminutes(Herbold,1990a,bGahlmann,1993).Thus,itseemsthatpositivetestresultsinanyinvitrotestsystemarecausedbythedegradationproductsofMDIinDMSO,ratherthanbyMDIitself.OneofthedegradationproductsofMDIisMDA,whichisknowntobegenotoxicandwhoseformationwasdetectedwhenMDIwasdissolvedinDMSO(Herboldetal.,1998).NoMDAcouldbedetectedinsolutionsofMDIinEGDE.ItisthereforeconcludedthatthepositiveresultsobtainedwithdiisocyanatesinDMSOsolutionsareduetotheformationofMDA.ThestabilityofMDIinamodelandarealtestenvironmentwasstudied(Seeletal.,1999).WhenMDIwasdissolvedinDMSO,morethan99%oftheMDIwasdegradedbeforethestartofincubationwithtestingredientsoftheSalmonellamutagenicityassay,and
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MDAwasdetectedat2.12.8%oftheMDIconcentrationwithin45sofincubation.TestsassessingthemutagenicpotentialofMDIinvitroandinvivoshownoconvincingevidenceofmutagenicactivity.
FemaleWistarratsweretreatedtopically(ontheback)with14CMDI(labelledinthering)inacetonetoinvestigatethepossibilityofsystemiccirculationandDNAbindingpotencyofMDI(Vock&Lutz,1997).About10%oftheradioactivitywasretainedatthesiteofapplication.DNAradioactivityintheliverwasatthelimitofdetection.Inasecondexperimentusingtopicaladministration,32PpostlabellinganalysisdidnotrevealisocyanateDNAadductsintheskin(Vock&Lutz,1997).
TissuesobtainedfromfemaleWistarratsexposedtoa0.9maerosolofMDIfor17hperday,5daysperweek,for1year,atlevelsof0,0.3,0.7,or2.0mg/m3,wereanalysedforDNAadductsusinga32Ppostlabellingmethod(Vocketal.,1996).Inthelung,neitherisocyanateadductsnorthearylamineadductwasdetectable.Thesamenegativeresultwasseenintheliver,bladder,kidney,respiratoryepithelium,andperipherallymphocytes.Intheolfactoryepithelium,ontheotherhand,thearylaminederivedDNAadductnucleotidesweredetectedatverylowlevels(510adductsper1010nucleotides).
8.6Reproductiveanddevelopmentaltoxicity
NospecificfertilitystudiesareavailableforMDI.
Inawellconducteddevelopmentalrangefindingstudy,conductedaccordingtoOrganisationforEconomicCooperationandDevelopment(OECD)GuidelineNo.414,matedfemaleWistarrats(8pergroup)wereexposedtoPMDIbyinhalation(wholebody)atexposurelevelsof0,2,8,or12mg/m3for6hperdayfromday6uptoandincludingday15ofpregnancy(WaalkensBerendsen&Arts,1992).Onday21ofpregnancy,thefemaleratsweresacrificedandacaesareansectionwasperformed.Noclinicalsignsormortalityrelatedtotreatmentwasobservedduringthestudy.Themeannumberofcorporalutea,implantationsites,earlyandlateresorptions,and,consequently,preandpostimplantationlossshowednostatisticallysignificantdifferencesamongthecontrolandtreatedgroups.Fromday6today9ofpregnancy,maternalbodyweightgainofthe8and12mg/m3groupswasslightlydecreased(notstatisticallysignificant)whencomparedwiththecontrolgroup.Nootherdifferenceswereobservedinbodyweightandbodyweightgain,carcassweight,ornetweightgainwhencomparedwiththecontrolgroup.Fetalbodyweightswerecomparableinallgroups,andnoexternaltreatmentrelatedabnormalitieswereobservedinthefetuses.TheNOAELofPMDIaerosolbyinhalationformaternaltoxicityis8mg/m3,basedontheincreasedlungweights(relativeweightincreasedby14%)anddecreasedfoodintakeat12mg/m3.TheNOAELofPMDIaerosolbyinhalationfordevelopmentaltoxicityinthisstudyis12mg/m3.
TheprenataltoxicityofPMDIinpregnantWistarratswasalsoinvestigatedbyaerosolinhalation(wholebody)accordingtoOECDGuidelineNo.414byBASF(1994).Twentyfivematedfemaleratspergroupwereexposedtoconcentrationsof1,4,or12mg/m3(MMAD
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relatedfindingsindamsandfetusesoccurredat1and4mg/m3.TheNOAELformaternalandfetaltoxicitywas4mg/m3,andtheNOAELfordevelopmentaleffectswas4mg/m3.
GravidWistarratswereexposedbywholebodyinhalationtocleanair(control)andtomonomeric4,4MDIat1,3,or9mg/m3for6hperdayfromday6today15postconception(Buschmannetal.,1996).TheMMADoftheaerosolwas1.1m.Ratsweresacrificedonday20.Theabsoluteandrelativelungweightsinthehighdosegroupweresignificantlyincreased(23%)comparedwiththeshamtreatedcontrolanimalsthisendpointwasnotexaminedintheotherexposuregroups.Treatmentdidnotinfluenceanyothermaternalorfetalparametersinvestigated,althoughaslightbutsignificantincreaseinlitterswithfetusesdisplayingasymmetricsternebrawasobservedaftertreatmentwiththehighestdose.Sincethenumberoftheeffectsobservedinthe9mg/m3groupwaswithinthelimitsofbiologicalvariability,aNOAELfordevelopmentaleffectsof9mg/m3wasdeterminedinthisstudy.
9.EFFECTSONHUMANS
Itiswelldocumentedthatisocyanatesareacauseofoccupationalasthma(Vandenplasetal.,1993).Humoralaswellascellularmechanismsareinvolvedinthepathogenesis.Immediateorlateallergicreactionsorbothcanoccur.ThespecifichumoralimmuneresponsecanbeIgEaswellasIgGmediated,butmanypatientswithsensitizationtoisocyanateshavenodemonstrativeserumantibodiesagainsttheisocyanates.SeveralpublicationsindicatethatcompleximmunologicalreactionsareinvolvedintheprocessofsensitizationtoMDI(Pezzinietal.,1984Tseetal.,1985Lissetal.,1988Cartieretal.,1989).
Toinvestigatetheimmunopathogenesisofdiisocyanatecausedasthma,diisocyanateexposedworkerswereevaluatedforinvitroproductionofantigenspecificmononuclearcellderivedhistaminereleasingfactor(HRF).ThemeanHRFresponsetodiisocyanatehumanserumalbumin(HSA)antigenswassignificantlygreater(p
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catalyst(componentB).Itwasmentionedthatthechemicalprotectivegloveswerenotroutinelyutilizedbyminerswhoweredescribedashavingskincontactleadingtochronicskinirritation.InanotherNIOSH(1994b)report,nasalandeyeirritationwerethetwomostfrequentlyreportedsymptomsafterMDIexposure.
Ahypersensitivitypneumonitistypeofreactionhasalsobeenreported.Vandenplasetal.(1993)investigatedninesubjectswhocomplainedofrespiratoryandgeneralsymptomsrelatedtoworkplaceexposure.AllthesubjectshadworkedinaplantwherearesinbasedonMDIwasusedinthemanufactureofwoodchipboards.TheyunderwentinhalationchallengesusingtheMDIresinforprogressivelyincreasingperiodsoftimeonseparatedays.Ineightsubjects,exposuretosubirritantamountsofMDIinducedapatternofreactionconsistentwithhypersensitivitypneumonitisi.e.,significantdecreasesinbothforcedexpiratoryvolumein1s(FEV1:31%range2340%)andFVC(23%range1735%)associatedwithariseinbodytemperatureandanincreaseinbloodneutrophils.SpecificIgGandIgEantibodiestoMDIHSAconjugateswerepresentinallsubjects.TheauthorsconcludedthattheMDIresincausedahypersensitivitypneumonitistypeofreactioninatleast8(4.8%)ofthe167potentiallyexposedworkersemployedintheplant.
Inacasewhohadexperiencedrepeatedattacksofaworkrelatedpulmonaryorsystemicdisease,associationwithexposuretoMDIwasexaminedbecauseofacuterespiratorydisorder,rhinoconjunctivitis,andalatesystemicreactionafterexposuretopolyurethanepyrolysisproducts,includingMDI(airlevel15g/m3)(Littorinetal.,1994).Spirometryshowedapartlyreversibleobstructivedysfunction,andaskinpricktestwaspositiveforMDIHSA.MDAwasdetectedinhydrolysedserumandurine.Inserum,specificIgG1,IgG4,andIgEantibodiesandaveryhightotalIgEweredetected.Thespecificantibodiesdeclinedduringthe5yearsafterexposure.Invitro,thecirculatingimmunecomplexesinserumincreasedaftertheadditionofMDIHSA.ThereactionsassociatedwithMDIexposure(incombinationwithexposuretopyrolysisproducts)hadfeaturescompatiblewithimmediatehypersensitivityandwithacomplementmediatedimmunecomplexrespiratoryreaction.
EighteenemployeesofasinglewoodproductsplantusingheatedMDIinthemanufactureofasyntheticwoodproductwithlowerrespiratorytractsymptomswerelaterconfirmedtohaveoccupationalasthmaafterexaminationoftherelationshipbetweenonsetofsymptoms,smokingbehaviour,priorexperience,andfamilyhistoryofrespiratorydisorder(Woellneretal.,1997).Allcasesoccurredduringa2.5yearperiodafterexposuretoanewmanufacturingprocessusingsteamheatedMDIresininanewmanufacturingfacility.Initially,workersdevelopedsymptomsrelatedtotheprocesswithpossiblehigherMDIexposuresandprobablehigherresintemperatures.Later,mostworkerswhodevelopednewsymptomsweremostlyexposedtoheatedboards.ThissuggeststhatMDIsensitizationarisesatlowertemperaturesthanwaspreviouslyconsideredlikelyforthissubstance.ItispossiblethatthereactionproductsofsteamandpolymersofMDI,aloneorincombinationwithMDI,maybethecausativeagents.
AfoundryworkerwhodiedatworkhadadiagnosisofoccupationalasthmainducedbyMDIassessed5yearsearlier,buthadhadapoorprognosisforoccupationalasthmaandhadcontinuedtobeexposedtoMDI(Carinoetal.,1997).Postmortemmicroscopicexaminationofthelungshowedepithelialdesquamation,eosinophilic/neutrophilicinfiltrationofthemucosa,dilatationofbronchialvessels,oedema,hypertrophy,anddisarrayofsmoothmuscle.
Theneuropsychologicalfunctioningoffivemensufferingallegedphysical,cognitive,andbehaviouralchangesfollowingexposuretoMDIwasinvestigated(Reidy&Bolter,1994).Thesubjectshadbeenexposedtohydrocarbonsolventaswell,butnoneofthemwassymptomaticuntilMDIwasintroducedtotheworkplace.Althoughthedurationandseverityofexposurevariedamongpatients,formalanalysisofMDIlevelswasnotcompletedduringtheexposureperiod.Atthetimeofassessment,fourofthefivepatientsremainedsymptomaticdespitehavinghadnocontactwithMDIforperiodsrangingfrom5to9months.Allpatientsreportedexperiencingsubjectivesymptoms
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consistingofrespiratorydistress,headaches,depression,irritability,forgetfulness,decreasedcalculatingability,wordfindingproblems,reducedconcentration,andsignificantemotionaldistressonanobjectivepersonalitymeasure.Despitethesedata,thesmallsamplesize,possibleselectionbiasforworkersinvolvedinlitigation,possibleconfoundingfactors,lackofpertinentmatchedcontrol,lackofobjectiveexposuredata,andlackofknowledgeonmechanismprecludethecredibilityofthefindings.
9.2Epidemiologicalstudies
9.2.1Irritationandsensitization
Bernsteinetal.(1993)reportedonlythreecasesofoccupationalasthmainacrosssectionalstudyof243workersexposedtoPMDIinaurethanemouldplantthathadbeendesignedtominimizeexposureonecasewasattributabletoaspill.Levelswerecontinuouslymonitoredandneverexceeded50g/m3.
Inanepidemiologicalstudyofoccupationaldermatitisinfivedifferentshoefactories,246workerswereinterviewed,examined,andpatchtestedusingstandardandoccupationalpatchtestproceduresoftheInternationalContactDermatitisResearchGroup(Mancusoetal.,1996).Noinformationonoccupationalexposurewasreported.Intwoworkerswithallergiccontactdermatitis,sensitizationtoMDIwasdetected.OneoftwoworkersreactedsimultaneouslytobothMDIandMDA.TheotheronereactedonlytoMDI.
Ahealthstudyofthe78workersinanironandsteelfoundryinVancouver,Canada,wascarriedout,andtheresultswerecomparedwiththosefoundin372railwayrepairyardworkers(Johnsonetal.,1985).MDIconcentrationsintheworkingenvironmentwereshowntosignificantlyinfluencelungfunction.ThefoundryworkerswereexposedtoPepSet,whichconsistsofMDIandphenolformaldehydeandtheirdecompositionproducts,aswellastosilicacontainingparticulate.Comparedwiththecontrols,thefoundryworkershadmorerespiratorysymptomsandasignificantlylowermeanFEV1andforcedexpiratoryflowfrom25%to75%oftheFVC(FEF2575,ormidexpiratoryflowrateoftheFVC).Threeworkershadradiographicevidenceofpneumoconiosis,and12hadasthma,definedasthepresenceofbronchialhyperreactivity,cough,andadditionalrespiratorysymptoms,suchaswheeze,chesttightness,orbreathlessness.SensitizationtoMDIisprobablythecauseofasthmaintheseworkers.
AcrosssectionalevaluationofworkersinasteelfoundryinwhichPMDIwasusedasacomponentofabindersystemusedtomakecoresandmouldswasperformed26currentlyexposed(groupI),6formerlyexposed(groupII),and14nonexposedworkers(groupIII)wereinvolved(Lissetal.,1988).ThemeannumberofMDIexposureyearswas8.6,1.1,and0yearsforgroupI,groupII,andgroupIII,respectively.SymptomscompatiblewithoccupationalasthmawereelicitedfromsevenworkersofgroupI,whereasnonewasfoundingroupIII.ThisstudydemonstratedthatinductionofbothMDIspecificIgGresponsesandIgEmediatedrespiratorysensitizationoccurredinapopulationofworkersexposedtoMDIinasteelfoundry.OneworkerfromgroupIwithasthmaticsymptomsexhibitedcutaneousreactivityandRASTbindingtoMDIHSA(25.5%).
Musketal.(1982)followed107polyurethanemanufacturingworkersexposedtoTDIalone(17),MDIalone(25),orboth(6)prospectivelyfor5years.MDIwasusedatthemanufacturingplantsduringonlythelast2yearsofthestudyperiod.Spirometricmeasurements(e.g.,FEV1)weremadeon94workersatthefifthyearovertheworkshift,onMondaymorningafteraweekendofnoexposure,andafter2weekvacations.Therewerenostatisticallysignificantdifferencesinthetotal5yeardecrementinFEV1amongexposedworkersversusFEV1valuesinunexposedworkers.Becauseoftherelativelylownumberofworkers(25)exposedtoMDI(lessthan0.04mg/m3),theshortstudy
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duration,confoundingfrompriorexposuretoTDI(0.05mg/m3)andpossiblytoaminecatalyst,andtheuncertaintyintheactualdurationofMDIexposure,thisstudyofferslimitedassurancethatMDIiswithouteffectonpulmonaryfunction.Theinvestigatorsdiscussedthepossibilitythattheremaybeselectionbias,becausethestudygroupdidnotincludeanysubjectwithsymptomssuggestinghypersensitivitytoisocyanatethosewhowereexperiencingadverseeffectsmayhavebeenincludedinthesmallnumbersofsubjectswhohadleftandbeenlosttofollowup.
In1976and1981,Phametal.(1988)prospectivelystudiedagroupof318polyurethanefoamworkers(including104women)whoweregroupedaccordingtotheirjobcategoryasfollows:unexposed,indirectlyexposed,anddirectlyexposed.Atfollowupin1981,onlyhalfoftheinitialcohortremained(114males,45females),althoughnoreasonsweregivenastowhytheotherhalfleft.The5yearlongitudinalchangesinFEV1inexposedgroupswerestatednottobesignificantlydifferentfromthecontrolpopulation.Anincreasedprevalenceofasthmawasreportedhowever,thelimitationsofthestudyprecludeanymeaningfulassociations.Thebasisforthediagnosisofasthmawasnotstated.Whethertherewasexposuretoothersubstancesthatcouldcauseasthmaorwhethertherewaspreexistingasthmawasnotreported,andguidelinesfollowedforperformingFEV1measurementswerenotstated.Exposurewasnotwellcharacterized.
EffectsonlungfunctionwereassessedbyDFG(1997)basedontheresultsofninestudiesnamely,Cavelieretal.(1977),Phametal.(1978,1986,1988),Martinetal.(1982),Diller&Herbert(1982),Musketal.(1982),Gee&Morgan(1985),andSulottoetal.(1990).Althoughthereweremanylimitations,suchasinvolvementofconfoundingfactorsinmixedexposuresandlackofknowledgeofactualexposureconcentrations,itwasconcludedthatsignificantimpairmentoflungspirometryvalueswasobservedinthecollectiveexposedtoPMDIconcentrationsupto0.87mg/m3.Inthecollectiveatconcentrationsbelow0.2mg/m3,nosignificantchangesinlungspirometrywerefound.However,significantlymorefrequentrespiratorysymptomsweresometimesobservedattheseconcentrations,althoughitisnotclearwhethertheywerecausedbysimultaneousexposuretoothercompounds.SuchsymptomswerenolongersignificantlymorefrequentatPMDIconcentrationsof0.1mg/m3.Withoneexceptioninwhichworkerswerepreviouslyexposedtoconcentrationsofupto0.9mg/m3,allthecollectiveexposedtoconcentrationsof0.05mg/m3orlesswaswithoutsymptoms.
WorkrelatedrespiratorydiseaseswerereportedintheUnitedKingdombyalmost800chestandoccupationalphysicianswhoparticipatedvoluntarilyintheSWORDprojectfrom1989to1992(Meredith&McDonald,1994).Outof5541newcasesreportedbetween1989and1991,28%wereoccupationalasthma.Isocyanatesweresuspectedasacausalagentofasthmain336casesoutof1528reportedfor19891991.
9.2.2Longtermexposureandcarcinogenicity
Cancerincidenceandmortalitypatternswereinvestigatedinacohortof4154workersemployedinSwedishpolyurethanefoammanufacturingplantsforatleast1year(Hagmaretal.,1993a).TDIhadbeenusedinalltheplantsandMDIinallbutone,soitwasimpossibletoevaluatetheirindividualeffects.Airborneexposuretotheisocyanateshadbeenmeasuredon618occasionsateachplanton724days.ThetimeweightedaveragelevelsofTDIhadnormallybeenlessthan0.1g/m3andwerecurrently0.02g/m3.ThecorrespondingvaluesforMDIhadbeenlessthan0.01g/m3.However,muchhighervaluesupto3mg/m3forTDIandupto0.35mg/m3forMDIhadbeenrepeatedlymeasured.Therewasalsoilldefinedexposuretoblowingagents,mouldlubricants,amineaccelerators,andvariousorganicsolvents.Therewasnoincreasedriskofdeathcausedbybronchialobstructivedisease.Thereducedincidence,againstcontrol,ofallmalignantneoplasmwasalmoststatisticallysignificant.The"noexposure"grouphadfewerrectalcancersthanexpected,whereasthe"apparentexposure"grouphadmorethanexpected.Asimilar,smallerdifferencewasseenwithnonHodgkinslymphoma.Whenaminimumlatencyperiodof10yearswasapplied,theincreasesagainst
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controlwereevenhigher,buttherewereveryfewcases.Asthecohortwasyoungwithrelativelyshortexposuretotheisocyanates,futurestudieswouldallowamoreconclusiveevaluation.AcasereferencestudywithinthecohortwasmadetoassessmorethoroughlytheassociationbetweenexposuretoTDIandMDIandriskofcancer(Hagmaretal.,1993b).Itwasfoundthatthetentativeassociations,derivedfromthepreviouscohortstudy,betweenexposuretoisocyanatesandexcessriskfornonHodgkinslymphomasandrectalcancerwerenotsupported.Instead,nonsignificantassociationswithprostatecancerandpossiblycoloncancerwereseen.
Aretrospectivemortalityandcancermorbiditystudywasconductedtoinvestigateassociationsbetweenhealthriskandexposuresfrompolyurethanefoamproduction,particularlyexposurestodiisocyanates(Sorahan&Pope,1993).Thestudypopulation(n=8288)wastakenfrom11factoriesinEnglandandWalesinwhichTDIwastheprincipalisocyanate(MDIrepresented5%oftheamountofTDIused).Thehighestexposurecategorycomprisedjobsinwhicheitherthe8htimeweightedaverageexposure(toisocyanates)during19781986wasgreaterthan0.04mg/m3orexcursionsabove0.1mg/m3occurredonmostdays.Theinvestigatorsdidnotfindanassociation(usingstandardizedmortalityratiosorSMRs)betweenexposuretodiisocyanatesandcancer.Thecohortwasyoung,andfollowupwasrelativelyshort.
10.EFFECTSONOTHERORGANISMSINTHELABORATORYANDFIELD
10.1Aquaticenvironment
ResultsofmoststudiesavailableonthetoxiceffectsofMDIonaquaticorganismsarebasedonnominalconcentrationsoftestsubstance.Inalltestssummarizedinthissection,MDIwasaddedtothetestsolution,andnoconcentrationmeasurementswereperformedsubsequentlyduringexposure.Althoughdifferentmethodswereappliedtosolubilizethetestsubstanceinthetestmedia(e.g.,stirringforseveralhours),theresultspresentedinsection5.1indicatethatonlyminoramountsoftheappliedMDIcouldhavebeenpresentinthetestsolution,astheMDIwouldhaverapidlyundergonehydrolysis.Asaresult,duetothevirtualunavailabilityofMDIinwater,evenforthehighestconcentrationstested,noadverseeffectsontheexposedtestorganismswereobserved.
Inshorttermtests,nominalconcentrationsintherangeof5003000mgMDI/litrecausednolethaleffectonfreshwaterfish(RhonePoulencChimie,1977Nakata,1983Caspersetal.,1986).Aquaticinvertebratesshowednoimmobilizationaftera24hexposuretonominalconcentrationsofupto1000mgMDI/litre(RhonePoulancChimie,1977Caspersetal.,1986).After21daysofexposuretothehighestnominalconcentrationtested(10mg/litre),PMDIhadnoeffectonthereproductionrateofDaphniamagna(Caspersetal.,1986).Blom&Oldersma(1994)observednoeffectsoncellmultiplicationofthefreshwateralgaScenedesmussubspicatusaftera3dayexposuretoanominalconcentrationof1640mgPMDI/litre.ConcerningtheimpactofPMDIonmicroorganisms,thehighestappliedconcentrationsofupto100mg/litrewerenotinhibitorytocellmultiplicationofEscherichiacoli(Fujiwara,1981)ortotherespirationrateofactivatedsludge(Caspersetal.,1986).
Heimbachetal.(1996)addedPMDIatconcentrationsof0,1,and10g/litreontopofthesedimentofthreeartificialoutdoorponds,simulatingaccidentalspillageinsmallstandingfreshwaterecosystems(seesection5.1).Thepondscontainednaturallakesedimentandgroundwater,towhichcagedfishwereadded.ThefateofthePMDIandecotoxiceffectsontheaquaticpopulationweremonitoredfor112days.
MDIpolymerizedtoinertpolyureaandstayedontopofthesediment,formingahardenedlayerattheinterfaceofthecompoundandwater.NoMDIwasfoundinthewaterorinthefishafterapplication.Neitherapplicationratecausedanydirecttoxiceffectontheaquaticcommunity,butsomesignificant
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indirecteffectsonpartsofthemacrobenthoswereobserved.Someofthemoreimmobilepopulations(Oligochaeta,Bivalvia,Diptera)werealmostcompletelywipedoutasaresultofphysicalobstructionbythepolyurealayer,lackofoxygen,andtoxiccarbondioxideconcentrations714daysafterapplication.
Mostofthemacrobenthospopulationsregaineddensitiesequivalenttothecontrolpopulationsafter2monthsofexposure,withtheexceptionofBivalvia(becauseoftheirlonggenerationtimes).Mobilepartsofthemacrobenthos(e.g.,Gastropoda)remainedunaffected.Theabundanceofsomezooplanktonspecies(Cladocera)wasclearlyreducedinthehighdosedpond28weeksafterapplication.Asaconsequence,therainbowtroutinthispond,whichwerefeedingonCladoceraastheirmainnaturalfoodsource,lostweight,andthreeofsixfishinthisponddied1monthaftertheapplicationofMDI.
10.2Terrestrialenvironment
ResultsfromanearthwormtoxicitytestconductedaccordingtoOECDGuidelineNo.207andaterrestrialplantgrowthtestconductedaccordingtoOECDGuidelineNo.208arepresentedinTable2.Inthesestudies,thetestsubstancewasinitiallydissolvedinacetone,whichwasthenmixedwithsand.Thesolventwasevaporatedandthecoatedsandmixedwithsoil.Thetreatedsoilwasthenusedforthestudies.NotoxiceffectofMDIontheterrestrialorganismstestedwasobserved.
Table2:ToxicityofMDItoterrestrialorganisms.a
Organisms Endpointb Loading(mg/kg)
Eiseniafetida(earthworm)
14dayLC50 >1000
14dayNOEL(weightincrease)
>1000
14dayNOEL(behaviour,appearance)
>1000
Avenasativa(oats) NOELemergence >1000
NOELsurvival(14days) >1000
NOELgrowth(14days) >1000
Lactucasativa(lettuce)
NOELemergence >1000
NOELsurvival(14days) >1000
NOELgrowth(14days) >1000
aSource:vanderHoevenetal.(1992a,b).
bLC50=medianlethalconcentrationNOEL=noobservedeffectlevel.
11.EFFECTSEVALUATION
11.1Evaluationofhealtheffects
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11.1.1Hazardidentificationanddoseresponseassessment
Thehealthendpointofmostconcernisanassociationbetweenexposuretoairbornepolymericand/ormonomericMDIandoccupationallyinducedasthma.Thereisabundantevidencenotonlyfromepidemiologicalstudiesandcasestudies,butalsofromanimalstudies.However,thereisinsufficienthumanevidencetodescribe(1)thenatureoftheMDIcontainingmaterial,(2)theconcentrationresponserelationship,or(3)themechanismofisocyanateinducedasthmaandsensitization.Althoughtherearenohumanoranimalstudiesthathaveexaminedtheoralrouteofexposure,itisunlikelythathumanswouldbeexposedbytheoralroute.Therefore,itisdifficulttoquantitativelyestimateriskfromhumanexposure.
TheavailablehumanevidencefromcancerincidenceandmortalitystudiesofworkersexposedtoisocyanatesisinadequatetodescribethecarcinogenicpotentialofpolymericormonomericMDI.Noassociationsbetweenisocyanatesandcancerincidenceweredemonstrated.TheincreaseintheincidenceofmostlybenignpulmonarytumoursinratsexposedtoMDIbyinhalationisnotconsideredtobeademonstrationofcarcinogenicity.Thepublishedstudieshaveanumberoflimitations(e.g.,shortdurationofexposure,concomitantexposuretoothersubstances),whichresultinlowpowertodetectcanceroccurrenceintargetorgansofinterest.ThefindingofplacentaltransferofMDIanditsdegradationproductfrompregnantratsexposedtoaerosoltofetusesdemandsfurtherstudyonitsrelevancetohumanriskassessment.
11.1.2CriteriaforsettingtolerableintakesorguidancevaluesforMDI
AnexampleofaguidancevaluecalculationisgivenintheUSEPAsIntegratedRiskInformationSystem(IRIS)(seewww.epa.gov/irisfordetails).TheBenchmarkConcentration(BMC)analysisdescribedthereinisbasedonthefindingofanincreaseinbasalcellhyperplasiaintheolfactoryepitheliuminthechronicinhalationstudywithmaleWistarrats(Reuzeletal.,1990,1994a).However,itshouldbenotedthatthisguidancevaluemaynotprotectagainstoccupationalsensitization.
Thevalueconsideredmostappropriateasabasisfordevelopmentofatolerableconcentration(TC)inairisthelower95%confidencelimitontheBMCatthe10%risklevel(BMC10)usingtheReuzeletal.(1990,1994a)dataset.TheBMC10isfirstconvertedtoahumanequivalentconcentration(HEC)byapplicationoftheRegionalDoseDepositedRatio(RDDR)calculatedusingacomputerprogramprovidedinUSEPA(1994).TheRDDRadjustsfordosimetricdifferencesbetweenlaboratoryanimalsandhumansbyapplyingnormalizingfactorstovariousareasoftherespiratorytract.
OncetheBMC10(0.14mg/m3)isderivedfromtheReuzeletal.(1990,1994a)datasetbyBMCanalysis,itismultipliedbytheRDDR(0.453).Theresultingvalue,0.06mg/m3,istheBMC10(HEC).ThreeuncertaintyfactorsareappliedtotheBMC10(HEC)10forintraindividualvariation(includingthepossibilityofgeneticpredisposition),101/2forthelackofreproductivedata,and101/2forinterspeciesvariationtoderiveahumanTCof6104mg/m3.
11.1.3Sampleriskcharacterization
Therearenoadequatedataavailabletoserveasabasisforestimatingriskofoccupationalasthma.Theexamplegivenhereisapragmaticapproachtoreduceoccupationalexposuretotheminimumpossible,becauseathresholdforthiseffectcannotbeestablished.
IntheGermanstudyevaluatinglungdecrement,significantreversibleadverseeffectsonlungfunctionwereobservedinpersonsexposedtoMDIconcentrationsabove0.2mg/m3.WhenMDIconcentrationswerekeptlargelybelowthisconcentration,significantchangesinlungspirometrywerenolongerseen,althoughtheincidenceofrespiratorysymptomswasincreasedsignificantly.Suchdisorderswerestillobserved,butnomorefrequentlythaninthegroupatconcentrationsbelow0.05mg/m3.Becauseoftheseobservations,0.05mg/m3wasestablishedastheMAK(themaximumconcentrationintheGermanworkplace)valueforMDI,tobereasonablypracticableunderworkplaceconditions,andthereisacontinuingremittoreduceexposurelevelsasfarasreasonablypracticablewithtechnologythatiscurrentlyavailable.
11.2Evaluationofenvironmentaleffects
Undernormalcircumstances,exposureislikelyonlyfromreleasestotheatmosphere.HighexposuresinvolvingMDIinambientenvironmentsareexpectedtoberare.Wherespillageistosoilorwater,MDIhasatransientexistenceduetoitsreactionwiththewatertoproducepredominantlyinsolublepolyureas.MDAmaybeformedonlyasaminorreactionproductandwillthusbepresentatlowconcentrations.ThepondstudyprovidesevidencethatMDIaccumulationthroughtheaquaticfoodchainisextremelyunlikely,asmightbeexpectedconsideringtheverylowsolubilityandhighreactivityofMDIinaqueoussolution.
AvailabledatashowthatthereisnoneedforconcernregardingtheeffectsofMDIonorganismsintheenvironment,althoughmoredetailedinformationregardingtheeffectsofminuteamountsofMDAformedintheenvironmentonorganismsisrequiredbeforeanyfirmconclusionscanbedrawn.
12.PREVIOUSEVALUATIONSBYINTERNATIONALBODIES
IARC(1999)concludedthatthereisinadequateevidenceforthecarcinogenicityofmonomericorpolymericMDIinhumansandlimitedevidenceforthecarcinogenicityofamixturecontainingmonomericandpolymericMDIinexperimentalanimals.ItsoverallevaluationwasthatMDI(industrialpreparation)isnotclassifiableastoitscarcinogenicitytohumans(Group3).
ForMDA,IARC(1986)concludedthattherewerenodatainhumansandsufficientevidenceforcarcinogenicityinanimals.ItsoverallevaluationwasthatMDAwaspossiblycarcinogenictohumans(Group2B).
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APPENDIX1SOURCEDOCUMENTS
JSOH(1994)
TheoriginalreviewinJapanesewastranslatedintoEnglishbytheNationalInstituteofHealthSciences(NIHS)andisavailablefromtheDivisionofChemBioInformaticsofNIHSatthefollowingaddress:
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NationalInstituteofHealthSciences1181Kamiyoga,SetagayakuTokyo,Japan
TheJapanSocietyforOccupationalHealth(JSOH,formerlytheJapanAssociationofIndustrialHealth)isanacademicorganizationconsistingofexpertsinoccupationalhealth,includingscientistsinuniversitiesandinstitutions,industrialphysicians,occupationalhealthnurses,industrialhygienists,managementstafffromhealthandsafetydepartments,andgovernmentofficialsinoccupationalhealthsectors.
TheCommitteefortheRecommendationofOccupationalExposureLimitsofJSOHreviewsscientificinformationonthehealtheffectsofchemicalsubstancesandphysicalagentswithspecialreferencetoexposureeffectandexposureresponserelationshipsandappliesitsresearchtothecreationofanOccupationalExposureLimit(OEL)andtothedocumentationofthereasoningbehindtheOEL.TheCommitteesubmitstheOELasaprovisionalOELtoameetingofJSOHcouncillorsandtoanannualgeneralmeetingofJSOHfortemporaryapproval,afterwhichtheprovisionalOELanddocumentationarepublishedinJSOHsofficialjournal,SangyoEiseigakuZasshi(formerlySangyoIgaku[JapaneseJournalofIndustrialHealth].TheCommitteeacceptsopinionsbasedonscientificaspectsoftheprovisionalOELuntilthenextannualgeneralmeeting.IfnoopinionscontrarytotheprovisionalOELarefiledwiththeCommittee,itisadoptedastheformalOELrecommendedbyJSOH.IfopinionscontrarytotheprovisionalOELarefiledwiththeCommitteeanddeemedvalid,theCommitteethen