OECD’S WORK ON ADVERSE OUTCOME PATHWAYSBob Diderich, 20 November 2015

bob.diderich@oecd.org

www.oecd.org/ehs

1736

Ch

em

icals

Chemicals on the market

Only 10 -20%has been

fully assessed

1900 2000

Growing concern over lack of toxicological data

Chemical Substances Control Law

Countries are improving their legislation to assess more chemicals in a shorter time frame

Standard toxicity testing is costly, time consuming and requires many animals

Costs€2,000 - €2,000,000

5000 animals / chemical

Test duration 30 – 720 days

Mutual Acceptance of Data

OECD Principles of Good Laboratory Practise and

Compliance Monitoring ProceduresOECD Test Guidelines

Mutual Acceptance of Data

BY AVOIDING DUPLICATIVE TESTING BY INDUSTRY ANDNON-TARIFF TRADE BARRIERS:

AT LEAST € 150 MILLION / YEAR

SAVINGS FROM MAD

OECD Test Guidelines based on non-animal methods

- skin and eye corrosion / irritation - phototoxicity - skin absorption - genotoxicity

Promoting the use of non-animal methods

Read across

Target Chemical

O NO

ClCl

Cl

(Q)SARPredictio

n

(Quantitative) StructureActivity Relationships

CH3

O

S O

O

Cl

Cl

O N

O

Cl

N

C

Cl

C

N

Cl

Cl

ClO N

O

NO

O

N

O

O

Cl

O N

O

Cl

N

O

O

OH

Cl

Cl Cl

Cl

ClO N

O

Cl

Cl

ON

O

Cl

Cl

OH

Cl Cl

Cl

Allergy

+ + +

+ + +

+ + -

OH

C

CH

C

Cl

C

Cl

CH

C

ClO N

O

C

CH

C

Cl

CH

CH

C

Cl

OH

C

CCl

C

Cl

C

Cl

C Cl

C

Cl

O N

O

C

CH

CH C

Cl

C N

O

O

CHO N

O

C

CH

CH CCl

C Cl

CH

CH3

O

SO

OC

CH

C

ClCH

CH

C

Cl

O N

O

C

CH

C

NO

O

CH

C N

O

OC

ClN

C

C

CCl

C

C

N

C

Cl

C Cl

C

Cl O NO

Cl

+ + +

+ + +

+ + -

Developing models to predict toxicity

• Free software application to predict the properties of chemicals (currently version 3.3)

• Estimate missing experimental values by read-across and trend analysis (grouping of similar chemicals, chemical categories)

www.oecd.org/env/hazard/qsar

QSAR Toolbox (1)

9

Target Chemical

O NO

C

CH

CCl

CCl

CH

CCl

Target Chemical

O NO

C

CH

CCl

CCl

CH

CCl

Developmental & Reproductive

toxicity

Need for mechanistic understanding

pathogenesis / time

Organelle

Cellular

Tissue

Organism

Organ

Population

MolecularMolecular Initiating Event (MIE)

Adverse Outcome (AO)Key Event (KE)

Identifying the mechanism at work

Reduced VTG uptake

OvaryLiver

Low Vitellogenin in blood vessles

Reduced VTG

production

Blood Vessel

Reduced circulating

VTG

Reduced E2

synthesis

Estrogen

Reduced E2 concentratio

n

Decreased spawning

Female

Aromatase

Testosterone

Aromatase Inhibition

Population reduction

Key events triggered by aromatase inhibition that lead to population reduction

Organelle

MolecularEnzyme binding (QSAR)

inhibition of aromatase (in vitro)

Cellular

TissueReduction VTG synthesis (in vitro) Reduction in estrogen synthesis (in

vitro)

OrganReduction egg production (in vivo)

OrganismDecreased spawning (in vivo)

PopulationPopulation decline

Early key events can be measured with non-animal tests, which can be used to predict the adverse outcome

Molecular (in vitro)

Cellular (in vitro)

Organism

Organ (in vivo)

Aromatase

VTG

Egg production

Endocrine Disruptor

Structure (QSAR)Enzyme binding

Results from structurally

related chemicalsTarget chemical

Aromatase

VTG

Enzyme binding

Endocrine Disruptor

Read-across based on mechanistic understanding

MIE1 KE KE AO1KE

Chemical MIE2 KE AO2

KEMIE3 KEX KE AO3

Chemical

concentration

KE KE

A chemical can trigger different MIEs leading to different adverse effects

MIE1 KE AO2

KE

Chemical MIE2

KE

KE AO3

MIE3 KE AO4KE

A chemical can trigger a network of AOPs

KE

Chemical 1 MIE KE AO4KE

Chemical 2 MIE

Chemical 1

Chemical 2

concentration

Use of AOP Networks to assess toxicity of mixtures

AOP Wiki

• Effectopedia provides visualisation for all pathway elements

• Capture all experimental information and models needed to make quantitative predictions

• Allow collaborative work between AOP developers

AOP

Opportu-nities for

colla-boration

Prioriti-sationrisk

assessment

Develop predictive

tools

Reduce Animal

use

Effective use of

existing knowledge

Benefits of AOPs

21

Initiating event Adverse Outcome

Alkylation of DNA Heritable mutations

Androgen receptor agonism Reproductive dysfunction

Aromatase inhibition Reproductive dysfunction

Protein Alkylation Liver Fibrosis

PPARα activation

Impaired fertility PPARγ activation

Binding of Antagonists to NMDAR

Learning and memory impairment

Binding of Agonists to NMDAR

AOPs under external review

THANK YOU FOR YOUR ATTENTION