may 4, 2020 opp docket 1200 pennsylvania ave. nw ... · neonicotinoids continuously stimulate...
TRANSCRIPT
![Page 1: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/1.jpg)
May4,2020
OPPDocketEnvironmentalProtectionAgencyDocketCenter(28221T)1200PennsylvaniaAve.NW.Washington,DC20460-0001RE:CenterforFoodSafety’scommentstoEPAontheProposedInterimRegistrationReviewDecisionsforSeveralNeonicotinoidPesticides:Imidacloprid,Clothianidin,Thiamethoxam,AcetamipridandDinotefuranDocketIDs:EPA-HQ-OPP-2008-0844: ImidaclopridEPA-HQ-OPP-2011-0865: ClothianidinEPA-HQ-OPP-2011-0581: ThiamethoxamEPA-HQ-OPP-2011-0920: DinotefuranEPA-HQ-OPP-2012-0329: AcetamipridCenterforFoodSafetyappreciatestheopportunitytocommentonEPA’sproposedinterimregistrationreviewdecisionsfortheabove-namedneonicotinoidinsecticides.
HUMANHEALTHASSESSMENTCommonMechanismofToxicityDemandsCumulativeRiskAssessmentThesefiveneonicotinoidsoperatebydisruptingneuraltransmissioninthecentralnervoussystemofinvertebrates.Bybindingtonicotinicacetylcholinereceptors(nAChRs)inthebrain,neonicotinoidscontinuouslystimulateneurons,resultingindeathaswellassublethaleffects(Simon-Delsoetal.2015).NeonicotinoidsaremorehighlytoxictoinvertebratesthanvertebratesbecausetheformerhavehavealargernumberofnAChRswithhighaffinitytotheseinsecticides.NeonicotinoidstargetprimarilythenAChRsubtypeα4β2ininsectsandmammals,andmammaliantoxicitycorrelateswithagonistactionandbindingaffinityatthesereceptors,theirprimarytargetinthebrain(TomizawaandCasida2005).Thissharedmechanismoftoxicitydemandscumulativeriskassessmentoftheseneonicotinoids,asrequiredundertheFoodQualityProtectionAct.EPAprovidesnoexplanationforitsfailuretoconductacumulativeassessment,beyondnotingthatithasnotmadeanofficialfindingastothefactthatneonicotinoidsshareacommonmechanismoftoxicitytohumans(e.g.EPAImidacloprid2020,p.17).EPArefusedtomakethisfindingdespiteabundantevidence,eveninregistrant-sponsoredanimalfeedingstudiesconductedforthehumanhealthassessment,thatneurotoxicityisthemostprominentandconsistentclassof
![Page 2: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/2.jpg)
2
adverseeffectsofallfiveneonicotinoids.Forinstance,imidaclopridviaoraladministrationinducestremors,decreasedmotoractivityandsimilareffectsinmultiplestudiesonratsanddogs(EPA6/22/17,p.3).Clothianidininducesdecreasedarousal,motoractivityandacousticstartleresponse;tremors;andotherneurotoxiceffectsinvariousanimalstudies(EPA9/7/17,p.13).Thiamethoxamtriggersdevelopmentalneuorologicaleffectsinrats,includingreducedbrainsizeandweight(EPA12/5/17,pp.5-6).Neurotoxiceffectsinducedbyacetamipridincludedecreasesinlocomotoractivity,alertness,reactivity,spontaneousactivity,rearing,muscletoneandgripstrength;tremors;anddepressedreflexesinrat,mouseand/orrabbitstudies(EPA12/15/17,pp.17-18).Dinotefuranlikewiseinduceddeclinesinmotoractivity,gripstrength,andbrainweightinanimalstudies(EPA9/12/17,p.5).EPArefusestoofficiallyaffirmacommonmechanismofhumantoxicitybetweenanyoftheseneonicotinoidsdespiteacknowledgingthefact.EPAstatesthatneurotoxicityisamongtheclassesofadverseeffects“commonlyobservedinmammaliantoxicitystudiesofneonicotinoids”(EPA9/7/17,p.12).Stillmoreexplicitly,EPAaffirmsthatneonicotinoidshaveaneurotoxicmodeofactionbothforinsectpestsandhumans:“Dinotefuranisaneonicotinoidandhasapesticidalandmammalianneurotoxicmodeofaction.Consistentwiththismodeofaction,changesinmotoractivitywereseeninacuteneurotoxicity(ACN)andsubchronicneurotoxicity(SCN)studies”(EPA9/12/17,p.20).EPAalsonotesthatdinotefuraninduced“changesinmotoractivitywhichareconsistentwitheffectsonthenicotiniccholinergicnervoussystem[nicotinylacetylcholinereceptors,asnotedabove]seenafterrepeatdosing”(EPA9/12/17,p.5).Fourofthefiveneonicotinoidsbelongtoacommonsubclass–thenitroguanidines–whilethefifth,acetamiprid,isacloselyrelatedcyanoamidine-substitutedneonicotinoid(TomizawaandCasida2005,Figure1).EPA“madeaprogrammaticdecisiontoaligntheregistrationreviewscheduleforallfournitroguanidine-substitutedneonicotinoids(clothianidin,dinotefuran,imidaclopridandthiamethoxam)”(EPA1/16/20),andsubsequentlyaddedacetamipridtothegroup.Thisdecisionmakesnosenseif,asEPAtacitlyassumes,entirelyseparateriskassessmentsforeachofthemisadequatetothetaskofensuringhumanandenvironmentalsafety.Independentscientistshaveassessedcumulativedietaryexposuretoneonicotinoidsonthebasisoftheircommonmechanismoftoxicity,employingrelativepotencyfactorstopermitexpressionofthecumulativetoxicityinimidacloprid-equivalentunits(Luetal.2018;Zhangetal.2019).EPAhasusedthismethodtoassessthetoxicityofrelatedgroupsofcompounds,suchasdioxins(Staskaletal.2010).Becausecumulativeexposuretoneonicotinoidswouldbeconsiderablyhigherthanexposuretoanysinglecompoundofitsclass,EPAhasunderestimatedbothhumanexposuretoandthehealthrisksofneonicotinoids.Totakeoneexample,EPA’sestimateddietaryexposuretoimidaclopridaloneisnearlyequaltotheacutesafetythreshold(population-adjusteddose,oraPAD)forinfants(84%)andtoddlers(93%)(EPA6/22/17,p.23,Table5.4.4).Cumulativeexposuretoallfiveneonicotinoidswouldalmostcertainlyexceedtheacutesafetythresholdforthesevulnerablegroups.EPAshouldabstainfromanyfinalregistrationreviewdecisionuntilithascompletedathoroughcumulativeriskassessmentofneonicotinoids.
![Page 3: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/3.jpg)
3
SafetyFactortoProtectInfantsandChildrenEPAisrequiredbytheFoodQualityProtectionAct(FQPA)toapply“anadditionaltenfoldmarginofsafety”toaccountfor“thespecialsusceptibilityofinfantsandchildren,”andinparticularthe“potentialforpre-andpostnataltoxicity…,”andreduceoreliminateitonlyif“reliabledata”demonstrateitisnotneeded.AccordingtoEPApolicy,the10xFQPAsafetyfactoristobeappliedwhentheyoungexhibitincreasedsusceptibilitytoapesticide(i.e.effectsnotseeninadultanimals)orincreasedsensitivity(theeffectsoccuratlowerdosesorincreasedseverityintheyoung)(FQPA2002,p.30).Basedpurelyonregistrantstudies,EPAfoundincreasedsusceptibilityorsensitivitytoneurotoxicharmsinyoungtestanimalsversusadultanimalsforfourofthefiveneonicotinoidsatissuehere:imidacloprid(“evidenceofanincreasedquantitativesusceptility”intherat,”EPA6/22/17,p.14);clothianidin(same,EPA9/7/17,p.13);thiamethoxam(same,EPA12/5/17,p.6);andacetamiprid(“increasedqualitativesusceptibility,”EPA12/15/17,p.17-18).Despitethesefindings,theclearmandateoftheFoodQualityProtectionAct,andEPA’spolicyprescriptionsregardingimplementationoftheFQPA,EPArejectedthedefault10xsafetyfactorforallfiveneonicotinoids.EPAshouldabstainfromanyfinalregistrationreviewdecisionuntilithascorrectlyappliedtheFQPA10xsafetyfactortoarriveatreferencedosesthatreflecttheincreasedtoxicityoftheseinsecticidestotheyoung.IndependentStudiesRevealGreaterMammalianSensitivitytoNeonicotinoidsThanRegistrantStudiesKaraetal.(2015)administeredviagavage0.5,2or8mg/kg/dayimidaclopridtoinfantandadultWistarratsfor3months.Learningactivitieswerediminishedsignificantlyat2and8mg/kg/daydosesininfantrats,butonlyat8mg/kg/dayinadultrats.Thisstudy’sNOAELforinfantratsof0.5mg/kg/dayis16-foldlowerthanthe8.0mg/kg/dayNOAEL(acuteandchronic)basedonasubchronicdogstudyconductedbyBayerAGin1990.1Thisstudysupportsanoralreferencedoseof0.005mg/kg/day(vs.EPA’s0.08mg/kg/day),andalsoprovidesfurthersupportforretainingthe10xFQPAsafetyfactor,giventhegreatersensitivityofinfantvs.adultrats.Burkeetal.(2018)infused0.5mg/kg/dayimidaclopridintopregnantCD-1miceviaanimplantedosmoticminipumpfromgestationday(GD)4topost-natal(PN)day21.Imidaclopridaccumulatedinliversandbrainsofmaternalmice,andwasfoundintracelevelsinoffspring.Offspringexhibitedanumberofneurobehavioralimpacts:elevatedmotoractivity,enhanced
1RufJ.1990.NTN33893Technical:SubchronicToxicityStudyonDogsinOralAdministration(Thirteen-WeekFeedingStudy).LabProjectNumber:18732:100176.UnpublishedstudypreparedbyBayerAG.305p.MRID42256328.
![Page 4: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/4.jpg)
4
socialdominance,reduceddepressivebehavior,andadiminutioninsocialaggressioncomparedtocontrols.Adultmaleoffspringhadreducedweight.Maternalanimalshadsignificantlyreducedfecundity(roughly8vs.13pupspermotherfortreatmentvs.controlgroups).Transientexposuretoimidaclopridoverthedevelopmentalperiodinducedlong-lastingchangesinbehaviorandbrainfunctioninmice.BasedonBurkeetal.(2018),theLOAELforimidaclopridis0.5mg/kg/day.ThisstudyalsosupportsapplicationoftheFQPA10xsafetyfactory.
ENVIRONMENTALASSESSMENTCumulativeToxicityAswithhumanhealth,EPAmustassessneonicotinoidscumulatively,inviewoftheircommonmechanismoftoxicitytoinsectsandothernon-targetorganisms(Xerces2016),andtheirfrequentco-occurrence(e.g.Krupkeetal.2012).Maloneyetal.(2018)reportedroughlyconcentration-additivetoxicityofvariousneonicotinoidmixturestotheaquaticinsectChironomusdilutus,withmildsynergismforthiamethoxam-imidacloprid.EPAmustalsoassesstheadditiveorsynergistictoxicityofneonicotinoidstogetherwithco-occurringformulationadditivesadotherpesticides(Xerces2016).Togiveanideaofthescopeoftheproblem,Sanchez-BayoandGoka(2014)reportthatinvariousstudies,atotalof161pesticideshavebeenfoundinbeehives:124inpollen,95inwaxand77inhoneyornectar.Forinstance,neonicotinoidsarestronglysynergizedbyinhibitorsofCPY450detoxificationenzymes,suchaspiperonylbutoxide,acommon“inertingredient”inover2,500pesticideformulations(TomizawaandCasida2005;Crossetal.2017).Imidaclopridexhibitssynergyinconcertwiththeadjuvantnonylphenylpolyethoxylate,R-11,towardsthecrustaceanCeriodaphniadubia(Chenetal.2010).Awiderangeofotherformulationadditivesandsurfactants,suchasorganosiliconesurfactants,makepesticidesmoretoxicandcanalsobetoxicintheirownrights(Mullin2015,Chenetal.2018).Thisisproblematic,becauseregulatorytoxicitytestsontheactiveingredientalonewilloftenunderestimatereal-worldformulationtoxicity.Forthisreason,Zhuetal.(2017)testedthetoxicitytohoneybeeoftheimidaclopridformulationAdvise2FLinbinarycombinationswithsevenotherpesticidestheycommonlyencounter,andfoundsynergistictoxicitybetweenimidacloprid/AdviseandDomark/tetraconazole,Transform/sulfoxaflor,andVydate/oxamyl,withmortalitysignificantlyincreasedby20%,15%and26%,respectively.Tsevtkovetal.(2017)foundthatbothclothianidinandthiamethoxamweretwiceasacutelytoxictohoneybeeworkerswithco-exposuretofield-realisticlevelsofthefungicideboscalid.Neonicotinoidshavefrequentlybeenfoundtosynergizewithergosterolbiosynthesisinhibitor(EIB)fungicides(reviewedinWoodandGoulson2017).Thompsonetal.(2014)exposedhoneybeestosprayedfungicidesatrealistic,worst-casescenarioconcentrationsandvariousneonicotinoids.Theyfoundmildsynergismonacontactbasisbetweenthiamethoxamandtebuconazole(synergismratioof2.6)andonanoralbasisbetweenclothianidinandtebuconazole(synergismratioof1.9),withsynergismratioequivalenttotheLD50ofthe
![Page 5: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/5.jpg)
5
neonicotinoiddividedbythatoftheneonicotinoidsplusfungicidemixture.Similarly,Sgolastraetal.(2016)foundsynergisminthreebeespecies(A.millifera[honeybee],B.terrestris[bufftailedbumble]andO.bicornis[redmasonbee])exposedtoLD10dosesofclothinadinandanon-lethaldoseofthefungicidepropiconazole,intheformofincreasedmortalityforthemixture.Thesearejustafewofmanystudiesthathavearrivedatsimilarfindings,thoughbecausemostassessonlybinarymixturesandpollinatorsareexposedtofarmorecomplexcombinationsofmultiplepesticides,thereportedresultsarelikelytosubstantiallyunderestimatethedegreetowhichneonicotinoidsaresynergizedbyco-exposuretootherpesticides.YetEPAmakesnoattempttoassesstheincreasedrisksposedbyneonicotinoidsuponco-exposurewithotherpesticides.DeclinesinInsectPopulationsWorldwideCoincidewithRiseofNeonicotinoidsMassivedeclinesininsectandpollinatorpopulationsworldwideTherehavebeenmanyreportsofdeclinesinvariousinsectspeciesovertheyears(Dirzoetal.2014),forinstancetheover80%reductioninthemigratorymonarchbutterflypopulationssincethemid-1990sinNorthAmerica(Pleasants2015).However,recentlytherehasbeengreatinterestinchartingtrendsinoverallinsectabundanceasamorerelevantmarkerofecosystemhealth.Forinstance,researchersinGerrmanydocumentedanastounding76%declineinflyinginsectbiomassin63Germannaturereservesfrom1989to2016(Hallmannetal.2017).Theypositagriculturalintensification,includingpesticideuse,asonepotentialcause,notingthatmostofthepreservesaresurroundedbycroplandthatmayserveasanecologicaltrapsorsinksforinsectswhoseoriginsareinthenaturalareas.Sanchez-BayoandWyckhuys(2019)review73historicalreportsofinsectdeclinesaroundtheworld,andfindthatLepidoptera(mothsandbutterflies),Hymenoptera(beesandwasps)anddungbeetleshavebeenmostimpactedamongterrestrialinsects.Theypredictextinctionof40%ofremaininginsectspeciesinthenextfewdecades,andregardhabitatlosstoagricultureandurbanizationaswellaspollution,particularlyfrompesticidesandfertilizers,asmajordrivers.Arecentmeta-analysisofstudiesacrosstheworldfindsaroughly9%reductioninterrestrialinsectabundanceperdecade,atrenddrivenlargelybyfindingsinNorthAmericaandpartsofEurope(vanKlinketal.2020).RiseininsecticidaltoxicityduetoneonicotinoidseedtreatmentsIntheU.S.,thetoxicityofinsecticideuseinagriculturehasincreaseddramaticallyoverthepasttwodecades.Researchersfoundthatinsecttoxicload–ametricthatadjuststheamountofinsecticidesusedbytheiracutepotencytohoneybees–hasincreasednine-foldonanoralbasissincejust1997(Douglasetal.2020).Themaindriverofthistrendistheseedindustry’smassivedeploymentofneonicotinoidseedcoatingsontheseedoffieldcrops(e.g.cornandsoybeans)thathadpreviouslynotbeenextensivelytreatedwithinsecticidesofanysort(DouglasandTooker2015).Becauseoftheirextremelyhighpotencyaswellasextentofusage,by2012neonicotinoidsalonecomprised98%oforalinsecttoxicload,equivalentto16billionhoneybeeoralLD50dosespertreatedhectare(Douglasetal.2020).ThemostdramaticincreasesoccurredintheHeartland(121-foldincrease)andtheNorthernGreatPlains(53-foldincrease),wherethemajorityofcornandsoybeans,nearlyall(corn)oraregrown(Ibid.).
![Page 6: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/6.jpg)
6
Whileneonicotinoidsaredeployedasfoliarandsoil-appliedsprays,seedtreatmentsemployingimidacloprid,clothianidinorthiamethoxamcompriseroughlythree-fourthsoftotalagriculturaluseofthefiveneonicotinoidcompoundsonaweightbasis.ThisisbasedonEPA’sscreeninglevelusageanalysesforeachofthefive:3millionlbs.seedtreatmentvs.justover1millionlbs.forfoliarandsoil-appliedsprays,annually,thoughthisisasubstantialunderestimatethanksinparttolackofdataonseedtreatmentssince2015.2YetEPAhasenactedlittleifanymitigationforthispredominantuseofneonicotinoids.NeonicotinoidExposureRoutesNeonicotinoiddustfromtreatedseedskillshoneybeesandotherinsectsSeedstreatedwithneonicotinoids(clothianidin,thiamethoxamorimidacloprid)andotherpesticides(oftenfungicides)cansticktogether,causingunevenplantspacing.Talcorsomeotherlubricantisaddedtoseedboxestoreducefrictionandensurethesmoothflowofseedduringplanting.Someportionoftheseedcoatingisabradedintheseedboxandcontaminatesthetalcwithhighlevelsoftheneonicotinoid.Thetalcisexpelledeitherwiththeseedorbehindtheplanterviaexhaustfan(Krupkeetal.2012).Thisseeddust,broadcastacrossthelandscape,hasbeenimplicatedinnumerousbeemortalityeventssince1999inItaly,France,Slovenia,GermanandCanadaaswellastheU.S.:“[i]nallcases,agreatnumberofdeadanddyingbeeswerefoundnearthehiveentrance”(Bonmatinetal.2015).Onestudyexaminedthethreatofneonicotinoid-lacedseeddusttohoneybeesinIndiana,andfoundthatover94%ofhoneybeeforagersintheStateofIndianaareatriskofexposuretovaryinglevelsofneonicotinoidinsecticides,includinginsomecaseslethallevelsduringtheplantingofcorn.Theyalsofoundthatdepositionofneonicotinoidresiduesonnon-targetlandsandwaterwaysoccursonover42%ofthestateofIndiana,andthatriskstopollinatorscouldbedramaticallyreduced,withnoyieldloss,bylimitinguseofseedtreatmentstosituationswheretheyareactuallyneeded(Krupkeetal.2017).EPAhasnotproposedanymitigationtoaddresslethalorsublethalexposuretoneonicotinoid-lacedseeddust.OtherexposureroutesAmajorpathwayofpollinatorexposuretoneonicotinoidsisthepollenandnectarofcropsfromtreatedseed.Inareviewof20studies,Godfrayetal.(2014)estimateaveragemaximumlevelsofneonicotinoidsof1.9ppbinthenectarof6.1ppbinthepollenofseed-treatedcrops,valuesinlinewiththosefoundinanupdatetothatreview(Godfrayetal.2015).WoodandGoulson(2017)reportexpectedresiduesinseveralcrops(corn,sunflower,rape,cotton)ascalculatedby2First,theseedtreatmentfiguresforeachrelevantcropthatcomprisethetotalarelong-termaverages(e.g.2005to2013forthiamethoxam,EPA1/26/16),andtheaveragesunderstateusagebecausetheproportionofcropseed,andinthecaseofcorntherateapplied,haveincreasedsteadilyoverthatperiod(DouglasandTooker2015).Second,theprivatesectorfirmthatEPAreliesuponforseedtreatmentusagedatastoppedcollectingitafter2014;andusageofneonicotinoidswastrendingsteadilyupwardforallmajorcrops(corn,soybeans,cottonandwheat)upuntilthattime,andthankstoinactiononthepartofEPAhasalmostcertainlycontinuedtoincreasesincethen(Hitajetal.2020).
![Page 7: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/7.jpg)
7
theEuropeanFoodSafetyAuthoritybasedonoutdoorstudiesandseedtreatmentratesauthorizedintheEuropesnUnion.Maximumexpectedresiduesinpollenrangedupto37ppmincorn(clothianidin);19ppminoilseedrape(clothianidinandthiamethoxam);and4ppminsunflower(imidacloprid).SeeTable1below.Guttationdroplets(smallwaterdropletsexudedbyplants)oftreatedplantscontainfourtofiveordersofmagnitude(10,000to100,000times)higherneonicotinoidconcentrationsthanthosefoundinnector(Girolamietal.2009,WoodandGoulson2017).Whilethepotentialforexposure(pollinatorvisitationofguttationdroplets)isuncertain,ahoneybeewouldonlyneedtoconsume0.005ultoreceiveanLD50dose(WoodandGoulson2017).Thus,eveninfrequentvisitationcouldcauseconsiderableharm.Neonicotinoidsarerelativelypersistentinsoil,andtheplantingofmanyfieldseveryyeartotreatedseeds(e.g.asinthecommoncorn-soybeanintheU.S.,withtreatedseedcomprisingamajorityofeachcrop)ensuresacontinualpresenceinsoil(e.g.Xuetal.2016).Variousstudiesfindsingledigitto50ppbconcentrationsofimidacloprid,clothianidinand/orthiamethoxamincropfields,withdetectionseveninfieldsthathadnotreceivedanytreatmentinthepreviousthreeyears(reviewedinWoodandGoulson2017).EPAdoesnotpaysufficientconsiderationtothisexposurepathway,inpartbecauseitisoflessersignificanceforhoneybees,thesurrogateforterrestrialinvertebratesinEPA’secotoxicityregulatoryscheme.Yetsoilcontactand/oringestionisanimportantexposurepathwayforground-nestingbumblebeesandmanyotherterrestrialinvertebratesthatresideinthesoil.
Source:WoodandGoulson(2017).Neonicotinoidshavealsobeendetectedinthetissuesofoff-fieldwildplants.Forinstance,Krupkeetal.(2012)foundthiamethoxam(upto2.9ppb)andclothianidin(upto9.4ppb)indandelionsnearatreatedcornseedfield,whilePecenkaandLundgren(2015)foundclothianidinintheleavesofmilkweedplantsadjacenttotreatedcornfields.InafieldstudyconductedintheU.K.,Botíasetal.(2015)placedhoneybeecoloniesnearoilseedrapeandwheatfieldsthatoriginatedfromtreatedseed.BasedonpollencollectedinJuneandAugustfromhoneybeeforagersreturningtothehives,97%ofthetotalneonicotinoidspresentinpollenwereofwildflowerorigin,fromplantsgrowinginhedgesalongthefieldmargins.
et al. (2014) reviewed 20 published studies to calculate anarithmetic mean maximum level of 1.9 ppb for nectar and6.1 ppb for pollen in treated crops, in line with the EFSAfindings.
Since 2014, a number of studies have been publishedwhich report neonicotinoid concentrations in the pollen andnectar of neonicotinoid-treated flowering crops. These resultshave been approximately in line with the concentrations re-ported by EFSA and Godfray et al. In oilseed rape treated withthiamethoxam, Botías et al. (2015) found average concentra-tions of 3.26 ng/g of thiamethoxam, 2.27 ng/g of clothianidinand 1.68 ng/g of thiacloprid in the pollen. Oilseed rape nectarcontained similar average concentrations of 3.20 ng/g ofthiamethoxam, 2.18 ng/g of clothianidin and 0.26 ng/g ofthiacloprid. Xu et al. (2016) found average levels ofclothianidin in oilseed rape of 0.6 ng/g. No pollen sampleswere taken. In maize pollen, Stewart et al. (2014) found
average thiamethoxam and clothianidin levels between thelimit of detection (LOD) of 1 to 5.9 ng/g across a range ofseed treatments. Xu et al. (2016) found average clothianidinconcentration of 1.8 ng/g in maize pollen. Additionally,Stewart et al. (2014) found no neonicotinoid residues in soy-bean flowers or cotton nectar.
Several studies published since 2013 have used free flyingbees to experimentally demonstrate that proximity to treatedflowering crops increases their exposure to neonicotinoids(Table 2). Using honeybees, neonicotinoid concentrations inpollen taken from foragers returning to nests placed next tountreated flowering crops ranged from0 to0.24ng/g comparedto pollen from nests next to treated flowering crops whichranged from 0.84 to 13.9 ng/g. There have been fewer studiesofbumblebees, andhence, the samplesize ismuchsmaller,withconcentrations of neonicotinoids in pollen fromuntreated areasranging from <0.1 to <0.3 ng/g compared to 0.4–0.88 ng/g for
Table 1 Summary of expectedresidues in pollen and nectar ofvarious neonicotinoid-treatedflowering crops calculated byEFSA from the review of outdoorfield trials
Crop Pesticide Application rates(g a.s./ha)
Residues in pollen (ng/g) Residues in nectar (ng/g)
Minimum Maximum Minimum Maximum
Oilseed rape Clothianidin 25–80 5.95 19.04 5 16
Sunflower Clothianidin 27 3.29 0.324
Maize Clothianidin 25–125 7.38 36.88 n/a n/aOilseed rape Imidacloprid 10–52.5 1.56 8.19 1.59 8.35
Sunflower Imidacloprid 24–35 3.9 1.9
Maize Imidacloprid 54–268 3.02 15.01 n/a n/aCotton Imidacloprid 75–100 3.45 4.6 3.45 4.6
Oilseed rape Thiamethoxam 8–33.6 4.592 19.29 0.648 2.72
Sunflower Thiamethoxam 16.4–20.8 2.378 3.02 0.59 0.75
Maize Thiamethoxam 63–101 13.419 21.513 n/a n/a
No nectar values are available for maize as this plant does not produce nectar. Blanks are where no minimumvalues were stated
Fig. 2 Number of studiespublished in scientific journals onneonicotinoids in each year.Opencircles, Bneonicotinoid*^; filleddiamonds, Bneonictotinoid* +bee*^; filled circle,Bneonicotinoid* + residue^; opentriangle, Bneonicotinoid* +water^; filled triangle,Bneonicotinoid* + soil^. Datafrom Web of Science
Environ Sci Pollut Res (2017) 24:17285–17325 17287
![Page 8: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/8.jpg)
8
Remarkably,directmeasurementsoftheneonicotinoidcontentofpollenandnectarofthesewildflowersshowedconcentrationsofthesameorderasandevengreaterthanthatfoundintreatedcropspollenandnectar.Indeed,othershavemadesimilarfindings.Inareviewofstudiespublishedsince2013,WoodandGoulson(2017)found:
“…averagelevelsofneonicotinoidsinwildplantsrangefrom1.0to7.2ng/ginwholeflowersamples,0.4to13.5ng/ginfoliagesamples,<0.1to1.5ng/ginnectarsamplesand<0.04to14.8ng/ginpollensamples.Duetothelimitednumberofstudiesavailable,itisdifficulttomakeacomparisonwithlevelsindirectlytreatedcropplants.However,theyarebroadlycomparabletothelevelsfoundinthetreatedcropitself.”
Neonicotinoidsarehighlywater-solubleandarealsofrequentlyfoundinwaterbodies,anotheravenueofexposuretotheselong-livedcompounds(Morrisseyetal.2015,Bonmatinetal.2015,WoodandGoulson2017).NeonicotinoidEffectsonPollinatorsAmajorweaknessofEPA’sassessmentisthefailuretoevaluatethesublethaleffectsofneonicotinoidsandtheirinteractionswithotherfactorssuchasdiseaseandpestpressure.ImpactsongrowthandreproductionWhitehornetal.(2012)simulatedexposureofbumblebeecoloniestoconcentrationsofimidaclopridinpollenandsugarwaterrealisticforseedtreatmentuseofthisneonicotinoid,andfoundsignificantlyreducedgrowthrateinthecoloniesandan85%reductionintheproductionofnewqueenscomparedtocontrols.Laycocketal.(2012)foundthatqueenlessmicrocoloniesofworkerbumblebeessubjectedtoarangeofimidaclopriddosesdeliveredinsugarsyrupexhibitedadose-dependentdeclineinfecundity,withrealisticdosesintherangeof1ppbreducingbroodproductionbyathird.Williamsetal.(2015)foundthatexposureofhoneybeequeenstofield-realisticconcentrationsofneonicotinoids(bee-collectedpollensupplementsspikedwith3ppbthiomethoxam+1ppbclothianidin)duringdevelopmentresultedincomprisedovariesandreducedqueensuccess.Tsetkovetal.(2017)quantifiedthedurationandmagnitudeofexposuretoneonicotinoidsoverfourmonthsinCanada’scorn-growingregion,andthenconductedrealisticexperimentsinwhichhoneybeecolonieswereexposedtoclothianidininanartificialpollensupplementwiththeconcentrationtimecoursematchingthatpreviouslyobserved.Theyfoundincreasedworkermortality,declinesinsocialimmunity(reducedhygienicbehavior)andincreasedqueenlessovertime.James(2019)foundthatmonarchadultsfeedafieldrealisticrateofimidaclopridfor22dayssufferednearly80%mortalitybyday22,comparedto20%inuntreatedcontrols.WeakenedimmunityThereisalargeandgrowingliteraturedemonstratingthatneonicotinoidexposureweakenspollinators’defensesagainstdiseasepathogensandpests.Alauxetal.(2010)foundthathoneybeesexposedtoimidaclopridandtheparasiticmicrosporidiaNosemasufferedhighermortalityandenergeticstressthanuntreatedbeesorthoseexposedtoonlyimidacloprid(IMI)orNosema.TheyalsofoundthattheIMI-Nosemagrouphadsignificantlyreducedglucose
![Page 9: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/9.jpg)
9
oxidaseactivity,whichenablesbeestosterilizecolonyandbroodfood,andhypothesizethatIMIandNosemasynergizetorenderhoneybeecoloniesmoresusceptibletoinfectionbypathogens.Pettisetal.(2012)exposedhoneybeecoloniesoverthreebroodgenerationstosublethaldosesofimidacloprid,thenchallengedwithNosema,whichproducedsignificantlyincreasedinfectionsversuscontrolsnotexposedtoimidacloprid.
“Thefindingthatindividualbeeswithundetectablelevelsofthetargetpesticide,afterbeingrearedinasub-lethalpesticideenvironmentwithinthecolony,hadhigherNosemainfectionsissignificant.Interactionsbetweenpesticidesandpathogenscouldbeamajorcontributortoincreasedmortalityofhoneybeecolonies,includingcolonycollapsedisorder,andotherpollinatordeclinesworldwide.”
Neonicotinoidexposurehasalsobeenassociatedwithincreasedsusceptibilitytoviraldisease.Forinstance,DiPriscoetal.(2013)foundthatclothianidinnegativelymodulatesNF-xBimmunesignalingininsectsandadverselyaffectshoneybeeantiviraldefensescontrolledbythistranscriptionfactor.ClothianidinenhancesthetranscriptionofageneencodingaproteinthatinhibitsactivationofNF-xB.Imidaclopridwasalsofoundtohavethiseffect.Theantiviralsuppressionledtoproliferationofdwarfwingvirus.
“Collectively,ourdatademonstratethattwoneonicotinoidinsecticides,eachrepresentingoneoftwoalternativestructuretypesinthegroupofnitroguanidines,activelypromoteDWV[dwarfwingvirus]replication.”
ArecentstudyonhoneybeescollectedfromawinterapiaryinFrancetestedtheeffectsofco-exposuretothiamethoxamandthechronicbeeparalysisvirus(CBPV).Theresearchersfoundthatco-exposuredidnotaffectbeesurvivalortheirabilitytometabolizethethiamethoxamtoclothianidin;howevertheyfoundthatco-exposureincreasedCBPVloads,whichreachedlevelsusuallyfoundinovertinfections,andwasassociatedwithdown-regulationofvitellogeninanddorsal-1agenetranscription,bothofwhichareinvolvedinimmunesystempathways.Sanchez-Bayoetal.(2016)reviewadditionalstudiesonthesubjectofneonicotinoidexposureandbeediseases.Thereisalsoevidencethatneonicotinoidsweakenplantdefenses,forinstancetospidermites,bysuppressingtheexpressionofplantdefensecompoundsandalteringthelevelsofphytohormonesinvolvedinplantdefenseincotton,cornandtomato(Szczepaniecetal.2013).OthersublethaleffectsNeonicotinoidexposurehasalsobeenassociatedwithimpairedlearning,memoryandforagingbehaviorsinvariousbeespecies,sublethaleffectsthatarelikelycontributingtobeedeclines(reviewedinWoodandGoulson2017;Godfrayetal.2014,2015).Foroneofmanyexamples,Tosietal.(2017)foundthatanacute,sublethaldoseofthiamethoxam(1.34ng/bee)triggeredexcitationandsignificantlyincreasedflightdurationamongforagers,whilechronicexposurereducedflightduration,distanceandvelocity.
![Page 10: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/10.jpg)
10
NeonicotinoidEffectsonOtherInvertebratesDouglasetal.(2015)foundthatslugsfeedingonneonicotinoid-treatedsoybeanseeds/seedlingsaccumulatedneonicotinoidsintheirtissues;andthatgroundbeetlesattackingtheseneonic-lacedslugsexperiencednervoussystemimpairment,withsubstantialmortality.Theyalsoshowedthatneonicotinoidssuppressedslugpredationbygroundbeetles,andwasassociatedwithasignificantyieldlossrelativetoanuntreatedsoybeanfieldcontrol.Similarly,Szczepaniecetal.(2011)foundthatapplicationofimidaclopridtoelmtreescausedanoutbreakofspidermites,aneffectmediatedbyareductioninthedensityofthemites’predatorsduetoimidacloprid-inducedmortality.Suchtritrophicimpactsofneonicotinoidusecouldwellbequitecommon,yetaremissedentirelybyEPA’sregulatoryguidelinetests.Douglasetal.(2015)alsodetectedneonicotinoidconcentrationsof54and279ppbintwoearthwormsfromathiamethoxam-treatedsoybeanfield.Whilenotevidentlyaffectedthemselves,earthwormpredatorsmighttakeupneonicotinoidresidueswiththeirprey,withpotentialadverseeffects.NeonicotinoidimpactsonvertebratesNeonicotinoidsposeasevereacuteriskofmortalitytobirdswhichconsumetreatedseeds.EPAnotesthat:
“Thehighestriskwasidentifiedforsmallsizebirdswhichwouldneedtoconsumelessthanasingletreatedsorghumandwheatseedtoexceedtheacutelevelofconcern,whilewithsmallormediumsizebirdsconsumingcotton,sorghum,andwheatseed,abirdwouldonlyneedtoconsume1-4seeds[two(cotton)orfour(sorghumandwheat)]toexceedtheacutelevelofconcern.”(EPAPIRRDImidacloprid,p.23).
Insecticidessotoxicthatconsumptionofjustoneorseveraltreatedseedsissufficienttokillobviouslyhavenoplaceinagriculture.Birdsmayalsobeatriskthroughconsumptionofneonicotinoid-containingprey,suchasslugsorearthworms.Sublethaleffectsmustalsobeconsidered.Engetal.(2017)foundthatmigratorywhite-crownedsparrowsexposedtosublethaldosesofimidaclopridsufferedsignificantdeclinesinbodyfatandmass,andfailedtoorientproperly.Afollow-upexperimentonthesamespeciesrevealedsimilarimidacloprideffects:reducedfoodconsumption,mass,fatandalteredlikelihoodofdeparturewhenexposedatamigratorystopover(Engetal.2019).ArecentstudyfoundthattheecholocationsystemofInsectivorousbatsmightbeimpairedbyexposuretoimidacloprid(Wuetal.2019).Endocrine-disruptingpotentialofneonicotinoidsEPAhasnotyetmadeanyfindingsregardingtheendocrinedisruptionpotentialofthesefiveneonicotinoids.Beforemakinganydeterminations,EPAshouldconsultindependentstudiesonthesubject.Forinstance,threerecentstudiessuggestimidaclopridisanendocrinedisruptor,withimplicationsforbothhumanhealthandwildlife(Yuanetal.2020,Mikolicetal.2018,PandeyandMohanty2015).
![Page 11: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/11.jpg)
11
COSTSANDBENEFITSOFNEONICOTINOIDUSEEPAasusualsconductsa“benefits”ratherthana“cost-benefit”assessmentofneonicotinoids.Examplesofcostsnotaccountedforarethesoybeanyieldreductionsattributabletopredationoftreatedsoybeanseedlingsbyslugs,whosepopulationsincreasethankstoreleasefromcontrolbygroundbeetles,whicharepoisonedwhentheyattempttoattackthem(Douglasetal.2015).Growingresistancetoneonicotinoidsinthripsandotherinsectsispredictable,giventheirprophylacticuse,everyyear,acrosshundredsofmillionsofacresofcropland,andisalreadyleadingtoadramaticincreaseininsecticideuseincotton(Husethetal.2018).EPAfailstoaccountforthefollow-oncostsofthisresistance,bothincreasedexpendituresoninsecticidesandenvironmentalharms,whichareadirectresultoftheAgency’sblanketapprovalsforvirtuallyunlimitedseedtreatmentuseofneonicotinoidinsecticides.EPAalsocounts“benefits”insituationswhereitfailstoconsiderlesschemical-intensiveandmorebeneficialalternatives.Forinstance,abeneficialfungus,Hirsutellacitriformis,naturallyinfestsandkillsthepsyllidvector;evenbetter,thedeadpysllidsremainoncitrusleavesforextendedperiods,spreadingthefungustootherpsyllids(O’Brian2013).AnotherpromisingbiocontrolpredatorisTamarixiaradiata,aparasiticwaspthatspecializesinkillingpsyllids(Lopez2013).Forbothfungusandwasp,pesticideuseforotherpurposesisanobstacletotheireffectiveness.Anotherneonicotinoiduseisforcontroloftheglass-wingedsharpshooter,aninsectthatpiercesplantsandfeedsontheirxylemfluids,butwhichalsovectorsaplantpathogenicbacterium,Xylellafastidiosa,thatinfestsgrapesandothervaluablecropsinCalifornia.Biocontroloptionsalsoexistforthispest,butwilllikelynotbepursueddiligentlyaslongasthereistheeasyoptionofneonicotinoidapplication(Irvinundated).Thisfailuretodevelopbiocontrolsolutionsisaclearcostoftheneonicotinoidregistrations.Ontheotherhand,thepredominantseedtreatmentuseofneonicotinoidsprovidelittleornobenefitintermsofyield.EPAitselfcametothisconclusionforsoybeans(EPA10/15/14),whichwasrecentlyconfirmedbyalonglistofagronomistsfromuniversitiesacrossthecountry(Mourtzinisetal.2019).AstudyinIndianafoundthesame“noyieldbenefit”ofneonicotinoidseedtreatmentsforcorn(Krupkeetal.2017).
OTHERREGULATORSSEEANDACTONRISKSTHATEPADISCOUNTSCanada’sPestManagementRegulatoryAgency(PMRA)–hardlyanenemyofpesticideuse–hasworkedjointlywithEPAonassessingneonicotinoids(EPA1/6/16).OnthebasisofmuchthesameevidenceasEPA,PMRAdecidedtherisksweretoogreat,especiallytoaquaticinvertebrates,andpossiblemitigationmeasuresineffective.Despitedelays,PMRAisstillofficiallycommittedtoaphase-out.In2018,theEuropeanFoodSafetyAuthorityexpandedapre-existingrestrictiononneonicotinoidstocoverallfiledcrops(Stokstad2018).EPAisthusaloneindenyingtheoverwhelmingevidenceofharmcausedbyneonicotinoidinsecticidestopollinatorsandotherwildlife.
![Page 12: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/12.jpg)
12
CONCLUSIONEPAisurgedtocanceltheregistrationsofthefiveneonicotinoidinsecticidesdiscussedinthesecomments.Attheveryleast,suspendtheuseofimidacloprid,thiamethoxamandimidaclopridasseedtreatments,particularlyforhighacreagecropslikecornandsoybeans.BillFreese,SciencePolicyAnalystCenterforFoodSafety
ReferencesAlaux,C.,J.L.Brunet,C.Dussaubat,F.Mondet,S.Tchamitchan,M.Cousin,J.Brillard,A.Baldy,L.P.Belzunces,Y.LeConte.2010.InteractionsbetweenNosemamicrosporesandaneonicotinoidweakenhoneybees(Apismellifera).EnvironmentalMicrobiology12(3):774-782.ArnasonR(2013).Noyieldbenefitfromneonicotinoids:scientist.TheWesternProducer,May10,2013.https://www.producer.com/2013/05/no-yield-benefit-from-neonicotinoids-scientist/.BonmatinJMetal.(2015).Environmentalfateandexposure;neonicotinoidsandfipronil.Environ.Sci.Pollut.Res.22:35-67.BotíasC,DavidA,HorwoodJ,Abdul-SadaA,NichollsE,HillE,GoulsonD(2015)Neonicotinoidresiduesinwildflowers,apoten-tialrouteofchronicexposureforbees.EnvironSciTechnol49:12731–12740.BurkeAPetal.(2018).MammalianSusceptibilitytoaNeonicotinoidInsecticideafterFetalandEarlyPostnatalExposure.ScientificReports8:16639.ChenJetal.(2018).Areorganosiliconsurfactantssafeforbeesorhumans?ScienceoftheTotalEnvironment612:415-421.ChenXDetal.(2010).Mixtureeffectsofthenonylphenylpolyethoxylate,R-11andtheinsecticide,imidaclopridonpopulationgrowthrateandotherparametersofthecrustacean,Ceriodaphniadubia.EcotoxicologyandEnvironmentalSafety73:132-137.
![Page 13: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/13.jpg)
13
Coulonetal.(2019).Influenceofchronicexposuretothiamethoxamandchronicbeeparalysisvirusonwinterhoneybees.PLoSOne14(8):e0220703.Cross,A.;Bond,C.;Buhl,K.;Jenkins,J.(2017).PiperonylButoxideGeneralFactSheet;NationalPesticideInformationCenter,OregonStateUniversityExtensionServices.npic.orst.edu/factsheets/pbogen.html.DiPriscoetal.(2013).Neonicotinoidclothianidinadverselyaffectsinsectimmunityandpromotesreplicationofaviralpathogeninhoneybees.PNAS110(46):18466-71.DouglasMRetal.(2020).County-levelanalysisrevealsarapidlyshiftinglandscapeofinsecticidehazardtohoneybees.ScientificReports10:797.DouglasMR&TookerJF(2015)Large-scaledeploymentofseedtreatmentshasdrivenrapidincreaseinuseofneonicotinoidinsecticidesandpreemptivepestmanagementinUSfieldcrops.EnvironmentalScience&Technology49(8):5088-5097.DouglasMR,RohrJR,TookerJF(2015).Neonicotinoidinsecticidetravelsthroughasoilfoodchain,disruptingbiologicalcontrolofnon-targetpestsanddecreasingsoyabeanyield.JApplEcol52:250–260.EngMLetal.(2019).Aneonicotinoidinsecticidereducesfuelinganddelaysmigrationinsongbirds.Science365:1177-80.EngMLetal.(2017).Imidaclopridandchlorpyrifosinsecticidesimpairmigratoryabilityinaseed-eatingsongbird.ScientificReports7:15176.EPA(12/15/17).Acetamiprid:DraftHumanHealthRiskAssessmentforRegistrationReview,DPBarcodeD441937,EPA-HQ-OPP-2012-0329-0025,EPA,December15,2017.EPA(12/5/17).Thiamethoxam:DraftHumanHealthRiskAssessmentforRegistrationReview,DPBarcodeD439309,EPA-HQ-OPP-2011-0581-0096,EPA,December5,2017.EPA(9/12/17).Dinetofuran:HumanHealthDraftRiskAssessmentforRegistrationReview,DPBarcodeD436969,EPA-HQ-OPP-2011-0920-0620,EPA,Sept.12,2017.EPA(9/7/17).Clothianidin:DraftHumanHealthRiskAssessmentinSupportofRegistrationReview,DPBarcodeD439294,EPA-HQ-OPP-2011-0865-0243,EPA9/7/17.EPA(6/22/17).Imidacloprid:HumanHealthDraftRiskAssessmentforRegistrationReview.EPA,June22,2017.EPA(1/16/20).ResponsefromthePesticideRe-evaluationDivisiontoCommentsontheDraftRiskAssessmentsandBenefitsAssessmentsSupportingtheRegistrationReviewofthe
![Page 14: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/14.jpg)
14
Nitroguanidine-substitutedNeonicotinoidInsecticides.EPA-HQ-OPP-2008-0844-1639,EPA,January16,2020.EPA(6/22/17).Imidacloprid:HumanHealthDraftRiskAssessmentforRegistrationReview,DPBarcodeD437947,EPA-HQ-OPP-2008-0844-1235,EPA,June22,2017.EPAImidacloprid(2020).Imidacloprid:ProposedInterimRegistrationReviewDecisionCase,Number7605,EPA,January2020.EPA(2002).DeterminationoftheappropriateFQPAsafetyfactor(s)intoleranceassessment.OfficeofPesticidePrograms,U.S.EnvironmentalProtectionAgency,February22,2002.GodfrayHCJetal.(2015).Arestatementofrecentadvancesinthenaturalscienceevidencebaseconcerningneonicotinoidinsecticidesandinsectpollinators.ProceedingsoftheRoyalSocietyB282:20151821.GodfrayHCJetal.(2014).Arestatementofthenaturalscienceevidencebaseconcerningneonicotinoidinsecticidesandinsectpollinators.ProceedingsoftheRoyalSocietyB281:20140558.HitajCetal.(2020).SowingUncertainty:WhatWeDoandDon’tKnowaboutthePlantingofPesticide-TreatedSeed.BioSciencebiaa019,https://doi.org/10.1093/biosci/biaa019HusethASetal.(2018).InsecticideResistanceSignalsNegativeConsequencesofWidespreadNeonicotinoidUseonMultipleFieldCropsintheU.S.CottonBelt.Environ.Sci.Technol.52(4):2314-2322.IrvinN(undated).Biologicalcontroloftheglassy-wingedsharpshooter(Homalodiscavitripennis)inCalifornia.AppliedBiologicalControlLaboratory,UniversityofCalifornia,Riverside.https://biocontrol.ucr.edu/irvin/gwssbiocontrol.html.JamesDG(2019).ANeonicotinoidInsecticideataRateFoundinNectarReducesLongevitybutNotOogenesisinMonarchButterflies,Danausplexippus(L.).(Lepidoptera:Nymphalidae).Insects10:276.KaraMetal.(2015).Insecticideimidaclopridinfluencescognitivefunctionsandalterslearningperformanceandrelatedgeneexpressioninaratmodel.InternationalJournalofExperimentalPathology96:332-337.KrupkeCHetal.(2017).Plantingofneonicotinoid-treatedmaizeposesrisksforhoneybeesandothernon-targetorganismsoverawideareawithoutconsistentcropyieldbenefit.JournalofAppliedEcology54:1449-58.
![Page 15: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/15.jpg)
15
KrupkeCHetal.(2012).MultipleRoutesofPesticideExposureforHoneyBeesLivingNearAgriculturalFields.PLoSOne7(1):e29268.LaycockI,LenthallKM,BarrattAT,CresswellJE(2012)Effectsofimidacloprid,aneonicotinoidpesticide,onreproductioninworkerbumblebees(Bombusterrestris).Ecotoxicology21:1937–1945.LopezR(2013).Citrusgrowersusepredatorwasptofightdiseasethreat.LosAngelesTimes,August3,2013.https://www.latimes.com/business/la-fi-predator-wasp-20130804-dto-htmlstory.html.LuCetal.(2018).NeonicotinoidResiduesinFruitsandVegetables:AnIntegratedDietaryExposureAssessmentApproach.Environ.Sci.Tech.52(5):3175-84.MaloneyEMetal.(2018).Canchronicexposuretoimidacloprid,clothianidin,andthiamethoxammixturesexertgreaterthanadditivetoxicityinChironomusdilutus?EcotoxicologyandEnvironmentalSafety156:354-365.Mikolić,A.andKaračonji,I.B.(2018).Imidaclopridasreproductivetoxicantandendocrinedisruptor:investigationsinlaboratoryanimals.ArchivesofIndustrialHygieneandToxicology69(2):103-108.MorrisseyCAetal.(2015).Neonicotinoidcontaminationofglobalsurfacewatersandassociatedrisktoaquaticinvertebrates:Areview.EnvironmentInternational74:291-303.MourtzinisSetal.(2019).NeonicotinoidseedtreatmentsofsoybeanprovidenegligiblebenefitstoUSfarmers.ScientificReports9:11207.MullinCA(2015).Effectsof‘inactive’ingredientsonbees.CurrenOpinioninInsectScience10:194-200.O’BrianD(2013).HelpingCitrusGrowersDealWithaNastyInvader.AgriculturalResearch,USDA’sAgriculturalResearchService,January2013.https://agresearchmag.ars.usda.gov/2013/jan/citrus.Pandey,S.P.andMohanty,B.(2015).Theneonicotinoidpesticideimidaclopridandthedithiocarbamatefungicidemancozebdisruptthepituitary–thyroidaxisofawildlifebird.Chemosphere122:227-234.PecenkaJRandLundgrenJG(2015).Non-targeteffectsofclothianidinonmonarchbutterflies.Naturwissenschaften102(3-4):19.Pettis,JSetal(2012).PesticideexposureinhoneybeesresultsinincreasedlevelsofthegutpathogenNosema.Naturwissenschaften99:153-158.
![Page 16: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/16.jpg)
16
Sanchez-BayoandWyckhuys(2019).Worldwidedeclineoftheentomofauna:Areviewofitsdrivers.BiologicalConservation232:8-27.Sánchez-BayoF,GoulsonD,PennacchioF,NazziF,GokaK,DesneuxN(2016).Arebeediseaseslinkedtopesticides?Abriefreview.EnvironInt89-90:7–11Sanchez-BayoandGoka(2014).PesticideResiduesandBees–ARiskAssessment.PLoSOne9(4):e94482.SgolastraFetal.(2016).Synergisticmortalitybetweenaneonicotinoidinsecticideandanergosterol-biosynthesis-inhibitingfungicideinthreebeespecies.Simon-DelsoNetal.(2015).Systemicinsecticides(neonicotinoidsandfipronil):trends,uses,modeofactionandmetabolites.EnvironSciPollutRes22:5-34.Staskal,D.F.;Birnbaum,L.S.;Haws,L.C.Applicationofarelativepotencyfactorapproachintheassessmentofhealthrisksassociatedwithexposuretomixturesofdioxin-likecompounds.Princ.Pract.MixturesToxicol.2010,67−97.StokstadE(2018).EuropeanUnionexpandsbanofthreeneonicotinoidpesticides.Science,April27,2018.https://www.sciencemag.org/news/2018/04/european-union-expands-ban-three-neonicotinoid-pesticides.SzczepaniecAetal.(2013).NeonicotinoidInsecticidesAlterInducedDefensesandIncreaseSusceptibilitytoSpiderMitesinDistantlyRelatedCropPlants.PLoSOne8(5):e2620.SzczepaniecAetal.(2011).NeonicotinoidInsecticideImidaclopridCausesOutbreaksofSpiderMitesonElmTreesinUrbanLandscapes.PLoSOne6(5):e20018.ThompsonHM,FrydaySL,HarkinS,MilnerS.(2014).Potentialimpactsofsynergisminhoneybees(Apismellifera)ofexposuretoneonicotinoidsandsprayedfungicidesincrops.Apidologie45(5):545-553.TomizawaMandCasidaJE(2005).NeonicotinoidInsecticideToxicology:MechanismsofSelectiveAction.Annu.Rev.Pharmacol.Toxicol.45:247-68.TosiSetal.(2017).Acommonneonicotinoidpesticide,thiamethoxam,impairshoneybeeightability.ScientificReports7:1201.TsvetkovNetal.(2017).Chronicexposuretoneonicotinoidsreduceshoneybeehealthnearcorncrops.Science356:1395-97.VanKlinketal.(2020).Meta-analysisrevealsdeclinesinterrestrialbutincreasesinfreshwaterinsectabundances.Science368:417-20.
![Page 17: May 4, 2020 OPP Docket 1200 Pennsylvania Ave. NW ... · neonicotinoids continuously stimulate neurons, resulting in death as well as sublethal effects (Simon-Delso et al. 2015). Neonicotinoids](https://reader034.vdocument.in/reader034/viewer/2022042710/5f680b9749526b553359f962/html5/thumbnails/17.jpg)
17
WoodTJandGoulsonD(2017).Theenvironmentalrisksofneonicotinoidpesticides:areviewoftheevidencepost2013.Environ.Sci.Pollut.Res.24:17285-325.Xerces(2016).RecommendationstoProtectPollinatorsfromNeonicotinoids:SuggestionsforPolicySolutions,RiskAssessment,ResearchandMitigation.XercesSocietyforInvertebrateConservation,November2016.https://xerces.org/sites/default/files/2018-05/NeonicsBeeRecommendations_XercesSociety.pdf.XuTetal.(2016).Clothianidininagriculturalsoilsanduptakeintocornpollenandcanolanectaraftermultiyearseedtreatmentapplications.EnvironmentalToxicologyandChemistry35(2):311-321.WhitehornPR,O’ConnorS,WackersFL,GoulsonD(2012)Neonicotinoidpesticidereducesbumblebeecolonygrowthandqueenproduction.Science336:351–352.WilliamsGRetal.(2015).Neonicotinoidpesticidesseverelyaffecthoneybeequeens.ScientificReports5:14621.WuC-Hetal.(2019).Effectsofimidacloprid,aneonicotinoidinsecticide,ontheecholocationsystemofinsectivorousbats.PesticideBiochemistryandPhysiology163:94-101.Yuan,X.,Shen,J.,Zhang,X.,Tu,W.,Fu,Z.andJin,Y.(2020).Imidaclopriddisruptstheendocrinesystembyinteractingwithandrogenreceptorinmalemice.ScienceofTheTotalEnvironment708:135163.ZhangQetal.(2019).Dietaryriskofneonicotinoidinsecticidesthroughfruitandvegetableconsumptioninschool-agechildren.EnvironmentInternational126:672-681.Zhuetal.(2017).Synergistictoxicityandphysiologicalimpactofimidaclopridaloneandbinarymixtureswithsevenrepresentativepesticidesonhoneybee(Apismellifera).PLoSOne12(5):e0176837.