LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS
THENEEDFORAUGMENTATIONOFREGULATORYPATH
2019-01-17 �1
AbhayDeshpande,Ph.D.Director-GlobalInnovation&Strategy-JRFGlobal
22February2019 �2
Contentsandflowofthoughts
• Whatisbotheringtheregulators?
• Replace/ReduceAnimals!!
• Usealternativemethods….invitro!Useread-across!
• HistoryofGuidelinesareupdates&revisions
• Consolidatetheguidelines….moredatawhileusingtheanimals
• EOGRTS
• HormoneanalysisinOECD407/408
• AoPs,appliedinthevitrostudiesmammalian/fishetc.
• ConclusionLATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
22February2019 �3
RegulatoryTrendsintheEU&theUS
• EuropeanUnion
• REACH,Biocides&Cropcareproducts
• Weightofevidence
• QSARmodels
• Invitromethods
• Groupingofsubstancesandread-across
• US
• EPAforTSCA&FiFRA(FederalInsecticide,Fungicide,andRodenticideAct)
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
Horizonisconstantlymoving
• TheEUregulatorsareinsistingonuseofforallthefutureregistrationneeds;
• ReadacrossforAcuteoralanddermaltoxicity
• invitrotestsforskinirritation/corrosion,eyeirritationaswellasskinsensitization
• Inhalationtoxicitystillremainsinvivo,butthenewguidelinesbasedonToxicClasscriteriausereducedanimals.
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Options??
Alternativemethods….insilico/invitro!•Grouping&Read-across
•WeightofEvidence/WoE
• QSAR•Non-animalmethods
https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testing-on-animals/weight-of-evidence
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
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Grouping&ReadAcross
• Userelevantinformationfromanalogoussubstancestopredictthepropertiesofthe‘target'substances.
• Eliminateexperimental(animal)testingbyusingtheconcept……justificationsmustestablishadequacyandappropriatenessofthedocument.
• MustbeKeydatabasedonidentifiablewithappropriatereferencestoIUCLID(*)substancedatasetwouldbenecessary.
• Predictionmustbebasedonstructuralsimilarity/dissimilarity.
• Aread-acrossapproachcanbeusedtodefendaconclusionforapropertyusingaweight-of-evidenceapproach.(*InternationalUniformChemicalInformationDatabase)
https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testing-on-animals/grouping-of-substances-and-read-across
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
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Read-AcrossAssessmentFramework(RAAF)
Process:
• Checktherobustnessofread-acrossadaptation.
• Hypothesizethejustificationforusingthedatafromonesubstancestructurallyrelatedsubstancetotheother,foreachproperty.
• Searchforexperimentaldataforcontradictionsagainsttheproposedhypothesisifany.
• Providecrediblesupportinginformation.
• Impuritiesandpotentiallydifferentsubstancecompositionsmustbutbehighlighted
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
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WeightofEvidence(WoE)
WeightofEvidencemustbebasedon;
•Publishedliterature•Datafromexistingstudies
•Epidemiologicaldata/humanexperience.
https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testing-on-animals/weight-of-evidence
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
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Weightofevidence:• Includes,asaminimum,twoseparatestudy/textbookvaluesrecordsforacertainproperty,singlevaluefromasecondarydatasourceisnotsufficient• Domainexperttoassessthereliability,relevance,adequacyoftheavailabledatatoassesscombinedevidenceisadequatetoavoidatest
• Theexpertjudgementshouldbetransparentandunderstandableappropriatelysupportedbydelineatingtheprocessofarrivingatconclusionandprovidingthereferences.
WeightofEvidence(WoE)
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
22February2019 �10
QSAR
• Mathematicalmodels(generatedbasedpublishedresearchdata)
• Predictthephysicochemical,biologicalandenvironmentalfatepropertiesofcompounds,basedontheirchemicalstructure.
• Limitations:Currently(Q)SARshavelimitationsinaccuratelypredictingcomplextoxicologicalproperties,notdeemedfitforpurposeforclassificationandlabellingorriskassessment.
https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testing-on-animals/qsar-models
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
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• Documentedformat:IULID
• Tobeusedonlywhenthetestresults,arenotavailable
• Considerusingadditionalparametersandlinkpotentialinteractionsbetweenthem.
• (Q)SARsmaybecoupledwithotherdataandusedinaweightofevidenceapproach.
• Onestudyrecordforeachchemicalstructurefor(Q)SARprediction.
QSAR
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
22February2019 �12
invitromethods
invitromethods• Testsystemisalive,butoutsideofalivingorganism
• Usuallyinvolvesisolatedcells/immortalized/reconstructedcelllines,rarelytissuesororgans
• Theycouldbeusedforsupportingpart/fullreplacementofanimaltests.
• Useofsufficientlywell-developedmethodsincompliancewithinternationallyagreedtestdevelopmentcriteria(ECVAM*).
https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testing-on-animals/in-vitro-methods
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
*EuropeanCentrefortheValidationofAlternativeMethods
22February2019 �13
• 2016onwards,theEUmandatesinvitrotestmethodsthedefaultforcertaintoxicologicalproperties.
•NoAcutedermalandeyeirritationandsensitizationtestswillbeaccepted.
•SensitizationcouldbedoneusingLLNAassaybutGPSisa“No-No”!
•Regulatormayacceptaninvitroassaydata,whichhasn’tbeeninternationallyvalidated,asdossierorsupportofWoE.
invitromethods
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
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Effortsaimedatachievingmaximaldatabyaddingadditionalendpointsintheexistinganimaltestingguidelines
•OECD443-EOGRTS-TheExtendedOneGenerationReproductionToxicityTest
•DevelopmentalToxguidelinewithimmunoandneurotoxcohorts
•OECD407/408
•Hormoneanalysis(T3,T4,TSH&Testosteroneestimationmandatory• Onhorizon:Plasmaconcentrationforestablishinglimitofexposure!
Consolidatetheguidelines….
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
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Guidelineupdating….OECDtestguidelines
Year NoofGuidelinesrevised
%revised Revisionperyear
2018 15 20.8% 20.8%2017 4 5.6% 5.6%2016 14 19.4% 19.4%2015 8 11.1% 11.1%
2008–2014 11 15.3% 2.2%1998-2007 8 11.1% 1.1%1981-1997 12 16.7% 1.0%
72
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
TheGuidelineHorizon@OECDisconstantlychanging!
• 77changesinthepast10years
• 30ofthe72OECDtestguidelines,havebeenreleasedfocusedoninvitromethodsaimedatanimalstudyreplacement!
• 15ofthe30havebeenreleasedduring2016tilldate!
• EUregulators:completelystoppedacceptanceofGuineaPigMaximizationtestforSkinsensitizationw.e.f.October11,2016!!
• Restofthechangesaimedatbringinoptionstoreduceanimals/reducepain/discomfort/achievemorefromtheexistingguidelineswithadditionalbiomarkerschippedin!
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2019-01-17 �17
AOPsareonhorizon…
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
NC3RsPathways-basedapproachesresource:Issue6:August2018
DPRAOECD442C
KeratinoSens/LuSens
OECD442D
hCLATOECD442E
KineticDPRAonitsway….
2019-01-17 �18
Should&CantheAnimaltestingbeavoided?
TestseffectivelyEliminated;
• RodentAcuteOral/Dermaltoxicity,Skinandeyeirritation,skinsensitization,
NewproductDevelopment:
• LD50/LC50/metabolismbasedtestsusingspecificcellsystemusinghumanprimary/immortalized/iPSCderiveddifferentiatedcells
• Zebrafishembryo
RegulatoryAccepted
• Skin&EyeIrritation/corrosiontests
• SkinsensitizationusingbatteryoftestsdrivenbyAoPsLATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
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Should&CantheAnimaltestingbeavoided?
Animaltestingbebestavoided,
• NC3Rs:wherever,thetestunequivocallyestablishesthattheexpectedsafetyassessmentneedsshouldbemetwithbythealternativetests!
• Antithesis:
• AnimaltestingisstillthebestwaytofindnewtreatmentsforpatientsGarattiniS,GrignaschiG,EurJInternMed(2016),http://dx.doi.org/10.1016/j.ejim.2016.11.013
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
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Ourtake@JRF:• Equilibriumisthelawoftheuniverse!• Itensuressteadystateandstability!•Widependulumswingsareanti-stability!
Rationalthinkingistheneedofthehour!!!
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
ForAnimaltesting AgainstAnimaltesting• Animaltestingisstillthebestway…….thereareseveralresearcherswhoopenly/inprivateconversation,supportthisview.
Avoidanimaltesting….therearepossiblyequalnumberofopinion-leaderswhosupportthisview.
2019-01-17 �21
ThankstoXIVthASC&Dr.Mayeeforthisopportunity
LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal
ThankyousomuchAudience.
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