State-of-the-Science of Endocrine Disrupting Chemicals 2012 Summary for Decision Makers

A summary and key messages prepared from an assessment of the state of the science of endocrine disruptors (SOS EDCs 2012) prepared by a group of experts for the World Health Organization and the United Nations Environment Programme.

Editors:

ke Bergman, Susan Jobling, Jerrold J. Heindel, Karen Kidd and R. Thomas Zoeller

WHO logo

UNEP logo

UN Logo

Contribution to IOMC ?????????????????????????????????????????????????????????????? Pending agreement with participating organizations

United Nations Environment Programme, 2012

This document is not a formal publication of the United Nations Environment Programme and the World Health Organization and all rights are reserved by the organizations. The views expressed therein are not necessarily the views of the organizations.

Why are we concerned about endocrine disruptors?

Summary for Decision Makers with Key Messages

1. Introduction
Thisdocumentpresentssummaryinformationandkeymessagesfordecisionmakersonendocrine disruptors,fromthefullreportentitled,StateoftheScienceofEndocrineDisruptingChemicals(SOSof EDCs2012)andispartoftheUnitedNationsEnvironmentProgramme's(UNEP)andWorldHealth Organization's(WHO)ongoingcollaborationtoaddressconcernsaboutthepotentialadverseeffectsof anthropogenicchemicals. Weliveinaworldinwhichmanmadechemicalshavebecomeapartofeverydaylife.Itisclearthat someofthesechemicalpollutantscanaffecttheendocrine(hormonal)systemandcertainofthese endocrinedisruptorsmayalsointerferewiththedevelopmentprocessesofhumansandwildlifespecies. Followinginternationalrecommendationsin1997bytheIntergovernmentalForumonChemicalSafety (IFCS)andbyEnvironmentalLeadersoftheEightregardingtheissueofendocrinedisruptingchemicals (EDCs),thejointInternationalProgrammeonChemicalSafety(IPCS)ofWHO,UNEPandILO (InternationalLabourOrganisation)developedin2002areportentitledGlobalAssessmentofthe StateoftheScienceofEndocrineDisruptors(Figure1) Thegeneralconclusionsfromtheirworkwerethatthereissufficientevidencetoconcludethatadverse endocrinemediatedeffectshaveoccurredinsomewildlifespeciesandthatexperimentaldatasupport thisconclusion.TheIPCS2002documentfurtherconcludedtheneedforbroad,collaborativeand internationalresearchinitiativesandpresentedalistofresearchneeds. Since2002,intensescientificworkhasimprovedourunderstandingoftheimpactsofEDCsonhuman andwildlifehealth.ThescientificreviewpublishedbytheEndocrineSocietyin2009andtheStateofthe artassessmentofendocrinedisruptersperformedwithinEU(2011)showsthescientificcomplexityof thisissue,withover500scientificarticlescitedthatfocusedonvariousaspectsofEDCs. Thesereviewsconcludedthatthereisemergingevidenceforadversereproductiveoutcomes(infertility, cancers,malformations)fromexposuretoEDCs,andthereisalsomountingevidenceforeffectsof chemicalsonthyroid,neuroendocrinesystem,obesityandmetabolism,andinsulinandglucose homeostasis. TheEndocrineSocietycalledfortimelyactiontopreventharm.AlsotheEuropeanSocietyforPaediatric Endocrinology(ESPE)andtheUSbasedPediatricEndocrineSociety(PES)haveputforwardaconsensus statementcallingforactionregardingendocrinedisruptorsandtheireffects. 1

Nowin2012,UNEPandWHOincollaborationwithinternationalexpertsaretakingastepforwardby developingadocumentonendocrinedisruptorswithscientificinformationonhumanandwildlife impactsandkeymessagesfordecisionmakersandothersconcernedaboutthefutureofhumanand wildlifehealth. ThereportonEDCs2012providesthestateofthescienceofendocrinedisruptors.Itstartsbyasking whatendocrinedisruptionisallaboutandthenreviewsendocrinedisruptingeffectsinhumansandin wildlife.Finally,thedocumentreviewssourcesofandexposurestoEDCs.

2. Key Messages
o o o Humanandwildlifehealthdependsontheabilitytoreproduceanddevelopnormally.Thisis notpossiblewithoutahealthyendocrinesystem. Threestrandsofevidencefuelconcernsoverendocrinedisrupters. Thehighincidenceandtheincreasingtrendsofmanyendocrinerelateddisordersinhumans. Observationsofeffectsinwildlifepopulations. Theidentificationofchemicalswithendocrinedisruptingpropertieslinkedtodisease outcomesinlaboratorystudies.

Theendocrinerelateddiseaseburdeninthehumanpopulationishigherthanever,puttingour futuregenerationsatrisk. Evidencehasstrengthenedthatthereisariseinendocrinerelateddiseasesinthehuman population.Althoughtimetrendsaresometimesdifficulttoestablish,duetothelackofuniform diagnosticcriteria,unfavorabletrendshavebecomeapparentinanumberofcountries. o Largeproportions(upto40%)ofyoungmeninsomecountrieshavelowsemenqualitywhich reducestheirabilitytofatherchildren. o Theincidenceofgenitalmalformationsinbabyboys,suchasnondescendingtestesand penilemalformationshasincreasedovertime,orleveledoffatunfavorablyhighrates. o Adversepregnancyoutcomes,suchaspretermbirthandlowbirthweight,haveincreasedin manycountries. o Neurobehavioralandthyroiddisordersaffectahighproportionofchildreninsomecountries, andhaveincreasedoverpastdecades. o Globalratesofendocrinerelatedcancers(breast,endometrial,ovarian,prostate,testisand thyroid)havebeenincreasingoverthepast40to50years. o Thereisatrendtowardearlieronsetofbreastdevelopmentinyounggirlsinallcountries wherethishasbeenstudied.Thisisariskfactorforbreastcancer. o Theprevalenceofobesityandtype2diabeteshasdramaticallyincreasedworldwideoverthe last40years.WHOestimatesthat1.5billionadultsworldwideareoverweightorobeseand thatthenumberwithtype2diabetesincreasedfrom153millionto347millionbetween1980 and2008.

Closeto800hundredchemicalsareknowntobecapableofinterferingwithhormonereceptors, hormonesynthesisorhormoneconversion.Onlyasmallfractionofthesechemicalshavebeen investigatedintestscapableofidentifyingovertendocrineeffectsinintactorganisms. o Thevastmajorityofchemicalsincurrentcommercialusehavenotbeentestedatall. o Thislackofdataintroducesenormousuncertaintiesaboutthetrueextentofrisksfrom chemicalsthatpotentiallycoulddisrupttheendocrinesystem. HumanandwildlifepopulationsallovertheworldareexposedtoEDCs. o ThereisglobaltransportofmanyEDCsthroughnaturalprocesses(oceanandaircurrents)as wellasthroughcommerce,leadingtoworldwideexposuretoEDCs. o Unliketenyearsago,weknowthathumansandwildlifeareexposedtofarmoreEDCsthan justpersistentorganicpollutants(POPs). o LevelsofsomenewerPOPsinhumansandwildlifearestillincreasing,andthereisalso exposuretolesspersistentandbioaccumulativebutubiquitouschemicals. o NewsourcesofexposuretoEDCsforhumans,inadditiontofoodanddrinkingwaterintake, havebeenidentified. o Childrencanhavehigherexposurestochemicalsthanadults. Numerouslaboratorystudiessupporttheideathatchemicalexposurescontributetoendocrine disordersinhumanandwildlife.ThemostsensitivewindowofexposuretoEDCsisduring criticalperiodsofdevelopment. o Developmentalexposurescancausechangesthat,whilenotevidentasbirthdefects,canlead topermanentchangesthatleadtoincreasedincidenceofdiseasesthroughoutlife. o Theseinsightsfromendocrinedisrupterresearchinanimalschangetheparadigmofcurrent toxicologicaltestingandscreeningfromthestudyofexposuresinadulthoodorjustduring developmenttostudiesthatencompassexposuresduringsensitivewindowsinfetallife, perinatallife,childhoodandpubertyandassessmentofeffectsacrossthelifespan. Thespeedwithwhichtheincreasesindiseaseshaveoccurredinrecentdecadesrulesout geneticfactorsasthesoleplausibleexplanation.Evidenceisstrengtheningthatenvironmental factors,includingexposurestoEDCs,contributetotheendocrinediseaseburden. o Itisnotpossibletoprovethatanassociationbetweenchemicalexposureanddiseaseinthe humanpopulationiscausedbyanendocrinemechanism.Thusthehumandatalinking exposuretoEDCsmustbeviewedinconjunctionwiththeanimalmodelandwildlifedata. Worldwide,therehasbeenafailuretoadequatelyaddresstheunderlyingenvironmentalcauses oftheseworryingdiseasetrends. o Healthcaresystemsdonothavemechanismsinplacetoaddressthecontributionof environmentalriskfactorstotheendocrinediseaseburden.Thebenefitsthatcanberealized byadoptingpreventativemeasuresfordealingwiththesediseaseshaveremainedlargely unrealized.

 Wildlifepopulationshavebeenaffectedbyendocrinedisruption,withnegativeimpactson growthandreproduction.Theseeffectsarewidespreadandhavebeendueprimarilyto persistentorganicpollutants(POPs).Bansofthesechemicalshavereducedexposureandledto recoveryofsomepopulations. o ItisthereforeplausiblethatadditionalEDCs,whichhavebeenincreasingintheenvironment andareofrecentconcern,arecontributingtocurrentpopulationdeclinesinwildlifespecies. Wildlifepopulationsthatarealsochallengedbyotherenvironmentalstressorsareparticularly vulnerabletoEDCexposures Humanandwildlifepopulationsallovertheworldareexposedtomanyofthesechemicals simultaneously.Thetruehealthrisksthatstemfromsuchmixedexposuresareunderestimated duetoconsiderationsofchemicalsonaonebyonebasis.Theeffectsofcombinedexposures arenotappropriatelyaddressed. o Endocrinedisruptersaregloballytransportedintheenvironmentthroughnaturalprocesses (oceanandaircurrents),leadingtoworldwideexposuretoEDCs. o Exposuretosomeofthesesubstanceshasriseninrecentyears.WhilethelevelsofsomePOPs havedecreased,exposuretocertainmorerecentlydevelopedPOPsisincreasing,andthereis alsoexposuretolesspersistentandbioaccumulativebutubiquitouschemicals. o NewsourcesofexposuretoEDCshavebeenidentified. Internationallyagreedandvalidatedtestmethodsfortheidentificationofendocrinedisrupters captureonlyalimitedrangeoftheknownspectrumofendocrinedisruptingeffects.This increasesthelikelihoodthatharmfuleffectsinhumansandwildlifeareoverlooked. o Formanyendocrinedisruptingeffects,agreedandvalidatedtestmethodsdonotexist, althoughscientifictoolsandlaboratorymethodsareavailable. o Foralargerangeofhumanhealtheffects,therearenoviablelaboratorymodels.This seriouslyhampersprogresswithunderstandingthefullscaleofrisks. DiseaseriskduetoEDCsisunderestimated. AfocusonlinkingoneEDCtoonediseaseseverelyunderestimatesthediseaseriskfromEDCs. WeknowthathumansandwildlifearesimultaneouslyexposedtomanyEDCsthusthe measurementofthelinkagebetweenmixturesofEDCstodiseaseismorephysiologically relevant.InadditionitislikelythatasingleEDCmaycausediseasesyndromesormultiple diseases,anareathathasnotbeenadequatelystudied. Animportantfocusshouldbeinreducingexposuresbyavarietyofmechanisms.Government bans,whilelimited,havebeeneffectiveatdecreasingexposures(e.g.tolead,chlorpyrifos,TBT, PCBsandsomeotherPOPs)andthereby,thehumanandwildlifediseaseburden. DespitesubstantialadvancesinourunderstandingofEDCs,uncertaintiesandknowledgegaps stillexistthataretooimportanttoignore.Thishampersprogresstobetterprotectthepublic andwildlife.Anintegrated,coordinatedinternationaleffortisneededtodefinetheroleofEDCs incurrentdeclinesinhumanandwildlifehealthandinwildlifepopulations.

3. Endocrine Systems and Endocrine Disruption

Forpurposesofthispaperwehaveadoptedthedefinitionofanendocrinedisruptorthatwasusedin theIPCS2002documentonendocrinedisruptors(SeethetextboxondefinitionofEDCs).Simplifiedthis meansthat;endocrinedisruptorsarechemicals,orchemicalmixtures,thatinterferewithnormal hormonesignaling. DefinitionofEDCs Anendocrinedisruptorisdefinedinagenericsenseas,anexogenoussubstanceor mixturethataltersfunction(s)oftheendocrinesystemandconsequentlycauses adversehealtheffectsinanintactorganism,oritsprogeny,or(sub)populations. Apotentialendocrinedisruptorisanexogenoussubstanceormixturethatpossesses propertiesthatmightbeexpectedtoleadtoendocrinedisruptioninanintact organism,oritsprogeny,or(sub)populations. Tounderstandendocrinedisruption,wemustunderstandthebasicfeaturesoftheendocrinesystem. Theendocrinesystemisacomplexsystemconsistingofmanyinteractingtissuesthattalktoeachother andtherestofthebodybychemicalsignalscalledhormones.Thehumanendocrinesystemisvisualized intheFigure2.Itisresponsibleforcontrollingalargenumberofprocessesinthebodyincludingearly processessuchascelldifferentiationduringdevelopmentandorganformation,tothecontrolofmost tissueandorganfunctionsthroughoutadulthood(Figure3).Ahormoneisamoleculeproducedbyan endocrineglandthattravelsthroughthebloodtoproduceeffectsondistantcellsandtissuesvia integratedcomplexinteractingsignalingpathways.Thereareover50differenthormones,andhormone relatedmolecules(cytokinesandneurotransmitters)thatintegrateandcontrolnormalbodyfunctions acrossandbetweentissuesandorgansoverthelifespan.Hormonesarecriticaltonormalfunctioningof everytissueandorganinbothvertebratesandinvertebrates,indeedthehormonesandtheirsignaling pathwaysarequiteconservedacrossspecies. Endocrinedisruptorsarethuschemicalsthatinterfereinsomewaywithhormoneaction,andinso doingcanproduceeffectswhichleadtoimpactsonhumanandwildlifehealth. ThediversesystemsaffectedbyEDCslikelyincludeallhormonalsystemsandrangefromthose controllingthedevelopmentandfunctionofreproductiveorganstothetissuesandorgansregulating metabolismandsatiety.Effectsonthesesystemscanleadtoobesity,infertilityorreducedfertility, learningandmemorydifficulties,adultonsetdiabetesorcardiovasculardiseaseaswellasavarietyof otherdiseases.WehaveonlyrecentlyunderstoodthatEDCscanaffectthesystemsthatcontrolfat developmentandweightgain.Thisisagoodexampleofcomplexphysiologicalsystemsthatare influencedbyEDCsthatwerenotknownjustafewyearsago.Generally,therearetwopathwaysby whichachemicalcoulddisrupthormoneaction:adirectactiononahormonereceptorproteincomplex, oradirectactiononaspecificproteinthatcontrolssomeaspectofhormonedeliverytotherightplace attherighttime(Figure3).BecauseEDCsactonthenormalhormonalorendocrinesystemstheyexhibit thesamecharacteristicsashormonesasshowninTable1. 5

Table1.ComparisonofHormoneandEndocrinedisruptorAction Hormones Actviareceptors Somehavemultiplereceptors Tissuespecificreceptorclassesandsubtypes Hormonesnormallybindsimilarlytoall receptorsubtypes Activeatlowdoses Bloodlevelsdonotalwaysreflectactivity Maybeboundtoserumproteinsinblood withsmall%free Nobioaccumulation Nonlineardoseresponserelationships Alwayssaturablewithvariabledynamic range Canexhibitnonmonotonicdoseresponse Highdoseeffectsnotsameaslowdose Tissueandlifestagespecificeffects Developmentaleffectspermanent Programsbrainandendocrinesystemfor adultfunction Differentendpointsvaryinsensitivity EndocrineDisruptors Someactonhormonereceptors Willcauseabnormalreceptorsfunction Likelyisoformspecificinteractions

Someactatlowdoses,othersvariable Bloodlevelsdonotalwaysreflectactivity Maybeboundtoserumproteins Effectsonhormonebloodlevelsmaynot reflectonhormoneaction Possiblebioaccumulation Nonlineardoseresponserelationships Alwayssaturablewithvariabledynamicrange Canexhibitnonmonotonicdoseresponse Highdoseeffectsnotsameaslowdose Tissueandlifestagespecificeffects Developmentaleffectspermanent Interfereswithprogrammingprocesses

Differentendpointsvaryinsensitivity ThusEDCSdontactlikegeneraltoxicantsbutactlikehormones.Sincehormonesactviabindingto receptors(Figure4)atverylowconcentrations,sodoEDCshavetheabilitytobeactiveatlow concentrations,manyintherangeofcurrenthumanexposures.AlsoEDCsactonavarietyof physiologicalprocessesinatissuespecificmannerandsometimesactviadoseresponsecurveswhich arenotlinear(nonmonotonic).Indeeditisnotpossibletoextrapolatelowdoseeffectsfromhighdose effects.Timingofexposuresisalsocriticalasexposuresduringdevelopmentandislikelyirreversible whileadultexposuresseemtogoawaywhentheEDCisremoved.Itisimportantthatthesespecific characteristicsofEDCsbetakenintoaccountwhenthetoxicityofchemicalswithpotentialEDCactivity isassessed.

4. Endocrine Disruptors and Human Health

ThedatalinkingexposurestoEDCsandhumandiseasesismuchstrongernowthanin2002.Since humanstudiescanonlyshowassociationsandnotcauseandeffect,itisimportanttousebothhuman andanimaldatatodeveloptheevidenceforalinkbetweenexposurestoEDCsandhumandisease.Even soitmayneverbepossibletohaveabsolutecertaintythataspecificexposurecausesaspecificdisease ordysfunctionduetothecomplexityofbothexposuresanddiseaseaetiology(Figure5)acrossthe lifespan. Ofparticularnoteisthatoverthepast10yearstherehasbeenadramaticshiftinfocusfrom investigatingassociationsbetweenadultexposurestoEDCsanddiseaseoutcomestolinking 6

developmentalexposurestodiseaseoutcomeslaterinlife.Thislatterapproachisnowconsideredthe mostappropriateapproachformostEDdiseases/dysfunctionsbasedondatapresentedabove(Section 8)cf.Figure6. Takingtheanimalmodeldataandhumanevidencetogether,thereisastronglikelihoodthatexposure toEDCsduringfoetallifeand/orduringpubertyplaysaroleintheincreasesseeninmaleandfemale reproductive,endocrinerelatedcancers,behaviouralandlearningproblemsincludingADHD,infections, asthma,andperhapsobesityanddiabetesinhumans

CurrentexposuretoawidevarietyofEDCscanimpair thehealthofourchildrenandtheirchildren!

5 Why are we concerned? Human Disease Trends

Weareconcernedbecause: Asignificantincreaseinreproductiveproblemsoverafewdecadesindicatesastrongroleof unidentifiedenvironmentalfactorsindiseaseaetiology. Incidencesofendocrinecancers,e.g.testiscancer(Figure7)andbreastcancer(Figure8),have alsoincreasedduringthesameperiods; Anincreasingnumberofchemicals,towhichallhumansinindustrializedareasareexposedhave beenshowntointerferewiththeinternalhormonesynthesisormetabolism; Experimentalanimalstudiesorinvitrostudieshaveshownthatmanyubiquitouschemicalscan interferewiththedevelopmentandfunctionofmammalianendocrinesystems; Therehasbeenadramaticworldwidedecreaseinhumanfertilityratesduringonegeneration andcurrentlythereisahighneedforassistedreproduction; Finally,wearenowbeginningtoseeingstudiesshowingassociationsbetweenexposurestoEDCs andseveralhealthproblemsinhumansofallages. ThereislittledoubtthatsomeEDCscaninteractwiththethyroidsysteminanimalsandhumans. Normalthyroidfunctionisveryimportantfornormalbraindevelopment,particularlyperinatally.EDCs havealsorecentlybeenlinkedtoasthma,birthdefects,neurodevelopmentaldisorders,obesity(Figure 9),cardiovasculardisease,diabetes,andmetabolicsyndrome.Manyofthesediseasesanddisordersare increasing,somewithglobalfigures.Theglobalhealthexpenditureondiabetesalonewasexpectedto total$376billionUSDin2010,andriseto490billionUSDin2030fully12%ofallpercapitahealthcare expenditures. Therearealsootheralarmingtrendsinhumanpediatrichealth.Theprevalenceofpediatricasthmahas morethandoubledoverthepast20years,andisnowtheleadingcauseofhospitalizationsandschool absenteeism.Birthdefectsaretheleadingcauseofinfantdeathandcertainbirthdefects,suchasthose ofthemalereproductiveorgansappeartobeontherise.Neurobehavioraldisorders,includingdyslexia, mentalretardation,attentiondeficithyperactivitydisorder,andautism,affect510%ofbabiesborn; autismspectrumdisordersnowoccurataratethatapproaches1%.Theincidenceofpediatricleukemia andbraincancerhasrisenaswellastheincidenceoftesticularcancer. 7

 Thesearestarkhealthstatistics.Allofthesecomplexnoncommunicablediseaseshavebothagenetic andanenvironmentalcomponentand,sincetheincreasesinincidenceandprevalencecannotbedue solelytogenetics,itisimportanttofocusonunderstandingthecontributionoftheenvironmentin thesechronicdiseasetrendsinhumans. Estimateshavebeenmadethatasmuchas28%ofhumandiseasesanddisordersaredueto environmentalfactors.Thisprovidesachallengetoidentifyandaddressthem,butalsoatremendous opportunitytoimprovehumanhealthbyimprovingelementsoftheenvironmentthatimpactpublic health.Therecognitionofthesechallengesandopportunities,alongwiththefactthatmanyofthemost prevalentdiseasesareassociatedwiththeendocrinesystem,hasledtoafocusonEDCs.

6. Endocrine Disruptors and Wildlife Health

Thereareabundantdatalinkingchemicalexposurestodeteriorationsinwildlifehealth,but uunderstandingtheroleofEDCsintheglobaldeclineofpopulationsorbiodiversityischallenging becauseofthepresenceofothernaturalorhumaninducedstressors,mixturesofchemicals(bothEDCs andnonEDCs),difficultyinassessingexposures,andourlimitedunderstandingoftheecologyofthe population.Declinesintheabundanceofonespecieswillinturnaffectthehealthandbalanceofits ecosystembecauseoftheinterdependenciesoforganismswithintheenvironment.Thebestevidence thatEDCsaffectwildlifepopulationscomesfromlongtermmonitoring;numbersofbirdsandmolluscs areclearlyincreasinginregionswheretheirexposurestopesticides(i.e.DDTandtributyltin)are reduced. Endocrinesystemfunctionandwildlifehealthhasbeencompromisedinspeciesaroundtheworld. StudiesofsealcoloniesinheavilypollutedareasoftheBalticandNorthSeasfoundhighratesoffemale reproductivepathologiesandreproductivefailure,whichcorrelatedwithindividualPOPcontamination. PerturbationsofthyroidandbonehomeostasisarerelatedtoPCBlevelsingreyseals(Figure10).In DutchandBelgiancoloniesofcommontern,eggswithhigherPOPstooklongertohatchandthese chicksweresmallerinsize.EspeciallyintheUK,butalsoinothercountries,fishhavebeenwidely affectedbyestrogensandantiandrogensinmunicipalwastewaters,resultinginincreasedlevelsofthe eggyolkproteinvitellogeninandintersexinmales.Theantifoulantsinshippaintstinandtriphenyltin havedisruptedmolluscsexualdevelopmentworldwide(Figure11).Bythe1970s,manyspecies,such asthecommerciallyimportantoyster,havecollapsedinheavilypollutedareas.Reductionsinexposure haveledtoarecoveryofthesepopulations. Thereareimportantparallelsbetweentheincreasingincidenceofhumandisordersandthoseobserved inwildlife.Forexample,testicularnondescentwasobservedin68%ofmalesinapopulationofblack deerinAlaska;similartrendswerealsoobservedinMontana,U.S.Thereisrecentevidencethatanimals livingnearhumansalsohaveincreasingbodyweight.Moreover,studiesofPCBexposedwildlifehave providedimportantinformationonexposurelevels,earlyandsubclinicaleffectsandclinical neurotoxicityofthesechemicals.Themechanismsunderlyingtheeffectsandtheoutcomesof exposuresareoftensimilartothoseinhumans.Indeed,linksbetweenanimalandhumanhealthare longstanding.Forexample,thestudyofanimalviruseshasledtonewinsightsintothemolecular mechanismsofsomehumancancers. 8

Inwildlife,relationshipsbetweenendocrinediseasesanddisordersandenvironmentalcontaminationby endocrinedisruptingcontaminantsarestronglysuggestedbyscientificdatainsomecontaminated regionsoftheworld.Thesestudiesreflectmainlyreproductivehealthwithlimitedstudiesonother partsoftheendocrinesystem.Studiesofwildlifeexposuresanddiseaseinareaswheretherearehigh incidencesofnonreproductiveendocrinediseasescouldhelptoidentifychemicalcontributorstothe causationofthesediseases,supporttheconclusionofcommonriskfactorsinsharedenvironmentsand showthevalueofwildlifeasimportantenvironmentalindicators.

EffectsofEDCsonwildlifedeclinewhentheirexposureisreduced.

7. Why are we concerned? Population Effects in Wildlife

Weareconcernedbecause: Thereisaworldwidelossofspeciesorreducedpopulationnumbersofamphibians,mammals, birds,reptiles,freshwaterandmarinefishes,andinvertebrates(Figure12.) Endocrinedisruptingchemicalshavebeenshowntonegativelyaffectbodysystemsthatare criticalforhealthandsurvivalofwildlife.ThereforeEDCscouldplayastrongroleintheetiology ofwildlifediseasesanddisorders,specieslossandpopulationdeclines. ThecurrentbodyburdensofpersistentorganicpollutantssuchasPCBs,organochlorinepesticides andmethylmercuryinsomefisheatingbirdsandmarinemammalpopulationsareatlevels knowntocauseeffectsonbreedingandontheimmunesystem(Figure13).Someofthese populationsarethreatenedorendangered. Legal,technicalandethicalconstraintstoworkingwithwildlife,notablythoselistedunder endangeredspecieslegislation,preventresearchtoinvestigatechemicalcausesofpopulations declinesintheseanimals. Anincreasingnumberofchemicals,towhichwildlifeareexposed,havebeenshowntointerfere withthehormonalandimmunesystemsofwildlifespecies.Mostofthesechemicalsarenot monitoredinecosystems.Exposedwildlifepopulationsareoftennotmonitoredeither. Experimentalanimalstudieshaveshownthatmanyubiquitouschemicalscaninterferewiththe developmentandfunctionoftheendocrinesystemsofwildlife,leadingtoeffectsonbehaviour, fecunditygrowthandsurvivalanddiseaseresistance.Thisincreasestheprobabilitythatexposure toEDCscouldleadtopopulationleveleffectsinwildlife. SubtleeffectsofEDCsonindividualsmayresultindevastatingeffectsonwildlifepopulationsover thelongterm.But,thisishardtoproveuntilthedeclinesinpopulationsareevident,atwhich pointitmaybetoolatetosavethesespecies.Thisiscorroboratedbyhistoricalevidenceshowing sucheffectsofPCBsandorganochlorinepesticidesonpopulationsofmarinemammalsandbirds.

ThereisnodoubtthatexposurestoEDCscanaffectthereproductivehealthofwildlifespecies,but therehavebeenfewstudiestranslatingtheseeffectstoimpactsatthepopulationlevel. Notwithstandingthis,higherratesofreproductiveproblemsarefoundinanimalswithhigherexposure toEDCsthaninthoseexposedtolowerconcentrations.Inaddition,aslevelsofEDCsdecline,some wildlifepopulationshaveshownrecovery.EvidencealsosuggeststhatEDCshaveaffectedimmune 9

function,therebyresultinginincreasedsusceptibilitytoinfectiousdiseasesinvertebrates,notably marinemammals.Takentogether,theevidencesuggeststhatexposuretoendocrinedisrupting contaminantsplaysasignificantroleinwildlifehealthtrends. Wildlifeacrosstheglobehavereproductiveproblemsanddiseases.

8. Sensitive Periods for Endocrine Disruptor Action Window of exposure

HormonesandthusEDCswhichacttoalterhormoneactions,actatalltimesduringlifefoetal development,infancy,earlychildhood,puberty,adulthoodandinaging.Infact,thetimingofhormone orEDCactiondeterminesthestrengthimpactoftheireffect.Intheadult,hormonesandEDCsare thoughttohavetransienteffectsontargetcellsandtissues.ThusthehormoneorEDCshasaneffect whenitispresent,butwhenthehormoneorEDCiswithdrawntheeffectdiminishesmuchlikeinsulin levelsrisingwhenbloodsugarishigh,andthendecliningwhenbloodsugardeclines. IncontrasttotheacuteactionsofhormonesorEDCsduringadulthood,theireffectsduring development(inuteroandinfancyandearlychildhoodinhumans)canbepermanentiftheexposure occursduringthetimeaspecifictissueisdeveloping.Thisiscalleddevelopmentalprogramming. Hormonescontrolnormaldevelopmentoftissuesfromthefertilizedspermandeggtothefully developedfetus.Sincesometissuescontinuedevelopingafterbirthlikethebrainandreproductive systemthesensitiveperiodforthesetissuesisextended,somefordecadesafterbirth.Theimportant pointisthatwhileatissueisstilldevelopingitismoresensitivetotheactionofhormonesandthus EDCs.InadditionanexposuretoahormoneorEDCduringdevelopmentcanhavelonglastingeffects, effectsthatmaynotshowupfordecadeslater. ThemechanismswherebyEDCexposureduringdevelopmentcanalterthedevelopmentofspecific tissuesleadingtoincreasedsusceptibilitytodiseaseslaterinlifeisjustbeginningtobeunderstood.Itis clearthathormonesplayanimportantroleincelldifferentiationthatleadstothedevelopmentof tissuesandorgans.Oncetissuesandorgansarefullydevelopedandactivethenhormoneshavea differentrole,tocontrolintegrationofsignalsbetweentissuesandorgansystemtomaintainproper balanceandnormalfunction.Developmentwhenhormonesarecontrollingcellchangestoformtissues andorgansisthusaverysensitivetimeframeforEDCsaction.IfanEDCispresentduringthe developmentalprogrammingofatissueitwoulddisruptthenormalhormonelevels,leadingtochanges intissuedevelopment;changeswhichwouldbestableacrossthelifetimeconferringsensitivityto diseaselaterinlife.Theseeffectsarenotlikelytobeevidentatbirthbutshowuponlylaterinlife,from afewmonthstodecadeslater(Figures14,15).ThusexposuretoEDCsduringdevelopmentissoserious anddamagingbecausethechangesthatoccurdueexposuretoEDCsduringdevelopmentare permanentbutinsidiousandsubtle,onlybeingdetectedoncomplexanalysisatthecellularlevel(Figure 16).Superficialassessmentatbirthmaynotdetectanyproblems.Thesedevelopmentaleffectsagain indicatethatbabiesandchildrenarenotjustlittleadults! EDCEffectsAcrossGenerations EDCshavealsobeenshowntoalsoproduceeffectsthatcancrossgenerations,transgenerational effects.Thuswhatapregnantmotherorwildlifeorganismisexposedtoduringpregnancymaynotonly affectthedevelopmentofheroffspringbutalsotheiroffspringoverseveralgenerations.Theincreasein 10

diseaseratesweareseeingtodaycouldbeinpartduetoexposuresofourgrandparentstoEDCs,and theseeffectscouldincreaseovereachgenerationduetobothtransgenerationaltransmissionofthe alteredprogrammingandalsocontinuedexposureacrossgenerations. Theincreasedincidenceofdiseasestodaycouldbetheresultofexposures ofourgrandmothersandmotherstoEDCs.Similarly,exposurestoday couldaffectgenerationstocome!

9. Occurrence and Exposures to Endocrine Disruptors

Since2002,alargenumberofotherchemicalsthanpersistentorganicpollutants(POPs)havebeen identifiedasEDCsandtheseincludechemicalsthathaveverydifferentproperties,sourcesandfatesin theenvironmentthanthePOPs.EDCsarebothmanmadeandnatural.Somearefoundinalargevariety ofmaterials,products,articlesandgoods.Theymayalsobebyproductsformedduringmanufacturingor combustionofwastes.EDCsarealsosubjectedtobiologicalandenvironmentaltransformationsthat mayformotherEDCs.EDCsarefoundamongmanyclassesofchemicalsincludingPOPs,currentuse pesticides,phytoestrogens,metals,activeingredientsinpharmaceuticals,andadditivesorcontaminants infood,personalcareproducts,cosmetics,plastics,textilesandconstructionmaterials.Oncereleased intotheenvironmentthemorepersistentchemicalscanbecarriedbyairandwatercurrentstoremote locationsandmanycanbeconcentratedthroughfoodwebstohighlevelsinhumansandothertop predators.Otherchemicalshaveshorterlifespansintheenvironmentbutareregularlyreleasedin effluents,inrunofffromagriculture,orfromurbanenvironments,resultinginhighenvironmentallevels nearthesource(Figure17).

HumanandwildlifeexposuretoEDCscomesfromhighlydiversesources.

WildlifeandhumansareexposedtoEDCsinseveraldifferentways.Air,water,soil,sediment,andfood aresourcesofEDCsforwildlife.HumanexposuretoEDCsoccursviaingestionoffood,dustandwater, inhalationofgasesandparticlesintheair,anddermaluptake(Figure18).TransferofEDCsfromthe mothertothedevelopingfetusthroughtheplacentaandtooffspringinmothersmilkalsooccursfor bothwildlifeandhumans.ChildrencanhavehigherexposurestoEDCsbecauseoftheirhandtomouth activities.ThesemultipleroutesofexposuretoavarietyofEDCsmeanthathumansandwildlifeare exposedtocomplexmixturesofEDCs.Atthistimetherearenodatashowinghowmixturesofvirtually hundredsofEDCsatlowconcentrationswillaffecthumanhealthandwildlife.Animalstudiesindicate thatmixturesofchemicalsproduceadditiveeffects.Thushundredsofchemicalseachatlevelsbelow toxicitycouldinteracttogethertocausehealthproblems. Severalhundredenvironmentalpollutantshavebeenmeasuredinhumansandwildlifearoundthe world,eveninremoteplacesliketheArctic.LevelsofEDCsinhumanandwildlifevarywiththeir location;somearehigherinpeopleandwildlifeinurbanorhighlyindustrializedareasorsiteswhere,for example,disposalofewasteoccurs,whereasothersarehigherinremoteenvironmentsbecauseoflong rangetransportbyairandoceancurrentsandfoodwebaccumulation.Afewexamplesofexposure aroundtheworldareshownintheFigures19and20.Therearenolongeranypristineareaswithout 11

environmentalpollutants.Inaddition,levelsofchemicalsinthebodyaretightlylinkedtotrendsintheir use.Therearegoodexampleswherebansorreductionsinchemicalusehaveresultedinreducedlevels inhumansandwildlife.Indeed,concentrationsofmanyPOPshavedeclinedbecausetheyarebeing phasedoutofuse.Incontrast,EDCsthatarebeingusedmorenowarefoundathigherlevelsinhumans andwildlife.Itisnotablehowwellproductionandexposurearefollowingeachother,asexemplifiedin Figure21. HundredsofchemicalsincommerceareknowntohaveEDeffects.However,thousandsofchemicalsare notlookedforbyanychemicalmethods.Itislikelythatthesechemicalsarecontributingtowildlifeand humanexposurestoEDCstheexposome.ThesituationisdescribedinFigure22.Sinceonlyavery limitednumberofallchemicalsincommercehavebeentestedfortheirendocrinedisruptingproperties, theremaybemanymorewithsuchproperties.AlsotheEDCmetabolitesorenvironmental transformationproducts,thebyproductsandproductsformeduponwastetreatmentarenotincluded andtheirEDeffectsaremainlyunknown.

10. The tip of the iceberg.

Becauseonlyasmallpercentageofthe145,000chemicalsincommercetodayhavebeenassessedfor endocrinedisruptingactivityandbecausemanychemicalsinconsumerproductsarenotidentified,we haveonlylookedatthetipoftheiceberg.HowmanyEDCsarethere?Wheredotheycomefrom? Whatarethehumanandwildlifeexposures?Whataretheireffectsindividuallyandinmixturesduring developmentandadulthoodandevenacrossgenerations?Whataretheirmechanism(s)ofaction? HowcantestingforEDCsbeimproved?Allofthesequestionsneedanswers.

11. Testing for EDCs

ItiscustomaryforregulatoryagenciestotestchemicalsforEDactivityusingspecificvalidatedguideline studiesthatexaminethreehighdosestodetermineaNOAEL(noadverseeffectlevel)andthen extrapolatingdownusingsafetyfactorstodeterminesafelevelsforhumansand/orwildlife.Thedoses declaredsafearenotactuallytested.ThesestudiesalsoassumeathresholdforEDCeffects,thatthere willbenoeffectsatlowdosesandthatthedoseresponsecurvewillbelinear.Asnotedaboveitisnow clearthatEDCswillhavenothresholdduetothepresenceofactivehormonepathways,andthatEDCs arelikelytohaveeffectsatlowdosesandthattheirdoseresponseswillnotbelinear.Sincethereare datafromhumanepidemiologystudiesshowingeffectsonhumandiseasesendpointslinkedtoEDC exposures,likelyoccurringatlevelstowhichhumansarecurrentlyexposed. Regulatoryguidelinestudiesalsofocusonhistopathologyandorganandbodyweightsastheendpoints. AsnotedaboveEDCscancausemanydiseases,diseaseendpointsthatarenotcurrentlyassessedin regulatorystudies.Alsoriskassessmentapproachesdontalwaysassesstoxicityduringdevelopment, whichisthemostsensitivetimeforEDCaction,andthenalsodonotfollowtheanimalsfortheir lifetime,whichisneededtoassessresultingdiseases.

12

12. Lessons from the Past

SohowdoweasasocietyprotectourhealthandthatoffuturegenerationsfromtheactionsofEDCs? Whatcanwelearnfromthepastthatwillhelpus? Onescenarioistobanachemicalshowntocausetoxicityanddisease.Overthelast40yearsonlya handfulofchemicalse.g.lead,POPs,tributyltin,somephthalateplasticizers,andchlopyrifoshave beenbannedinmostcountriesandsometimesthesebansonlyconcernspecificuses.Nonetheless, therehavebeenclearbenefitsforhumanandwildlifehealthfromthedeclininguseofthesechemicals. Oneofthebestexamplesofpositiveactionisthebanningofresidentialuseoftheorganophosphate pesticidechlorpyrifosintheUSin2000.Chlorpyrifoshasbeenshowntobeapotentneurotoxicant causingdevelopmentaldelays,attentionproblemsandADHDinchildren.Todaythemanufacturerhas phasedoutproductsforresidentialusesaroundtheworld:itisstillusedworldwideasaninsecticideon fruitsandvegetablesincommercialagriculture.FollowingtheresidentialbanintheUSchildrensblood levelsinNewYorkdeclinedsignificantlywithinoneyearandwerereducedtolessthanhalfwithintwo years. Tributyltinisparticularlyinterestingasitwasbannedfromuseonshiphullsduetothereproductive effectsithadonmarineanimals.Inharborswheretributyltinusehasdeclined,environmentallevels havedecreasedandsotoohavetheeffectsofthisEDConthewildlifelivingintheseareas.Howeveritis stillusedasafungicideonnumerousplantsandisandsomeformsoforganotinsmakeupacomponent inPVCplastic. POPslikePCBsandDDTwerebannedinmanycountriesover20yearsagoduetotheirenvironmental persistenceandtoxicity.Asaresult,theirlevelsinhumansandwildlifehavedeclinedinrecentdecades. BirdpopulationsexposedtohighlevelsofDDTinthe1950sthrough70sinNorthAmericaandEurope areshowingclearsignsofrecovery(Figure23).Howevertherearestudiesshowingthatcurrentlow levelsofthesepersistentchemicalsarestillcausingharmbecausetheyortheirbreakdownproducts remainintheenvironmentlongaftertheyarenolongerused. PCBswerebannedinthe1970sbecauseoftheirpersistenceinthe environmentandpotentialcarcinogenicity.PCBsalsointerferewith thyroidhormonesystemaffectingchildhoodlearningandmemory, effectsthatwouldnotbeidentifiedusingcurrentgovernment mandatedtoxicitystudies. Leadisanimportantexampleofinactioninthefaceoftoxicitydata.Leadwasaknownneurotoxicant sincetheRomantimes;nonethelessitwasusedingasolineandpaintaroundtheworld.Theimpactof leadonchildrenisprofoundbecauseitcausesirreversibledamagetodevelopingboneandbraintissues. ThemostdamagingimpactresultedfromtheuseofleadingasolinewhichcausedanestimatedIQloss offivepointstomillionsofchildrenworldwide. 13

 Thebanontetraethylleadingasolineonlyoccurredafterdecadesofinaction,whensubstituteswere available.IndeedthebanwasnotspecificallybecauseofthedatashowingIQlossinchildrenassociated withleadexposurearoundtheworldbutduetotheeconomicanalysisshowingitcostthegovernments lossofincomeduetolowereducationalachievement.Furtherleadinterferedwiththenewcatalytic convertersoncarsusedtoreduceairpollution.Nonetheless,followingthebanintheUSleadlevelsin childrenfelldramaticallyshowingthatthebanhadahugeimpact(Figure24). Whiletheseareexamplesofsuccess,thescientificdatawaspresentmanyyearsbeforethepolicies werechangedandthechemicalwasbanned.Duringthattimechildrenshealthcontinuedtobeharmed. Sothequestioniswhenaretheresufficientdatatoact?Perhapstheanswerisinmakingmoreuseof theprecautionaryprincipletobanorrestrictchemicalsinordertoreduceexposureearly,evenwhen therearesignificantbutincompletedataandbeforethereissignificantandlonglastingharm.

13. Concluding Remarks

Endocrinedisruptingchemicalshavethecapacitytointerferewithtissueandorgandevelopmentand functionandthereforetheymayaltersusceptibilitytodifferenttypesofdiseasesthroughoutlife.Thisis aglobalthreatthatneedstoberesolvedusingbothprovensolutionsthatareavailablebutunderutilized andthedevelopmentofnewinnovativeapproachesandsolutions. Progress Wearestartingtounderstandwhendiseasesanddisordersstartandsomeimportantfactors,like exposuretoEDCsduringdevelopmentandthroughoutthelifespan,thatinteractwithourgenetic backgroundtoincreasesusceptibilitytoavarietyofdiseases.Itisclearthatmostifnotalldiseaseshave theiroriginduringdevelopment.ItisalsoclearthatexposuretoEDCsduringdevelopmentcan,as demonstratedinanimalmodels,andinanincreasingnumberofhumanstudies,resultinincreased susceptibilitytoandincidenceofavarietyofdiseases.Theseincludethemajorhumandiseasesthatare increasingaroundtheworld.Thesediseasesanddysfunctionsareincreasedatlevelsofexposurewithin thenormalhumanpopulation.Itisalsoclearfromhumanstudiesthatweareexposedtoperhaps hundredsofenvironmentalchemicalsatanyonetime.Itisnowvirtuallyimpossibletoexaminean unexposedpopulationaroundtheglobe.Thereisanincreasingburdenofdiseaseacrosstheglobe,and perhapsforfuturegenerationstowhichEDCsarelikelyplayinganimportantrole! Futureneeds WiththeinformationthatispresentlyavailableaboutadverseeffectsofEDCswearenowpoisedtohave animportantimpactondiseaseprevention.Whilemuchoftheworldsfocusisoninterventionwith drugstoreducetheimpactofdisease,acostlyandineffectiveprocess,wecanusetheinformationon howandwhenEDCsacttoactuallypreventdiseasefromoccurringbyreducingexposuresduring development.Thisisaprovensolutionasdescribedaboveforlead.Preventionofdiseaseisalways betterthanintervention,bothintermsofcostandhumansufferingverseshealthandwellbeing:the benefitsofearlyactionoutweighthecosts. Totakeadvantageofourcurrentknowledgetoimprovehumanandwildlifehealthbypreventionof environmentallyinduceddiseasewehaveidentifiedthefollowingneeds. 14

A.StrengtheningKnowledgeofEDCs:Itiscriticaltomovebeyondthepiecemeal,onechemicalata time,onediseaseatatime,onedoseapproachcurrentlyusedbyscientistsstudyinganimalmodels, humansorwildlife.Understandingtheeffectsofthemixturesofchemicalsthathumansandwildlifeare exposedtoisincreasinglyimportant.AssessmentofEDCactionbyscientistsneedstotakeintoaccount thecharacteristicsoftheendocrinesystemthatarebeingdisruptede.g.lowdoseeffectsandnon monotonicdoseresponses,tissuespecificityandwindowsofexposuresacrossthelifespan.Team sciencethatcombinesknowledgefromwildlife,animalandhumanstudiesisneededtoprovideamore holisticapproachforidentifyingthechemicalsthatareresponsiblefortheincreasedincidenceof diseaseanddysfunction.TheknownEDCsmaynotberepresentativeofthefullrangeofmolecular structuresandpropertiesduetoafartoonarrowfocusonhalogenatedchemicalsformuchexposure assessmentsandtestingforEDeffects.ThusresearchisneededtoidentifyotherpossibleEDCs. Endocrinedisruptionisnolongerlimitedtoestrogenic,androgenicandthyroidpathways.Chemicals alsointerferewithmetabolism,fatstorage,bonedevelopment,theHPAaxis,andtheimmunesystem andthissuggeststhatallendocrinesystemscanandwillbeaffectedbyEDCs.Together,thesenew insightsstressacriticalneedtoacquireabetterunderstandingoftheendocrinesystemtodetermine howEDCsaffectnormalendocrinefunction,howwindowsofexposuremayaffectdiseaseincidence (particularlyforchildhoodrespiratorydiseases),andhowtheseeffectsmaybepassedontogenerations tocome. Furthermorenewapproachesareneededtoexaminemixturesofendocrinedisruptorsondisease susceptibilityandetiologyasexaminationofoneendocrinedisruptoratatimeislikelytounderestimate theriskfromendocrinedisruptors.AssessmentofhumanhealthduetoEDCsneedstoinvolveboththe assessmentofchemicalmixturesonasinglediseaseaswellasasingleexposureonmultiplediseases. Sincehumanstudies,whileimportantcannotshowcauseandeffect,itiscriticaltodevelopmechanistic andcauseandeffectdatainanimalstosupportthestudiesonhumans. B.ImprovedTestingforEDCs:Itisimportanttorecognizethattheidentificationofhumanorwildlife healtheffectsofchemicalexposuresinepidemiologicalstudiesisanindicationthatthepremarket evaluationofchemicaleffectsfailedtoaccuratelypredicttheirtoxicity. Relevantanimaltestswithwhichtoensurethesafetyofwildlifepopulationsfromendocrinedisruptors arenotavailableformostwildlifegroups.Formanyinvertebratespecies,essentialforthehealthy functioningofecosystems,basicknowledgeoftheirendocrinesystemsislacking,makingitimpossible todevelopassaystoidentifyendocrinedisruptingchemicalsthatcouldharmtheseanimals. TestingstrategiescurrentlyemployedaroundtheworldarebasedonthepremisethatEDCscanbe evaluatedinthesamemannerasacutetoxicants;thisimpliesthattestsathighdoseswillinformus aboutlowdoseexposures.Italsoimpliesthatoneendpointofhormoneactioncaneffectivelybeused topredicttheactionofanEDCatallendocrineendpoints.However,aswehavenotedabove,hormone actionisquitecomplexanddependsonthedevelopmentalstageandtheendpointbeingevaluatedand thatEDCsactlikehormonesandnotasgeneraltoxicants.Therefore,itispredictablethatendocrine disruptingchemicalswillexerteffectsthatarealsoquitecomplexandthatarenotcapturedusing strategiesdesignedtodetectacutetoxicitywithalimitedrangeofexposureparadigms(onlythreehigh dosestested)andendpointsevaluated).Manytestsdonotencompassthesensitivedevelopmental periodoriftheydo,theyarenormallynotcarriedoutthroughoutlifetimetoassesslatenteffects.Thus 15

tomoveforwardthereisaneedforareassessmentofGovernmentmandatedtestingmethodsfocusing onhowbesttodetectEDCs. C.ReducingExposuresandtherebyVulnerabilitytoDisease:Inordertopreventorreducehealth effectsfromEDCs,itisimperativethatweknowtheEDCsthathumansandwildlifeareexposedto,and whatthelevelsofEDCsareinblood,placenta,amnioticfluidandothertissues.Wealsoneedthis informationacrosslifespans,sex,ethnicities(orspeciesofwildlife)andregions.Manyinformationgaps currentlyexistwithregardtowhatisfoundinhumanandwildlifetissues,especiallyfordeveloping countriesandforchemicalsthatarelesspersistentinthebody.Longtermrecordstounderstand changesinexposuresexistonlyforPOPsandonlyforafewcountries. Inaddition,thereisaneedtocontinueexpandingthelistofchemicalscurrentlyexaminedtoones includedinmaterialsandgoods,andchemicalbyproducts;wecannotassessexposurewithoutknowing thechemicalstotarget.Thecomprehensivemeasurementsofallexposureeventsduringlifetimeis needed,asopposedtosingletimebiomonitoring,andthisrequireslongitudinalsampling,particularly duringcriticallifestagessuchasfoetaldevelopment,earlychildhoodandthereproductiveyears. WildlifeandhumansareexposedtoawidevarietyofEDCsgreatlydifferingintheirphysicochemical properties.Further,thesecompoundsaregenerallypresentattracelevelsandincomplexmatrices requiringhighlyselectiveandsensitivemethods.Thewiderangeofdifferentcompoundclassesrequires avarietyofanalyticalapproachesandtechniques,makingitchallengingtounderstandallofthe differentchemicalsintheenvironmentandinhumanandwildlifetissues.Thereisagrowingneedto developnewanalyticaltechniquesandapproachestoprioritizetheassessmentofEDC.Thereisglobal transportofEDCsthroughnaturalprocesses(oceanandaircurrents)aswellascommerce,leadingto worldwideexposures.NewroutesofexposuretoEDCs,inadditiontofoodintake,havebeenidentified andincludeindoorenvironmentsandelectronicsrecyclinganddumpsitesindevelopingcountries.The sourcesandroutesofexposuretoEDCsneedtobefurtherinvestigated. D.Information:Identifyingendocrineactivechemicalsfromallofthechemicalsusedandreleased worldwideisamajorchallengeanditislikelythatwearecurrentlyonlyassessingthetipofthe iceberg.Itispossibletotracehighproductionvolumechemicals(HPVCs),butthatisnotthecasefor thenumerousadditivesandprocesschemicals.Addinggreatlytothecomplexityaretheunknownor unintendedbyproductsthatareformedduringchemicalsmanufacturing,duringcombustionprocesses, andviaenvironmentaltransformations,thusaddingontothenumberofchemicalsinourenvironment. Whiletheactiveingredientsinpharmaceuticalsandpesticideshavetobedocumentedonthefinal product,thisisnotthecaseforchemicalsinarticles,materialsandgoods.Personalhygieneproducts andcosmeticsrequiredeclarationsoftheingredientsandthenumberofchemicalsappliedinthis sphereofusescountsinthethousands.ManysourcesofEDCsarenotknownbecauseoflackof chemicalconstituentdeclarationsinproducts,materialsandgoods.Weneedtoknowwherethe exposuresarecomingfrom. E.Creatingenablingenvironmentsforscientificadvances,innovationanddiseaseprevention:The problemofexposuretoEDCsandtheireffectsondiseaseinhumansandwildlifeisaglobalproblem whichwillrequireglobalsolutions.Moreprogramsareneededwhichfostercollaborationsanddata sharingamongscientistsandbetweengovernmentalagenciesandcountries.Toprotecthumanhealth fromtheproblemsresultingfromthecombinedeffectsofEDCsexposuresandfrompoornutrition,and poorlivingconditions,thereisaneedtodevelopprogramsandcollaborationsbetweendevelopedand 16

developingcountries.Thereisalsoneedtostimulatenewadaptiveapproacheswhichbreakdown institutionalandtraditionalscientificbarriersandstimulateinterdisciplinaryandmultidisciplinaryteam science.

[AlistoftheFiguresusedinthisdocumentwillfollow,referringtheiroriginandanypotentialscientificarticlefrom wherethediagramswereredrawn.Copyrightpermitshavebeenobtainedforallillustrationshavingaparticular source]

17

FiguresforSum maryforDecisionm makers

Introduc ction(Sectio on1)

Fig gure1.Cove eroftheIPCS S2002docum ment. neSystemsa andEndocrin neDisruptio on(TextSection3) Endocrin

Figure2.Overviewo ofEndocrineSystem.Figu ureshowsen ndocrineglandsandsom eexamplesof m esproduced. hormone

WindowsofD Development t.Eachtissuehasaspecificwindow duringdevelopment Figure3.SensitiveW isforming.T Thatisthese ensitivewind dowforeffec ctsofEDCs.N Noticethats ometissuec continue wheniti developi ingafterbirt thandintoin nfancyandc childhoodpro ovidingalon ngerwindow wforexposur resto affectpr rogramming. .

Figure4.Exampleof fhormoneac ction.Many hormonesactviabindingtospecific creceptors(2)to stimulatethesynthe esisofnewproteins(6)w whichthenco ontroltissuefunction.So omehormon nesalso actviare eceptorsonthemembra ane,inthatc casetheactio onsmoreimmediateinn nature.

Endocrin neDisruptor rsandHuma anHealth(Te extSection4 4)

Figure5.DiseasesinducedbyED DCs.

Figure6.Childrenar reamongthe emostvulne erablehuman ns Whyare eweconcern ned?Huma anDiseaseTr rends(TextS Section5)

Figure7.Testicularc cancerratesacrossEurop pe

eastcancerin ncidenceacr rossEurope Figure8.Femalebre

Figure9.Incidenceo ofoverweigh htadultsinse everalcountries. t

Endocrin neDisruptor rsandWildlifeHealth(T TextSection6)

Figure10 0.Greysealscullwithhighlyeroded bonetissuerelatedtoPOPs

maleandfemale numundatum m)showingimposex,i.e. ithasbothm m Figure11.Commonwelk(Buccin genitalia a.

Whyare eweconcern ned?PopulationEffects sinWildlife (TextSectio on7)

rtebrates)ov Figure12.Populationdeclinesin nwildlife(ver ver30years, ,19702000 0.

Figure13.BritishColumbiaskille erwhales(O Orcinusorca)andharbourseals(Phoc cavitulina)co ontain highleve elsofthereg gulatedpolyc chlorinatedb biphenyls(PCBs)andmo oderatelevellsofthe polybrom minateddiph henylethers(PBDEs).

 Sensitive ePeriodsfor rEndocrineDisruptorAc ctionWind dowofexpos sure(TextSe ection8)

4.Earlyexpo osuresinlifemaybeman nifestedanytimeinlife. Figure14

/dysfuctiono originatingfr romearlyexp posures. Figure15.Examplesofdiseases/

 Figure16.Whichchi ildhasbeenexposedtoE EDCsduringdevelopmen ntandisthus smoresusce eptible todiseas seonsetlate erinlife? nceandExposurestoEn ndocrineDisr ction9) ruptors(Sec Occurren

Figure17.EDCsfindtheirwayintotheenviro onmentviap pointanddif ffusesources s,asexemplified here.

 Figure18 8.Exposures stoEDCscom mesfrommu ultiplesources,enteringthebodyvia aingestion, inhalatio onandskinu uptake.

9.EDCsaref foundinwild dlifeworldw ide;PFOSco oncentrations(ng/gwetw weight)inliverof v Figure19 marinem mammals.

0.SomeEDC Csarehighes stinwildlifef fromareasw withhighche emicaluse,e e.g.BDE209 Figure20 concentr rations(ng/g gfat)inbirdtissues.

Figure21.Humanex aseswhenp xposuretoan nEDCdecrea productionislowered,asdescribedb bythe timecou urseofindus strialDEHPproductionin nGermanyan ndmediandailyintakeo ofDEHPinun niversity students s.

 Figure22.Anillustra ationofthec complexityo ofmeasuringchemicals,includingpot tentialEDCs, ,in environm mentalmedia. Lessonsfromthepa ast(Section1 11)

overafterab banofthech hemicale.g. Figure23.WildlifepopulationsaffectedbyE DCscanreco gDDEconcentrationsinospreyeggs (ppmwetw weight)inrela ationtonum mberofospre eynests declining occupied dinOregon( (USA).

4.Banonlea adingasolineandtheim mpactofthisdecisiononchildrensblloodleadlev vels. Figure24