Programme: Workshop on Innovations in Pesticide Safety Testing and Chemical Risk Assessment for DNT

PROGRAMME Workshop on critical innovations in pesticides safety testing and chemical risk assessment for developmental neurotoxicity (DNT) 28-30 October 2024

2

Programme OECD Workshop on Critical Innovations in pesticides safety testing and chemical risk assessment, for developmental neurotoxicity DNT

Day 1 – 28 October 2024 Theme: Leverage on available experience from applying DNT-In vitro Battery (IVB) data 9h00 Welcome by the OECD Patience Browne and Anne Gourmelon, OECD Environment Directorate 9h15 Welcome by the CRP and introduction to the Programme Lieve Herman, CPR Scientific Advisory Body

Session 1: Lessons learned from existing IATA case studies using DNT-IVB data Chairs: Iris Mangas, European Food Safety Authority (EFSA), Italy and Tim Shafer, United States Environmental Protection Agency (US EPA), United States Build off previous OECD IATA Case Studies on DNT and the Initial Recommendations on Evaluation of Data from the DNT-IVB published in 2022 and 2023, respectively. These efforts identified the need to elaborate on what was learned so far and identify the focus of additional efforts to accelerate the uptake of DNT-IVB for regulatory purposes. The ultimate goal of the first theme is to take a step forward from those efforts and discuss specific solutions to specific issues that were raised from the case studies to address different regulatory problem formulations (e.g., IVIVE, AOPs, in vivo and in vitro uncertainties, applicability domain, molecular characterisation, etc.).

09h30 US Division of Translational Toxicology (DTT): IATA case study for DNT to prioritise a class of chemicals Helena Hogberg, NICEATM, US Division of Translational Toxicology (DTT), NIEHS, United States (presentation: 20min; technical Q&A: 5min) 09h55 Case studies from large European (Horizon 2020) projects to refine testing strategies Marcel Leist, University of Konstanz, CAAT-Europe, Germany (presentation: 20min; technical Q&A: 5min) 10h20 US EPA Case-studies: Prioritisation, Weight of Evidence and Waiving in vivo DNT test studies Tim Shafer, United States Environmental Protection Agency (US EPA), United States

3 (presentation: 20min; technical Q&A: 5min) Tea/Coffee Break (10h45-11h15) 11h15 EFSA’s IATA Case Studies for hazard identification and characterisation lessons learnt Iris Mangas, European Food Safety Authority (EFSA), Italy (presentation: 20min; technical Q&A: 5min) 11h40 Industry perspective on leveraging the mechanistic understanding from the DNT-IVB to optimise the development of safe pesticides Agnes Karmaus, Syngenta, United States (presentation: 20min; technical Q&A: 5min) 12h05 Inclusion of the DNT-IVB in EU’s Pesticides Risk Assessment – a European Member State Perspective Verena Haudek-Prinz, Austrian Agency for Health and Food Safety, Austria (presentation: 20min; technical Q&A: 5min) Lunch break (12h30-13h30) 13h30 IATA for chemical classification: special considerations when using DNT-IVB data Martin Paparella, University of Innsbruck, Austria (presentation: 20min; technical Q&A: 5min) 13h55 DNT-IVB data application for screening chemicals: industry’s perspective Sue Marty, Dow Chemicals, United States (presentation: 20min; technical Q&A: 5min)

4

Session 2: Exposure assessment and Quantitative In vitro to in vivo extrapolation (QIVIVE) Chairs: Cecilia Tan, United States Environmental Protection Agency (US EPA), United States, US and Jochem Louisse, European Food Safety Authority (EFSA), Italy In risk assessment, tiered testing is a stepwise approach that combines existing information on both exposure and hazard with the goal of obtaining uncertainty levels acceptable to the regulatory need on both. Positive activity in one or more assays in the DNT-IVB should be coupled with existing exposure information and adequate uncertainty analysis to determine whether the data is acceptable for the regulatory need. The need to perform PBK modellingfacilitated QIVIVE of DNT-IVB data has been highlighted in the IATAs published with hazard characterisation or risk assessment problem formulations. Further work and a road map are needed to develop a tiered exposure modelling framework that will allow the use of the DNT-IVB in vitro bioactivities to derive a PoD (Point of Departure) for human health risk assessment.

14h20 Towards quantitative in vitro to in vivo extrapolation of DNT IVB data: principles and considerations for regulatory application Jochem Louisse, European Food Safety Authority (EFSA), Italy (presentation: 20min; technical Q&A: 5min) 14h45 Maternal exposure and development neurotoxicity effects in offsprings: tiered modelling approaches Cecilia Tan, United States Environmental Protection Agency (US EPA), United States (presentation: 20min; technical Q&A: 5min) Tea/Coffee break (15h15-15h45) 15h45 Deltamethrin - PBK/IVIVE strategy to consider developmental neurotoxicity (DNT) in vitro data for human health risk assessment Katrin Bothe and Dennis Mueller, Bayer, Germany (presentation: 20min; technical Q&A: 5min) 16h10 QIVIVE in developmental neurotoxicity: The role of in vitro distribution kinetics Nynke Kramer, Wageningen University, The Netherlands (presentation: 20min; technical Q&A: 5min) 16h35 Panel Discussion of Sessions 1 and 2 Prioritisation of Future Efforts: Identification of common strengths and limitations of the approaches used among the various case studies. Aims to decide on the selection of strengths that can be standardised/reused and to identify current limitations (i.e., technical, lack of data, lack of specific guidance, etc.) that need development efforts. Within those limitations, identify those that must be solved to use the DNT-IVB data as PoD and those that would be nice to decrease the uncertainty when doing so and summarise future research or regulatory goals for each of them.

Moderator: Patience Browne, OECD Environment Directorate 17h30 END OF DAY 1

5

Day 2 – 29 October 2024 Theme: Regulatory implementation of the DNT-IVB 09h00 Break-out group discussion on case studies, guided by charge questions.

What can be a short-medium term plan for the use of the DNT-IVB for: 1. Use of DNT-IVB data as complementary information as part of the WoE in an IATA 2. Moving forward to an agreed tiered testing strategy 3. DNT Defined approach development Breakout (BO) group

Topic

Moderators

BO group 1

Use the DNT-IVB data as complementary information and part of the WoE in an IATA. What are the next steps for standardisation?

Moderators: Iris Mangas & Jochem Louisse

BO group 2

Moving forward to an agreed-tiered testing strategy. What is still missing?

Moderators: Josh Harrill & Ellen Fritsche

BO group 3

Defined approach/es development for DNT testing. Are we there yet?

Moderators: Helena Hogberg & Agnes Karmaus

Tea/Coffee Break (during the BO session)

Theme: Tiered testing strategy for application of DNT-IVB

Session 3: Tiered testing, Additional Assays and Non-Mammalian Animal Models– What do they have to offer to the DNT-IVB? Chair: Ellen Hessel, RIVM, The Netherlands The third session will focus on strategies for tiered testing, improvements to the current DNT-IVB, and non-mammalian models for DNT. It will be an opportunity to identify any knowledge gained from CROs’ or researchers’ experience with additional assays to cover neurodevelopmental processes not represented in the DNT-IVB and non-mammalian animal models. It will also highlight any areas of research that will inform revisions to Initial Recommendations.

11h30 The EFSA DNT-RAP project - Laboratory transferability and accessibility of the DNT-IVB test methods Katharina Koch, IUF – Leibniz Research Institute for Environmental Medicine, DNTOX, Germany (presentation: 25min; technical Q&A: 5min) Lunch break (12h00-13h30)

6 13h30 Transfer of, data generation from, and comparison to existing data from the developmental neurotoxicity in vitro battery Megan Culbreth, Human Foods Program, U.S. Food and Drug Administration (FDA), United States (presentation: 25min; technical Q&A: 5min) 14h00 Tiered testing and considerations for integrating additional assays and models to the DNT-IVB Ellen Fritsche, SCAHT - Swiss Centre for Applied Human Toxicology, Switzerland (presentation: 25min; technical Q&A: 5min) 14h30 High-throughput Phenotypic Profiling with Cell Painting as a potential first-tier DNT Screen Joshua Harrill, Center for Computational Toxicology and Exposure (CCTE), United States Environmental Protection Agency (US EPA), United States (presentation: 25min; technical Q&A: 5min) 15h00 3D human stem cell-derived models for developmental neurotoxicity studies Lena Smirnova, Center for Alternatives to Animal Testing (CAAT), Johns Hopkins Bloomberg School of Public Health, United States (presentation: 25min; technical Q&A: 5min) Tea/Coffee break (15h30-16h00) 16h00 The added value of non-mammalian animal models to fill the gaps in developmental neurotoxicity Lee Ellis, National Research Council of Canada, Canada (presentation: 25min; technical Q&A: 5min) 16h30 Panel Discussion of Session 3 Future directions: The ultimate goal of this discussion is to develop a roadmap through which improvements to the Initial Recommendations can be made. Specifically, i) identify the status of assay transfers and determine what additional efforts are needed, if any, ii) begin to define more clearly tiered testing approaches to DNT and how to implement them, and iii) understand the value of alternative species and how they fit into the current DNT-IVB. Moderator: Tim Shafer, United States Environmental Protection Agency (US EPA), United States 17h30 END OF DAY 1

7

Day 3 – 30 October 2024 Session 3: Tiered testing, Additional Assays and Non-Mammalian Animal Models– What do they have to offer to the DNT-IVB? (Cont.)

09h00 Plenary feedback from breakout groups and discussion Moderators from breakout groups: Iris Mangas European Food Safety Authority (EFSA), Italy, Josh Harrill United States Environmental Protection Agency (US EPA), United States and Helena Hogberg NICEATM, US Division of Translational Toxicology (DTT), NIEHS, United States 10h00 Developing new assays to predict glia-related KNDPs with transcriptomics data support Oddvar Myhre, Norwegian Institute of Public Health, Norway (presentation: 25min; technical Q&A: 5min) 10h30 Microglia for Studying Developmental Neurotoxicity Kelly Carstens, United States Environmental Protection Agency (US EPA) (presentation: 25min; technical Q&A: 5min)

Tea/Coffee Break (11h00-11h30) 11h30 Evaluation of neurotoxicity for pesticide-related compounds in human iPS cell-derived neurons using microelectrode array: Japanese experience Yasunari Kanda, Division of Pharmacology, National Institute of Health Sciences, Japan (presentation: 25min; technical Q&A: 5min)

Theme: Develop Action Plans to Implement Recommendations 12h00 Open Discussion-Workshop Results and Next Steps Participants are invited to reflect on the presentations and discussions of the last two days and contribute to this agenda item to shape the recommendations, outcomes, and action plans for 1) Updating the Initial Recommendations to include transferability, 2) Efforts to develop tiered testing, and 3) Efforts to develop an IATA framework template and move gradually to defined approach(es) for DNT. Moderators: Iris Mangas, European Food Safety Authority (EFSA), Italy, Tim Shafer, United States Environmental Protection Agency (US EPA), United States and Helena Hogberg, NICEATM, US Division of Translational Toxicology (DTT), NIEHS, United States, United States

8

12h45 Wrap-Up and Leaving Address by the CRP Lieve Herman, CPR Scientific Advisory Body 13h00 Conference closes

Workshop on critical innovations in pesticides safety testing and chemical risk assessment for developmental neurotoxicity (DNT) Sign up for the Chemical Safety Newsletter: https://login.oecd.org/

Follow us on social media: @OECD_ENV https://www.linkedin.com/company/oecd-environment/ https://bit.ly/youtube-chemical-safety