OECD ACTIVITY ON ALTERNATIVE METHODS- INTEGRATED APPROACHES TO TESTING

AND ASSESSMENT AND THE QSAR

TOOLBOX-

Presented by Masashi Horie from OECD5-6 November 2018ECOPA 2018 SymposiumHow new experimental tools in life sciences challenge the 3Rs vision

OECD Work on Predictive Toxicology

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OECD Hazard

Assessment activities

Development of IATA for defined hazard

endpoints; Guidance on Grouping of Chemicals

OECD QSAR PROJECT

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• Free software application to support filling data gaps for hazard assessment by chemical category approach.

• Contains databases, structural characteristics (profilers), and tools to estimate missing experimental values by read-across, by trend analysis and/or by (Q)SAR models.

• Is co-owned by ECHA and OECD and maintained by OECD member countries (updating 1-2 times/year)

• Already is widely used and supported by governmental organizations, research institutions and industry (about 13,000 users) 4

What is OECD QSAR Toolbox?

• (Q)SAR Project launched in 2003

– Aim: improve the use of (Q)SARs in regulatory settings

– Drivers: avoid unnecessary use of laboratory animals

– The QSAR Toolbox: a major work item in accomplishing the aim

• Agreed in 2004 on OECD Principles for the validation, for regulatory purposes, of (Q)SAR models

1) A defined endpoint

2) An unambiguous algorithm

3) A defined domain of applicability

4) Appropriate measures of goodness-of–fit, robustness and predictivity

5) A mechanistic interpretation, if possible

• Released OECD QSAR Toolbox v1.0 in March 20o8

OECD QSAR Project History

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• Released the latest version 4.2 released in February 2018:

– Now 69 profilers including 12 updated profilers and 5 updated metabolism simulators;

– Now 55 databases with ~70 000 chemicals and ~2 116 700 data points including 7 updated databases and 5 new databases.

– Extended Predefined substance type: UVCB substances, polymers

– Improved alert performance functionalities accounting for metabolism

– Automated/Standardized workflows for Skin sensitization and Ecotox endpoints

– New report generation system (including the RAAF scenario)

http://www.oecd.org/chemicalsafety/risk-assessment/oecd-qsar-toolbox.htm

New Features of the QSAR TB

version 4

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• Toolbox helps industry and authorities to

✓Use the methodologies to group chemicals into categories and

✓Refine and expand the categories approach

✓ Provide a mechanistic transparency of the formed categories

✓ Fill data gaps by read-across, trend analysis and (Q)SARs

✓ Ensure uniform application of read-across

✓ Support the regulatory use of (Q)SAR approach

✓ Improve the regulatory acceptance of (Q)SAR methods

QSAR Toolbox Today

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Interlinkage of OECD developed tools

Tools

Indicates that the information contains substance related data formatted according to the OHTs.

(Planned)

Indicates the flow of information to a tool

(Planned)

OECD encourages

database developers

curating effects

information to consider

using OHTs to increase

the ability to share data.

OECD promotes the interlinkage of tools developed to support chemical management in a regulatory context – Includes QSAR Toolbox

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IATA CASE STUDIES PROJECT

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Objective:

– Increase experience with the use of Integrated Approaches for Testing and Assessment (IATA) by developing case studies, which constitute examples of predictions that are fit for regulatory use

– Create common understanding of using novel methodologies and the generation of considerations/guidance stemming from these case studies

Deliverables:

– Case studies followed by guidance documents on approaches

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IATA Case Studies Project

http://www.oecd.org/chemicalsafety/risk-assessment/iata-integrated-approaches-to-testing-and-assessment.htm

Gather existing information

Problem formulation

Weight of Evidence Assessment: Adequate information for decision-making?

Generate additional information

Weight of Evidence assessment: Adequate information for decision-making?

Regulatory

conclusion

YES

NO

YES

NO

General workflow in IATA

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Toolbox provide:(Q)SAR, read-across, in chemico, in vitro, ex vivo, in vivo, grouping chemical

IATA Case Studies Project – Use of

ToolboxYear-No.

(Lead)Title

IATA topics

AOP1 UR2 NAM3 L/N4

2018-1 (JP) Testicular Toxicity of Ethylene Glycol Methyl Ether (EGME)-Related Chemicals X X

2018-2 (US) The Use of a Defined Approach for Identifying Estrogen Receptor Active Chemicals X X X

2017-1 (CAN/US) Estrogenicity of Substituted Phenols X X X X

2017-2 (CAN)Prioritization of chemicals using the Integrated Approaches for Testing and Assessment (IATA)-based Ecological Risk Classification

X X X

2017-3 (JRC) Case study on grouping and read-across for nanomaterials genotoxicity of nano-TiO2 X X

2017-4 (ICAPO)A Case Study on the Use of Integrated Approaches for Testing and Assessment for Sub-Chronic Repeated-Dose Toxicity of Simple Aryl Alcohol Alkyl Carboxylic Esters: Read-Across

X X X

2016-1 (JP) Repeated-Dose Toxicity of Phenolic Benzotriazoles X X

2016-2 (US) Pesticide Cumulative Risk Assessment & Assessment of Lifestage Susceptibility X X

2016-3 (ICAPO) 90-Day Rat Oral Repeated-Dose Toxicity for Selected n-Alkanols: Read-Across X X X

2016-4 (ICAPO) 90-Day Rat Oral Repeated-Dose Toxicity for Selected 2-Alkyl-1-alkanols: Read-Across X X X

2016-5 (JRC/BIAC)Chemical Safety Assessment Workflow Based on Exposure Considerations and Non-animal Methods

X X

2015-1 (CAN/US) In Vitro Mutagenicity of 3,3’ Dimethoxybenzidine (DMOB) Based Direct Dyes X X

2015-2 (CAN) Repeat Dose Toxicity of Substituted Diphenylamines (SDPA) X X

2015-3 (JP) Hepatotoxicity of Allyl Ester Category X X

2015-4 (Japan)Bioaccumulation Potential of Biodegradation Products of 4,4'-Bis (chloromethyl)-1,1'-biphenyl

X X

*1: AOP: Use of mode of action/adverse outcome pathways *3: NAM: Use of new approach methodologies*2: UR: Uncertainty reporting *4: L/N: Low/no toxicity prediction

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Year-No. (Lead

How to use Toolbox for identifying analogues

2015-1 (Canada)

To predict microbial metabolism of category members by using metabolic simulator.

2015-2 (Canada)

To search for additional SDPAs with required endpoint data and meeting somestructural criteria

2015-4 (Japan)

To extract other source chemicals with target endpoint data

2016-1 (Japan)

To calculate structural similarity and to predict metabolites from category members by the metabolism simulator.

2016-3,4 (ICAPO)

To predict metabolites by metabolism simulators for comparison of potential metabolic products within category members and to compare toxicophoreswithin category members based on profilers.

2017-4 (ICAPO)

To confirm similarity in regards to in silico toxicokinetics based on the liver metabolism simulators and in silico toxicodynamics based on the mechanistic and endpoint profilers

Example for use of Toolbox in IATA:

Identifying analogues

REPORT ON CONSIDERATIONS FROM CASE STUDIES ON INTEGRATED APPROACHES FOR TESTING AND ASSESSMENT (IATA) Third Review Cycle (2017) Series on Testing and Assessment No. 289http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=ENV/JM/MONO(2018)25&docLanguage=En

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Example for use of Toolbox in IATA:

Prioritisation [2017-2 (Canada)]

PRIORITISATION OF CHEMICALS USING THE INTEGRATED APPROACHES FOR TESTING AND ASSESSMENT (IATA)-BASED ECOLOGICAL RISK CLASSIFICATION Series on Testing and Assessment No. 291http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=ENV/JM/MONO(2018)27&docLanguage=En

Profilers in the Toolbox was used to identify the chemicals which have the following potential effects:

• Endocrine-mediated effect

• Mode of action (acute aquatic toxicity)

• Protein and DNA binding

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OECD WORK ON PREDICTIVE

TOXICOLOGY – AN EVOLUTION

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To a large extent based on in vivo tests, conducted in accordance with standardised test guidelines or protocols such as OECD Test Guidelines.

Current Regulatory Toxicity Testing

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Adverse Outcome Pathways as a

Mechanistic Framework

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• Development of (Q)SARs

• Grouping of chemicals into chemical categories

• Development of testing strategies

• Interpretation and integration of results from non-standard test methods

• Selection of methods for Test Guideline development/refinement

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Examples of how AOPs can be used

in the development of IATA

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Already some elements of theseare in the Toolbox

FUTURE OF TOOLBOX

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The Future of QSAR Toolbox

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• Central regulatory tool for hazard assessment and regulatory decisions

– Simplification (automated workflows, Web API)

– More QSARs/ADME data/profilers

– Link with molecular pathways/AOPs

• Open, extensible platform for categorisation, QSARs and toxicological data

– Providing functionalities via web service (Profiler, Calculator/QSAR, Simulator, Access to data)

– Possibility of docking external QSARs by Web Services

– Publication of the Toolbox API (docking external modules and repository of Toolbox extensions)

– Straightforward and transparent donation procedure for external modules

• Knowledge platform combining classical and mechanistic data with (Q)SARs and knowledge extraction/integration tools

– More DBs integrated with the TB

– Link with an AOP KB portal (Effectopedia, AOP Wiki, …)

– Link between adverse effects (phenotypic changes) and toxicological pathways

– New extensions for handling ‘omics data

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Thank you for your attention

Further information: Masashi.HORIE@oecd.org

OECD QSAR Toolbox Website:http://www.oecd.org/chemicalsafety/risk-assessment/oecd-qsar-toolbox.htm• Download the QSAR Toolbox

• Guidance Documents and Training Materials

• Help Desk

• Public Discussion Forum

etc.