Catherine Willett, Humane Society of the United States, Humane Society International

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Approaches to Testing and Assessment (IATA) Catherine

1 The Use of Adverse Outcome Pathways (AOPs) to Support Chemical Safety Decisions within the Context of Integrated Approaches to Testing and Assessment (IATA) Catherine Willett, Humane Society of the United States, Humane Society International

2 Outline: Why o Need for faster, predictive approach to toxicology What o Purpose, definition How o AOP Wiki o Guidance o Evaluation When o Integrated Approaches to Testing and Assessment o Use in decision making

cellular components, preferably of human origin.

3 Need for faster, predictive toxicology Transform toxicity testing from a system based on whole animal testing to one founded primarily on in vitro methods that evaluate changes in biologic processes using cell, cell lines, or cellular components, preferably of human origin. Including tests that assess critical mechanistic endpoints involved in the induction of overt toxic effects rather than the effects themselves. National Academy of Sciences, 2007

4 Linking molecular information to adverse outcomes: Adverse Outcome Pathways?

Linking molecular information to adverse outcomes: Adverse Outcome Pathways Chemical properties Protein binding DNA binding Receptor/ligand binding Gene activation Protein production Altered

5 Linking molecular information to adverse outcomes: Adverse Outcome Pathways Chemical properties Protein binding DNA binding Receptor/ligand binding Gene activation Protein production Altered signaling Altered physiology Altered tissue development or function Impaired development Impaired reproduction lethality Impaired reproduction/ survival, Population crash Conceptually, an AOP can be viewed as a sequence of events commencing with initial interactions of a stressor with a biomolecule in a target cell or tissue (i.e., molecular initiating event), progressing through a dependent series of intermediate events and culminating with an adverse outcome. AOPs are typically represented sequentially, moving from one key event to another, as compensatory mechanisms and feedback loops are overcome. OECD AOP User s Handbook:

6 AOP Provides Organization for Understanding and Relating Data Toxicity Pathways Regulatory Endpoints Toxicants Macro - Molecular Interactions Cellular Responses Organ Responses Organism Responses Population Responses High Throughput Tox Guideline Studies Mechanistic Toxicology Data Bioindicators (e.g. Molecular Epi) Epidemiology Eco Field Studies

7 Essential Elements of an AOP Chemical properties Protein binding DNA binding Receptor/ligand binding Gene activation Protein production Altered signaling Altered physiology Altered tissue development or function Impaired development Impaired reproduction lethality Impaired reproduction/ survival, Population crash KER 1 KER 2 KER 3 KER 4 MIE KE 1 KE 2 KE 3 AO Molecular Initiating Event (MIE): Initial point of chemical interaction Adverse Outcome (AO): Adverse outcome of regulatory significance Key Events (KEs) - nodes Change in biological state Measurable and essential for progression Key Event Relationships (KERs) - edges Connections between two key events Critical for assembling evidence in support of the AOP Villeneuve, et al. Tox Sci., 2014, 142:

8 AOP Knowledgebase: information storage, evaluation, and linkage

9 Five Principles of AOP Development 1. AOPs are not chemical specific 2. AOPs are modular (consisting of KEs and KERs) that can be shared between two or more pathways 3. An individual AOP is a pragmatic unit of development and evaluation 4. For most real-world applications, AOP networks are the functional unit of prediction 5. AOPs are living documents Villeneuve, et al. Tox Sci., 2014, 142:

10 AOP WIKI: information storage and evaluation

11 AOP WIKI: KER and AOP confidence evaluation Biological Plausibility: between KE upstream and KE downstream? High (strong): Extensive understanding of KER Moderate: KER is plausible Low (weak): some empirical support Essentiality: are downstream KEs prevented if upstream KE s blocked? High (strong): direct evidence from experimental studies Moderate: indirect evidence Empirical Evidence: amount, quality, consistent, inconsistent? High (strong): extensive evidence for temporal, dose-response Moderate: multiple reports of consistent evidence, some inconsistent Low (weak) No or contradictory evidence Low (weak): limited or no studies and/or significant inconsitencies OECD (2014) User s Handbook Supplement to the Guidance Document for Developing and Assessing AOPs.

12 Carole Yauk

13 AOP in context of hazard and risk assessment Adverse Outcome Pathway, Ankley 2010, Villeneuve 2014 Borrowed from Steve Edwards

14 AOPs in action Data organization Hypothesis generation Weight-of-evidence interpretation Prediction MIE KER1 KE 1 KER2 KE 2 KER3 KE n KERn Adverse outcome Assay 1 Assay 2 Assay 3 Assay n Integrated testing strategy

Integrated Approach to Testing and Assessment (IATA): OECD working definition Problem formulation Gather existing information MORE INFORMATION NEEDED?

15 Integrated Approach to Testing and Assessment (IATA): OECD working definition Problem formulation Gather existing information MORE INFORMATION NEEDED? Design non-testing strategy Design testing strategy Repeat until question is answered to necessary certainty a structured approach that strategically integrates and weights all relevant data to inform regulatory decisions regarding potential hazard and/or risk and/or the need for further targeted testing and therefore optimising and potentially reducing the number of tests that need to be conducted. Report of the Workshop on a Framework for the Development and Use of Integrated Approaches to Testing and Assessment OECD Series on Testing and Assessment No. 215

16 Using an AOP within the context of an IATA AOP provides biological rationale o o For weight-of-evidence interpretation For design of integrated, iterative testing strategy Transparent communication of certainty Quantitative information allows prediction

Regulatory acceptance of IATA: specific case Defined Approaches (DA) Several different possibilities for combining information How do regulators deal with

17 Regulatory acceptance of IATA: specific case Defined Approaches (DA) Several different possibilities for combining information How do regulators deal with different IATA to satisfy same information request? Proper guidance is crucial DA possibly covered by MAD? (Mutual Acceptance of Data) (J. Baroso, European Commission. 2014)

IATA Provide consistent description of individual information sources to allow easy comparison between

18 Regulatory acceptance of IATA: specific case Defined Approaches Goal of EC-led OECD project: Provide guidance on development, evaluation and application of IATA Develop harmonized template for describing IATA Provide consistent description of individual information sources to allow easy comparison between methodologies Evaluate different IATA for specific uses Include list of case examples (Defined Approaches)

AOP-supported IATA example: Skin Sensitization Skin sensitization IATA: Exposure?

Event Cellular Effects human Cell Line Activation Test (h-clat; OECD 442E) Organ

19 AOP-supported IATA example: Skin Sensitization Skin sensitization IATA: Exposure? ADME? In vitro skin Existing absorption ifnormation (OECD 428) Molecular Initiating Event Cellular Effects human Cell Line Activation Test (h-clat; OECD 442E) Organ Effects Individual Effects Question to be answered: Screening? Hazard ID? GHS C&L? Sub-classification? QSARs; Direct Peptide Reactivity Assay (DPRA; OECD 442C) KeratinoSens (OECD 442D) MUSST (U-SENS) LuSens Local Lymph Node Assay (LLNA, OECD 429)-mouse

85% h-clat 78% DPRA + LuSENS 85% Combinations (1 out of 2 is positive) DPRA + mmusst 81%

20 Skin Sensitization IATA: looking for the optimal testing strategy for hazard ID Compared to human Accuracy Standard animal test LLNA 89% DPRA 87% Individual tests LuSens 82% mmusst 85% h-clat 78% DPRA + LuSENS 85% Combinations (1 out of 2 is positive) DPRA + mmusst 81% DPRA + h-clat 83% LuSens + mmusst 80% LuSens + h-clat 82% 2 out of 3 DPRA + LuSens + mmusst 94%

21 Regulatory acceptance of IATA: specific case Defined Approaches

22 Regulatory acceptance of IATA: specific case Defined Approaches Examples of different IATA for skin sensitization:

23 In Summary AOPs can support decision making at every level, and in several ways: o support WoE arguments o support ITS design o transparent communication of uncertainty o predicting outcome AOP Wiki is crowd-sourced, open to everyone o The more participation, the better it will become!

24 In Summary Designed to answer a specific question Hypothesis driven Can be AOP supported More than one IATA possible for a given question Regulatory acceptance as Defined Approaches

25 Thank you! Catherine Willett, PhD Director, Regulatory Testing Risk Assessment and Alternatives Humane Society of the United States Humane Society International Coordinator, Human Toxicology Project Consortium

Introduction to Adverse Outcome Pathways and the AOP Wiki

Introduction to Adverse Outcome Pathways and the AOP Wiki Sunday July 20, 2017 10:00 AM - 12:00 PM Sheraton Seattle, Aspen Room 10:00: Introduction to the OECD AOP Programme and Online Training course