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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)


Horizonisconstantlymoving

• TheEUregulatorsareinsistingonuseofforallthefutureregistrationneeds;

• ReadacrossforAcuteoralanddermaltoxicity

• invitrotestsforskinirritation/corrosion,eyeirritationaswellasskinsensitization

• Inhalationtoxicitystillremainsinvivo,butthenewguidelinesbasedonToxicClasscriteriausereducedanimals.

�4LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal

22February2019 �5

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


22February2019 �6

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


22February2019 �7

Read-AcrossAssessmentFramework(RAAF)

Process:

• Checktherobustnessofread-acrossadaptation.

• Hypothesizethejustificationforusingthedatafromonesubstancestructurallyrelatedsubstancetotheother,foreachproperty.

• Searchforexperimentaldataforcontradictionsagainsttheproposedhypothesisifany.

• Providecrediblesupportinginformation.

• Impuritiesandpotentiallydifferentsubstancecompositionsmustbutbehighlighted


22February2019 �8

WeightofEvidence(WoE)

WeightofEvidencemustbebasedon;

•Publishedliterature•Datafromexistingstudies

•Epidemiologicaldata/humanexperience.

https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testing-on-animals/weight-of-evidence


22February2019 �9

Weightofevidence:• Includes,asaminimum,twoseparatestudy/textbookvaluesrecordsforacertainproperty,singlevaluefromasecondarydatasourceisnotsufficient• Domainexperttoassessthereliability,relevance,adequacyoftheavailabledatatoassesscombinedevidenceisadequatetoavoidatest

• Theexpertjudgementshouldbetransparentandunderstandableappropriatelysupportedbydelineatingtheprocessofarrivingatconclusionandprovidingthereferences.

WeightofEvidence(WoE)


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



• Documentedformat:IULID

• Tobeusedonlywhenthetestresults,arenotavailable

• Considerusingadditionalparametersandlinkpotentialinteractionsbetweenthem.

• (Q)SARsmaybecoupledwithotherdataandusedinaweightofevidenceapproach.

• Onestudyrecordforeachchemicalstructurefor(Q)SARprediction.

QSAR



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


*EuropeanCentrefortheValidationofAlternativeMethods


• 2016onwards,theEUmandatesinvitrotestmethodsthedefaultforcertaintoxicologicalproperties.

•NoAcutedermalandeyeirritationandsensitizationtestswillbeaccepted.

•SensitizationcouldbedoneusingLLNAassaybutGPSisa“No-No”!

•Regulatormayacceptaninvitroassaydata,whichhasn’tbeeninternationallyvalidated,asdossierorsupportofWoE.

invitromethods



Effortsaimedatachievingmaximaldatabyaddingadditionalendpointsintheexistinganimaltestingguidelines

•OECD443-EOGRTS-TheExtendedOneGenerationReproductionToxicityTest

•DevelopmentalToxguidelinewithimmunoandneurotoxcohorts

•OECD407/408

•Hormoneanalysis(T3,T4,TSH&Testosteroneestimationmandatory• Onhorizon:Plasmaconcentrationforestablishinglimitofexposure!

Consolidatetheguidelines….



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


TheGuidelineHorizon@OECDisconstantlychanging!

• 77changesinthepast10years

• 30ofthe72OECDtestguidelines,havebeenreleasedfocusedoninvitromethodsaimedatanimalstudyreplacement!

• 15ofthe30havebeenreleasedduring2016tilldate!

• EUregulators:completelystoppedacceptanceofGuineaPigMaximizationtestforSkinsensitizationw.e.f.October11,2016!!

• Restofthechangesaimedatbringinoptionstoreduceanimals/reducepain/discomfort/achievemorefromtheexistingguidelineswithadditionalbiomarkerschippedin!

�16LATESTTRENDSINSAFETYEVALUATIONOFAGROCHEMICALS-AbhayDeshpande,JRFGlobal

2019-01-17 �17

AOPsareonhorizon…


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

2019-01-17 �19

Should&CantheAnimaltestingbeavoided?

Animaltestingbebestavoided,

• NC3Rs:wherever,thetestunequivocallyestablishesthattheexpectedsafetyassessmentneedsshouldbemetwithbythealternativetests!

• Antithesis:

• AnimaltestingisstillthebestwaytofindnewtreatmentsforpatientsGarattiniS,GrignaschiG,EurJInternMed(2016),http://dx.doi.org/10.1016/j.ejim.2016.11.013


http://dx.doi.org/10.1016/j.ejim.2016.11.013

�20

Ourtake@JRF:• Equilibriumisthelawoftheuniverse!• Itensuressteadystateandstability!•Widependulumswingsareanti-stability!

Rationalthinkingistheneedofthehour!!!


ForAnimaltesting AgainstAnimaltesting• Animaltestingisstillthebestway…….thereareseveralresearcherswhoopenly/inprivateconversation,supportthisview.

Avoidanimaltesting….therearepossiblyequalnumberofopinion-leaderswhosupportthisview.

2019-01-17 �21

ThankstoXIVthASC&Dr.Mayeeforthisopportunity


ThankyousomuchAudience.

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