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HSDB - 2015 - chlorpyrifos

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View record in another database: HSDB Download this Record Print Select Record My List Permalink CHLORPYRIFOS CASRN: 2921882 For other data, click on the Table of Contents Overview: IDENTIFICATION: Chloropyrifos is an insecticide that does not occur naturally. Chlorpyrifos has a slight skunky odor and is a white to tan crystallike solid. Chlorpyrifos is very volatile but not very reactive or flammable. Chlorpyrifos does not mix well with water. USE: Chloropyrifos is used in agriculture in containers with treated baits. On the farm it is used to control ticks on cattle and as a spray to control crop pests. Chlorpyrifos is also used on golf courses and to control public health pests such as fire ants and mosquitoes. Products containing chlorpyrifos are also used to treat wood fences and utility poles. It is no longer registered for use inside homes except as bait in containers. Chlorpyrifos has been used to control cockroaches, fleas and termites. It has been the active ingredient in pet flea and tick collars. EXPOSURE: Exposure to chlorpyrifos is mostly by inhaling indoor air and ingesting food containing chlorpyrifos . It has rarely been found in drinking water and outdoor air. However, high fog water concentrations relative to air concentrations have been reported in some US farm areas. Farm workers, chemical sprayers or people that work in chlorpyrifos production facilities are at the highest risk of exposure. Those who use the insecticide for homes and gardens are also at a higher risk of exposure. Animal exposure to chloropyrifos may also occur in the environment. This pesticide is toxic to birds and wildlife, and extremely toxic to fish, aquatic organisms and bees. Its primary release is through spraying of farm crops. In soil, chlorpyrifos is stable for about 10 days but is broken down by sunlight after 15 days. Without light, it breaks down much slower. Chlorpyrifos does not move in soil. If released to water, it does not bioconcentrate in fish. If released in air, chlorpyrifos may break down by reaction with chemicals in the air or absorb to dust particles. In air, chlorpyrifos can be carried long distances. RISK: Chlorpyrifos affects the nervous system of people, pets, and other animals the same way it affects the target pest. Chloropyrifos can inhibit the nervous system enzyme acetyl cholinesterase in humans, leading to overstimulation of the nervous system causing nausea, dizziness, and confusion. At very high exposures (from spills or accidents), respiratory arrest and death can occurs. Chlorpyrifos does pose acute and reproductive risks to many nontarget aquatic and terrestrial animals. In general, estuarine species are more at risk than freshwater species. Birds appear to be more at risk than most mammals. The US EPA has decided that there is "evidence of noncarcinogenicity for humans" for chlorpyrifos (1). (15; SRC, 2015) [FOR MORE INFORMATION: (1) National Pesticide Information Center. Chlorpyrifos. Available from, as of May 21, 2014: http://npic.orst.edu/index.html (2) National Library of Medicine Household Products Database. Chlorpyrifos. Available from, as of May 21, 2014: http://hpd.nlm.nih.gov/ (3) USEPA/OPPTS; Reregistration Eligibility Decisions (REDs) Database. Chlorpyrifos. Interim Document. February 2002. Available from, as of May 21, 2014: http://www.epa.gov/pesticides/reregistration/status.htm (4) Center for Disease Control and Prevention Agency for Toxic Substances and Disease Registry. Chlorpyrifos. Sept 1997. Available from, as of May 21, 2014: http://www.atsdr.cdc.gov/ (5) USEPA; Pesticide Product Label System. Product Label for Chlorpyrifos Technical. June 27, 2013. Available from, as of Oct 14, 2014: http://oaspub.epa.gov/pestlabl/ppls.home **PEER REVIEWED** Animal Toxicity Studies: TOXNET Home > Multidatabase Search Results > Full Record HSDB: CHLORPYRIFOS CASRN: 2921882 This record appears in multiple databases. Mobile Help FAQs TOXNET Fact Sheet Training Manual & Schedule
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    OccupationalExposureStandards

    CHLORPYRIFOSCASRN:2921882

    Forotherdata,clickontheTableofContents

    Overview:

    IDENTIFICATION:Chloropyrifosisaninsecticidethatdoesnotoccurnaturally.Chlorpyrifos hasaslightskunkyodorandisawhitetotancrystallikesolid.Chlorpyrifos isveryvolatilebutnotveryreactiveorflammable.Chlorpyrifos doesnotmixwellwithwater.USE:Chloropyrifosisusedinagricultureincontainerswithtreatedbaits.Onthefarmitisusedtocontrolticksoncattleandasaspraytocontrolcroppests.Chlorpyrifos isalsousedongolfcoursesandtocontrolpublichealthpestssuchasfireantsandmosquitoes.Productscontainingchlorpyrifos arealsousedtotreatwoodfencesandutilitypoles.Itisnolongerregisteredforuseinsidehomesexceptasbaitincontainers.Chlorpyrifos hasbeenusedtocontrolcockroaches,fleasandtermites.Ithasbeentheactiveingredientinpetfleaandtickcollars.EXPOSURE:Exposuretochlorpyrifos ismostlybyinhalingindoorairandingestingfoodcontainingchlorpyrifos .Ithasrarelybeenfoundindrinkingwaterandoutdoorair.However,highfogwaterconcentrationsrelativetoairconcentrationshavebeenreportedinsomeUSfarmareas.Farmworkers,chemicalsprayersorpeoplethatworkinchlorpyrifos productionfacilitiesareatthehighestriskofexposure.Thosewhousetheinsecticideforhomesandgardensarealsoatahigherriskofexposure.Animalexposuretochloropyrifosmayalsooccurintheenvironment.Thispesticideistoxictobirdsandwildlife,andextremelytoxictofish,aquaticorganismsandbees.Itsprimaryreleaseisthroughsprayingoffarmcrops.Insoil,chlorpyrifos isstableforabout10daysbutisbrokendownbysunlightafter15days.Withoutlight,itbreaksdownmuchslower.Chlorpyrifos doesnotmoveinsoil.Ifreleasedtowater,itdoesnotbioconcentrateinfish.Ifreleasedinair,chlorpyrifos maybreakdownbyreactionwithchemicalsintheairorabsorbtodustparticles.Inair,chlorpyrifos canbecarriedlongdistances.RISK:Chlorpyrifos affectsthenervoussystemofpeople,pets,andotheranimalsthesamewayitaffectsthetargetpest.Chloropyrifoscaninhibitthenervoussystemenzymeacetylcholinesteraseinhumans,leadingtooverstimulationofthenervoussystemcausingnausea,dizziness,andconfusion.Atveryhighexposures(fromspillsoraccidents),respiratoryarrestanddeathcanoccurs.Chlorpyrifos doesposeacuteandreproductiveriskstomanynontargetaquaticandterrestrialanimals.Ingeneral,estuarinespeciesaremoreatriskthanfreshwaterspecies.Birdsappeartobemoreatriskthanmostmammals.TheUSEPAhasdecidedthatthereis"evidenceofnoncarcinogenicityforhumans"forchlorpyrifos (1).(15SRC,2015)

    [FORMOREINFORMATION:(1)NationalPesticideInformationCenter.Chlorpyrifos.Availablefrom,asofMay21,2014:http://npic.orst.edu/index.html(2)NationalLibraryofMedicineHouseholdProductsDatabase.Chlorpyrifos.Availablefrom,asofMay21,2014:http://hpd.nlm.nih.gov/(3)USEPA/OPPTSReregistrationEligibilityDecisions(REDs)Database.Chlorpyrifos.InterimDocument.February2002.Availablefrom,asofMay21,2014:http://www.epa.gov/pesticides/reregistration/status.htm(4)CenterforDiseaseControlandPreventionAgencyforToxicSubstancesandDiseaseRegistry.Chlorpyrifos.Sept1997.Availablefrom,asofMay21,2014:http://www.atsdr.cdc.gov/(5)USEPAPesticideProductLabelSystem.ProductLabelforChlorpyrifosTechnical.June27,2013.Availablefrom,asofOct14,2014:http://oaspub.epa.gov/pestlabl/ppls.home**PEERREVIEWED**

    AnimalToxicityStudies:

    TOXNETHome > MultidatabaseSearchResults > FullRecord

    HSDB:CHLORPYRIFOS CASRN:2921882 Thisrecordappearsinmultipledatabases.

    Mobile Help FAQs TOXNETFactSheet TrainingManual&Schedule

  • ToxicitySummary:

    IDENTIFICATIONANDUSE:Chlorpyrifos (CPF)isacolorlesstowhitecrystallinesolidwithamildmercaptanodor.CPFisanorganophosphateinsecticide,acaricide,andmiticideusedtocontrolfoliageandsoilborneinsectpestsonavarietyoffoodandfeedcrops.ItisregisteredforuseintheU.S.butapprovedpesticideusesmaychangeperiodicallyandsofederal,stateandlocalauthoritiesmustbeconsultedforcurrentlyapproveduses.HUMANEXPOSUREANDTOXICITY:CPFcancausecholinesteraseinhibitioninhumansleadingtoanoverstimulatednervoussystemcausingnausea,dizziness,confusion,andrespiratoryparalysisanddeathatveryhighexposures.Significantchangesinplasmacholinesteraseinhibitionwereseeninrepeateddosesof0.1mg/kgofCPFbutnotinsingledoses.Organophosphatepoisoningmaymimicacutecomplicationsinpregnancy,suchaseclampsiaandseizures.Poisoningduringpregnancymayresultinseriousadverseeffectsforbothmotherandthefetusorneonate.Promptdiagnosisandtreatmentincludinggeneralsupportivemeasuresanduseofspecificpharmacologicalagentssuchasatropineandoximesarenecessarytoavoidadverseoutcomes.ANIMALSTUDIES:CPFaffectscardiaccholinesterase(ChE)activityandmuscarinicreceptorbindinginneonatalandadultrats.Doseandtimerelatedchangesinbodyweightandcholinergicsignsoftoxicity(involuntarymovements)werenotedinbothagegroups.With1xLD(10),relativelysimilarmaximalreductionsinChEactivityandmuscarinicreceptorbindingwerenoted,butreceptorbindingreductionsappearedearlierinadultsandweremoreprolongedinneonates.Studieswereperformedindogstofindoutwhetherexposurelimitsthatprotectbrainacetylcholinesterase(AChE)willprotectperipheraltissueAChEafterexposuretoCPF.TheresultsshowthatredbloodcellsAChEismoresensitivethanbrainorperipheraltissueAChEtoinhibitionbyCPF,andthatprotectionofbrainAChEwouldprotectperipheraltissueAChE.FetalorneonatalexposuretoCPForrelatedorganophosphatepesticidesleadstoabnormalitiesofbraincelldevelopment,synapticfunction,andbehavior.Studiesinratsindicateprofoundeffectsonserotonin(5HT)systemsthatoriginateduringCPFexposureandthatarestillpresentat2monthsposttreatmentintheyoungadult.Findingsat5monthsofagereplicatethoseseeninyoungadulthoodandstronglysuggestthattheeffectsofneonatalCPFexposureon5HTsystemsarepermanent.DevelopmentalexposuretoCPFalterscellsignalingbothinthebrainandinperipheraltissues,affectingtheresponsestoavarietyofneurotransmittersandhormones.Whentestedinadulthood,CPFexposedmaleanimalsdisplayedelevationsinplasmacholesterolandtriglycerides,withoutunderlyingalterationsinnonesterifiedfreefattyacidsandglycerol.Similarly,inthepostprandialstate,maleratsshowedhyperinsulinemiainthefaceofnormalcirculatingglucoselevelsbutdemonstratedappropriatereductionofcirculatinginsulinconcentrationsafterfasting.Apparentlysubtoxicneonatalchlorpyrifos exposure,devoidofeffectsonviabilityorgrowth,produceametabolicpatternforplasmalipidsandinsulinthatresemblesthemajoradultriskfactorsforatherosclerosisandtype2diabetesmellitus.CPFwasevaluatedforclastogenicpotentialusingratlymphocytestreatedfor4hourswithconcentrationsofupto5000mg/mLwithandwithoutmetabolicactivation.Noincreaseinchromosomalaberrationswasdetected.ECOTOXICITYSTUDIES:Intoxicationinthebobwhitewascharacterizedbyreducedfoodconsumptionanddiarrheain48hr,followedbylethargy,wingdroop,muscularincoordination,tremorsandtetanyimmediatelyprecedingdeath.TherewasasignificantcorrelationbetweenChEactivityandtotalfoodconsumption.AmajorspillageoftheinsecticideDursban(500L)occurredalongtheRiverRoding,Essex,UKon2Apr1985.Within30to40hr,Dursbanhadenteredtidalreachesoftheriver,26kmdownstreamfromthespillagepoint.90%ofthepreviousbiomassoffish(4740kg)andallaquaticarthropodswerekilledovera23kmstretchoftheRiverRoding.Mollusksandannelids,whicharerelativelytolerantofchlorpyrifos ,survived.

    **PEERREVIEWED**

    EvidenceforCarcinogenicity:

    CancerClassification:GroupEEvidenceofNoncarcinogenicityforHumans

    [USEPAOfficeofPesticidePrograms,HealthEffectsDivision,ScienceInformationManagementBranch:"ChemicalsEvaluatedforCarcinogenicPotential"(April2006)]**PEERREVIEWED**

    A4Notclassifiableasahumancarcinogen.

    [AmericanConferenceofGovernmentalIndustrialHygienists.ThresholdLimitValuesforChemicalSubstancesandPhysicalAgentsandBiologicalExposureIndices.ACGIH,Cincinnati,OH2014,p.20]**PEERREVIEWED**

    NonHumanToxicityExcerpts:

    /LABORATORYANIMALS:AcuteExposure/...Organophosphorus(OP)insecticidescanpotentiallyinfluencecardiacfunctioninareceptormediatedmannerindirectlybyinhibitingacetylcholinesteraseanddirectlybybindingtomuscarinicM(2)receptors.YounganimalsaregenerallymoresensitivethanadultstotheacutetoxicityofOPinsecticidesandagerelateddifferencesinpotencyofdirectbindingtomuscarinicreceptorsbysomeOPtoxicantshavebeenreported..../Thestudy/comparedtheeffectsofthecommonOPinsecticidechlorpyrifos (CPF)onfunctionalsignsoftoxicityandcardiaccholinesterase(ChE)activityandmuscarinicreceptorbindinginneonatalandadultrats.Dosageswerebasedonacutelethality(i.e.,0.5and1xLD(10):neonates,7.5and15mg/kgadults,68and136mg/kg).Doseandtimerelatedchangesinbodyweightandcholinergicsignsoftoxicity(involuntarymovements)werenotedinbothagegroups.With1xLD(10),relativelysimilarmaximalreductionsinChEactivity(95%)andmuscarinicreceptorbinding(approximately30%)werenoted,butreceptorbindingreductionsappearedearlierinadultsandweremoreprolongedinneonates....TheresultssuggestthatChEactivity(primarilyBChE)inneonatalheartmaybeinherentlymoresensitivetoinhibitionbysomeanticholinesterasesandthattoxicologicallysignificantbindingtomuscarinicreceptorsmaybepossiblewithacutechlorpyrifos intoxication,

  • potentiallycontributingtoagerelateddifferencesinsensitivity.

    [HowardMDetalToxicology238(23):15765(2007)]**PEERREVIEWED**PubMedAbstractFulltext:PMC2954647

    /LABORATORYANIMALS:AcuteExposure/Thisstudyexaminedtheacuteeffectsofchlorpyrifos (CPF)oncholinesteraseinhibitionandacetylcholinelevelsinthestriatumoffreelymovingratsusinginvivomicrodialysis.Adult,maleSpragueDawleyratsweretreatedwithvehicle(peanutoil,2ml/kg)orCPF(84,156or279mg/kg,sc)andfunctionalsignsoftoxicity,bodyweightandmotoractivityrecorded.Microdialysiswasconductedat1,4and7daysafterCPFexposureformeasurementofacetylcholinelevelsinstriatum.Ratswerethensacrificedandthecontralateralstriatumanddiaphragmwerecollectedforbiochemicalmeasurements.Fewovertsignsofcholinergictoxicitywerenotedinanyrats.Bodyweightgainwassignificantlyaffectedinthehighdose(279mg/kg)grouponly,whilemotoractivity(nocturnalrearing)wassignificantlyreducedinallCPFtreatedgroupsatoneday(84mg/kg)orfrom14days(156and279mg/kg)afterdosing.Cholinesteraseactivitiesinbothdiaphragmandstriatumweremarkedlyinhibited(5092%)inatimedependentmanner,buttherewererelativelyminimaldoserelatedchanges.Incontrast,timeanddosedependentchangesinstriatalacetylcholinelevelswerenoted,withsignificantlyhigherlevelsnotedinthehighdosegroupcomparedtoothergroups.Maximalincreasesinstriatalacetylcholinelevelswereobservedat47daysafterdosing(84mg/kg,79fold156mg/kg,1013fold279mg/kg,3557fold).Substantiallyhigheracetylcholinelevelswerenotedwhenanexogenouscholinesteraseinhibitorwasincludedintheperfusionbuffer,butCPFtreatmentrelateddifferencesweresubstantiallylowerinmagnitudeunderthoseconditions.TheresultssuggestthatmarkeddifferencesinacetylcholineaccumulationcanoccurwithdosagesofCPFelicitingrelativelysimilardegreesofcholinesteraseinhibition.Furthermore,theminimalexpressionofclassicsignsofcholinergictoxicityinthepresenceofextensivebrainacetylcholineaccumulationsuggeststhatsomecompensatoryprocess(es)downstreamfromsynapticneurotransmitteraccumulationlimitstheexpressionoftoxicityfollowingacuteCPFexposure.

    [KaranthSetalToxicolApplPharmacol216(1):1506(2006).]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:AcuteExposure/Whenratsweregiven10,50,or100mg/kgchlorpyrifos orallyandobserved1,8,and15hourslater,cholinergiceffectsoccurredonlyonday1in100mg/kgtreatedfemalerats.Onefemalerattreatedwith50mg/kghadtremors,twoexhibitedincoordination,andoneshowedpronouncedlacrimation.Onemaleratgiven100mg/kgexhibitedonlyminimaltremor,andonemaleexhibitedincoordinationandlacrimation.Ratstreatedwith50or100mg/kgweresignificantlyhypoactiveonlyonday1.Thus,cholinergiceffectswerewidespreadat100mg/kg,minorat50mg/kg,moderatedoverafewdays,andweremoresevereinfemalesthanmales.

    [Bingham,E.Cohrssen,B.Powell,C.H.Patty'sToxicologyVolumes195thed.JohnWiley&Sons.NewYork,N.Y.(2001).,p.793]**PEERREVIEWED**

    /LABORATORYANIMALS:AcuteExposure/Organophosphate(OP)pesticidesarelikelytoaltertheregulationofbloodpressure(BP)because(i)BPcontrolcentersinthebrainstemutilizecholinergicsynapsesand(ii)theirreversibleinhibitionofacetylcholinesteraseactivitybyOP'scausescholinergicstimulationintheCNS.Thisstudyusedradiotelemetrictechniquestomonitorsystolic(S),diastolic(D),mean(M)BP,pulsepressure(systolicdiastolic),heartrate(HR),coretemperature(T(c)),andmotoractivityinmaleLongEvansratstreatedwiththeOPpesticidechlorpyrifos (CHP)atdosesof0,5,10,and25mg/kg(p.o.).At15:00hr10and25mg/kgCHPledtoparallelelevationsinSBP,MBP,andDBPwithin2hrafterdosing.BPincreased1520mmHgabovecontrolsandincreasespersistedthroughoutthenightandintothenextday.HRdecreasedslightlyinratsadministered25butnot10mg/kgCHP.T(c)wasreducedbytreatmentwith25mg/kgCHPandthenincreasedabovecontrolsthenextday.Motoractivitywasreducedbytreatmentwith25butnot10mg/kgCHP.Pulsepressurewaselevatedby24mmHgfor40hrafterexposureto10and25mg/kgCHP.TheincreaseinBPwithoutanincreaseinHRsuggeststhatCHPincreasestotalperipheralresistanceandmayalterthebaroreflexcontrolofBP.CholinergicstimulationoftheCNSmayexplaintheinitialeffectsofCHPonBPhowever,thepersistentelevationsuggestsaninvolvementofneurohumoralpressorpathways.

    [GordonCJ,PadnosBKToxicology146(1):113(2000)]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:AcuteExposure/Anaerosolpreparationcontaining2.5%chlorpyrifos wasappliedtothetailandumbilicusofnewbornpigs.Mortalitywas7/7pigstreated03hrafterbirth,3/5pigstreatedat2430hr,and0/3pigstreated3036hrafterbirth.Clinicalsignsconsistentwithorganophosphatetoxicosisweredemonstratedbypigsthat/later/diedorwereeuthanizedinextremis.Bloodandbraincholinesteraseactivitiesweredepressedinaffectedpigscomparedtocontrols.Only1/3pigstreated3036hrafterbirthhadadiagnosticallysignificantdepressioninbloodcholinesterase.Theseresultsindicatethatpigletsonedayorlessofagearesusceptibletoorganophosphatetoxicosisbycutaneousabsorptionofchlorpyrifos .

    [LongGGetalVetHumToxicol28(4):2979(1986)]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:AcuteExposure/Thedermalirritationpotentialoftechnicalgradechlorpyrifos (purity,99%)wastestedinastudyconducted...insixyoungmaleNewZealandwhiterabbits,towhich500mgofthematerial(moistenedwithwater)wereappliedunderagauzepatchonclippedintactskinonthetrunkandthencoveredwithanocclusivedressing.Thedressingswereremovedafter4hrandtheskinwipedtoremoveresidualmaterial.Theskinwasexaminedforsignsofirritation1,24,48,and72hrafterremovalofthepatchandscoredforirritationonthebasisofasystemrecommendedbytheUSEnvironmentalProtectionAgency.Furtherassessmentswereconductedafter4,5,and6daystodeterminethereversibilityoftheeffects.Slighterythema(score1)wasnotedonthreeofsixtestsitesat1hr,andthiseffectpersisteduntil72hratonesiteanduntilday5inanotheranimal.Noskinirritationwasseenonday6.

    [FAO/WHOPesticideResiduesinFood,ToxicologicalEvaluations,Chlorpyrifos(1999).Availablefrom,asofSeptember17,2007:http://www.inchem.org/documents/jmpr/jmpmono/v99pr03.htm**PEERREVIEWED**

    /LABORATORYANIMALS:AcuteExposure//Mild/dermalirritation,rabbit...resolvedwithin7days

  • [USEPA/OfficeofPesticideProgramsInterimReregistrationEligibilityDecisionDocumentChlorpyrifosp.24.CaseNo.0100(September2001)Availablefrom,asofAugust24,2007:http://www.epa.gov/pesticides/reregistration/status.htm**PEERREVIEWED**

    /LABORATORYANIMALS:AcuteExposure/Slightirritation/torabbiteyes/resolvedwithin24hrs.

    [USEPA/OfficeofPesticideProgramsInterimReregistrationEligibilityDecisionDocumentChlorpyrifosp.24.CaseNo.0100(September2001)Availablefrom,asofAugust24,2007:http://www.epa.gov/pesticides/reregistration/status.htm**PEERREVIEWED**

    /LABORATORYANIMALS:AcuteExposure/Theocularirritationpotentialoftechnicalgradechlorpyrifos (purity,99%)wastested...insixyoungmaleNewZealandwhiterabbits,100mgoftestmaterialbeingplacedintotherighteyeandtheuntreatedlefteyeservingasacontrol.Therewerenosignsofcornealoriridialirritation.Slighttomoderateconjunctivalredness(meanDraizescore,1at1hr,0.83at24hr),slightchemosis(meanDraizescore,0.83at1hr,0.16at24hr),anddischarge(meanDraizescore,1.6at1hr,0.83at24hr)wereseenupto24hrafterinstillation,butnosignsofirritationwerereportedat48hr.

    [FAO/WHOPesticideResiduesinFood,ToxicologicalEvaluations,Chlorpyrifos(1999).Availablefrom,asofSeptember17,2007:http://www.inchem.org/documents/jmpr/jmpmono/v99pr03.htm**PEERREVIEWED**

    /LABORATORYANIMALS:AcuteExposure/Usingradiotelemetrytomonitorbloodpressureandcoretemperature,studies...haveshownthataprolongedhypertensiveresponseiselicitedinratsexposedtochlorpyrifos ...Chlorpyrifos inhibitsacetylcholinesteraseactivity,resultingincentralandperipheralstimulationofcentralcholinergicpathwaysinvolvedinbloodpressureregulation.Thespontaneouslyhypertensiverathasbeenshowntobemoresensitivetocentralcholinergicstimulation.Therefore,.../itwas/hypothesizedthattheseratswouldbemoresusceptibleandsustainagreaterhypertensiveresponsewhenexposedtochlorpyrifos .Heartrate,cardiaccontractility,coretemperature,andbloodpressureweremonitoredbyradiotelemetryinSHRsandtheirWistarKyoto(WKY)normotensivecontrolsfollowingexposuretochlorpyrifos (10mg/kgor25mg/kg,orally).BaselinebloodpressureofSHRswasapproximately35mmHgabovethatofWKYspriortodosing.SHRsexhibitedagreaterandmoresustainedelevationindiastolic,meanandsystolicbloodpressurefollowingexposureto25mg/kgofchlorpyrifos .Theriseinbloodpressurelastedforapproximately56hoursinSHRscomparedtoapproximately32hoursinWKYs.Chlorpyrifos alsoledtoaprolongedelevationindaytimeheartrateinbothstrains.Therewasatransientelevationincardiaccontractilityinbothstrainslastingapproximately7hrafterexposuretochlorpyrifos .Thehypothermicresponsetochlorpyrifos wassimilarinmagnitudeanddurationforbothstrains.Plasmacholinesteraseactivitymeasured4hrafterexposureto25mg/kgchlorpyrifos wasinhibitedtoapproximately40%ofcontrollevelsinbothstrains.UsingtheSHRstrainasamodeltostudysusceptiblepopulations,thedatasuggestthatindividualswithageneticpredispositiontohypertensionmaybemoresusceptiblefromexposuretoorganophosphatebasedinsecticide,asmanifestedbyanexacerbatedhypertensiveresponse.

    [SmithEG,GordonCJBasicClinPharmacolToxicol96(6):50311(2005).]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:SubchronicorPrechronicExposure/...CD1micewereexposedtoabroadrangeofacute(12.5100.0mg/kg)andsubacute(1.5625mg/kg/dayfrom5to30days)CPForaldoses.Functionalandbiochemicalparameterssuchasbrainandserumcholinesterase(ChE)andliverxenobioticmetabolizingsystem,includingthebiotransformationofCPFitself,havebeenstudiedandthenoobservedeffectlevels(NOELs)identified.MiceseemtobemoresusceptiblethanratsatleasttoacuteCPFtreatment(oralLD504.5foldlower).Thespeciesrelateddifferenceswerenotsoevidentafterrepeatedexposures.InmiceagoodcorrelationwasobservedbetweenbrainChEinhibitionandclassicalcholinergicsignsoftoxicity.AfterCPFrepeatedtreatment,miceseemedtodevelopsometolerancetoCPFinducedeffects,whichcouldnotbeattributedtoanalterationofP450mediatedCPFhepaticmetabolism.CPFinducedeffectsonhepaticmicrosomalcarboxylesterase(CE)activityandreducedglutathione(GSH)levelsobservedatanearlystageoftreatmentandthenrecoveredafter30days,suggestthatthedetoxifyingmechanismsareactivelyinvolvedintheprotectionofCPFinducedeffectsandpossiblyintheinductionoftoleranceinlongtermexposure.Themousecouldbeconsideredasuitableexperimentalmodelforfuturestudiesonthetoxicactionoforganophosphoruspesticidesfocusedonmechanisms,longtermandagerelatedeffects.

    [CometaMFetalToxicology234(12):90102(2007)]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:SubchronicorPrechronicExposure/Acomparativestudyof5organophosphorusinsecticides,leptophos,EPN,cyanofenphos,chlorpyrifos anddiazinon,wasconductedusing1/10ththeLD50valuestostudytheirinvivointeractionwith6serumenzymesfromoraladministrationfor4weeksinwhiterats.Leptophos,chlorpyrifos anddiazinonexertedsignificantinhibitionofglutamicoxaloacetictransaminase,glutamicpyruvictransaminase,glutamyltransferaseandlactatedehydrogenase.

    [EnanEEetalJEnvironSciHealth(B)17(5):54970(1982)]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:SubchronicorPrechronicExposure/Thisstudywascarriedouttoevaluatetheeffectsoforganophosphate(OP)insecticidechlorpyrifosoncardiacmorphologyandfunctioninrabbitsusingechocardiography.TwentyNewZealandmalerabbitsweredividedequallyintofourgroups.Rabbitswereexposedtochlorpyrifos indrinkingwateratconcentrationsof0,125,250or375ppmfor90days.Thecomparisonamongthegroupsindicatedthat375ppmchlorpyrifos resultedinsignificantdecrease(p

  • /LABORATORYANIMALS:SubchronicorPrechronicExposure/Whenchlorpyrifos wasadministeredtomonkeysfor6months,bothplasmaandredcellcholinesteraseswereinhibitedatdosagesof2.0and0.4mg/kg/day,butonlytheplasmaenzymewasinhibitedatadosageof0.08mg/kg/day.

    [Hayes,W.J.,Jr.,E.R.Laws,Jr.,(eds.).HandbookofPesticideToxicology.Volume2.ClassesofPesticides.NewYork,NY:AcademicPress,Inc.,1991.,p.1066]**PEERREVIEWED**

    /LABORATORYANIMALS:ChronicExposureorCarcinogenicity//In/atwoyeartoxicityandoncogenicstudy,chlorpyrifos ,99.6%purityat0,0.5,5.0,and15.0ppm/wasadministered/inthediet/toCD1mice/.NOEL=15ppm(notoxicity).Nooncogenicity.

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:ChronicExposureorCarcinogenicity/Inastudyofcarcinogenicity...technicalgradechlorpyrifos (statedpurity,95.9%)wasmixedinmaizeoilandincorporatedintoacommerciallyavailablepowderedanimaldiettoproducedietaryconcentrationsof0(control),5,50,and250ppm,calculatedtobeequalto0.71.1,6.112,and3255mg/kgbw/dayinmalesand0.71.2,6.612,and3462mg/kgbw/dayinfemales.Thetestdietswereadministeredtogroupsof64CD1/mice/ofeachsex,3weeksold,foratleast79weeks,terminalsacrificebeingundertakenduringweeks8082.Theanimalscontinuedtoreceivethetreateddietsuntilschedulednecropsy....Bloodsmearswerepreparedfromallmiceafter12and18monthsfordifferentialleukocytecounts...Plasma,erythrocyte,andbraincholinesteraseactivitywasdeterminedinfiveanimalsofeachsexateachdoseat9and18months.Allanimalswereexaminedgrossly,theexaminationincludingallexternalsurfaces,thecranial,thoracic,abdominal,andpelviccavities,andthecarcass.Alargenumberoforgansandtissuesfromallanimalswerefixedforhistopathologicalexaminationtheeyes,kidneys,livers,lungs,andthyroids/parathyroidsfromanimalsatalldoseswereexamined,aswereothertissuesfromcontrolandanimalsatthehighdoseandthosefromanimalsthatdiedduringthestudy.Therewasnoadverseeffectonsurvival,andnotreatmentrelatedincreaseintheincidenceofneoplasticlesions.Treatmentrelatedclinicalsigns(ocularopacities,excesslacrimation,andcranialhairloss)andreductionsinbodyweightsandfoodconsumptionwereobservedat250ppm(approximately32mg/kgbw/day)....Plasmacholinesteraseactivitywasinhibitedatalldoses.Determinationsoferythrocytecholinesteraseactivityrevealed>20%inhibitionat42weeksandabout30%inhibitionatweek78inanimalsat250ppmbutconsiderableintragroupvariationatotherdoses....inhibitionoferythrocytecholinesteraseactivitywas...statisticallysignificant.../at/29%inmalesat78weeksand41%infemalesat42weeksinanimalsat50ppm.Significantinhibitionofbraincholinesteraseactivity(p

  • females,aslightincreaseinthedegreeofvacuolationoftheadrenalzonafasciculata(malesonly),andaslightincreaseindiffuseretinaldegenerationin10mg/kg/dayfemales.

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:ChronicExposureorCarcinogenicity/Verylittleisknownabouttheeffectsofchronicexposuretorelativelylowlevelsofanticholinesteraseinsecticidesorhowtheeffectsofchronicexposurecomparetothoseofhigher,intermittentexposure.Tothatend,adultmaleratswerefedananticholinesteraseinsecticide,chlorpyrifos (CPF),for1yearatthreelevelsofdietaryexposure:0,1,or5mg/kg/day(0+oil,1+oil,and5+oil).Inaddition,halfofeachofthesegroupsalsoreceivedabolusdosageofCPFincornoil("spiked"animals60mg/kginitiallyand45mg/kgthereafter)every2months(0+CPF,1+CPF,5+CPF).Animalswereanalyzedafter6or12monthsofdosing,andagain3monthsaftercessationofdosing(i.e.,"recovery"animalssixexperimentalgroupswithn=46/group/timepoint).Cholinesterase(ChE)activitywasmeasuredinretina,wholeblood,plasma,redbloodcells,diaphragm,andbrain[pons,striatum,andtherestofthebrain(referredtosimplyas"brain")].Muscarinicreceptordensitywasassessedinretina,pons,andbrain,whereasdopaminetransporterdensityandthelevelsofdopamineanditsmetaboliteswereassessedinstriatum.Cholinesteraseactivityat6and12monthswasnotdifferentinanyofthetissues,indicatingthatasteadystatehadbeenreachedpriorto6months.The1+oilgroupanimalsshowedChEinhibitiononlyintheblood,whereasthe5+oilgroupexhibited>or=50%ChEinhibitioninalltissuestested.Onedayafterthebolusdose,allthreegroups(0+CPF,1+CPF,5+CPF)showed>or=70%ChEinhibitioninalltissues.Muscarinicreceptordensitydecreasedonlyinthebrainofthe5+oiland5+CPFgroups,whereasdopaminetransporterdensityincreasedonlyat6monthsinallthreespikedgroups.Striataldopamineordopaminemetabolitelevelsdidnotchangeatanytime.ThreemonthsafterCPFdosingended,allendpointshadreturnedtocontrollevels.Thesedataindicatethat,althoughchronicfeedingwithorwithoutintermittentspikeddosageswithCPFproducessubstantialbiochemicalchangesinadoseandtissuerelatedmanner,therearenopersistentbiochemicalchanges.

    [PadillaSetalToxicolSci88(1):16171(2005)]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:ChronicExposureorCarcinogenicity/Chickenpullets203daysofageatstartofexperiment,wereexposedbyfeeding25mg/kgtechnicalgradechlorpyrifos (2.48mg/kg/daydailydose)for365days./Toxicsigns/observedwerereducedbloodcholinesteraseactivity(78%ofnormal).Chickenpullets(sameasparameter)fed50mg/kgtechnicalgradechlorpyrifos (20.4mg/kg/daydailydose)for365days,exhibitednoeffectonfeedconsumption,bodyweight,eggproduction,feedefficiency,eggweight,interioreggquality,andeggshellthickness.Reducedbloodcholinesteraseactivity(24%ofnormal).

    [ShermanM,HerrickRBHawaiiAgricExpStnSeriesNo.1487(1972)ascitedinNat'lResearchCouncilCanadaEcotoxicologyofChlorpyrifosp.147(1978)NRCCNo.16079]**PEERREVIEWED**

    /LABORATORYANIMALS:DevelopmentalorReproductiveToxicity/Fetalorneonatalchlorpyrifos (CPF)exposureaffectsserotonin(5HT)synapticfunctionandrelatedbehaviorsinadulthood....thecriticalperiodanddosethresholdforeffectson5HT/wereexamined/and...theiremergenceinadolescence/wasassessed/.PregnantratsweregivenCPF(1or5mg/kg/day)fromgestationaldays(GD)1720orGD912and5HTlevelsandturnoverwereevaluatedonpostnatalday30thelowerdoseliesbelowthethresholdforinhibitionoffetalbraincholinesterase.GD1720exposureincreased5HTturnoverinbrainregionscontainingeither5HTprojectionsorcellbodies,withapreferentialeffectinmales.ShiftingtheexposuretoGD912alsoaugmented5HTactivitybutonlyinthecerebralcortexandwithoutsexpreference.Similar,butlessereffectswereseenfordopamineturnoverinthesameregions.Theseresultsindicatethat,inacriticaldevelopmentalperiod,apparentlysubtoxicexposurestoCPFproducelongtermactivationof5HTsystems.

    [SlotkinTA,SeidlerFJReprodToxicol23(3):4217(2007)]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:DevelopmentalorReproductiveToxicity/Sixteen/NewZealandWhiterabbits/does/groupweredosedwith0,25,100,or250mg/kg/day3,5,6trichloro2pyridinol(TCP,purity99.7%)bygavageinaqueous0.5%Methocelongestationdays719inateratologystudy.MaternalNOEL=100mg/kg/day(minormaternalbodyweightdecrementduringtreatment).DevelopmentalNOEL=25mg/kg/day(hydrocephalyanddilatedcerebralventricles).Thelatterobservationswerenotstatisticallysignificantlyincreasedineitherofthetwohigherdosegroupscomparedtoconcurrentcontrols,howeverhistoricalbackgroundincidenceswereverylow(comparehydrocephalylitterincidencesof2/13and3/13at100and250mg/kg/day,respectively,toahistoricalincidenceof1/839litters)....

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:DevelopmentalorReproductiveToxicity/...14HY/CR(aNewZealandWhitevariety)rabbitspergroupweredosedbygavageincornoilwithchlorpyrifos (Pyrinex Technical,purity96.1%)ondays719p.c.at0,1,9,81,or140mg/kg/day.MaternalNOEL=81mg/kg/day(bodyweightgaindecrementduringtreatmentperiod).DevelopmentalNOEL=81mg/kg/day[reducedcrown/rumplength,reducedfetalweight,ossificationdelays(indicatedbynonossificationoffifthsternebraand/orxiphisternum)]....

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:DevelopmentalorReproductiveToxicity/Chlorpyrifos ,0,0.1,1,10,and25mg/kg/day/wasadministered/bygavage/tomice/NOELformaternalfunctionaltoxicity=1mg/kg/day[cholinesterase(ChE)effectsassalivation,tremors,etc.].ChEenzymeNOEL=0.1mg/kg/day(significantinhibitionof

  • maternalplasmaChEat1mg/kg/day).DevelopmentaltoxicityNOEL=10mg/kg/day(decreasedfetallengthandweight,delayedossificationinskull,sternebrae)....TeratogenicNOEL>25mg/kg/day(HDT)fetotoxicNOEL=10mg/kgfetotoxicLEL=25mg/kg(decreasedfetallength,increasedskeletalvariants)PlasmaandRBCChENOEL=0.1mg/kg/day....

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:DevelopmentalorReproductiveToxicity/Ratswereorallyfedwithdifferentdosesviz.9.6,12and15mg/kg/dfromGD020andexaminedforevidenceoffetotoxicityandteratogenecitytoevaluatethepotentialeffectsoftechnicalchlorpyrifos (97%).Fetotoxiceffectswerenotobservedattesteddoselevelsasevidencedbynumberofimplantations,numberofcorporaluteaandlivefetuses/dam,butsignificantalterationswerenotedinpercent...resorptionandfetalweight.Therewerenomajormalformations,butsomeminoranomaliessuchasreducedparietalossificationandabsenceofphalangesfoundsignificantinhighdosewerenotconsideredascompoundrelatedeffects.Ontheotherhandtheaccumulationofchlorpyrifos residue..was/greater/inbrain(0.0328ug/g)thaninliver(0.0071ug/g).Thelevelofresidueinfetuseswasinthefollowingorder:liver(0.0531ug/g)>brain(0.0364ug/g)>placenta(0.040ug/g)>amnioticfluid(0.0010ug/g).Although,thetotalresiduewashigherinfetuses(0.0447ug/g)thanindams(0.0120ug/g),theabsenceofabnormalitiesinfetalgrossmorphology,visceralandskeletonsuggestthattechnicalchlorpyrifos attesteddoselevelsisnonteratogenicinrats.

    [AkhtarNetalJToxicolSci31(5):5217(2006)]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:DevelopmentalorReproductiveToxicity/...21pregnantCDrats/groupweredosedwithPyrinex Technical(chlorpyrifos ),purity96.1%bygavageincornoilondays615p.c.at0,0.5,2.5,or15mg/kg/day.NomaternalChENOELwasidentified(doserelatedplasmaChEinhibitionatalldoselevelsatday15p.c.,withrestorationofnormalChEactivityinallbuthighdosedamsbyp.c.day20.MaternalfunctionalNOEL=2.5mg/kg/day(tremorsin3/21dams,transientfoodconsumptionreduction,modestbutconsistentbodyweightdecrement).DevelopmentalNOEL=2.5mg/kg/day(slightincreaseinearlyresorptions).Noadversereproductiveeffectatdoselevelssufficienttoelicitcholinergicresponses.

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:DevelopmentalorReproductiveToxicity/FourgroupsofSpragueDawleyratswereusedinatwogeneration(onelitterpergeneration)studyofreproductivetoxicityinwhichdietscontainingchlorpyrifos (purity,97.898.5%)atdosesof0,0.1,1,or5mg/kgbwperdaywereadministered....Clinicalobservationswereperformeddailyonallanimals...Bodyweightsandfoodconsumptionwererecordedweeklybeforeandafterbreeding....Inhibitionofcholinesteraseactivityinplasma,erythrocytes,andbrainwasmeasuredin10F0andF1parentalanimalsofeachsexatnecropsyafter19and21weeksofexposure.CompletenecropsieswereconductedonallF0andF1adults,andincludedocularexaminationsandcollectionofmanytissues.Histopathologicalexaminationsweremadeoftheadrenals,brain,grosslesions,andreproductivetissues(cervix,coagulatingglands,epididymides,ovaries,oviducts,pituitary,prostate,seminalvesicles,testes,uterus,andvagina)ofcontrolsandanimalsatthehighdose....TenF1andF2pupsofeachsexperdosewereautopsiedgrossly.Nosignificanteffectsoftreatmentwereseenonclinicalsigns,foodintake,orbodyweight....PlasmacholinesteraseactivitywasinhibitedinparentalF0andF1ratsofeachsexat1mg/kgbwperday(4057%)andat5mg/kgbwperday(

  • 24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:DevelopmentalorReproductiveToxicity/Chlorpyrifos ,(technicalgrade DursbanFinsecticide,AGR273801),98.5%purity,wasfedinthedietto30SpragueDawleyrats/sex/groupthrough2generationswith1litterpergeneration.Concentrationswereadjustedasneededtoachieveexposuresof0,0.1,1.0,and5.0mg/kg/day.Treatmentbeganapproximately10and12weekspriortobreedingfortheF0andF1adults,respectively.Cholinesterase(ChE)inhibitionNOEL=0.1mg/kg/day(PlasmaandRBCChEinhibitionat1.0and5.0mg/kg/day).ParentalNOEL=1.0mg/kg/day(increaseddegreeofvacuolationinzonafasciculata,especiallyinmalesalteredtinctorialpropertiesinthistissueinfemales).ReproductiveNOEL=1.0mg/kg/day(slightlyreducedpupweightsandslightlyreducedpupsurvivalat5.0mg/kg/day).TherewerenoclinicalsignsspecificallyindicatingChEinhibition....

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:DevelopmentalorReproductiveToxicity/Chlorpyrifos ,anorganophosphatepesticide,wasevaluatedforpotentialteratogenicityanddevelopmentaltoxicityinmice.Pregnantfemalesweregivenasingleintraperitonealinjection(40or80mg/kg)onday10ofgestationandfetuseswereevaluatedongestationday17.At80mg/kg,chlorpyrifos treatmentresultedinasignificantreductioninnumbersoflivefetuses,andincreaseinresorptions,versuscontrollitters.Therewasnoindicationofmaternaltoxicity.Externalandskeletalmalformationswereobservedat80mg/kg,butnot40mg/kg.Ratesoffetuseswithcleftpalateincreasedsignificantly(p

  • /LABORATORYANIMALS:Neurotoxicity/Twostudieswereperformedtofindoutwhetherexposurelimitsthatprotectbrainacetylcholinesterase(AChE)willprotectperipheraltissueAChEafterexposuretochlorpyrifos (CPF),anorganophosphateinsecticide.Inamethodsdevelopmentstudy,maledogs(3/dose)wereexposedto0.0,0.3,0.6,or1.2mg/kg/dayCPFintheirdietsfor4weeks.Mixedcholinesterase(mChE),AChE,andbutyrylcholinesterase(BuChE)activitiesweremeasuredinplasma,RBC,brain,leftatriumandventricle,diaphragm,quadriceps,andnodoseganglia.Plasma,brainandperipheraltissueBuChEwasinhibitedatalldoselevels.WhileRBCAChEwasinhibitedatalldoses,brainandperipheralAChEactivitieswereunaffected.Inthemainstudy,dogs(4/sex/dose)wereexposedto0.0,0.5,1.0,or2.0mg/kg/dayCPFintheirdietsforsixweeksandRBCAChEwassignificantlyinhibitedatalldosesinbothsexes.Diaphragm,quadriceps,andnodosegangliaAChEwasunaffectedbytreatment.BrainAChEwasdecreasedbyapproximately6%comparedtocontrolsinhighdosegroups,andthiswasconsideredathresholdeffect.LeftatriumAChEinhighdosedogswas25.5%less(males)and32.1%greater(females)thancontrolsthesedifferenceswereattributedtochance.WhileperipheraltissueandbrainAChEwerenotaffectedfollowingexposureto1.0mg/kg/day,RBCAChEwasinhibitedatalldoses.TheseresultsshowthatRBCAChEismoresensitivethanbrainorperipheraltissueAChEtoinhibitionbyCPF,andthatprotectionofbrainAChEwouldprotectperipheraltissueAChE.

    [MarableBRetalRegulToxicolPharmacol47(3):2408(2007)]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:Neurotoxicity/Whenratswereexposedto0.1,1,5,15mg/kg/daychlorpyrifos viathedietfor13weeks,mildclinicaleffects(perinealsoiling)werenotedinfemalesgiven5and15mg/kg/day.Plasmacholinesterasewassignificantlyinhibitedinmalesandfemalesgiven1mg/kgormore,RBCcholinesterasewassignificantlyinhibitedinfemalesgiven1mg/kgormore,and,braincholinesterasewasinhibitedinbothmalesandfemalesgiven5or15mg/kg.Motoractivityofmalesandfemalesgiven15mg/kgmildlydecreasedonlyatweek4ofexposure,andnotreatmentrelateddifferenceswereapparentsubsequently,consistentwiththeoccurrenceoftoleranceuponrepeatedexposuretochlorpyrifos .

    [Bingham,E.Cohrssen,B.Powell,C.H.Patty'sToxicologyVolumes195thed.JohnWiley&Sons.NewYork,N.Y.(2001).,p.793]**PEERREVIEWED**

    /LABORATORYANIMALS:Neurotoxicity/FemaleLongEvansratsweredosedbygavageincornoilwith0,1,3,or10mg/kg/daychlorpyrifos (98.1%purity)for4weeks.Thecognitivestudywasadelayedmatchingtopositiontaskdesign.Cognitivetestingwasdoneduringeachofthetreatmentweeksandfor4weeksthereafter,bymethodsdescribedbelow.Ratswereplacedonmodestfoodrestrictiontoprovideincentivetoseekthefoodrewardinthestudy.Ratsweretrainedandselectedforthestudy,basedonpositionalmemoryperformance.Inagiventest,aratwaspresentedwithoneoftworetractablelevers.Theratwastopresstheleveroffered,crossthecageandinterruptabeamatthefoodcupwithin10seconds,andthenreturntothesideofthecagewiththelevers.Atthistime,bothleverswouldbepresented.Theratwasexpectedtoselectandpressthecorrectlever(i.e.,theonejustpresentedafewsecondsearlier)within10secondsafterleavingthefoodcupstation.Acorrectchoicemadeafoodrewardavailableatthefoodcup.Inadditiontotheabovetest,thetaskwasmademoredifficultbyinvolvingprogressivelylongerdelays(upto15seconds)betweenthefirstleverpressandthetimeinwhichanosepokeinthefoodcupwouldextendthelevers(calledthedelayedmatchingtopositionorDMPTparadigm).Theseratswerealsoexaminedtwicedailyontreatmentdaysduringthe4wkdosingperiod:observationswereabout3hrand21hrafterthemostrecenttreatment.Satellitegroupsof6/dose/intervalwereusedforChEassaysandbrainNTEassaysonthedayfollowingthelasttreatment,and1monthafterthelasttreatment....NOELforclinicalobservationsis1mg/kg/day(miosis).ThereisnoNOELforChEinhibition(markedinhibitionofplasmaandRBCChEandmodest(8%)inhibitionofbrainChEat1mg/kg/day).SomehighdoseobservationsassociatedwiththeDMPTtestswereappropriatelyconsideredbyinvestigatorstohavebeenattributabletomotorslowingand/ordecreasedmotivation(increasedactualtotaldelay,increasedvoidtrials,anddecreasednumbersofnosepokespertrial).Noneofthesewerenotedaftertheendofthetreatmentperiod.

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:Neurotoxicity/Concernhasbeenraisedregardingpotentialadverseeffectsonthenervoussystemfollowingchildhoodexposuretochlorpyrifos (O,OdiethylO3,5,6trichloro2pyridylphosphorothioate).Thisstudyexaminedtheoutcomesofdailyoraldosingwithchlorpyrifos ,fromearlypostnatallifetoadolescence.MaleandfemaleLongEvansratsweredosedwithchlorpyrifos 0,2,or6mg/kg/day,5days/wk,beginningonpostnatalday11(PND11)andendingPND46(total,26doses).BrainswerecollectedfromasubsetofratsonPND18andPND41(23hoursafterthepreviousdose),andcholinesterase(ChE)activity,muscarinicreceptorbinding(QNBasligand),andbrainweightswereevaluated.TheremainingratsweretestedusingafunctionalobservationalbatteryandmotoractivityonPND17,27,40,81,and123thus,testswereconductedbothduringandafterthedosingperiod.Attheendofdosing,astepthroughpassiveavoidancetaskwasusedtoevaluatelearningandmemory,andoxotremorinewasadministeredtodeterminethefunctionalstatusofthecholinergicsystem.Bodyandbrainweightswerenotaltered.ChEwasinhibitedinadosedependentmannerinbothblood(3573%inhibition)andbrain(755%inhibition).SomewhatlessinhibitionwasdetectedonPND41,inspiteofongoingdosing.ReceptordownregulationwassuggestedbydecreasedQNBbinding(12%lower)inthehighdosegroups(bothsexes),andanattenuationofoxotremorineinducedhypothermia(females).Passiveavoidanceperformancewasnotaltered.Increasedactivity(females)andexcitability/reactivity(males)wereobservedatPND17.OnPND27,onlydepressedresponsestosensorystimuliwereevident.Mosteffectswereobtainedonlyinthehighdosegroup,andgenderdifferenceswereobservedthelowdoseproducedbehavioraleffectsonlyinfemales.Persistentneurobehavioralalterations,uptoPND123,werenotdetectedintheserats.

    [MoserVCetalSocietyofToxicologyBehavNeurochemOutcomesofRepeatedOralAdminofChlorpyrifosinPostnatal/JuvenileRats(2000)]**PEERREVIEWED**

    /LABORATORYANIMALS:Neurotoxicity/Thepurposethepresentstudywastodetermineiftoleranceisdevelopedtoallbehavioraleffectsproducedbyasinglehighdoseofchlorpyrifos (CPF).Forthis,thestudywasdividedintwophasesinthefirstphase,...thetimecourseoftheeffectsproducedbytreatmentwithahighdoseofCPF(250mg/kgsc)onratlocomotoractivityandanxietybehaviorsrecordedonanopenfield,aswellasonAChEinhibition/wasstudied/.ResultsshowedthatCPFproducedamaximuminhibitionofAChE(72%ofinhibition)2daysafteritsadministration,exhibitingapartialrecoveryofitsactivitybyday30(55%ofinhibition).OnlocomotoractivityCPFproducedabiphasiceffectareductiononlyonday2,andanincreaseonday30.Ananxiolyticlikeeffectwasonlyobservedwithin2and5daysafterCPFtreatment.TheseresultsindicatethatthetolerancehasbeendevelopedtothebehavioraleffectsproducedbyscadministrationofCPF,butwitha

  • differenttimecourse.Inthesecondphase,sincedisturbancesincholinergicsystemmighttriggerdopaminergicdysfunctions,...thelocomotoractivity/wastested/followingchallengewithamphetamine(1mg/kgip)at11and30daysafterCPFtreatment.DataobtainedshowedthatamphetamineproducedanincreaseintotaldistancesandrearinginvehicleandCPFgroupsondays11and30.However,CPFgroupexhibitedlowerincreaserelativetovehiclegroupinbothdays.ThiseffectisindependentofthepercentageofAChEinhibitionandtherefore,ofchangeinthecholinergicsystem.DataarediscussedunderthelightoftheadaptativemechanismsunderlyingtherecoveryofthecholinergicoverstimulationafterscexposuretohighdosesofCPF.

    [LopezCrespoGAetalNeurotoxicology28(3):5417(2007).]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:Neurotoxicity/...Inthisstudy,thebehavioralandneurochemicaleffectsofchronic,intermittent,andsubthresholdexposurestotheOPpesticide,chlorpyrifos (CPF),wereinvestigated.RatswereinjectedwithCPFs.c.(doserange,2.518.0mg/kg)everyotherdayoverthecourseof30daysandthenweregivena2weekCPFfreewashoutperiod.Inbehavioralexperimentsconductedduringthewashoutperiod,dosedependentdecrementsinawatermazehiddenplatformtaskandaprepulseinhibitionprocedurewereobserved,withoutsignificanteffectsonopenfieldactivity,Rotorodperformance,gripstrength,oraspontaneousnovelobjectrecognitiontask.Afterwashout,levelsofCPFanditsmetabolite3,5,6trichloro2pyridinolwereminimalinplasmaandbrainhowever,cholinesteraseinhibitionwasstilldetectable.Furthermore,the18.0mg/kgdoseofCPFwasassociatedwith(brainregiondependent)decreasesinnervegrowthfactorreceptorsandcholinergicproteinsincludingthevesicularacetylcholinetransporter,thehighaffinitycholinetransporter,andthealpha(7)nicotinicacetylcholinereceptor.Thesedeficitswereaccompaniedbydecreasesinanterogradeandretrogradeaxonaltransportmeasuredinsciaticnervesexvivo.Thus,lowlevel(intermittent)exposuretoCPFhaspersistenteffectsonneurotrophinreceptorsandcholinergicproteins,possiblythroughinhibitionoffastaxonaltransport.Suchneurochemicalchangesmayleadtodeficitsininformationprocessingandcognitivefunction.

    [TerryAVJretalJPharmacolExpTher322(3):111728(2007).]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:Neurotoxicity/Thepresentstudyinvestigatedtheeffectofchlorpyrifos onNMDAreceptorsubunitsNR2AandNR2Binjuvenileandadultrats.Chlorpyrifos wasadministeredwiththedoseof40and70mg/kgtojuvenileandadultrats,respectively.Chlorpyrifos significantlyinhibitedtheAChEactivityinjuvenileandadultrats(p

  • /LABORATORYANIMALS:Neurotoxicity/...Ratsweredosedwithchlorpyrifos (CPF),anOPpesticidewhichinhibitsbloodandbrainChEofratsforweeksafterasingleinjection.LongEvansratsweretrainedtoperformanappetitivetestofmemoryandmotorfunctionandweretheninjecteds.c.with0,60,125or250mg/kgofCPFinpeanutoilandtested5days/weekfor7weeks.Unconditionedbehaviorwasalsoratedforsignsofcholinergictoxicity.CPFinhibitedChEactivityinwholebloodinadoserelatedmannerformorethan53days.ThedegreeandtimecourseofChEinhibitioninbloodandbrainandthedownregulationofmuscarinicreceptorsinbrainafter125mg/kgofCPFcloselyparalleledthepreviouslyreportedeffectsof25dailyinjectionsof0.2mg/kgof/diisopropylfluorophosphate/(DFP).Inaddition,CPFtreatedratsweresubsensitivetooxotremorineinducedhypothermiaforatleast32daysafterCPF.However,functionaldeficits(inworkingmemoryandmotorfunction)appearedwithin2daysafterinjectionofCPFandrecoveredwithin3weeks,longbeforeChEactivityandreceptordensityreturnedtocontrollevels.

    [BushnellPJetalJPharmacolandExperTherapeutics266(2):100717(1993)]**PEERREVIEWED**

    /LABORATORYANIMALS:Neurotoxicity/Chlorpyrifos (purity98.1%)wasadministeredinasingleoralgavageto10Fischer344rats/sex/groupatlevelsof0,10,50or100mg/kg.Bodyweightsofmidandhighdoseratsweresignificantlyreducedonday2butnotonday8or15.Clinicalsigns(increasedperinealsoiling)inmidandhighdoseratsandFOBobservations(incoordination,decreasedmuscletone,tremor,increasedlacrimationandsalivation)inhighdosefemaleswereseensoonafterdosing(day1).Motoractivitywasreducedinmidandhighdoseratsonday1somereductionspersistedtoday8inhighdosefemales.NOEL(Bodywt.,Clinicalsigns,FOBandmotoractivity)=10mg/kg.Nohistopathologicchanges.NOEL(histopathology)=100mg/kg.

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:Neurotoxicity/Chlorpyrifos ,purity98.1%,wasadministeredinthefeedatconcentrationsof0,0.1,1,5or15mg/kgto10Fischer344rats/sex/groupfor13weeks.Highdosemalesandfemaleshadreducedmotoractivityatweek4.Perinealsoiling(lowincidence)wasobservedfor5and15mg/kg/daygroupsNOEL(forclinicalsigns,FOB,motoractivity)=1mg/kg/day.Nohistopathologicfindings.NeuropathologicNOEL=15mg/kg/day.

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:Neurotoxicity/Cognitiveandmotorimpairmentoftenfollowacutepoisoningwithanorganophosphorous(OP)pesticide.However,thepersistenceoftheseeffectsandtheconditionsnecessaryfortheirappearancearenotclear:twospecificconcernsarewhethersymptomaticpoisoningisnecessaryforpersistenteffects,andwhetherinhibitionofcholinesterase(ChE)activityisaprotectivemetricofOPexposure.Thisstudyexaminedtheeffectsofchronicdietaryandrepeatedhighlevelacuteexposuretothepesticidechlorpyrifos (diethyl3,5,6trichloro2pyridylphosphorothionate,CPF)onlearningandattention.Beginningat3monthsofage,maleLongEvansratsreceiveddietaryCPFatadailydoseof0,1,or5mg/kgfor1year.HalfofeachdietarygroupalsoreceivedanacuteoraldoseofCPF(initialdoseat60mg/kg,5dosesat45mg/kg)every2months.Beginning2weeksbeforethefourthacutedose,behavioralassessmentswereconductedontheeightratsineachofthesixexposuregroups(0Oil,0CPF,1Oil,1CPF,5Oil,and5CPF).Usinganautoshapingprocedure,thegroupslearnedtopressaleverforfoodinthefollowingorder:5Oil,5CPF,1Oil,and0Oil.The0CPFand1CPFgroupsdidnotlearntheresponseinthree50trialsessions.ChronicCPFdidnotaffectacquisitionofotherbehaviorsrequiredbyasignaldetectiontask(SDT)designedtoassesssustainedattention.ThesixthacuteCPFdosesignificantlydisruptedtheSDTinalldosedgroups.Twomonthsaftertheendofdosing,performanceoftheSDTwasimpairedinthe5CPFgroup.ThesedatasuggestthatlearningthecontingencybetweenanactionandrewardmaybeacceleratedbychronicexposuretoCPFandinhibitedbyprevioussymptomaticexposuretoCPF,andthatpersistentcognitiveimpairmentmayfollowifCPFexposureinhibitsbrainChEactivityandisaccompaniedbyacutedosessufficienttoinducesignsoftoxicity.

    [SamsamTEetalToxicolSci87(2):4608(2005)]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:Neurotoxicity/...Groupsofthree18montholdwhiteLeghornhensweregivensingleoraldosesofchlorpyrifos (purity,100%)at0,75,150,or300mg/kgbwwithatropine(20mg/kgbwsubcutaneouslyatthetimeofthefirstdoseofchlorpyrifos andadditionaldosesasneededtomaintainthehensfor4days).Fourdaysaftertreatment,whenthehenswerekilled,brainacetylcholinesteraseactivitywasdepressedby0,58,75,and86%andneuropathytargetesteraseactivityby0,21,40,and77%atthethreedoses,respectively.Inafurtherstudy,18hensweregivencornoilaloneand15atropineprotectedhensweregivenchlorpyrifos atasingleoraldoseof150mg/kgbw.Threecontrolswerekilledonday0,andthreetreatedandthreecontrolhenswerekilledondays1,2,4,8,and16.Brainacetylcholinesteraseactivitywasinhibitedby86,82,72,43,and29%ondays1,2,4,8,and16aftertreatment,andbrainneuropathytargetesteraseactivitywasinhibitedby30,28,38,29,and6%.Nosignsoforganophosphateinduceddelayedneuropathywereobserved.

    [FAO/WHOPesticideResiduesinFood,ToxicologicalEvaluations,Chlorpyrifos(1999).Availablefrom,asofSeptember17,2007:http://www.inchem.org/documents/jmpr/jmpmono/v99pr03.htm**PEERREVIEWED**

    /LABORATORYANIMALS:Neurotoxicity/...Zebrafish(Daniorerio)withtheirclearchorionandextensivedevelopmentalinformationbaseprovideanexcellentmodelforassessmentofmolecularprocessesoftoxicantimpactedneurodevelopment....methods/weredeveloped/forassessingspatialdiscriminationlearninginadultzebrafishpersistingeffectsofdevelopmentalchlorpyrifos (CPF)exposureonswimmingactivityandlearningafterlowandhighdosesofCPF(10and100ng/mL)administeredtozebrafishembryosonDays15postfertilization(pf).Inthecurrentstudy,...methods/weredeveloped/forbehavioralassessmentofCPFexposureonswimmingactivityinnewlyhatchedzebrafish....Zebrafishembryoswereexposedto10ng/mLCPF,100ng/mLCPF,orvehiclecontrol(25uL/mLDMSO)(n=810/treatmentgroup).Eachtreatmentgroupwaskeptinatotalvolumeof25mLofeggwater(60mg/mLInstantOcean)includingDMSOwithorwithoutCPFmixedto

  • abovedilutionsinanincubatorsetat28.5degreesC.CPFdilutionsorvehiclewerechangeddailywithexposureendingonDay5pf.TestingoflarvalzebrafishwasperformedonDays6and9pf.Thefishwereplacedinthetestcylinderwith1.5mlofeggH(2)O(28.5degreesC).Aftera2minacclimationperiod,theswimmingactivityofthefishwasmeasuredfora3mintestingsession.The100ng/mLCPFdosecausedsignificantslowingofswimmingactivityonDays6and9pfandhadpersistingeffectsofimpairingspatialdiscriminationanddecreasingresponselatencyinadulthood.Developmentalexposureto10ng/mLofCPFdidnotcauseasignificantchangeinlocomotoractivityduringtheperiodsoonafterhatching.CPFexposureduringearlydevelopmentcausedclearbehavioralimpairmentsdetectableduringtheposthatchingperiod.Inapreviousstudy,wefoundthatearlydevelopmentalCPFexposurecausedbehavioralalterationsinzebrafish,whichlastedthroughoutadulthood.ThemolecularmechanismsbywhichearlydevelopmentalCPFexposureproducesthesebehavioralimpairmentsexpressedinadulthoodcannowbestudiedinthezebrafishmodel.

    [LevinEDetalNeurotoxicolTeratol26(6):71923(2004).]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:Neurotoxicity/CD1micewereexposedtotheorganophosphatepesticidechlorpyrifos (CPF)bothprenatally(gestationaldays1518doses0,3or6mg/kg)andpostnatally(postnataldays1114,doses0,1or3mg/kg).Whenfourmontholds,femalesunderwentasocialrecognitiontestinwhichultrasoundvocalizations(USVs)andsocialinvestigationbehavioremittedbyaresidentfemaleinthepresenceofafemalepartnerweremeasuredduringtwosubsequent3minsessions(intervalbetweenthetwosessions45min).ThroughoutthesocialrecognitiontestamarkedincreaseinUSVswasfoundinfemalesprenatallytreatedwiththehighestCPFdoseUSVincreasewasalsoparalleledbyaselectiveincreaseinfrequencyandnotindurationofsocialinvestigation.TheseresultsconfirmthatdevelopmentalexposuretoCPFinduceslonglastingalterationsinthesocialbehaviorrepertoireofthemouse,thusextendingourpreviousobservationsontheeffectsofpostnatalCPFonmaleagonisticbehaviortothefemalesex.Theyalsosuggestthatsocialrecognitioncanbeeasilyandrapidlyassessedinthefemalemousemakingitpossibletoevaluate,primarilybymeansofUSVemission,evensubtlealterationofsocialbehavioralpatternsdissociatedfromcognitivecomponentsofindividualrecognition.

    [VenerosiAetalNeurotoxicolTerato28(4):46671(2006).]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:Neurotoxicity//Ina/subchronicorganophosphateinduceddelayedneurotoxicity(OPIDN)studyinlayingchickenhens,chlorpyrifos ,technical(approx.96%purity),/wasadministeredat/0,1,5,and10mg/kg/day.Noevidenceofdelayeddistalneuropathy.10mg/kg/daychlorpyrifos causedweightloss,diminishedegglayingcapacity,andtransientabnormalgait(fullyreversiblebetweendosingperiods,andnotpersistentthroughoutstudy).

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /LABORATORYANIMALS:Neurotoxicity/Chlorpyrifos wasadministeredsubcutaneouslytoneonatalratsatdosesof1or5mg/kgbw/dayonpostnataldays14,orat5mg/kgbw/dayondays1114,andthetwogroupsofpupswereexaminedonpostnataldays5and10or15and20,respectively.Signsofinterferencewiththeadenylcyclasesignalingcascadeweredeterminedintheheartanddevelopingbrainstemandcerebellum.Pupstreatedonpostnataldays14at1mg/kgbw/dayshowednosignsoftoxicity,whiletherewassignificantmortality(>50%)at5mg/kgbw/day.Pupstreatedonpostnataldays1114at5mg/kgbw/dayshowednodeathsorclinicalsigns.Nosignificantchangesintheweightsofthebrainregionwerefoundattheseapparentlynontoxicdoses.Cholinesteraseactivityinthebrainstemofthepupsgiven1mg/kgbw/daywasinhibitedby25%whenmeasured24hrafterthelastdose,butrecoverywassubstantial(60%whenmeasured24hrafterthelastdose,butrecoverywasagainsubstantial(

  • alterationsintheionichomeostasiscausinglossofcellularintegrity.Ourpreviousstudieshaveshowntheageassociatedinteractiveeffectsinratcentralnervoussystem(CNS)uponcoexposuretochlorpyrifos (CPF)andcoldstressleadingtomacromolecularoxidativedamage.ThepresentstudyelucidatesapossiblemechanismbywhichCPFandcoldstressinteractioncause(s)mitochondrialdysfunctioninanagerelatedmanner.Inthisstudy,theactivitylevelsofKrebscycleenzymesandelectrontransportchain(ETC)proteincomplexeswereassessedintheisolatedfractionofmitochondria.CPFandcoldstress(15and20degC)exposureeitherindividuallyorincombinationdecreasedtheactivitylevelofKrebscycleenzymesandETCproteincomplexesindiscreteregionsofratCNS.ThefindingsconfirmthatcoldstressproducessignificantsynergisticeffectinCPFintoxicatedagingrats.ThesynergismbetweenCPFandcoldstressat15degCcausedahigherdepletionofrespiratoryenzymesincomparisonwithCPFandcoldstressaloneandtogetherat20degCindicatingtheextentofdeleteriousfunctionalalterationsindiscreteregionsofbrainandspinalcord(SC)whichmayresultinneurodegenerationandlossinneuronalmetaboliccontrol.Hence,coexposureofCPFandcoldstressismoredangerousthanexposureofeitheralone.Amongthediscreteregionsstudied,thecerebellumandmedullaoblongataappearstobethemostsusceptibleregionswhencomparedtocortexandSC.Furthermore,thestudyrevealsagradualdecreaseinsensitivitytoCPFtoxicityastheratmatures.

    [BashaPM,PoojaryACellMolNeurobiol34(5):73756(2014)]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:Neurotoxicity/Theneurodevelopmentaleffectsoftwoorganophosphorus(OP)insecticides,chlorpyrifos (CPS)andmethylparathion(MPS),oncholinesterase(ChE)activityandmuscarinicacetylcholinereceptor(mAChR)bindingwereinvestigatedinneonatalratbrain.Animalswereorallygavagedusinganincrementaldosingregimenfrompostnatalday1(PND1)untilPND8withalow,medium,andhighdosageforbothCPSandMPS.OnPND4andPND8,ChEactivitywasmeasuredinwholebrainwhilethetotalandsubtypedensitiesofmAChRsweremeasuredinthreebrainsections:areaanteriortoopticchiasma(anteriorforebrain),areafromtheopticchiasmatothemedulla/pons(posteriorforebrain)andthemedulla/ponsexcludingthecerebellum.Theligands(3)Hpirenzepine,(3)HAFDX384,(3)H4DAMP,and(3)HQNBwereusedtomeasurethemaximalbindingoftheM1,M2/M4,andM3subtypesandtotalmAChRreceptors,respectively.Intheanteriorandtheposteriorforebrain,thelevelsofallmAChRsnearlydoubledfromPND4toPND8,whileinthemedulla/pons,M1andM3subtypemAChRdensitieswerelowanddidnotincreaseandM2/M4subtypeandtotalmAChRslightlyincreasedfromPND4toPND8.ReductionofChEactivityandmAChRbindingbyCPSorMPSwasmoreevidentinratsatPND8thanatPND4.WithrespecttomAChRbinding,thegreatesteffectswereobservedinthemedulla/ponsandtheleasteffectswereobservedintheposteriorregionoftheforebrain.TheseresultsdemonstratethatOPsexertadverseeffectsonratcentralnervoussystemdevelopmentthroughthecholinergicsysteminanageandregiondependentmanner.

    [GuoRossSXetalToxicolSci.100(1):11827(2007).]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:Neurotoxicity/Fetalorneonatalexposuretochlorpyrifos (CPF)orrelatedorganophosphatepesticidesleadstoabnormalitiesofbraincelldevelopment,synapticfunction,andbehavior.Recentstudiesinratsindicateprofoundeffectsonserotonin(5HT)systemsthatoriginateduringCPFexposureandthatarestillpresentat2monthsposttreatmentintheyoungadult.Todetermineifthesechangesarepermanent,...1mg/kgofCPFdaily/wasadministered/toneonatalratsonpostnataldays14,aregimendevoidofsystemictoxicity,and...5HTsynapticmarkers/wereexamined/at5monthsofage:radioligandbindingto5HT1Aand5HT2receptorsandtothe5HTtransporter.Therewereglobalelevationsinallthreesynapticproteins,withpronouncedsexselectivity(effectsonmales>females)andaregionalhierarchyofeffects,viz.striatum>midbrainapproximatelybrainstem>cerebralcortex.Becausethereisanormalsexdisparityfor5HTsynapticproteins,withfemaleshavinghighervaluesthanmales,theincreasecausedbyCPFexposureinmalescompletelyeliminatedthisdifference.Ourfindingsat5monthsofagereplicatethoseseeninyoungadulthoodandstronglysuggestthattheeffectsofneonatalCPFexposureon5HTsystemsarepermanent.

    [SlotkinTA,SeidlerFJBrainResDevBrainRes158(12):1159(2005)]**PEERREVIEWED**PubMedAbstract

    /LABORATORYANIMALS:Neurotoxicity/Thefibroblastgrowthfactor(FGF)superfamilyofneurotrophicfactorsplayscriticalrolesinneuralcelldevelopment,brainassembly,andrecoveryfromneuronalinjury....Twoorganophosphatepesticides,chlorpyrifos anddiazinon,/wereadministered/toneonatalratsonpostnataldays14,usingdosesbelowthethresholdforsystemictoxicityorgrowthimpairment,andspanningthethresholdforbarelydetectablecholinesteraseinhibition:1mg/kg/daychlorpyrifos and1or2mg/kg/daydiazinon.Usingmicroarrays,...theregionalexpressionofmRNAsencodingtheFGFsandtheirreceptors(FGFRs)intheforebrainandbrainstem/wereexamined/.Chlorpyrifos anddiazinonbothmarkedlysuppressedfgf20expressionintheforebrainandfgf2inthebrainstem,whileelevatingbrainstemfgfr4andevokingasmalldeficitinbrainstemfgf22.However,theydifferedinthattheeffectsonfgf2andfgfr4weresignificantlylargerfordiazinon,andthetwoagentsalsoshoweddissimilar,smallereffectsonfgf11,fgf14,andfgfr1....Thefactthattherearesimilaritiesbutalsonotabledisparitiesintheresponsestochlorpyrifos anddiazinon,andthatrobusteffectswereseenevenatdosesthatdonotinhibitcholinesterase,supportstheideathatorganophosphatesdifferintheirpropensitytoelicitdevelopmentalneurotoxicity,unrelatedtotheiranticholinesteraseactivity.Effectsonneurotrophicfactorsprovideamechanisticlinkbetweenorganophosphateinjurytodevelopingneuronsandtheeventual,adverseneurodevelopmentaloutcomes.

    [SlotkinTAetalEnvironHealthPerspect115(6):90916(2007).]**PEERREVIEWED**PubMedAbstractFulltext:PMC1892141

    /LABORATORYANIMALS:Neurotoxicity/Previousstudieshaveindicatedthatjuvenileratsaremoresusceptiblethanadultstotheacutetoxicityfromexposuretotheorganophosphorusinsecticidechlorpyrifos (CPF)andagedependentdifferencesinmetabolismandsensitivitytocholinesterase(ChE)inhibitionmayberesponsible.MetabolisminvolvesCYP450activationanddetoxificationofCPFtoCPFoxonand3,5,6trichloro2pyridinol(TCP),aswellascholinesterase(acetylandbutyrylcholinesterase),carboxylesterase(CaE),andAesterase(PON1)detoxificationofCPFoxontoTCP.ThepharmacokineticsofCPF,TCP,andtheextentofblood(plasma/RBC),andbrainChEinhibitioninratsweredeterminedonpostnataldays(PND)5,12,and17followingoralgavageadministrationof1and10mgCPF/kgofbodyweight.Ashasbeenseeninadultanimals,forallpreweanlingagesthebloodTCPexceededtheCPFconcentration,andwithineachagegrouptherewasnoevidenceofnonlinearkineticsoverthedoserangeevaluated.Consistentwithpreviousresults,youngeranimalsdemonstratedagreatersensitivitytoChEinhibitionasevidentbytheagedependentinhibitionofplasma,RBC,andbrainChE.Thebrainmaybeparticularlysensitiveinyoungeranimals(i.e.PND5)duetosubstantiallylowerlevelsofChEactivityrelativetolaterpreweanlingstagesandadults.OfparticularimportancewastheobservationthateveninratsasyoungasPND5,theCYP450metaboliccapacitywasadequatetometabolizeCPFtobothTCPandCPFoxonbasedonthedetectionofTCPinbloodandextensiveChEinhibition(biomarkerofCPFoxon)atallages.Inaddition,theincreaseinthebloodTCPconcentration(approximately3fold)inPND17ratsrelativetothe

  • responseintheyoungerrats,areconsistentwithanincreaseinCYP450metaboliccapacitywithage.Thisisthefirstreportedstudythatevaluatedboththepharmacokineticsoftheparentpesticide,themajormetabolite,andtheextentofChEinhibitionasafunctionofpreweanlingage.Theresultssuggestthatinthepreweanlingrat,CPFwasrapidlyabsorbedandmetabolized,andtheextentofmetabolismandChEinhibitionwasagedependent.

    [TimchalkCetalToxicology220(1):1325(2006)]**PEERREVIEWED**PubMedAbstract

    /DEVELOPMENTALNEUROTOXICITY/Thisstudywascarriedouttoinvestigatetheeffectofinuteroexposuretothecholinotoxicants,nicotineandchlorpyrifos ,aloneorincombinationonneurobehavioralalterationsandneuronalmorphologylaterinadultage.Inthepresentstudy,90daysold(correspondingtoahumanadultage)maleandfemaleoffspringratswereevaluatedforneurobehavioral,andneuropathologicalalterationsfollowingmaternal,gestationalexposuretonicotineandchlorpyrifos (O,OdiethylO3,5,6trichloro2pyridinylphosphorothioate),aloneandincombination.FemaleSpragueDawleyrats(300350g)withtimedpregnancyweretreatedwithnicotine(3.3mg/kg/day,inbacteriostaticwaterviascimplantationofminiosmoticpump),chlorpyrifos (1.0mg/kg,daily,dermal,in75%ethanol,1.0mL/kg)oracombinationofbothchemicals,ongestationaldays(GD)420.Controlanimalsreceivedbacteriostaticwaterviascimplantationofminiosmoticpumpanddermalapplicationof70%ethanol.Theoffspringatpostnatalday(PND)90wereevaluatedforneurobehavioralperformance,changesintheactivityofplasmabutyrylcholinesterase(BChE)andacetylcholinesterase(AChE),andneuropathologicalalterationsinthebrain.Neurobehavioralevaluationsincludedbeamwalkscore,beamwalktime,inclineplaneperformanceandforepawgriptime.MaleandfemaleoffspringfrommotherstreatedwithnicotineandCPF,aloneorincombinationshowedimpairmentsintheperformanceofneurobehavioraltests,indicatingsensorimotordeficits.Femaleoffspringfrommotherstreatedwithacombinationofnicotineandchlorpyrifos showedsignificantincreaseinplasmaBChEactivity.BrainregionalAChEactivityshoweddifferentialincreasesinmaleandfemaleoffspring.Brainstemandcerebellumoffemaleoffspringfrommotherstreatedwithnicotineorchlorpyrifos ,aloneorincombinationshowedincreasedAChEactivity,whereasbrainstemofmaleoffspringfrommotherstreatedwithnicotinealoneoracombinationofnicotineandchlorpyrifos showedincreaseinAChEactivity.Also,maleoffspringexposedinuterotonicotineexhibitedincreasedAChEactivity.HistopathologicalevaluationsusingcresylvioletstainingshowedadecreaseinsurvivingPurkinjeneuronsinthecerebelluminoffspringofalltreatmentsgroups.Anincreaseinglialfibrillaryacidicprotein(GFAP)immunostainingwasobservedincerebellumwhitematteraswellasgranularcelllayer(GCL)ofcerebellumfollowingallexposures.Theseresultsindicatethatinuteroexposuretonicotineandchlorpyrifos ,aloneandincombinationproducedsignificantsensorimotordeficitsinmaleandfemaleoffspring,differentialincreaseinbrainAChEactivity,adecreaseinthesurvivingneuronsandanincreasedexpressionofGFAPincerebelluminadultoffspringratsatacorrespondinghumanadultage.Collectively,thisstudydemonstratesthatmaternalexposuretoenvironmentalneurotoxicchemicals,i.e.,nicotineandchlorpyrifos leadstodevelopmentalabnormalitiesintheoffspringthatpersistlatterintoadulthood.

    [AbouDoniaMBetalArchToxicol80(9):62031(2006)]**PEERREVIEWED**PubMedAbstract

    /DEVELOPMENTALNEUROTOXICITY/Chlorpyrifos (CPS),aknownneurotoxicant,isawidelyusedagriculturalorganophosphorusinsecticide.TheeffectsofpostnatalexposuretoCPSontheexpressionofmRNAfortwofactorscriticaltobraindevelopment,nervegrowthfactor(NGF)andreelin,wereinvestigatedintheforebrainofrats.Inaddition,theexpressionofmRNAforthemuscarinicacetylcholinereceptor(mAChR)M(1)subtypeandcellspecificmarkersfordevelopingneurons(betaIIItubulin),astrocytes(glialfibrillaryacidicprotein,GFAP),andoligodendrocytes(myelinassociatedglycoprotein,MAG)wasalsoinvestigated.OraladministrationofCPS(1.5or3.0mg/kg)orthecornoilvehiclewasperformeddailyfrompostnataldays(PNDs)1through6.NosignsofoverttoxicityorofcholinergichyperstimulationwereobservedafterCPSadministration.BodyweightwassignificantlydifferentfromcontrolsonPND7inbothmalesandfemalesexposedto3.0mg/kgCPS.QuantitativePCRwasperformedontheforebrain.TheexpressionofNGF,reelin,andM(1)mAChRmRNAwassignificantlyreducedwithbothdosagesofCPSinbothsexes.betaIIITubulinmRNAexpressionremainedunchangedafterexposure,whereasMAGmRNAexpressionwassignificantlydecreasedwithbothdosagesofCPSinbothsexes,suggestingeffectsonthedevelopingoligodendrocytes.Incontrast,GFAPmRNAlevelsweresignificantlyincreasedwithbothdosagesofCPSinbothsexes,suggestingincreasedastrocytereactivity./The/...findingsindicatethatdosagesofCPSwhichcausesignificantcholinesteraseinhibitionbutdonotexertoverttoxicitycanadverselyaffecttheexpressionlevelsofcriticalgenesinvolvedinbraindevelopmentduringtheearlypostnatalperiodintherat.

    [BetancourtAMToxicolSci.92(2):5006(2006).]**PEERREVIEWED**PubMedAbstract

    /DEVELOPMENTALNEUROTOXICITY/Developmentalexposuretotheorganophosphorousinsecticidechlorpyrifos (CPF)induceslongtermeffectsonbrainandbehaviorinlaboratoryrodents.Weevaluatedinadultmicethebehavioraleffectsofeitherfetaland/orneonatalCPFexposureatdosesnotinhibitingfetalandneonatalbraincholinesterase.CPF(3or6mg/kg)wasgivenbyoraltreatmenttopregnantfemalesongestationaldays1518andoffspringweretreatedsc(1or3mg/kg)onpostnataldays(PNDs)1114.Serumandbrainacetylcholinesterase(AChE)activitywasevaluatedatbirthand24hfromterminationofpostnataltreatments.OnPND70,malemicewereassessedforspontaneousmotoractivityinanopenfieldtestandinasocioagonisticencounterwithanunfamiliarconspecific.Virginfemalesunderwentamaternalinductiontestfollowingpresentationoffosterpups.Bothsexesweresubjectedtoaplusmazetesttoevaluateexplorationandanxietylevels.GestationalandpostnatalCPFexposure(higherdoses)affectedmotoractivityintheopenfieldandenhancedsynergicallyagonisticbehavior.PostnatalCPFexposureincreasedmaternalresponsivenesstowardpupsinfemales.MiceofbothsexesexposedtopostnatalCPFshowedreducedanxietyresponseintheplusmaze,aneffectgreaterinfemales.Altogether,developmentalexposuretoCPFatdosesthatdonotcausebrainAChEinhibitioninduceslongtermalterationsinsexspecificbehaviorpatternsofthemousespecies.LateneonatalexposureonPNDs1114wasthemosteffectiveincausingbehavioralchanges.ThesefindingssupportthehypothesisthatdevelopmentalCPFmayrepresentariskfactorforincreasedvulnerabilitytoneurodevelopmentaldisordersinhumans.

    [RicceriLetalToxicolSci93(1):10513(2006).]**PEERREVIEWED**PubMedAbstract

    /GENOTOXICITY/Chlorpyrifos (95.7%)primaryrathepatocytestestedforunscheduledDNAsynthesisat106,3.13x106,x105,3.16x105and1x104MtriplicateculturesinasingletrialnoevidenceofUDStoxicityatthehighestconcentration.

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust

  • 24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /GENOTOXICITY/Chlorpyrifos ,purityof98.6%,wasevaluatedforclastogenicpotentialusingratlymphocytestreatedfor4hourswithconcentrationsof0(DMSO),5,16.7,50,167.7,500,1667.0or5000mg/mL(Assay1)and0,5.0,16.7,50.0and167.0mg/mL(Assay2)withandwithoutS9metabolicactivation.Cultureswereharvested24hoursaftertreatmentinAssay1and24and48hoursaftertreatmentinAssay2.Noincreaseinchromosomalaberrationsatthehighestscorabledoselevelsof167mg/mL(withoutS9)and50mg/mL(withS9).

    [CaliforniaEnvironmentalProtectionAgencyDepartmentofPesticideRegulationChlorpyrifosSummaryofToxicologicalData(2001).Availablefrom,asofAugust24,2007:http://www.cdpr.ca.gov/docs/toxsums/pdfs/253.pdf**PEERREVIEWED**

    /GENOTOXICITY/...Chlorpyrifos .../was/studiedfor...potentialofformingDNAmonoadducts,DNAinterstrandcrosslinks,andDNAproteincrosslinksinprimarymousehepatocytesviatheassaysofbioluminescence,ethidiumbromidefluorescence,andK+SDSprecipitation.DNAinterstrandcrosslinkswerealsomeasuredoncalfthymusDNA.Itwasshownthatchlorpyrifos couldnotformDNAadducts.

    [CuiYetalMutatRes604(12):3641(2006)]**PEERREVIEWED**PubMedAbstract

    /GENOTOXICITY/DursbanwasscreenedformutagenicitybytherecassayprocedureusingdifferentstrainsofBacillussubtilis,aswellasreversionassaysonplatesutilizingauxotrophicstrainsofEscherichiacoli(WP2)andSalmonellatyphimurium(Amesseries).Resultswerenegative.

    [ShirasuYetalMutatRes40:19(1976)]**PEERREVIEWED**PubMedAbstract

    /GENOTOXICITY/Genotoxicityandembryotoxicityofchlorpyrifos (CPF)and2metaboliteswereevaluatedusingchickembryo,Chinesehamsterovarycell(CHO),andbyexaminingblastocystsfromsuperovulatedcowscrossedtochlorpyrifos treatedbulls.Testcompoundswereadministeredto3dayoldembryosbyaircellmethod.LD50was1,500ug/L/embryowhenmortalitywascheckedthroughandincluding17daysofdevelopment.ThemetabolitesweremoreembryotoxicthantheCPF.CPFanditsmetabolitesdidnotincreasethesisterchromatid(SCE)frequencyabovebackgroundatanydosagein3dayoldchickembryoassay.Noneofthecompoundsincreasedsisterchromatidfrequenciesin3pointdosagetests(1,10,100ug/L)usingChinesehamsterovarycells.Studiesofbovineblastocystsdidnotrevealevidenceofchromosomeaberrationsordevelopmentalanomaliesassociatedwithpesticideapplication.

    [MuscarellaDEetalEnvironMutagen6(1):1323(1984)]**PEERREVIEWED**PubMedAbstract

    /ALTERNATIVEandINVITROTESTS/Chlorpyrifos (CPF)isanorganophosphorusinsecticidethatelicitstoxicitythroughinhibitionofacetylcholinesterase(AChE).YounganimalsaremarkedlymoresensitivethanadultstotheacutetoxicityofCPF....Acetylcholine(ACh)releaseanditsmuscarinicreceptormediatedregulation(i.e.muscarinicautoreceptorfunction,MAF)duringmaturation/wereevaluated/asapossiblecontributingfactortoagerelateddifferencesinsensitivity.Corticalandstriatalsliceswereprelabeledwith[(3)H]cholinechloride,superfusedinthepresenceorabsenceoftheanticholinesterasephysostigmine(PHY,20M)andstimulatedtwice(S1andS2)withahighconcentrationofpotassiumchloride(20mM).DepolarizationstimulatedAChrelease(DSAR)waslowestinneonatal,intermediateinjuvenileandmarkedlyhigherinadulttissues.MAFwasnotdetectableintissuesfromneonatalratsbutwaspresentinjuvenileandadulttissues.AChreleaseandMAFwerestudiedat4,24and96hrfollowingoralexposuretoCPF(0,0.5or1xLD10).Ingeneral,4060%and8090%maximalAChEinhibitionfollowedexposuretotherespective0.5and1xLD10dosages.DSARwasdecreasedinneonatalcortex1dayafterLD10exposurebutincreasedinjuvenilestriatum1dayafterLD10treatment.Inadults,DSARwasreducedat4and24hrafterexposure,butincreased96hrafterCPFexposure.Injuveniles,MAFwasreducedinbothbrainregionsat24hrafter0.5LD10exposureandat24and96hrafterLD10exposureincortex.AlaterreductioninMAFwasnotedinadulttissues(i.e.onlyat96hrafterLD10treatment).Together,theresultssuggestthatAChreleasedynamicsinbrainvarymarkedlyduringpostnatalmaturationandthatacuteCPFexposurecanalterAChreleaseinanagerelatedmanner.Thefunctionalstatusofpresynapticprocessesregulatingneurotransmitterreleasemaycontributetoagerelatedneurotoxicityelicitedbyhighdoseexposurestochlorpyrifos .

    [WonYKetalNeurotox22:3746(2001)]**PEERREVIEWED**

    /ALTERNATIVEandINVITROTESTS/Prolongedexposuretoorganophosphate(OP)pesticidesmayproducecognitivedeficitsreflectiveofhippocampalinjuryinbothhumansandrodents.RecentworkhasindicatedthatmicrotubuletraffickingisalsoadverselyaffectedbyexposuretotheOPpesticidechlorpyrifos ,suggestinganovelmodeofOPinducedneurotoxicity.Thepresentstudiesexaminedeffectsofprolongedexposuretochlorpyrifos oxon(CPO)onacetylcholinesterase(AChE)activity,immunoreactivity(IR)ofmicrotubuleassociatedproteins,neuronalinjury,andtubulinpolymerizationusinginvitroorganotypicsliceculturesofrathippocampusandbovinetubulin.CultureswereexposedtoCPO(0.110uM)incellculturemediumfor17days,aregimenproducingprogressivereductionsinAChEactivityof1560%.Cytotoxicity(somaticuptakeofthenonvitalmarkerpropidiumiodide),aswellasIRofalphatubulinandmicrotubuleassociatedprotein2(a/b)[MAP2],wasassessed1,3,and7daysafterthestartofCPOexposure.Asearlyas24hafterthestartofexposure,CPOinduceddeficitsinMAP2IRwereevidentandprogressiveineachregionofsliceculturesatconcentrationsaslowas0.1uM.CPOexposuredidnotalteralphatubulinIRatanytimepoint.Concentrationdependentinjuryinthecornuammonis(CA)1pyramidalcelllayerandtoalesserextent,CA3anddentatecells,wasevident3daysafterthestartofCPOexposure(>or=0.1uM)andwasgreatestafter7days.TubulinpolymerizationassaysindicatedthatCPO(>or=0.1uM)markedlyinhibitedthepolymerizationofpurifiedtubulinandMAPrichtubulin,thougheffectsonMAPrichtubulinweremorepronounced.ThesedatasuggestthatexposuretoCPOproducesaprogressivedecreaseinneuronalviabilitythatmaybeassociatedwithimpairedmicrotubulesynthesisand/orfunction.

    [PrendergastMAetalNeuroscience146(1):3309(2007]**PEERREVIEWED**PubMedAbstractFulltext:PMC1955434

  • /ALTERNATIVEandINVITROTESTS/...InvitroinhibitionstudiesindicatedthatChEinneonataltissueswasmarkedlymoresensitivetoinhibitionbytheactivemetaboliteofchlorpyrifos (i.e.,chlorpyrifos oxon,CPO)thanenzymeinadulttissues(IC(50)values:neonates,17nMadults,200nM).ChelationoffreecalciumwithEDTAhadrelativelylittleeffectoninvitrocholinesteraseinhibition,suggestingthatdifferentialAesteraseactivitywasnotresponsiblefortheagerelateddifferenceincholinesterasesensitivitybetweenagegroups.PreincubationofneonatalandadulttissueswithselectiveinhibitorsofAChEandbutyrylcholinesterase(BChE)indicatedthatamajority(8290%)ofChEactivityintheheartofbothneonatesandadultswasBChE.Therapidonset(by4hrafterdosing)ofchangesinmuscarinicreceptorbindinginadultheartmaybeareflectionofthemorepotentdirectbindingtomuscarinicreceptorsbychlorpyrifos oxonpreviouslyreportedinadulttissues.TheresultssuggestthatChEactivity(primarilyBChE)inneonatalheartmaybeinherentlymoresensitivetoinhibitionbysomeanticholinesterasesandthattoxicologicallysignificantbindingtomuscarinicreceptorsmaybepossiblewithacutechlorpyrifos intoxication,potentiallycontributingtoagerelateddifferencesinsensitivity.

    [HowardMDetalToxicology238(23):15765(2007)]**PEERREVIEWED**PubMedAbstractFulltext:PMC2954647

    /OTHERTOXICITYINFORMATION/Thecardiovascularactionsofanticholinesteraseagentsarecomplex,sincetheyreflectbothganglionicandpostganglioniceffectsofaccumulatedAChontheheartandbloodvessels.ThepredominanteffectontheheartfromtheperipheralactionofaccumulatedAChisbradycardia,resultinginafallincardiacoutput.Higherdosesusuallycauseafallinbloodpressure,oftenasaconsequenceofeffectsofanticholinesteraseagentsonthemedullaryvasomotorcentersoftheCNS./Anticholinesteraseagents/

    [Hardman,J.G.,L.E.Limbird,P.B.,A.G.Gilman.GoodmanandGilman'sThePharmacologicalBasisofTherapeutics.10thed.NewYork,NY:McGrawHill,2001.,p.183]**PEERREVIEWED**

    /OTHERTOXICITYINFORMATION/...FreshlyeclosedfirstinstarlarvaeofDrosophilamelanogastertransgenicforhsp70(hsp70lacZ)Bg(9)werefedon0.015150.0ppbdichlorvosandchlorpyrifos mixedfood.Virginflieseclosingfromthenormalandcontaminatedfoodwerepairmatedtoexaminetheeffectofthetestchemicalsonreproductionoftheexposedorganisms.Expressionofhsp70,sexpeptide(SPorAcp70A),accessoryglandprotein(Acp36DE)andtissuedamagewasexaminedinreproductiveorgansofadultfly.Exposedorganismsexhibitedadosedependentsignificantlyreducedreproductiveoutcomeandmaleswerefoundtobemoresensitivethanfemales.Hsp70expressionwasrestrictedonlywithinthetestislobesofmaleflywhileitwasnotinducedintheovaryofthefemale.Inconcurrencewithabsenceofhsp70expressionintheaccessoryglandsofmalefly,tissuedamagewasevidentinthem.Acp70AandAcp36DEexpressionwerefoundtobesignificantlydownregulatedatthehigherconcentrationsofthetestchemicals.Thestudysuggeststhat(i)dichlorvosismoredeleterioustoflyreproductioncomparedtochlorpyrifos withanadverseeffectonAcp70AandAcp36DEexpressionrequiredtofacilitatenormalreproduction(ii)hsp70maybeusedasamarkerofcellulardamageagainstdichlorvosandchlorpyrifos inDrosophila.

    [GuptaSCetalToxicology238(1):114(2007)]**PEERREVIEWED**PubMedAbstract

    /OTHERTOXICITYINFORMATION/Themainfeatureofthetoxicmechanismoforganophosphoruspesticidesisinhibitionoftheesteraseenzymeactivity,inparticularofcholinesterase,whichplaysanimportantphysiologicalpart.Organophosphoruspesticidescanalsoindirectlyinteractwiththebiochemicalreceptorsofacetylcholine./Organophosphoruspesticides/

    [InternationalLabourOffice.EncyclopediaofOccupationalHealthandSafety.Vols.I&II.Geneva,Switzerland:InternationalLabourOffice,1983.,p.1638]**PEERREVIEWED**

    /OTHERTOXICITYINFORMATION/LiverRNAandDNAisolatedfrommalemiceipinjectedwith2doses(5and15mg/kgbodyweight)oflabeledchlorpyrifos werehydrolyzed.RadioactivityresultingfromincorporationandalkylationofRNAandDNAwasmeasured.Labeled7ethylguaninewasfoundinRNAhydrolysate.InDNAhydrolysate(14)C7ethylguaninewasmissingandmajorradioactivitywasfoundin2unknownpeaks,oneofwhichcorrespondsto3x102%oftheapplieddose.Theresultsindicatethattheextentofalkylationobtainedwithchlorpyrifos ishighascomparedwithotherorganophosphateswithmethylesters.

    [MostafaIYetalZNaturforsch(C)38(56):4614(1983)]**PEERREVIEWED**PubMedAbstract

    EcotoxicityExcerpts:

    /BIRDSandMAMMALS/Dietary11daytoxicantfeedingtestswereusedtodetermineeffectsofchlorpyrifos onmallards.Avoidanceoffoodwasnotedatallconcentrationstested(561124ppm)withconsequentialdecreaseinweightgrowth.

    [KenagaEEetalAstmSpecTechPubl(STP693,AvianMammWildlToxicol):3644(1979)]**PEERREVIEWED**

    /BIRDSandMAMMALS/This/study/wasdesignedtodeterminetheeffectofusingtwodifferentagesofmallard(Anasplatyrhynchos)adultswithinthefirstbreedingseasononreproductivetestsunderstandardToxicSubstancesControlActavianreproductiveguidelines.Theadultagegroupswere7and11monthsattestinitiation.Thetestchemicalwasanorganophosphateinsecticide,chlorpyrifos .Chlorpyrifos exposurereducedadultbodyweight,brainacetylcholinesteraseactivity,eggproduction,eggshellthickness,eggweight,andday0ducklingweightinbothagegroups.Statistically,adultageaffectedonlyducklingday14weight.However,threeofthe7monthhensproducedphenotypicallydifferentducklings,suggestingthepresenceofadifferentgenotypewhichmayhaveimpactedtheday

  • 14weight.Overallagerangingbetween7and11monthsattestinitiationdidnotaffectthismallardreproductivetest.Inaddition,theresultsofthisstudydemonstratetheimportanceofusingphenotypicallyandgenotypicallysimilartestbirds.

    [GileJD,MeyersSMArchEnvironContamToxicol15(6):7516(1986)]**PEERREVIEWED**PubMedAbstract

    /BIRDSandMAMMALS/Nosignificantreproductiveeffectswereobservedformallardsreceiving8ppm(mg/kgoffeed)chlorpyrifos intheirdiet.Birdsreceiving80ppmchlorpyrifos hatchedsignificantly(p

  • approachestheBMC(02.5).Thepeakchlorpyrifos concentrationdetectedat0.482ug/LisneartheBMC(1SD)estimate.

    [SandahlJF,JenkinsJJEnvironToxicolChem21(11):24528(2007).]**PEERREVIEWED**PubMedAbstract

    /AQUATICSPECIES/Brainacetylcholinesterase(AChE)activitywasevaluatedaftertwodifferentswimmingtestsinCohosalmon(Oncorhynchuskisutch238+/5g)given96hrexposuresto0,5,10,20,or40ug/Lofchlorpyrifos .BrainAChEactivitydecreasedinaconcentrationdependentmanner(AChEactivitieswere81.8,52.2,37.3,and21.3%ofcontrolforthe5,10,20,and40ug/Lexposures,respectively),whereasswimmingperformancewasimpairedafterathresholdofAChEimpairmentwasreached.Specifically,forswimmingperformance(U(crit))measuredusingtheestablishedrampU(crit)test(duration,152+/8min),thisthresholdoccurredwithAChEactivityof68.5%+/18.1%ofcontrol.Forarapidaccelerationtest(U(deltav),whereVrepresentsvelocity27.6+/0.8min),thisvaluewas52.6%+/15.4%ofcontrol.Bothswimprotocolsresultedinsimilarmaximumswimspeeds(controlrampU(crit)andU(deltav)valuesof3.44+/0.09and3.71+/0.13bodylengths/sec,respectively),andperformancewassignificantlyreducedafter20and40ug/Lexposuresinbothgroups(rampU(crit)values:86.4and83.6%,respectively,ofcontrolU(deltav)values:85.2and77.8%,rsepectively,ofcontrol).Althoughbothtestsyieldedsimilarswimspeeds,postexerciseplasmalactateconcentrationsweregreaterfortheU(deltav)test(11.3+/0.6vs8.6+/0.5mmol/L),indicatingagreateranaerobiceffort.Thisincreasewasexaggeratedafter10ug/Lofchlorpyrifos (14.6+/1.3mmol/L),indicatingthatanaerobicmusclewasusedtoattainthesamespeed.GiventhethresholdrelationshipbetweenAChEinhibitionandswimmingperformance,cohosalmonappearabletomaintainintegratedswimmingactivitydespitesignificantimpairmentofanunderlyingneurologicalcontrolmechanism.

    [TierneyKetalEnvironToxicolchem26(5):9981004(2007)]**PEERREVIEWED**PubMedAbstract

    /AQUATICSPECIES/Influenceofbodysizeoninhibitionofbrainacetylcholinesterase(AChE)activityofjuvenileNiletilapia,Oreochromisniloticusbychlorpyrifosandcarbosulfanwasinvestigatedconcerningitspotentialuseinthebiomonitoringofanticholinesterasepesticidesintropicalwaterbodies.Threesizegroupsoffish(fry:34cm,fingerlings:68cm,subadults:1012cmintotallength)wereexposedtoaseriesofconcentrationsofchlorpyrifos (0.512ug/L)orcarbosulfan(110ug/L),andconcentrationresponseforinhibitionandrecoveryoftheAChEenzymewasevaluatedincomparisontothecontrolsatdifferenttimepoints,2,6,10,and14days.TheAChEactivitiesofthecontrolfishfollowedtheorderofdecreasingactivity,fry>fingerlings>subadults.AChEactivitiesofthefrywerenearly2foldhigherthanthatofthesubadults.Following48hrofpesticideexposure,theAChEactivityofthethreesizegroupsoffishdecreasedsignificantlyincomparisontotherespectivecontrolsinaconcentrationdependentmanner.Theactivitywasgreatlyinhibitedinthefry(3985%)comparedtosubadults(1847%)exposedtothemostofthesimilarconcentrationsofthepesticides.Medianeffectiveinvivoinhibitionconcentrations(48hrIC50)ofchlorpyrifos forfry,fingerlings,andsubadultstageswere0.53,0.75,and3.86ug/L,respectively,whereasthecorrespondingvaluesforcarbosulfanwere3.37,7.02,and8.72ug/L.Whenfishweremaintainedintheinitialpesticidemediumfor14days,AChEactivityrestoredgraduallydependingontheinitialpesticideexposureconcentrationandthesizegroupofthefish.ResultsindicatethatbrainAChEofNiletilapiaisapromisingbiomarkerforassessmentofanticholinesterasepesticidecontaminationsinwater.However,bodysizeofNiletilapiashouldbetakenintoaccountwhenusingthisbiomarkerinbiomonitoringprograms.

    [ChandrasekaraLW,PathiratneAEcotoxicolEnvironSaf67(1):10919(2007)]**PEERREVIEWED**PubMedAbstract

    /AQUATICSPECIES/Thejointtoxicityofesfenvalerateandchlorpyrifos tothefatheadminnow(Pimephalespromelas)andtheaquaticmidgelarvae(Chironomustentans)wasdeterminedusingcomparisonstoindependentaction(IA)andconcentrationaddition(CA)models.Equipotentmixturesofthetwoinsecticideswereusedforinitialtestingofbothspecies.Asecondarystudyevaluatingtheeffectsoflowlevelchlorpyrifos onesfenvaleratetoxicityalsowasperformed.Forfatheadminnows,theequipotentmixtureandthelowlevelchlorpyrifos exposureresultedintoxicitygreaterthanthatpredictedbyeithermodel.Inbothstudies,however,theobservedconcentrationscausing50%effect(EC50)werewithinafactoroftwoofthevaluespredictedbytheCAmodel.Formidges,theobservedEC50sweresimilartothevaluespredictedbytheCAmodel,whereastheIAmodelslightlyunderpredictedtoxicity.Theobservanceoftoxicitythatwasnotpredictedbyeitheroftheconceptualmodelstestedlikelyresultsfromatoxicokineticinteractionoccurringbetweenthetoxicants.

    [BeldenJB,LydyMJEnvironToxicolChem25(2):6239(2006).]**PEERREVIEWED**PubMedAbstract

    /AQUATICSPECIES/Sublethalstudiesofchlorpyrifos ,O,OdiethylO(3,5,6trichloro2pyridyl)phosphorothioateonmosquitofish,Gambusiaaffiniswerecarriedoutinvivo,for20daystoassessthelocomotorbehaviorinrelationtobioaccumulationandinteractionwithatargetedenzyme,acetylcholinesterase(AChE,EC:3.1.1.7).Fishexposedtosublethalconcentrationof60ug/L(1/5ofLC50)wereunderstress,andreducedtheirlocomotorbehaviorlikedistancetravelledperunittime(m/min)andswimmingspeed(cm/sec)withrespecttothelengthofexposure.Thealterationinlocomotorbehavioroffishmaybeduetoanaccumulationofacetylcholine(ACh),aneurotransmitteratsynapticjunctions,duetotheinhibitionofAChEenzymeactivity(40to55%)inbrainandalsobioaccumulationofthetoxicantindifferentpartsoffish.Thebioaccumulationvaluesindicatedthattheaccumulationofchlorpyrifos wasmaximuminviscerafollowedbyheadandbody.Theaveragebioconcentrationvaluesare0.109,0.009and0.004ug/gforviscera,headandbodywithdepurationratesof2.24,1.69and0.39ng/hrrespectively.Itisevidentfromtheresultsthatthesublethalconcentration[1/5ofLC50equivalenttoLowestObservedEffectConcentration(LOEC)]ofchlorpyrifos canabletoalterthelocomotorbehaviorofG.affinisinrelationtothelengthofexposure.ThefindingsrevealedthatthelocomotoractivityoftestorganismcouldbeconsideredasasuitablemarkertoevaluatetheaffectoftoxicantevenatLOEClevels.

    [RaoJVetalIntJEnvironResPublicHealth2(34):47883(2005)]**PEERREVIEWED**PubMedAbstract

    /AQUATICSPECIES/Pesticideswithchlorpyrifos andendosulfanasactiveelementareusedforpestcontrolonagriculturallandsandarehighriskinputsinaquaticsystems.TheacutetoxicityoftheseinsecticidesinthefreshwaterprawnPalaemonetesargentinuswasevaluated.Theresultswereusedtodeterminethelowestobservedeffectandnoobservedeffectconcentrations.Individualgrowthofprawnsinrelationtochlorpyrifos andendosulfanexposurewasanalyzed.LC50valuestochlorpyrifos andendosulfanexposurewere2.98ug/Land14.10at24hoursand0.49ug/Land6.28ug/Lat96hoursofexposure,respectively.Thesizeincrementofprawnswasthesameinalltreatmentscephalothoraxlengthincreasedlinearlypermolt.Theintermoltperiodwasinfluencedbythetoxiceffectof

  • pesticidesduringrearingtime,andthisdecreasedwiththemoltcyclescomparedwiththenormalgrowthpattern.TheresultssuggestthatjuvenilesofP.argentinusaresensitivetochlorpyrifos andendosulfanpollution.

    [MontagnaMC,CollinsPAArchEnvironContamToxicol53(3):3718(2007).]**PEERREVIEWED**PubMedAbstract

    /AQUATICSPECIES/...Theinvitroandinvivoeffectsofawidelyusedorganophosphorouspesticide,chlorpyrifos ,onChEactivitywereinvestigated.TheresultssuggestthatG.pulexpossessonlyoneChEwhichdisplaysthetypicalpropertiesofanacetylcholinesterase,since:(1)ithydrolysestothesubstrateacetylthiocholineatahigherratethanallothertestedsubstratesand(2)itishighlysensitivetoeserinesulphateandBW284c51,butnottoisoOMPA.Invitroandinvivoinhibitionswereobservedforhighlydifferentcontaminationlevels,whichsuggeststhatbioaccumulationandbiotransformationmechanismsareinvolved.InvivoAChEinhibitionwasobservedatrealisticenvironmentalconcentrations,withlethaleffectsappearingatinhibitionshigherthan50%.TheresultsofthisstudyshowthevalueofG.pulexasasentinelorganismforenvironmentalassessment.

    [XuerebBetalToxicology236(3):17889.Epub(2007).]**PEERREVIEWED**PubMedAbstract

    /AQUATICSPECIES/Theacutetoxicityofchlorpyrifos anditsprincipalmetabolite3,5,6trichloropyridinol(TCP)aloneandincombinationtoacladoceran,Daphniacarinata,wasstudiedinbothcladoceranculturemediumandnaturalwatercollectedfromalocalsuburbanstream.TCPwasfoundtobemoretoxicthanitsparentchemicalchlorpyrifos toDaphniasurvivalincladoceranculturemedium.However,TCPinnaturalwaterwasnottoxictoD.carinataupto2ug/L.TheLC(50)valuesforchlorpyrifos ,TCPandchlorpyrifos+TCPwere0.24,0.20and0.08ug/L,respectively,incladoceranculturemedium.Althoughtheparentchemicalsandtheirdegradationproductscoexistinnaturalwaters,theexistingguidelinesforwaterqualityarebasedonindividualchemicals.Theresultsofthisinvestigationsuggestthatchlorpyrifos andTCPcaninteractsynergistically,additivelyorantagonistically,resultinginanincreaseordecreaseintheoveralltoxicityofthemixturecomparedtoindividualcompounds.Theindigenousmicroorganismsinnaturalwatercouldplayasignificantroleindegradationofthesecompoundstherebyinfluencingtheirtoxicityinreceivingwaters.Thisstudyclearlysuggeststhatthejointactionofpesticidesandtheirdegradationproductsshouldbeconsideredinthedevelopmentofwaterqualityguidelines.Toourknowledge,thisisthefirststudyontheinteractiveeffectofchlorpyrifos andTCPtoacladoceranandsuggeststhatthesetwocompoundsarenontoxicwhenpresenttogetheratconcentrationsupto0.12ug/L.However,thesecompoundstogetheractadditivelyatandabove0.5ug/Ltofreshwaterinvertebratesandthereforepollutionwiththesecompoundsmayadverselyaffectnaturalecosystems.

    [CaceresTetalWaterRes41(19):4497503(2007).]**PEERREVIEWED**PubMedAbstract

    /AQUATICSPECIES/Fatheadminnows(Pimephalespromelas)wereexposedtoDursbanfor200daysincludingareproductiveperiodoftheirlifecycle.Survivalof1stgenerationwasadverselyaffectedat2.68ug/Lwithin60days.Asignificantnumberofdeformitiesoccurredat2.68ug/Lwithin30days.Growthwassignificantlydecreasedat2.68ug/Lwithin30daysandat1.21ug/Lby60days.Maturationofthefirstgenerationfishwasreducedatallexposurelevelsandreproductionwassignificantlyreducedat0.63ug/Landabove.Growthandestimatedbiomassof30dayoldsecondgenerationfishwasgreatlyreducedat0.12ug/L.Brainacetylcholinesterase(AChE)activitywasinhibitedat0.27ug/Landabove.AChEinhibitionrangedfromnear10%infishexposedto0.12ug/Lto89%forthoseexposedto2.68ug/L.

    [JarvinenAWetalEcotoxicolEnvironSafety7(4):42334(1983)]**PEERREVIEWED**PubMedAbstract

    /AQUATICSPECIES/Threeacetylcholinesterase(AChE)formsweredetectedandrecoveredfromfootorgilltissuesofthebenthonicbivalvemolluskScapharcainaequivalvis.Astudywasperformedtoinvestigatechangesincatalyticandhydrodynamicfeaturesoftheseenzymes,aswellasintheirexpressionlevels,aftera4dayora15dayexposuretoasublethalconcentration(0.1uL/L)ofthepesticidechlorpyrifos (CPF).Bothconsideredorganshold,ineitherCPFexposedoruntreatedanimals,twononamphiphilicAChEforms,G2andG4,whichcopurifiedonaprocainamidecontainingaffinitygelandwereseparatedbydensitygradientcentrifugation.AthirdAChEform,anamphiphilicmembraneanchoredG2,wasalsopurif


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