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Page 1: 96 scientifiques contestent l'évaluation de l'EFSA sur le glyphosate classé « cancérogène probable » par l’OMS.

November27,2015Mr.VytenisAndriukaitisCommissionerHealth&FoodSafetyEuropeanCommissionRuedelaLoi/Wetstraat2001049BrusselsBelgiumCc:(emailonly)Mr.PhilHogan,EuropeanCommissionerforAgricultureandHumanDevelopmentDr.LadislavMiko,DeputyDirector-General,DGHealth&FoodSafetyDr.BernhardUrl,ExecutiveDirector,EFSADr.GiovanniLaVia,Chair,ENVICommitteeEFSAPanelonPlantProtectionProductsandtheirResiduesMr.ChristianSchmidt,MinisterofFoodandAgricultureDr.HelmutTschiersky,PresidentoftheFederalOfficeofConsumerProtectionandFoodSafety(BVL)ProfessorDr.Dr.AndreasHensel,President,BFRDr.ChristopherWild,Director,IARCMr.JimJones,AssistantAdministrator,USEPA

Openletter:ReviewoftheCarcinogenicityofGlyphosatebyEFSAandBfRDearCommissionerAndriukaitis,Weareagroupofindependentacademicandgovernmentalscientistsfromaroundtheworldwhohavededicatedourprofessionallivestounderstandingtheroleofenvironmentalhazardsoncancerrisksandhumanhealth.WehavebandedtogetherandwritetoyouatthistimetoexpressourdeepconcernovertherecentEuropeanFoodSafetyAgency(EFSA)decision[1]thatthewidelyusedherbicide,glyphosate“isunlikelytoposeacarcinogenichazardtohumans.”WeaskthatyouforwardthelettertotherepresentativesofallEUmemberstatesbeforethenextmeetingoftheStandingCommitteeonPlants,Animals,FoodandFeed(December10/11).TheEFSAdecision,basedupontheRenewalAssessmentReport[2]providedbytheGermanFederalInstituteforRiskAssessment(BfR),runscountertothefindingearlierthisyearbytheInternationalAgencyforResearchonCancer(IARC),thehighlyrespectedcancerarmoftheWorldHealthOrganizationthatglyphosateisaprobablehumancarcinogen.ThisIARCclassificationisbasedonacomprehensiveassessmentofthepeer-reviewedtoxicologicandepidemiologicliteratureundertakenovera12-monthperiodbyaWorkingGroupof17independentexpertscientists.TheIARCreviewlinkedglyphosatetodose-relatedincreasesinmalignanttumorsatmultipleanatomicalsitesinexperimentalanimalsandtoanincreasedincidenceofnon-Hodgkinlymphomainexposedhumans.

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WereviewedthesetwodifferingdecisionsonthehumancarcinogenicityofglyphosateandconcludethattheIARCWGdecisionisbyfarthemorecredible.TheIARCWGdecisionwasreachedrelyingonopenandtransparentproceduresbyindependentscientistswhocompletedthoroughconflict-of-intereststatementsandwerenotaffiliatedorfinanciallysupportedinanywaybythechemicalmanufacturingindustry.Itisfullyreferencedanddependsentirelyonreportspublishedintheopen,peer-reviewedbiomedicalliterature.ItispartofalongtraditionofdeeplyresearchedandhighlycrediblereportsonthecarcinogenicityofhundredsofchemicalsissuedoverthepastfourdecadesbyIARCandusedtodaybyinternationalagenciesandregulatorybodiesaroundtheworldasabasisforriskassessment,regulationandpublichealthpolicy.Incontrast,theBfRdecisionisnotcrediblebecauseitisnotsupportedbytheevidenceanditwasnotreachedinanopenandtransparentmanner.Accordingly,weurgeyouandtheEuropeanCommissiontodisregardtheflawedEFSAfindingonglyphosateinyourformulationofglyphosatehealthandenvironmentalpolicyforEuropeandtocallforatransparent,openandcrediblereviewofthescientificliterature.TheIARCWorkingGroupDecisionTheInternationalAgencyforResearchonCancer(IARC)MonographsProgrammeidentifiesenvironmentalcausesofcancerinhumansandhasevaluatedmorethan950agentssince1971.TheMonographsProgrammeevaluateschemicals,drugs,mixtures,occupationalexposures,lifestylesandpersonalhabits,physicalagentsandbiologicalagents.MonographsarewrittenbyanadhocWorkingGroup(WG)ofinternationalscientificexpertsoveraperiodofabout12monthsendinginaneight-daymeeting.TheWGevaluatesallofthepublically-availablescientificliteratureonagivensubstanceand,throughatransparentandrigorousprocess[3],reachesadecisiononthedegreetowhichthescientificevidencesupportsthatsubstance’sabilitytocauseornotcausecancer.ForMonograph112[4],17expertscientistsevaluatedthecarcinogenichazardfor4insecticidesandtheherbicideglyphosate[5].TheWGconcludedthatthedataforglyphosatemeetsthecriteriatobeidentifiedasaprobablehumancarcinogen.ThisfindingstirredgreatdebategloballyonthesafetyofglyphosateandledtoacarefulevaluationbynumerousagenciesoftheIARCmonographresultswhentheybecameavailableonJuly29,2015.TheBfRAddendumInOctober,2015,theEFSAreported[1]ontheirevaluationoftheRenewalAssessmentReport[2](RAR)forglyphosate.EFSAconcludedthat“glyphosateisunlikelytoposeacarcinogenichazardtohumansandtheevidencedoesnotsupportclassificationwithregardtoitscarcinogenicpotential”.Addendum1(theBfRAddendum)oftheRAR[2]discussesthescientificrationalefordifferingfromtheIARCWGconclusion.

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WehaveseriousconcernswithregardtothescientificevaluationintheBfRAddendumandfeelthatitismisleadingregardingthepotentialforadose-dependentcarcinogenichazardfromexposuretoglyphosate.SincetheBfRAddendumisthebasisfortheEuropeanFoodSafetyAgency(EFSA)conclusion[1],itiscriticalthatweexpresstheseconcerns.WearealsoconcernedaboutsomeoftheimplicationsoftheBfRAddendumregardingtheuseofhumandatainidentifyingcarcinogenichazards.OurcommentstotheBfRAddendumwillfocusonthehumanevidence,theanimallaboratoryevidenceandthemechanisticevidence.TheHumanEvidenceTheBfRagreeswiththeIARCWGthatthereis“limitedevidenceinhumansforthecarcinogenicityofglyphosate”.IntheIARCreviewprocess,limitedevidenceisassignedif“ApositiveassociationhasbeenobservedbetweenexposuretotheagentandcancerforwhichacausalinterpretationisconsideredbytheWorkingGrouptobecredible,butchance,biasorconfoundingcouldnotberuledoutwithreasonableconfidence.”[3]TheEFSAconclusionthat“glyphosateisunlikelytoposeacarcinogenichazardtohumans”isinappropriatewhenavailabledatasupportthedeterminationoflimitedevidenceofcarcinogenicityinhumans.TheBfRAddendum(p.ii)characterizestheIARCinterpretationas“precautionary”andthattheBfRtakesamore“cautiousview”ofthisclassificationbecause“noconsistentpositiveassociationwasobserved”,“themostpowerfulstudyshowednoeffect”andthatthestudies“couldnotdifferentiatebetweentheeffectsofglyphosateandtheco-formulants”.Wewillconsiderthefirsttwoargumentshereanddiscussthethirdargumentattheendofthisletter.ThefindingoflimitedevidencebytheIARCWGwasfornon-Hodgkinlymphoma(NHL).High-qualitycohortstudiesareparticularlyvaluablefordeterminingthecarcinogenicityofanagentbecausetheirdesigncanfacilitateexposureassessmentandreducethepotentialforcertainbiases.TheAgriculturalHealthStudy[6](AHS)wastheonlycohortstudyavailableprovidinginformationonthecarcinogenicityofglyphosate.ThestudyhadanullfindingforNHL(RR1.1,0.7-1.9)withnoapparentexposureresponseintheresults.TheBfRreferstothisstudyas“themostpowerfulstudy”andnotesthatitwas“negative”forNHL.Severalpotentiallimitationsofcase-controlstudiesarelaidoutinepidemiologytextbooks[7,8].TheBfRusestheselimitationstolabelallofthecase-controlstudiesasunreliable.Thisgivestheimpressionthatallofthestudiesareequalinqualityandunusableforanoverallevaluation.Thisisnotthecase:well-designedcase-controlstudiesarerecognizedasanefficientalternativetocohortstudies[8].AnIARCWGcarefullyevaluatesalloftheavailableepidemiologydata,lookingatthestudy’sstrengthsandweaknesses.Thisiskeytodeterminingwhetherthepositiveassociationsseenincase-controlstudiesareareliableindicationofanassociationorsimplyduetochanceormethodologicalflaws.Toprovideareasonableinterpretationofthefindings,anevaluationneedstoproperlyweightstudiesaccordingtotheirqualityratherthansimplycountthenumberofpositivesandnegatives.Themeta-analysescitedintheIARCMonograph[9]anddonebytheWG

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areexcellentexamplesofanobjectiveevaluationoftheexistenceofaconsistentpositiveassociation;bothmeta-analysesshowedastatisticallysignificantassociation.TheBfRprovidednojustificationfortheirevaluationof“noconsistentpositiveassociation”.Finally,despitethepotentialadvantagesofprospectivecohortstudiesversuscase-control,therearefewercasestoincludeinanalyses,dependingonthefollow-uptimeresultinginlimitedstatisticalpower.Therewereonly92NHLcasesincludedintheAHSunadjustedanalysisandfewerinadjustedanalyses,comparedto650inapooledcase-controlanalysisfromtheUnitedStates[10].ThefinalBfRconclusion(p.21)that“therewasnounequivocalevidenceforaclearandstrongassociationofNHLwithglyphosate”ismisleading.IARC,likemanyothergroups,usesthreelevelsofevidenceforhumandata[3].Sufficientevidencemeans“thatacausalrelationshiphasbeenestablished”betweenglyphosateandNHL.IARCdoesnotstatethattheevidenceissufficient.BfRconcludesthattheIARCdesignationoflimitedevidencewasnotapplicablebecausetherewasnot"anunequivocalandconsistentexcess".Infact,thatistheequivalenttothecriteriaforsufficientevidence,notlimitedevidence.ThusBfR’sconclusionisequivalenttoconcludingthereisnotsufficientevidence.Legitimatepublichealthconcernsarisewhen"causalityiscredible”,i.e.,whenthereislimitedevidence.BfR’slanguageismisleadingandnotinternationallyacceptableandthusfailstomeetECGuidelines.EvidencefromAnimalCarcinogenicityStudiesWefindtheconclusionsoftheBfRregardingtheanimalcarcinogenicitydatatobescientificallyunacceptable.TheIARCWGreviewfoundasignificantpositivetrendforrenaltumorsinCD-1mice[11],araretumoralthoughnocomparisonsofanyindividualexposuregrouptothecontrolgroupwerestatisticallysignificant.Asignificantpositivetrendmeansthatthepatternseeninthedatasupportsanincreasingriskwithincreasingdose.TheWGalsoidentifiedasignificantpositivetrendforhemangiosarcomainmaleCD-1mice[12],againwithnoindividualexposuregroupsignificantlydifferentfromcontrols.Finally,theWGalsosawasignificantincreaseintheincidenceofpancreaticisletcelladenomasintwostudiesinSprague-Dawleyrats[13-15].Inoneoftheseratstudies,thyroidglandadenomasinfemalesandliveradenomasinmaleswerealsoincreased.Thus,glyphosatewaspositiveformalignanttumorsinbothofthemousestudiesexaminedandforbenigntumorsintwoofthefiveratstudiesexamined.BytheIARCreviewcriteria[3],theevidenceinthemouseconstitutessufficientevidenceinanimalsandtheincreasedincidencesofbenigntumorsconstitutesadditionalsupport.TheBfRagreed,stating(p.43)"itisobviousthatIARCconcludeson“sufficientevidenceofcarcinogenicity”becausetheabovecriteriaforthisconclusionarefullymet.”TheIARCWGreachedthisconclusionusingdatathatwerepubliclyavailableinsufficientdetailforindependentscientificevaluation(arequirementoftheIARCPreamble[3]).BasedontheBfRAddendum,itseemstherewerethreeadditionalmousestudiesandtwoadditionalratstudiesthatwereunpublishedbutavailableforreview.BfRreportedontwoadditionalstudieswithapositivetrendforrenaltumors,oneinCD-1mice[16],andoneinSwiss-Webstermice[17].Oneofthesestudies[16]alsoreportedapositivetrendforhemangiosarcoma.Moreover,BfRreportedtwostudiesinCD-1miceshowingsignificanttrendsformalignant

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lymphoma[16,18].Forallofthemousetumorsdescribedabove,apositivetrendwasseenagainsttheconcurrentcontrol.However,inallstudiesinCD-1mice,includingthosereviewedbytheIARC,theBfRdismissestheobservedtrendsintumorincidencebecausetherearenoindividualtreatmentgroupsthataresignificantlydifferentfromcontrolsandbecausethemaximumobservedresponseisreportedlywithintherangeofthehistoricalcontroldata(Table5.3-1,p.90).Caremustbetakeninusinghistoricalcontroldatatoevaluateanimalcarcinogenicitydata.Invirtuallyallguidelines[3,19],scientificreports[20]andpublications[21-23]onthisissue,therecommendedfirstchoiceistheuseoftheconcurrentcontrols.Forinstance,thePreambletotheIARCMonographsstates,“itisgenerallynotappropriatetodiscountatumorresponsethatissignificantlyincreasedcomparedwithconcurrentcontrolsbyarguingthatitfallswithintherangeofhistoricalcontrols…”.Whenusinghistoricalcontroldata,theyshouldbefromstudiesinthesametimeframe,forthesameexactanimalstrain,preferablyfromthesamelaboratoryorthesamesupplierandpreferablyreviewedbythesamepathologist[19].ThiswasnotthecaseforthehistoricalcontroldatabaseusedbyBfR.Oneofthemousestudies[11]wasclearlydonebeforethishistoricalcontroldatabasewasdeveloped,onestudy[16]usedCrj:CD-1miceratherthanCrl:CD-1mice,andonestudy[12]didnotspecifythesubstrainandwasreportedin1993(probablystartedpriorto1988);henceonlyasinglestudy[18]usedthesamemousestrainasthehistoricalcontrols,butwasreportedmorethan10yearsafterthehistoricalcontroldatasetwasdeveloped.Interestingly,thehistoricalcontroldatausedbytheBfR[24]wasfromstudiesinsevenlaboratoriesusingtheCharlesRiverLaboratoryCD1mice.Itisimportanttonotethatthereisasecondreport[25]bythesameauthorswithalargercontroldatabaseusingthesamemousestrainfrom11laboratoriesoverthesametimeperiod(1987-2000)showingverydifferentresults.Forexample,the2000publication[24]showsfiveandfourstudiesoutof46withrenaladenomas(nomorethantwoinanyonestudy)andrenaladenocarcinomas(oneineachstudy)respectivelywhereasthe2005report[25]showsonlyonestudyeachoutof54studieswithasinglerenaladenomaandasinglerenaladenocarcinoma;allotherstudieshadnorenaltumors.Giventhisevidence,itisclearthatBfRdifferedfromstandardscientificpracticesinordertoreachtheirconclusions.BfRreportedsevenpositivemousestudieswiththreestudiesshowingincreasesinrenaltumors,twowithpositivefindingsforhemangiosarcomas,andtwowithpositivefindingsformalignantlymphomas.BfRadditionallyreportedtwopositivefindingsfortumorsinrats.Eliminatingtheinappropriateuseofhistoricaldata,theunequivocalconclusionisthatthesearenotnegativestudies,butinfactdocumentthecarcinogenicityofglyphosateinlaboratoryanimals.MechanisticInformationTheBfRAddendumdismissestheWGfindingthat“thereisstrongevidencethatglyphosatecausesgenotoxicity”bysuggestingthatunpublishedevidencenotseenbytheIARCWGwasoverwhelminglynegativeandthat,sincethestudiesthatwerereviewedwerenotdoneunderguidelineprinciples,theyshouldgetlessweight.Tomaintaintransparency,IARCreviewsonlypubliclyavailabledata.ThustheuseofconfidentialdatasubmittedtotheBfRmakesitimpossibleforanyscientistnotassociatedwithBfRtoreviewthisconclusionwithscientific

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confidence.Furtherskewingtheirinterpretation,theBfRdidnotincludeevidenceofchromosomaldamagefromexposedhumans[24]thatwashighlightedintheIARCMonograph.TheBfRconfirms(p.79)thatthestudiesevaluatedbytheIARCWGonoxidativestresswerepredominantlypositivebutdoesnotagreethatthisisstrongsupportforanoxidativestressmechanism.Theyminimizethesignificanceofthesefindingspredominantlybecauseofalackofpositivecontrolsinsomestudiesandbecausemanyofthestudiesusedglyphosateformulationsandnotpureglyphosate.TheWGconcludedthat(p.77)“Strongevidenceexiststhatglyphosate,AMPAandglyphosate-basedformulationscaninduceoxidativestress”.Fromascientificperspective,thesetypesofmechanisticstudiescanplayakeyroleindistinguishingbetweentheeffectsofmixtures,puresubstancesandmetabolitesandweencouragetheBfRtocarefullyreviewthisscience.Finally,westronglydisagreethatdatafromstudiespublishedinthepeer-reviewedliteratureshouldautomaticallyreceivelessweightthanguidelinestudies.Onceachemicaloritsformulationsareonthemarket,themajorityoftheresearchdoneonthesechemicalswillbedonebyresearchlaboratoriesusingvariousmodelstoaddressspecificissuesrelatedtotoxicitythatwilloftennothavetestingguidelinesassociatedwiththem.Thesepeer-reviewedandpublishedfindingshavegreatvalueinunderstandingmechanismsofcarcinogenicityandshouldbegivenappropriateweightinanevaluationbasedonstudyqualityandnotjustguidelinerules.GeneralCommentsSciencemovesforwardbasedondata,carefulevaluationofthosedataandarigorousreviewofthefindingsandconclusions.Oneimportantaspectofthisprocessistransparencyandtheabilitytoquestionordebatethefindingsofothers.Thisensuresthevalidityoftheresultsandprovidesastrongbasisfordecisions.ManyoftheaspectsoftransparencydonotexistfortheRAR[2]ortheBfRAddendum.Forexample,citationsforalmostallofthereferences,eventhosefromtheopenscientificliterature,havebeenredactedfromthedocument.Theabilitytoobjectivelyevaluatethefindingsofascientificreportrequiresacompletelistofthecitedsupportingevidence.Asanotherexample,therearenoauthorsorcontributorslistedforeitherdocument,arequirementforpublicationinvirtuallyallscientificjournals.ThisisindirectcontrasttotheIARCWGevaluationlistingallauthors,allpublicationsandpublicdisclosureofpertinentconflictsofinterestpriortotheWGmeeting[26].Asecondimportantaspectofthescientificprocessisacarefulevaluationandanalysisofthefacts.Severalguidelineshavebeendevisedforanalyzingcarcinogenicitydata,mostafterconsultationwithscientistsfromaroundtheworld.OneofthemostwidelyusedguidelinesistheOECDguidanceontheconductanddesignofchronictoxicityandcarcinogenicitystudies[19]whichiscitedintheBfRAddendum.ThisOECDguidanceisincontradictiontothemethodsusedbytheBfRforbothhistoricalcontrolsandfortrendanalysis;thetworeasonsgivenbytheBfRfordismissingthesedata.Thus,BfRusesthe

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conceptoftestingguidelinestoexcludesubstantivescientificevidencefromtheirriskassessmentandignoreOECDguidelinesinaddressingtheimportantissuesofhistoricalcontrolsandtrendanalyses.Duetothepotentialpublichealthimplicationsofthisextensivelyusedpesticideitisessentialthatallscientificevidencebefreelyavailable,reviewedopenlyinanobjectivemanner,andthatfinancialsupport,conflictsofinterestandaffiliationsofauthorsbefullydisclosed.ManyaspectsoftheevaluationconductedbytheBfRandEFSAdonotmeetthisfundamentalobjectivecriteriaandraisesignificantquestionsofvalidity.SummaryTheIARCWGconcludedthatglyphosateisa“probablehumancarcinogen”puttingitintoIARCcategory2Aduetosufficientevidenceofcarcinogenicityinanimals,limitedevidenceofcarcinogenicityinhumansandstrongmechanisticdata.

• TheIARCWGfoundanassociationbetweennon-Hodgkinlymphomaandglyphosatebasedontheavailablehumanevidence.

• TheIARCWGfoundsignificantcarcinogeniceffectsinlaboratoryanimalsfortwotumortypesintwomousestudiesandbenigntumorsintworatstudies.

• Finally,theIARCWGconcludedstrongevidenceofgenotoxicityandoxidativestressforglyphosate,entirelyfrompubliclyavailableresearch,includingfindingsofDNAdamageintheperipheralbloodofexposedhumans.

IntheirRAR,BfRconcluded(Vol.1,p.160)“classificationandlabelingforcarcinogenesisisnotwarranted”and“glyphosateisdevoidofgenotoxicpotential”.

• BfRagreedwiththeIARConlimitedevidenceinhumansbutthendismissedtheassociationas“insufficientlyconsistent”withnojustification.

• UsinganinappropriatehistoricalcontroldatasetinanincorrectmannerandignoringestablishedOECDguidelinescitedintheirreport,BfRdismissedevidenceofrenaltumorsin3mousestudies,hemangiosarcomain2mousestudiesandmalignantlymphomain2mousestudies.Thus,BfRincorrectlydiscardedalloftheglyphosate-inducedcarcinogenicfindingsinanimalsaschanceoccurrences.

• TheBfRignoredimportantlaboratoryandhumanevidenceofgenotoxicity.

• TheBfRconfirmedthatglyphosateinducesoxidativestressanddismissedthisfindingforlackofanyotherfindingbecausetheyhaddismissedalloftheotherevidence.

Themostparsimoniousscientificexplanationofthecancersseeninhumansandlaboratoryanimalssupportedbythemechanisticdataisthatglyphosateisaprobablehumancarcinogen.Onthebasisofthisconclusionandintheabsenceof

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contraryevidence,itisreasonabletoconcludethatglyphosateformulationsshouldalsobeconsideredprobablehumancarcinogens.WebelievethattheargumentspromotedbytheBfRtonegatethehuman,animalandmechanisticevidencearefundamentallyandscientificallyflawedandshouldberejected.Westronglyobjecttothealmostnon-existentweightgiventostudiesfromtheliteraturebytheBfRandthestrongrelianceonnon-publiclyavailabledatainalimitedsetofassaysthatdefinetheminimumdatanecessaryfortheapprovalofapesticide.WebelievethattheIARCWGevaluationofprobablycarcinogenictohumansaccuratelyreflectstheresultsofthepublishedscientificliteratureonglyphosateand,onthefaceofit,theunpublishedstudiestowhichtheBfRrefers.Conversely,theBfRevaluation,andconsequentlytheEFSAevaluation,donotreflecttheavailablescience.Thus,repeatingourearlierrequest,weurgeyouandtheEuropeanCommissiontodisregardtheflawedEFSAfindingonglyphosateinyourformulationofglyphosatehealthandenvironmentalpolicyforEuropeandtocallforatransparent,openandcrediblereviewofthescientificliterature.TheviewsexpressedinthisletteraretheopinionofthescientistswhoarelistedbelowandDONOTimplyanendorsementorsupportfortheseopinionsbyanyorganizationstowhichtheyareaffiliated.Sincerely,Prof.ChristopherJ.Portier(CorrespondingAuthor)SeniorContributingScientist,EnvironmentalDefenseFund,Washington,DCVisitingProfessor,MaastrichtUniversity,Maastricht,TheNetherlandsAdjunctProfessor,EmoryUniversity,Atlanta,Georgia,USAHonoraryProfessor,UniversityofQueensland,Brisbane,Queensland,AustraliaFormerDirector,NationalCenterforEnvironmentalHealth,Atlanta,USAFormerDirector,AgencyforToxicSubstancesandDiseaseRegistry,Atlanta,USAFormerAssociateDirector,USNationalToxicologyProgram,RTP,NC,USACH-3600Thun,[email protected]+41796057958BruceArmstrongMBBS,DPhil(Oxon),FFAPHM,FAAEmeritusProfessorSydneySchoolofPublicHealthTheUniversityofSydney,AustraliaDistinguishedProfessorBruceCBaguleyAucklandCancerSocietyResearchCentreTheUniversityofAucklandAuckland,NewZealandProf.Dr.med.XaverBaurInstituteforOccupationalMedicine

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CharitéUniversityMedicineBerlin14195Berlin,GermanyIgorBeliaev,PhD,DrScAssociateProfessorofGeneticToxicologyHead,LaboratoryofRadiobiologyCancerResearchInstituteSlovakAcademyofScienceBratislava,SlovakRepublicandProfessor,LaboratoryofRadiobiologyDepartmentofEcologicalandMedicalProblemsProkhorovGeneralPhysicsInstituteRussianAcademyofScienceMoscow,RussiaProfessorRobertBelléLaboratoiredeBiologieintégrativedesmodèlesmarins(UMR8227,CNRS-UPMC)UniversitéPierreetMarieCurieStationBiologique29680RoscoffFranceDr.FiorellaBelpoggiDirectorCesareMaltoniCancerResearchCenterRamazziniInstitute40010Bentivoglio(Bologna),ItalyProf.AnnibaleBiggeriDirectorBiostatisticsUnitInstituteforCancerPreventionandResearchDepartmentofStatisticsComputerScienceApplications"G.Parenti"UniversityofFlorence,ItalyMaartenC.Bosland,DVSc,PhDProfessorofPathologyDepartmentofPathologyCollegeofMedicineUniversityofIllinoisatChicagoChicago,IL60612USAProf.PaoloBruzziMD,MPH,PhDDirector,UnitofClinicalEpidemiologyNationalCancerResearchInstituteSanMartino–ISTHospitalGenoaITALYProf.Dr.LygiaThereseBudnik

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UniversityofHamburg,Hamburg,GermanyEuropeanSocietyforEnvironmentalandOccupationalMedicine.Dr.MereteD.Bugge,PhDSeniorPhysicianSTAMI,NationalInstituteofOccupationalHealthOslo,NorwayKathleenBurns,PhDDirectorSciencecorpsLexington,MA,USAGloriaM.CalafPh.D.Director,InstitutodeAltaInvestigaciónUniversidaddeTarapacáArica-ChileandAdjunctAssociateResearchScientistColumbiaUniversityMedicalCenterCenterforRadiologicalResearchNewYork,NewYorkUSADavidO.Carpenter,M.D.Director,InstituteforHealthandtheEnvironmentUniversityatAlbanyRensselaer,NY12144USAHillaryM.Carpenter,Ph.D.,ToxicologistMinnesotaDepartmentofHealth,RetiredMaplewoodMN55109USALizbethLópez-CarrilloSeniorResearcherNationalInstituteofPublicHealthCuernavaca,Morelos,MexicoProf.RichardClappProfessorEmeritusBostonUniversitySchoolofPublicHealthBoston,MAUSAProf.PierluigiCocco,M.D.,HonFFOMChair,OccupationalMedicineDepartmentofPublicHealth,CLinicalandMolecularMedicineUniversityofCagliari,ItalyPietroComba,PhD,Head,UnitofEnvironmentalEpidemiologyDepartmentofEnvironmentandPrimaryPrevention

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IstitutoSuperiorediSanità,Rome,ItalyDrDarioConsonni,MD,MPH,PhDOccupationalPhysicianandEpidemiologistEpidemiologyUnit,DepartmentofPreventiveMedicineFondazioneIRCCSCa'Granda-OspedaleMaggiorePoliclinicoMilan,ItalyDevraDavis,Md,PhDVisitingProfessor,TheHebrewUniversity,HadassahMedicalSchool,JerusalemVisitingProfessor,OndukuzMayisUniversityMedicalSchool,Samsun,TurkeyPresident,EnvironmentalHealthTrustJacksonHole,WYUSAAnneclaireDeRoos,MPH,PhDAssociateProfessorEnvironmental&OccupationalHealthDornsifeSchoolofPublicHealthDrexelUniversityPhiladelphia,PAUSAPaulA.Demers,Ph.D.DirectorOccupationalCancerResearchCentre,CancerCareOntarioProfessorDallaLanaSchoolofPublicHealth,UniversityofTorontoToronto,CanadaDr.JamieDeWittAssociateProfessorofPharmacology&ToxicologyBrodySchoolofMedicine,EastCarolinaUniversityGreenville,NC,USADr.FrancescoForastiereDirectorEtiologicalandAnalyticalEpidemiologyDepartmentofEpidemiology,LazioRegionalHealthServiceRome,ItalyDr.JonathanHFreedman,Ph.D.Professor,DepartmentofPharmacologyandToxicologyUniversityofLouisvilleSchoolofMedicineLouisville,Kentucky40202USAProf.LinFritschiSchoolofPublicHealth,CurtinUniversityPerth,AustraliaDr.CarolineGausAssociateProfessorEnvironmentalToxicology

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TheUniversityofQueenslandBrisbane,AustraliaJuliaMGohlke,PhDAssistantProfessorDepartmentofPopulationHealthSciencesVirginia-MarylandCollegeofVeterinaryMedicineVirginiaTechBlacksburg,VA24061-0395,USAProfessorMarcelGoldbergEmeritusProfessorofepidemiologyParisDescartesUniversityParis,France.Prof.EberhardGreiserEmeritusProfessorofepidemiologyandmedicalstatisticsAssociateProfessor,CenterforSocialPolicyResearch,BremenUniversity,CEO,Epi.ConsultGmbH,Musweiler,Rhineland-Palatinate,Germany.Prof.PerGustavsson,MDHeadofUnitofOccupationalMedicineInstituteofEnvironmentalMedicine,KarolinskaInstituteCentreforOccupationalandEnvironmentalMedicine,StockholmCountyCouncilStockholm,SwedenDr.JohnniHansenSeniorScientistDanishCancerSocietyResearchCenterCopenhagen,DenmarkDr.LennartHardell,MD,PhDDepartmentofOncologyUniversityHospitalOrebra,SwedenDr.MichaelHauptmannHead,BiostatisticsBranchNetherlandsCancerInstituteAmsterdam,TheNetherlandsWeiHuang,ScD(HSPH2003)Professor,PekingUnivSchoolofPublicHealthViceDirector,PekingUnivInstituteofEnvironmentalMedicineKeyLabofMolecularCardiovascularResearchMinistryofEducationBeijing,China,100191JamesHuff,PhDFormerly,AssociateDirectorForChemicalCarcinogenesis

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NationalInstituteOfEnvironmentalHealthSciencesResearchTrianglePark,NorthCarolinaUSAProfessorMargaretO.JamesJackC.MasseyProfessorofPharmacy,ProfessorofMedicinalChemistryUniversityofFloridaGainesville,FloridaUSACWJameson,PhDCWJConsulting,LLCRetiredDirectorfortheReportonCarcinogensNationalToxicologyProgram/NationalInstituteofEnvironmentalHealthSciencesNationalInstitutesofHealthCapeCoral,FLUSAProfessorAndreasKortenkampHumanToxicologyInstituteofEnvironment,HealthandSocietiesBrunelUniversityLondonUxbridge,UB83PH,UnitedKingdomProf.Dr.AnnetteKopp-SchneiderHeadofDiv.BiostatisticsGermanCancerResearchCenter69120Heidelberg,GermanyProfessorHansKromhoutChairinExposureAssessmentandOccupationalHygieneChairinEpidemiologyofHealthEffectsofElectromagneticFieldsDivisionofEnvironmentalEpidemiologyInstituteforRiskAssessmentSciencesUtrechtUniversityUtrecht,TheNetherlandsProf.MarceloL.Larramendy,Ph.D.PrincipalResearcherNationalCouncilofScientificandTechnologicalResearch(CONICET)SchoolofNaturalSciencesandMuseumNationalUniversityofLaPlataLaPlata,ArgentinaPhilipJ.Landrigan,MD,MSc,FAAPDeanforGlobalHealthArnholdInstituteforGlobalHealthProfessorofPreventiveMedicine&PediatricsIcahnSchoolofMedicineatMountSinaiNewYork,NY10029USA

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LawrenceH.Lash,Ph.D.ProfessorandAssociateChairDepartmentofPharmacologyWayneStateUniversitySchoolofMedicineDetroit,MI48201USADariuszLeszczynski,PhD,DScAdjunctProfessorDepartmentofBiosciencesDivisionofBiochemistry&BiotechnologyUniversityofHelsinki,FinlandProf.CharlesF.Lynch,MD,PhDDepartmentofEpidemiologyCollegeofPublicHealthUniversityofIowaIowaCity,IA,USAProf.CorradoMagnaniMDProfessorofMedicalStatisticsHeadoftheCancerEpidemiologyUnitUniversityofEasternPiedmontNovara,ItalyDanieleMandrioli,MDAssociateDirectorCesareMaltoniCancerResearchCenterRamazziniInstitute40010,Bentivoglio(Bologna),ItalyFrancisLMartinCentreforBiophotonics,LEC,BailriggLancasterUniversityLancasterLA14YQ,UKDr.RonMelnick,PhDRonMelnickConsulting,LLCRetiredSeniorToxicologistNationalToxicologyProgram/NationalInstituteofEnvironmentalHealthSciencesNationalInstitutesofHealthChapelHill,NCUSADr.EnzoMerler,PhDDirectorRgionalRegistryonMesothelioma,VenetoRegion,ItalyDepartmentofPrevention,OccupationalHealthUnitNationalHealthServicePadua,Italy

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PaolaMichelozziDirectorEnvironmentalEpidemiologyUnitDepartmentofEpidemiologyLazioRegionRome,ItalyDr.LuciaMiligi,SeniorEpidemiologist,OccupationalandEnvironmentalEpidemiologyUnit,ISPO-CancerPreventionandResearchInstitute,Florence,ItalyAnthonyB.Miller,MDProfessorEmeritusDallaLanaSchoolofPublicHealth,UniversityofTorontoToronto,CanadaDr.DarioMirabelliEpidemiologistUnitofCancerEpidemiology,UniversityofTurinandCPO-Piemonte10126TorinoItalyFranklinE.Mirer,PhD,CIHProfessor,EnvironmentalandOccupationalHealthSciencesCityUniversityofNewYorkSchoolofPublicHealthNewYork,NY10035USAMichaelM.Müller,PhDEUROTOXRegisteredToxicologistHeadoftheToxicologicalLaboratoryUnitDepartmentofOccupational,SocialandEnvironmentalMedicineUniversityMedicalCenterGöttingen37073GöttingenGermanyDrSaloshniNaidoo(MBChB,FCPHM,MMed,PHD)ChiefSpecialist/HeadofDisciplinePublicHealthMedicineSchoolofNursingandPublicHealthUniversityofKwaZulu-NatalDurben,SouthAfricaProf.MelissaJ.Perry,ScD,MHS,FACEProfessorandChairofEnvironmentalandOccupationalHealthProfessorofEpidemiologyMilkenInstituteSchoolofPublicHealthProfessorofBiochemistryandMolecularBiologySchoolofMedicineandHealthSciencesTheGeorgeWashingtonUniversityWashington,DC20051USA

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Dr.MariaGraziaPetronioHeadofUnitofHealthandEnvironment-DepartmentofPreventionLocalHealthAuthority-Empoli,Florence,ItalyProfessorofEnvironmentalHygieneSchoolofSpecialization“HygieneandPreventiveMedicineUniversityofPisa,ItalyVice-PresidentforCentralItalyAreaofInternationalSocietyofDoctorsforEnvironment,ItalyDrRobertaPirastuResearcherDepartmentofBiologyandBiotechnology"CharlesDarwin"SapienzaRomeUniversity,ItalyProf.MiquelPorta,MD,MPH,PhDProfessorandSeniorScientist,HospitaldelMarInstituteofMedicalResearch(IMIM)andSchoolofMedicineUniversitatAutònomadeBarcelonaBarcelona,Catalonia,SpainRalphJ.Portier,PhDDistinguishedProfessorofEnvironmentalSciencesDepartmentofEnvironmentalSciences,SchooloftheCoast&EnvironmentLouisianaStateUniversityBatonRouge,LA70803USAKennethSRamos,MD,PhD,PharmBAssociateVicePresidentforPrecisionHealthSciencesProfessorofMedicineDirectorofCenterforAppliedGeneticsandGenomicMedicineUniversityofArizonaHealthSciencesTucsonAZ.85737USALarryW.Robertson,MPH,PhD,ATSProfessorandDirector,IowaSuperfundResearchProgramandtheInterdisciplinaryGraduatePrograminHumanToxicologyTheUniverityofIowaIowaCity,Iowa,USAMartinRöösli,PhDHeadoftheEnvironmentalExposuresandHealthUnitSwissTropicalandPublicHealthInstituteAssociatedInstituteoftheUniversityofBasel4002Basel,SwitzerlandMattK.Ross,PhDAssociateProfessor

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CollegeofVeterinaryMedicineMississippiStateUniversityMississippiState,MS39762USAProf.DeoduttaRoy,MS,M.Phil.,Ph.D.DepartmentofEnvironmentalandOccupationalHealthRobertStempelCollegeofPublicHealthandSocialWorkFloridaInternationalUniversityMiami,FL33199-0001USAIvanRusyn,MD,PhDProfessor,VeterinaryIntegrativeBiosciencesTexasA&MUniversityCollegeStation,TX77843-4458USAPauloSaldiva,MD,PhDProfessorofPathology,FacultyofMedicine,UniversityofSãoPaulo,BrazilCoordinatoroftheNationalInstituteofIntegratedRiskAssessmentNationalResearchCouncil,BrazilJenniferSass,PhDSeniorScientistNaturalResourcesDefenseCouncilandProfessorialLecturer,GeorgeWashingtonUniversityWashington,DCUSAKaiSavolainen,MD,Ph.D.,ResearchProfessorDirector,NanosafetyResearchCentreFinnishInstituteofOccupationalHealthHelsinki,FinlandAssocProf.PaulT.J.Scheepers,PhD,ERTWorkgroupLeaderandHead,ResearchLabMolecularEpidemiologyRadboudInstituteforHealthSciencesRadboudUniversityMedicalCenterNijmegen,TheNetherlandsProf.Dr.ConsolatoSergi,MSc,MD,PhD,FRCPCFullProfessorofPathologyandFullProfessorofPediatrics(Adjunct)UniversityofAlberta,Edmonton,Alberta,CanadaEllenKSilbergeld,PhDProfessor,EnvironmentalHealthSciencesJohnsHopkinsBloombergSchoolofPublicHealthBaltimoreMD21205USAProf.MartynT.SmithSchoolofPublicHealth

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UniversityofCalifornia,BerkeleyBerkeley,CAUSAProf.BernardW.StewartFacultyofMedicine,UniversityofNewSouthWalesHead,CancerControlProgramSouthEastSydneyPublicHealthUnitRandwickNSW2031AustraliaPatriceSutton,MPHResearchScientistUniversityofCalifornia,SanFrancisco,ProgramonReproductiveHealthandtheEnvironmentSanFrancisco,USADr.FabioTateoResearcherIstitutodiGeosceinzeeGeorisorse(CNR)35131Padova,ItalyProf.BenedettoTerraciniProfessorofCancerEpidemiology(retired)UniversityofTorinoTorino,ItalyProf.Dr.med.Dr.rer.nat.HeinzW.ThielmannFormerDivisionHeadattheGermanCancerResearchCenter,HeidelbergRetiredProf.ofBiochemistry,FacultyofPharmacy,HeidelbergUniversityMemberofCommitteeonHealthHazardsofChemicalsoftheDeutscheForschungsgemeinschaftGermanyDavidB.Thomas,MD,DrPHProfEmeritus,SchoolofPublicHealthandCommunityMedicineUniversityofWashingtonandMember,FredHutchinsonCancerResearchCenterSeattle,WA,U.S.A.Prof.HarriVainioProfessorofEnvironmentalandOccupationalHealthDean-ElectFacultyofPublicHealth,KuwaitUniversity,KuwaitKuwaitCity,KuwaitJohnE.Vena,Ph.D.ProfessorandFoundingChairDepartmentofPublicHealthSciencesMedicalUniversityofSouthCarolinaCharlestonSC29425USA

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ProfessorPaoloVineisChairinEnvironmentalEpidemiologyImperialCollegeLondon,UKProfessorElisabeteWeiderpass,M.D.,M.Sc.,Ph.D.Head-DepartmentofResearchHead-GroupofEtiologicalCancerResearchInstituteofPopulationBasedCancerResearchCancerRegistryofNorway,Oslo,NorwayDepartmentofCommunityMedicine,FacultyofHealthSciencesUniversityofTromsø,TheArcticUniversityofNorway,Tromsø,NorwayDepartmentofMedicalEpidemiologyandBiostatisticsKarolinskaInstitutet,Stockholm,SwedenGeneticEpidemiologyGroupFolkhälsanResearchCenter,Helsinki,FinlandDennisD.Weisenburger,M.D.Professor/Chair,DepartmentofPathologyCityofHopeMedicalCenterDuarte,CA91010USAProfessorTraceyJ.Woodruff,PhD,MPHDirectorUniversityofCalifornia,SanFrancisco,ProgramonReproductiveHealthandtheEnvironmentSanFrancisco,USAProf.Dr.rer.nat.IreneWitte(retired)InstituteforBiologyandEnvironmentalSciencesUniversityofOldenburgGermanyDr.TakashiYorifujiAssociateProfessorOkayamaUniversityOkayama,JapanIlJeYu,PhD,ProfessorDirector,InstituteofNanoproductSafetyReserchHoseoUniverstiy,Asan,KoreaDr.PaolaZambonPastDirectorVenetoTumorRegistryUniversityofPaduaPadovaItalyProf.Dr.HajoZeeb

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Head,DepartmentofPreventionandEvaluation,Leibniz-InstituteforPreventionResearchandEpidemiology-BIPSBremen,GermanyProf.Shu-FengZhou,MD,PhDAssociateDeanforInternationalResearchandChairCollegeofPharmacyUniversityofSouthFloridaTampa,Florida,USA

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_______________________________________________________________________________________References1. EuropeanFoodSafetyAuthority,Conclusiononthepeerreviewofthe

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3. IARC.PREAMBLETOTHEIARCMONOGRAPHS2006;Availablefrom:http://monographs.iarc.fr/ENG/Preamble/CurrentPreamble.pdf.

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7. Checkoway,H.,N.Pearce,andD.Kriebel,Researchmethodsinoccupationalepidemiology.2nded.Monographsinepidemiologyandbiostatistics.2004,NewYork:OxfordUniversityPress.xiv,372p.

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9. Schinasi,L.andM.E.Leon,Non-Hodgkinlymphomaandoccupationalexposuretoagriculturalpesticidechemicalgroupsandactiveingredients:asystematicreviewandmeta-analysis.IntJEnvironResPublicHealth,2014.11(4):p.4449-527.

10. DeRoos,A.J.,etal.,Integrativeassessmentofmultiplepesticidesasriskfactorsfornon-Hodgkin'slymphomaamongmen.OccupEnvironMed,2003.60(9):p.E11.

11. Epa,Glyphosate;EPAReg.#524-308;mouseoncogenicitystudy,B.WilliamDykstra.Toxicology,Editor.1985.

12. JCFA,Evaluationofcertainfoodadditivesandcontaminants:Forty-ninthreportoftheJointFAO/WHOExpertCommitteeonFoodAdditives.1999,JointCommitteeonFoodAdditives(includingC.Portier),WorldHealthOrganization/FoodandAgricultureOrganization:Geneva.p.96.

13. Epa,SecondpeerreviewofGlyphosate.1991.p.1-19.14. Epa,Glyphosate-EPARegistrationNo.524-308-2-YearChronic

Feeding/OncogenicityStudyinRatswithTechnicalGlyphosate,I.WilliamDykstra.ToxicologyBranch,Editor.1991.

15. Epa,Glyphosate;2-YearCombinedChronicToxicity/CarcinogenicityStudyinSprague-DawleyRats-ListAPesticideforReregistration,B.WilliamDykstra.Toxicology,Editor.1991.p.1-29.

16. Sugimoto,18-MonthOralOncogenicityStudyinMice.Unpublished,designatedASB2012-11493inBfRRAR,1997.

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17. Unknown,Achronicfeedingstudyofglyphosate(rounduptechnical)inmice.unpublished,designatedABS2012-11491inBfRRAR,2001.

18. Unknown,GlyphosateTechnical:DietaryCarcinogencityStudyintheMouse.Unpublished,designatedABS2012-11492inBfRRAR,2009.

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24. Giknis,M.andC.Clifford,SpontaneousNeoplasticLesionsintheCrI:CD-1(ICR)BRMouse.2000,CharlesRiverLaboratories.

25. Giknis,M.andC.Clifford,SpontaneousNeoplasticLesionsintheCrI:CD-1(ICR)BRMouseinControlGroupsfrom18Monthto2yearStudies.2005,CharlesRiverLaboratories.

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