Integrated Approaches to Testing and Assessment (IATA · PDF fileIntegrated Approaches to...
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Integrated Approaches to Testing and
Assessment (IATA) – ex. Skin Sensitisation
10th EPAA Annual Conference
Brussels, 2014
João Barroso
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Chemical Observe
adverse effects Animal model
Pancreatic tumor
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Animal-intensive Questionable human relevance Expensive Very time-consuming
Conventional Toxicology
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Biological Profiling
Cheminformatics Exposure modeling
DATA INTEGRATION
PREDICT SAFETY
Cell cultures 3D tissues Genomics
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Vision: Next Generation Safety Assessment
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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.
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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.
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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
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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
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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
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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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