EnvironmentalToxicology:InterconnectionsBetweenHumanHealthandEcologicalIntegrity

EnvironmentalToxicology:InterconnectionsBetweenHumanHealthandEcologicalIntegrity

WilliamH.Benson,PhDDirector,NationalHealthandEnvironmentalEffectsResearchLaboratory

OfficeofResearch&Development,U.S.EnvironmentalProtectionAgency*

*ThispresentationdoesnotrepresentEPApolicyandmentionofproductsortradenamesdoesnotconstitutearecommendationforuseorendorsement.

Overview• WhatHasMadeaCareerinEnvironmentalToxicology

Rewarding• EnvironmentalandScientificChallengesforthe21stCentury• ParadigmShiftinRegulatoryToxicology

– AdverseOutcomeFramework• InterconnectionsBetweenHumanHealthandEcological

Integrity– SOT-SETACPellstonWorkshopFindings

• ConceptsforSystemsThinkinginEnvironmentalToxicology

WhatHasMadeaCareerinEnvironmentalToxicologyRewarding

• Fosteringandworkinginateamenvironment• Advancingthestateofscienceandvalueofscience• Trainingandmentoringthenextgenerationofscienceleaders• Nurturingofaworkenvironmentthatcelebratescivilityandjoyof

science• Encouragingasocialconscience– publicservice• Conducttherightscience,right– scienceforapurpose

Leadingscienceisaboutleadingpeople

ScienceforaPurpose

QUESTIONSDevelopfocusedandinsightfulsciencequestionsraisedbythe

problem

PROBLEMUnderstandtheproblemfacing

society

RESEARCHPRODUCTSHighqualitypeer-reviewedmodels,

methods,papersasproducts

STRATEGICPRODUCTSIntegratedproductsthatwillbeusedtohelpsolveproblem

APPROACHESDevelopscientifically

soundmeanstoaddresstheproblem

Dotherightsciencefortherightreasonandmakea

difference

21stCenturyChallenges• Climateadaptationandresilience• Changingenergylandscape• Multi-pollutantexposure• Increasingnitrogenandphosphoruslevelsimpairwater

quality• Susceptibility&environmentaljustice• Thousandsofnewindustrialchemicalsandpesticides

eachyear• Chemical,biological,radiological-basedterrorism• Emergingmaterials,biotechnology,syntheticbiology

ResearchtoAddressScientificChallenges• Innovative – fostercreativityandstimulate

transformationalchange• Integrative – workcollaborativelyacrossdisciplines• Systemsthinking– holisticapproachtoanalysisonthe

waythatasystem’sconstituentpartsinterrelateandhowsystemsworkovertimeandwithinthecontextoflargersystems

• Solution–oriented – emphasisondevelopingsustainablesolutions

• Responsive – providerelevantandtimelyresultstoinformenvironmentaldecision-making

• Translational – endusersreceivethenecessaryinformationtoutilizeresearchproductstosolveenvironmentalproblems

TheGreatChemicalUnknownScientificAmerican(November2010)303,92

• Onlyatinyfractionofthecompoundsaroundushavebeenevaluatedforrisk– ChemicalsusedbyU.S.consumers

andindustry:>100,000– Testedinvivo:<500

• Waterqualitycriteria/standards:– Approximately100pollutants

UniverseofChemicalsintheEnvironment

Thisunknownisaconsequenceoftheconventionalapproachemployedforregulatorytoxicitytesting

ConventionalApproachtoGeneratingDataforChemicalRiskAssessment

• Wholeanimaltestsfocusedonapicalresponses(survival,growth,reproduction)atorganismlevel

• WiderangeofpotentiallyadverseeffectsassessedwithoutnecessarilyunderstandinghoworwhytheyoccurAdvantages:Well-defined,easilyunderstoodendpoints;substantialhistory/experience;“gold”standarddatasetsforhighprioritychemicals; invivosystemsareintegrativeresponsesDisadvantages:Resource- (money,animal)andtime-intensive(esp.forchronictests);impossibletotestmorethanafewchemicals;relianceonapicalresponseslimitsextrapolation(chemical-chemical;species-species;lab-field)

AParadigmShiftinRegulatoryToxicology

PredictingChemicalToxicitywithLimitedData• Identify“normal”biologicalpathwayswhose

perturbationresultsinadverseresponsestochemicals

• Determinechemicalcharacteristicsthatenablethemtoperturbthesepathways

• Developapproachestomeasureorpredictthesecharacteristics– Insilico(computational)methods(e.g.,QSAR,

networkmodels)– Invitro(e.g.,HTP)toxicitypathwayassays– Invivotestswithpathway-basedendpoints

(“biomarkers”)

-1

0

1

2

3

4

5

6

-2 -1 0 1 2 3 4 5 6 796-h

Log

LC

50 (m

g/L)

Log Kow

FatheadMinnowAcuteToxicity

ComputationalApproachesforPredictiveToxicology:QSARs

ToxCast>600assays,>2000chemicals

IntroductionInVitroApproachestoPredictiveToxicology:HTPTesting

InVivoApproachestoPredictiveToxicology• Invivoexposures/testshelpobviateuncertaintiesassociatedwithcomputational/invitro

systems(e.g.,metabolism,pharmacokinetics,integrative,pathwaycomplexity,etc.)• Evolvingtechnologiesinmolecularbiology/analyticalchemistry(e.g.,‘omics)enablerapid

measurementoflargenumbersofbiologicalchangesassociatedwithshort-termperturbations(hours-days)

• Concurrentadvancesinsystems/networkbiologyenableanincreasinglycoherentevaluationofthistypeofhighcontentdata,aswellasmoretraditionalbiomarkerinformation(e.g.,PCR,ELISA,RIA,histology)

AnAdverseOutcomePathway(AOP)isaconceptualframeworkthatportraysexistingknowledgeconcerningthelinkagebetweenadirectmolecularinitiatingevent andanadverseoutcome,atalevelofbiologicalorganizationrelevanttoriskassessment.

ChemicalProperties

Receptor/LigandInteraction

DNABinding

ProteinOxidation

Geneactivation

Proteinproduction

Alteredsignaling

Alteredphysiology

Disruptedhomeostasis

Alteredtissuedevelopment/

function

Lethality

ImpairedDevelopment

ImpairedReproduction

Toxicant CellularResponses

OrganResponses

OrganismResponses

Structure

Recruitment

Extinction

PopulationResponses

Macro-MolecularInteractions

Environ.Toxicol.Chem.29(3):730-741(2010)

NovelAttributesoftheAOPFramework• Establishescommon,unambiguousterminologyasbasisfor

communicationamongscientistsandbetweenscientistsandriskassessors

• Promotesachemical“agnostic”approachtounderstandingpathwayperturbation,highlightingevaluationofchemicalsbasedonbiologicalsimilarity

• Providesabasisforestablishmentofcausallinkagesbetweenmolecular/biochemicalendpointsandapicaloutcomesthatcanbeassessedasto“fitforpurpose”usingWoE-basedapproaches*

*Becker,R.A.,etal.2015.Increasingscientificconfidenceinadverseoutcomepathways:ApplicationoftailoredBradford-Hillconsiderationsforevaluatingweight-of-evidence.Regul.Toxicol.Pharmacol.72(3):514-537.

HowDoesaPathway-BasedApproachEnhancePredictiveChemicalAssessments?

• Providesbasisforusingalternative/mechanisticdatatopredictpossibleadverseeffects

• Focuses/optimizestestingneededtoassessrisks• Enhancescross-speciesextrapolationofchemicaleffects• Supportsassessmentofeffectsofchemicalmixtures

Receptor activation

Protein binding DNA binding

Gene activationProtein production Altered signaling

Altered tissue Disrupted

homeostasis

Malformations Organ dysfunction

Lethality

KeyEventRelationships

KeyEvents

AdverseOutcome

ChemicalInitiator(s)

MolecularInitiatingEvent

O

O

O

RegulatoryAcceptanceoftheAOPConcept

• DevelopmentofknowledgebaseforderivationandarchivingofAOPs(AOP-KB)

• PublishformalguidanceforAOPdevelopment,WoE assessmentandimplementation(2013/4)

WORKPLANFORDEVELOPMENT,ASSESSMENT,ANDUSEOFADVERSEOUTCOMEPATHWAYS(AOPs)

Organisation forEconomicCooperationandDevelopmentExtendedAdvisoryGrouponMolecularScreeningandToxicogenomics

http://www.oecd.org/env/ehs/testing/molecularscreeningandtoxicogenomics.htm

SOT-SETACPellston Workshop–InterconnectionsBetweenHumanHealthandEcologicalIntegrity(June2000)

• PolicyConceptsandApplications

• BiologicalBasesforSimilaritiesandDifferences

• CharacteristicsandImplicationsofInterconnections

ConceptualModel

DiGiulioandBenson(2002)

TheNaturalSystem

PhysicalEnvironment Biota

Naturalresources Humanpopulations

Climate Non-humanpopulations

Environmentalstressors Populationproductivity

Natural System Elements

NaturalSystemOutputsPositiveFlows NegativeFlowsRawMaterials PathogensEnergyresources ClimateextremesMinerals NaturaldisastersAirWaterLandSoilForests

EnvironmentalAmenitiesOpenspaceVisibilityNaturalAestheticsRecreationalOpportunities

MaterialsRecyclingHabitatMaintenance

Natural System Outputs

TheSocialSystem

Institutional Cultural

Economic Traditions/Customs

Political BeliefSystems

Legal Values/Attitudes

Religious Science/KnowledgeBase

Educational Technology

Social System Elements

SocialSystemOutputs

Benefits Stressors

Privategoodsandservices PollutionPublicgoodsandservices WasteTechnologicalinnovations HabitatdestructionNewscience/newknowledge UrbansprawlNewphilosophies/ethicalstandards OverpopulationStability/justice/socialharmony Resourcedepletion

Social System Outputs

Well-Being

Category

IndividualWell-Being

SocialSystemWell-Being

NaturalSystemWell-Being

Defining Well-Being

Category Measures

Individualwell-being

Health HealthstatusWealth Income,jobs, education

SocialJustice

AccesstolegalandpoliticalsystemsAccess tocleanandhealthyenvironmentAccesstojobsIncomedistributionFeelingsofbeingtreatedfairlySenseofempowerment

Psychological,Spiritual Lifesatisfaction

Social systemwell-being

Sustainability

PopulationgrowthConsumption patternsInstitutionalperformanceManageabilityofinstitutionalconflictandchangeProvisionsforfuturegenerations

SocialJustice

IncomedistributionEducational attainmentOccupationalcategoriesAccesstolegalandpoliticalsystemsAccesstoenvironmentalquality

PeaceandStability Absenceofwar,famine,socialunrest

Naturalsystem well-being

Health

DiseaseburdenReproductive capacityDemographicstructureFunctionalandstructuralintegrity

Wealth Qualityandquantityofhabitat

Sustainability SystempersistenceandrelianceProductivity

Defin

ingWell-B

eing

ConceptualModel• RequirementsforImplementation

– Greaterstakeholderinvolvementanduseofdecisionsciencetoencouragesystemsthinkingaboutcomplexproblems

– Effectivecommunicationamongscientists,policy-makers,andthepublic–acknowledgeareasofuncertaintyandbeproactive

– Reducefragmentationofregulatorysystemssothatconcernsforprotectionofhumanhealtharenotsegregatedfromconcernsforprotectionofecosystems–anintegratedapproach

– Communityinvolvement–uselocalknowledgewhilerespectingthevalues,traditionsandprioritiesofacommunity

A.AlonsoAguirre,EnvironmentalScienceandPolicy,GeorgeMasonUniversity,Fairfax,VA,USATP097

ConservationMedicine,EcoHealth andOneHealth:EvolvingParadigmsBuildingTransdisciplinaryCollaborations,IntegrativeResearchandLocalCapacity

OneHealthisthecollaborativeeffortofmultipledisciples–Workinglocally,nationally,andglobally–toattainoptimalhealthforpeople,animals,plants,andourenvironment

ConceptualModel

DiGiulioandBenson(2002)

UnderstandingBiological&PhysicalSystemsInformsDecisionMaking

Needtoutilizesystems-basedthinkingandapproachesat

multiplescalestosolveenvironmentalchallenges

ComputationalScience

Experimental&ObservationalScience

• LargeDataSets• AlternativeModels• Speciesextrapolation

• Knowledgegaps• Novelapplications

SocialSystemOutputs• Wastes• Interventions

NaturalSystemOutputs• Ecosystemservices• Rawmaterials• Energy

NaturalSystem• Physical

Environment• Biota

SocialSystem• Institutions• Culture• Economies

EnvironmentalIntegrity

Robust&ResilientEconomy

HumanHealth&Wellbeing

Environ.Toxicol.Chem.35(10):2383-1392(2016)

Thankyou!

KeyReferences• Aguirre,A.A.,VR.Beasley,T.Augspurger,W.H.Benson,andJ.Waley.2016.Onhealth– Transdisciplinary

opportunitiesforSETACleadershipinintegratingandimprovingthehealthofpeople,animalsandtheenvironment.Environ.Toxicol.Chem.35(10):2383-1392.

• AmericanVeterinaryMedicalAssociationOneHealthInitiativeTaskForce.2008.OneHealth:ANewProfessionalImperative.Schaumberg,IL,USA.

• Ankley,G.T.,R.S.Bennett,etal.2010.Adverseoutcomepathways:Aconceptualframeworktosupportecotoxicologyresearchandriskassessment.Environ.Toxicol.Cem.29(3):730-741.

• Becker,R.A.,G.T.Ankley,etal.2015.Increasingscientificconfidenceinadverseoutcomepathways:ApplicationoftailoredBradford-Hillconsiderationsforevaluatingweight-of-evidence.Regul.Toxicol.Pharmacol.72(3):514-537.

• DiGiulio,RT.andW.H.Benson(eds.).2002.InterconnectionsBetweenHumanHealthandEcologicalIntegrity.SETACPress,Pensacola,FL.

• Fischetti,M.2010.TheGreatChemicalUnknown.Sci.Amer.303:92.