Integrated Approaches to Testing and Assessment (IATA) ex. Skin Sensitisation

Transcription

1 Integrated Approaches to Testing and Assessment (IATA) ex. Skin Sensitisation João Barroso 10 th EPAA Annual Conference Brussels, 2014

2 Conventional Toxicology Chemical Animal model Pancreatic tumor Observe adverse effects Animal-intensive Questionable human relevance Expensive Very time-consuming 2

3 Vision: Next Generation Safety Assessment Biological Profiling Cell cultures 3D tissues Genomics Cheminformatics Exposure modeling DATA INTEGRATION PREDICT SAFETY 3

4 Integrated Approaches to Testing and Assessment (IATA): Proposed Working Definition 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. 4

5 Integrated Approaches to Testing and Assessment (IATA): Proposed Working Definition 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. 5

6 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 Key Event 1 Covalent interaction with skin proteins Key Event 3 Dendritic Cells (DCs) Induction of inflammatory cytokines and surface molecules Mobilisation of DCs Key Event 2 Keratinocyte responses Activation of inflammatory cytokines Induction of cytoprotective genes Key Event 4 T-cell proliferation Histocompatibility complex presentation by DCs Activation of T cells Proliferation of activated T-cells Adverse Outcome Inflammation upon challenge with allergen 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 6

7 From Adverse Outcome Pathways to Practical Applications priority setting hazard identification Integrated Approaches to Testing and Assessment (IATA) classification & labelling risk assessment Mechanistic information toxicokinetics Adverse Outcome Pathways Alternative Methods Toolbox in chemico assays in vitro assays in silico models chemical categories 7

8 Information Sources within IATA Physico-chemical data In silico data In chemico data In vitro data In vivo data Exposure considerations Assessment using WoE or predefined approaches or combination of both 8

9 Examples of Published Data Integration Strategies for Skin Sensitisation Nukada et al. (2013) Toxicology in Vitro 27, Jaworska et al. (2013) Journal of Applied Toxicology Bauch et al. (2012) Regulatory Toxicology and Pharmacology 63,

10 Development of IATA for skin sensitisation Several possibilities of combining information (contextspecific 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! 10

11 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 11

12 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. 12

13 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 13

14 Food for Thought 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 14

15 Thank you for your attention! Joint Research Centre (JRC) The European Commission s in-house science service Serving society - Stimulating innovation - Supporting legislation 15