Integrated Approaches to Testing and

Assessment (IATA) – ex. Skin Sensitisation

10th EPAA Annual Conference

Brussels, 2014

João Barroso

Chemical Observe

adverse effects Animal model

Pancreatic tumor

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Animal-intensive Questionable human relevance Expensive Very time-consuming

Conventional Toxicology

Biological Profiling

Cheminformatics Exposure modeling

DATA INTEGRATION

PREDICT SAFETY

Cell cultures 3D tissues Genomics

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Vision: Next Generation Safety Assessment

Integrated Approaches to Testing and Assessment (IATA): Proposed Working Definition

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A structured approach used for hazard identification

(potential), hazard characterisation (potency) and/or safety

assessment (potential/potency and exposure) of a chemical

or group of chemicals, which strategically integrates and

weights all relevant data to inform regulatory decision

regarding potential hazard and/or risk and/or the need for

further targeted and therefore minimal testing.

Integrated Approaches to Testing and Assessment (IATA): Proposed Working Definition

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Where sufficient understanding of Adverse Outcome

Pathways (AOPs) exists, such framework would provide a

solid scientific basis for development of IATA.

Within such an AOP-driven IATA, the different information

used to inform a regulatory decision would target key

events along the defined toxicity pathway.

Skin Sensitisation: First Case of AOP-driven IATA Development

Chemical

Structure

& Properties

Molecular

Initiating Event

Cellular

Response

Organ

Response

Organism

Response

Metabolism

Penetration

Electrophilic

substance

Covalent

interaction with

skin proteins

• Induction of inflammatory

cytokines and surface

molecules

• Mobilisation of DCs

• Activation of inflammatory

cytokines

• Induction of cytoprotective

genes

• Histocompatibility

complex presentation

by DCs

• Activation of T cells

• Proliferation of

activated T-cells

• Inflammation upon

challenge with

allergen

Dendritic Cells (DCs)

Keratinocyte responses

Key Event 1

Key Event 2

Key Event 3

Key Event 4 Adverse

Outcome T-cell proliferation

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

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From Adverse Outcome Pathways to Practical Applications

Mechanistic information

• toxicokinetics

• Adverse Outcome Pathways

Alternative Methods Toolbox

• in chemico assays

• in vitro assays

• in silico models

• chemical categories

Integrated Approaches to

Testing and Assessment

(IATA)

• classification & labelling

• risk assessment

• priority setting

• hazard identification

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Assessment using WoE or predefined approaches or combination of both

Physico-chemical data

In silico data

In chemico data

In vitro data

In vivo data

Exposure considerations

Information Sources within IATA

Nukada et al. (2013) Toxicology in Vitro 27, 609-618

Bauch et al. (2012) Regulatory Toxicology and Pharmacology 63, 489-504

Jaworska et al. (2013) Journal of Applied Toxicology

Examples of Published Data Integration Strategies for Skin Sensitisation

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• Several possibilities of combining information (context-

specific and substance-tailored).

• Some information will be covered by Mutual Acceptance of

Data (MAD), but final decision will not.

• There is therefore a risk of disharmonisation in the

application and interpretation of IATA.

• Proper guidance is crucial!

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Development of IATA for skin sensitisation

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OECD Project: Development of a Guidance Document on the Evaluation and Application of

IATA for Skin Sensitisation

Led by the European Commission

Project run under TF-HA (endorsed in June 2013)

Currently under development

Aims of the EC Led OECD Project

• Develop an AOP-driven IATA framework covering different regulatory needs across multiple industry sectors.

• Provide guidance on the development, evaluation and application of IATA.

• Provide a consistent description of individual information sources to allow for easy comparison between methodologies.

• To develop a harmonised template for describing IATA solutions.

• To include examples of compiled case studies.

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Six Principles: Essential Information for Regulatory Application of an IATA

1. A defined endpoint

2. A defined purpose

3. A description of the rationale underlying the construction of the IATA

4. A description of the individual information sources constituting the IATA

5. A description of how the individual information sources are integrated to derive the final prediction/assessment

6. A description of the known uncertainties associated with the IATA application

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• Lots of mechanistic knowledge exists but not being sufficiently explored to support the use of alternatives for safety assessment decisions (via IATA)

• This knowledge should be collected, evaluated and used to generate further AOP knowledge and guide method development and application in safety assessment

• But, in the short term, it should be better used to facilitate the regulatory acceptance of mechanistically based methods and support the development of mechanistically informed IATA

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Food for Thought

Thank you for your attention!

Joint Research Centre (JRC)

The European Commission’s in-house science service

www.jrc.ec.europa.eu

Serving society - Stimulating innovation - Supporting legislation

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