oecd’s work on adverse outcome pathways bob diderich, 20 november 2015 bob.diderich@oecd.org
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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
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