opentoxeuro 2016 integratingscientific ... · opentox2016 rheinfelden / regulatoryacceptance/ rex...

OpenTox Euro 2016

Integrating Scientific Evidence supporting Risk Assessment

Building Bridges Event; Rheinfelden, 28-Oct-2016

Rex FitzGeraldSCAHT / Universität BaselMissionsstrasse 64, 4055 Baselwww.scaht.org

Regulatory acceptance of new methods

2OpenTox 2016 Rheinfelden / Regulatory acceptance / Rex FitzGerald / 28-Oct-2016

Drug discovery

Disease modelling

Lead development

Regulatory chemical safety

testing

Environmental hazard

prioritization

• Physicochemistry• Receptor binding• Permeability and

transporters• Drug interactions• Screening for cardiotoxicity,

genotoxicity, cytotoxicity• Mechanistic toxicity assays

Are the data• Reliable?• Relevant?


GLP -> GIVIMP, GCCP…

Data reliability

Data relevancePathway analysis framework

- chemical-specific WHO Mode Of Action (MOA)- chemical agnostic OECD Adverse Outcome Pathway (AOP)

Data interpretationOECD Integrated Approaches to Testing and Assessment (IATA)


Reliability


"…we found considerable guidance for in vivo and human studies,

but only one paper addressed in vitro studies exclusively.

The guidance for (Q)SAR studies and physico-chemical studies was

scant but authoritative."


Relevance


http://www.ebtox.org/


Principles of AOP DevelopmentMolecular initiating event (MIE)

Key events (KEs)

Adverse outcome AO

OECD AOP framework

Key event definition:Ø essential to the AOØ causally linked to KEup and KEdownØ experimentally measurable


AOP networks can represent conservation and divergence of toxicological responses across taxa, life stages, etc.

ER Antagonism

HepatocyteReduced

VTG prodn

OvaryImpaired Oocyte

Dev.

FemaleDecreased

ovulation/spawning

PopulationDeclining Trajectory

AromataseInhibition

GranulosaReduced

E2 synthesis

AR AgonismHypothalamic

Neurons(-) Feedback

CYP17, CYP11A Inhibition

PlasmaReduced

circulating E2

Reduced bone density Osteoperosis

Corp.AllataReduced JH

synthesis

HemolymphReduced JH

concns

Fat BodyReduced

VTG prodn

Poor nutritional status

AOPs Support An Integrated Approach to ToxicologyPrinciples of AOP DevelopmentAOPnetworks


Teeguarden JG et al 2016. Environ Sci Technol. 50:4579


"The novel test methods used to identify the modes of action will need to be validated in the sense that their reliability and relevance will need to be demonstrated when used to make regulatory decisions."


http://www.ebtox.org/work-groups/Tox21/


…referring to the future of toxicology, Crofton offered a quote from Yogi Berra, “It’s pretty far, but it doesn’t seem like it.”


Interpretation


The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins; Part 1: Scientific Evidence. OECD Series on Testing and Assessment No.168 ENV/JM/MONO(2012)10/PART1


Regulatory in vitro identification of human skin sensitizers using an AOP-based combination of assays:

§ covalent protein binding(In Chemico Direct Peptide Reactivity Assay; OECD 442C)

§ keratinocyte inflammation(ARE-Nrf2 Luciferase; OECD 442D; KeratinoSens™)

§ dendritic cell activation(human Cell Line Activation Test h-CLAT or modified myeloid U937 dendritic cell activation-based skin sensitization test mMUSST)

OECD in vitro skin sensitization testing

The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins; Part 2: Use of the AOP to Develop Chemical Categories and Integrated Assessment and Testing Approaches. OECD Series on Testing and Assessment No.168 ENV/JM/MONO(2012)10/PART2


Bauch C et al 2012Regul Toxicol Pharmacol.

opentoxeuro 2016 integratingscientific ... · opentox2016 rheinfelden / regulatoryacceptance/ rex...

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