Deliverable D1.10 AWP Y4 including PARC Project Portfolio WP1 – T1.2

DELIVERABLE D1.10 P-A-R-C HORIZON-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 Partnership for the Assessment of Risks from Chemicals Deliverable D1.10 AWP Y4 including PARC Project Portfolio WP1 – T1.2 DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 1 PU = Public PP = Restricted to other programme participants (including the Commission Services) RE = Restricted to a group specified by the consortium (including the Commission Services) CO = Confidential, only for members of the consortium (including the Commission Services) Technical reference Work package WP1 - Coordination and Management Task T1.2 - Scientific steering and implementation of Annual Work Plans Dissemination level 1 PU Lead Beneficiary/ Responsible AE ANSES Contributing Participants All PARC participants Responsible author(s) Pascal Sanders, ANSES, [email protected], Christophe Rousselle, ANSES, [email protected] Co-authors PARC Coordination Team, ANSES, [email protected], WP co-leaders, Task co-leaders Reviewers PARC Coordination Team, ANSES, [email protected], WP co-leaders, Task co-leaders Due date of deliverable 31/12/2024 Actual submission date 11/02/2025 Second submission date 27/06/2025 DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 3 Document history “Funded by the European Union. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them.” Version Date Reviewer name/Institutions Short description of changes 1 04/10/2024 WP co-leaders,Task co-leaders and Project managers and partners involved in their WPs and Tasks First draft with modifications in track changes 2 18/10/2024 WP co-leaders and PARC CT only Review of the first draft 3 25/10/2024 PARC CT only Review of the first draft 4 08/11/2024 GB and GSB members Review of the first draft 5 13/12/2024 WP co-leaders,Task co-leaders and Project managers Update of the draft taking into account GB and GSB’s comments and addition of the new projets to validated to be started Y4 6 03/01/2025 WP co-leaders and PARC CT only Final review of the draft AWPY4 7 11/02/2025 PARC CT only Final review of the draft AWPY4 Addition of the financial sections of the AWPY4 8 27/06/2025 WP co-leaders,Task co-leaders, Project managers and PARC CT Comments received from HaDEA were taken into account and budget information have been updated (Table 2.3.a, 2.3.b and 2.3.c) DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 4 Abstract This Annual Work Plan (AWP) describes the activities to be implemented during the ‘PARC year’, including the updated Project Portfolio. The AWP covers the period from May 2025 to April 2026 (M37-M48) which are referred to as ‘PARC years’. Key Words Work Plan, Project Portfolio Period M37-M48 DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 5 Table of contents Document history _______________________________________________________________________________ 3 Abstract __________________________________________________________________________________________ 4 Key Words _______________________________________________________________________________________ 4 Table of contents ________________________________________________________________________________ 5 List of abbreviations ____________________________________________________________________________ 6 Structure of the Annual Work Programme ____________________________________________________ 8 1. Coherence with part B of the proposal ___________________________________________________ 8 1.1 Annual Work Plan (AWP) objectives __________________________________________________ 8 1.2 Expected impacts______________________________________________________________________ 10 1.3 Correspondence with part B of the proposal ___________________________________________ 14 1.4 Update of the PARC Project Portfolio ____________________________________________________ 15 2. Annual Work Programme Activities ____________________________________________________ 21 2.1 Annual Work Programme ____________________________________________________________ 21 2.1.1 Structure of the Annual Work Programme __________________________________________________________________ 21 2.1.2 Timing of the different programmed activities and their components ____________________________________ 21 2.2 Detailed work description ________________________________________________________________ 21 Table 2.2.a: Annual Work Programme Activities for each set of activities _______________________________________ 21 Table 2.2.b: AWP Set of Activities _________________________________________________________________________________ 153 Table 2.2.c: Additional Deliverables List __________________________________________________________________________ 154 2.3 Resources to be committed _____________________________________________________________ 155 Table 2.3.a: Summary effort table _________________________________________________________________________________ 155 Table 2.3.b: Other major cost items (travel, equipment, infrastructure, goods and services) _________________ 162 Table 2.3.c: Overview of planned budget per project and per Work Package __________________________________ 174 DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 6 List of abbreviations AA: Anti-Androgenicity ADME: Absorption, Distribution, Metabolism and Excretion AE: Affiliated Entity AEP: Aggregated Exposure Pathways AI: Artifical Intelligence AO/ AON/ AOP: Adverse Outcome/ AO Network/ Pathway API: Application Programming Interfaces ASR/ AWPs: Annual Summary Report/Work Plans BBB: Blood Brain Barrier BCSFB: Blood-cerebrospinal Fluid Barrier BIODA: Documentation of Biological Organisms BMD: Benchmark dose BNNs: Bayesian Neural Networks BPR: Biocides Products Regulation CA: Consortium Agreement CEC: Chemicals of Emerging Concern CDIF: Cross-Domain Implementation Framework CG: Core Group CL/ ML: Chemical Leader/ Methodology Leader CLP: Classification, Labelling and Packaging CMS: Content Management System COPCSD: Common Open Platform on Chemical Safety Data CPDC: Common Platform for Data on Chemicals CSS: Chemicals Strategy for Sustainability CT: ANSES PARC Coordination Team DILI: Drug-Induced Liver Injury DEPB: Data and Ethics Protection Board DBS: Dried Blood Spots DL: Deep Learning DMP: Data Management Plan DNT/ANT: Developmental and Acute Neurotocixity ML: Machine Learning MIEs: Molecular Initiating Events MoA: Mode of Action MS: Member States MTA: Material Transfer Agreement M4M: Metadata 4 Machines MRA: Mixture Risk Assessment NAMs: New Approach Methodologies NGRA: Next Generation Risk Assessment NGTxC: Non-Genotoxic Carcinogens NHs: National Hubs NHCs: National Hub Coordinators NHCPs: National Hub Contact Points NTS: Non-Targeted Screening OECD: Organisation for Economic Co-operation and Development OO: Operational Objectives OoC: Organ-on-Chip OORF: OECD Omics Reporting Framework OSOA: One Substance One Assessment PDB: Protein Data Bank PEC: Predicted Environmental Concentrations PEH: Personal Exposure and Health PFAS: perand polyfluoroalkyl substances PFDP: PARC FAIR Data Policy PBK: Physiologically Based Kinetic PBMC: Peripheral Blood Mononuclear Cells PBPK: Physiologically Based Pharmacokinetic PBTK: Physiologically Based Toxicokinetic PM: Project Manager PMT: Persistent Mobile and Toxic DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 7 DoA: Description of Action DTA: Data Transfer Agreement EATS: Estrogen, Androgen, Steroidogenesis, and Thyroid EBD: Environmental Burden of Disease EC: European Commission ECHA: European Chemicals Agency ED/ EDCs: Endocrine Disrupters / endocrine disrupting compounds EDA: Effect-Directed Analysis EFSA: European Food Safety Authority EMG: Effect Marker Group EOSC: European Open Science Cloud ERA: Environmental Risk Assessment EWS: Early Warning System FAIR: Findable, Accessible, Interoperable, and Reusable FIP: FAIR Implementation Profiles FIT: FAIR Implementation Taskgroup GA: Grant Agreement GB: Governing Board GDPR: General Data Protection Regulation GEQUAS: German External Quality Assessment Scheme GFF: Go Fair Foundation GIVIMP: Good In Vitro Methods Practices GNN: Graph Neural Networks GPR: Gaussian Process Regression GS: Grant Signatory GSB: Grant Signatory Board GUPRIs: Global Unique Persistence Resolvable Identifiers HA: Hazard Assessment HBM: Human BioMonitoring HBM GV: Health-based Guidance Values HIA: Health Impact Assessment HRMS: High Resolution Mass Spectrometry IATA: Integrative Approaches for testing and Assessment IB: International Board PoC: Prof of Concept POD: Point of Departure POP: Persistant Organic Pollutant 3PPF: Three-Point FAIRification Framework PPPR: Plant Protection Products Regulation PT: Proficiency Testing QA/QC: Quality Assurance / Quality Control QAWG: Quality Assurance Working Group QIVIVE: Quantitative in vitro / in vivo Extrapolation QSAR: Quantitative Structure Activity Relationship RA/RM: Risk Assessment / Risk Management RAiD: Research Activity Identifier REAL: Real Exposure Concentrations R&I: Research and Innovation RQ: Risk Quotient RRM: Rapid Response Mechanism SAM: Stress Addition Model SCCS: Scientific Committee on Consumer Safety SDGs: Sustainable Development Goals S2PD: Science-to-Policy Dialogue SAICM: Strategic Approach to International Chemicals Management SF: Stakeholder Forum SG: Specialty Group SO: Specific Objectives SPM: Suspended Particulate Matter SRIA: Strategic Research and Innovation Agenda SS: suspect screening SSbD: Safe-and-Sustainable-by-Design SSO: Single-Sign-On STOP: Source to Outcome Pathways SOP: Standard Operating Procedures SVM: Support Vector Machine DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 8 IPR: Intellectual Property Rights IVIVE: in vitro - in vivo extrapolation JRC: Joint Research Centre KIC: Knowledge and Innovation Communities KEs: Key Events KERs: Key Event Relationships LCA: Life-cycle assessment MAF: Mixture Assessment Factor MB: Management Board MCRA: Monte Carlo Risk Assessment MDC: Metabolic Disrupting chemicals MEA: Multi Electrodes Array MEC: Measured Environmental Concentrations SWB: Silicone Wristbands T/TL: Task/Task co-leaders TTC: Toxicological Threshold of Concern THSD: Thyroid Hormone System Disruptors TKTD: Toxicokinetic-toxicodynamic modelling TRC: Test Readiness Criteria TRL: Technology Readiness Level UCWG: Use Case Working Group(s) UNEP: United Nations Environment Programme US-EPA: US Environmental Protection Agency US-NTP: US National Toxicology Program WGCNA: Weighted Gene Corralation networks for analysis WHO: World Health Organization WoE: Weight-of-Evidence WP/ WPL: Work Package / WP co-leaders WWTP: Wastewater treatment plants ZFe: Zebrafish embryo Structure of the Annual Work Programme 1. Coherence with part B of the proposal 1.1 Annual Work Plan (AWP) objectives The objectives of this fourth year are aligned with the specific objectives of PARC. SO1 - To achieve a high scientific policy and societal impact, EU and national risk assessors and regulatory entities come together with the scientific community in a cross-disciplinary network to set priorities for research and innovation in chemical Risk Assessment (RA) OO1-Maintaining a high management level through meeting of Boards. For the year 4, meetings of the PARC governance bodies will be organised to discuss the PARC progression, indicators, sustainability, as well as the strategy for the AWPY5. OO2-National Hubs (NHs) will continue their activities to gather national needs, encourage cooperation and identify potential synergies. At the national levels, the discussion will focus on the ways to elaborate sustainable framework for the prioritized PARC activities to share options with the Governing Board (GB), Management Board (MB) and Grant Signatory Board (GSB). DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 9 OO3-Based on the work done during Y3 on the priorisation process and review of needs, the review of new projects and monitoring on on-going ones will be performed. Several projects and case studies will end during Y4 while others will start. Some of the new projects will take the handover of previous ones. The lessons learned from the first year of PARC will be also discussed for further improvement of the process. OO4-Using PARCopedia, the chemical RA community will be enabled to find, co-create and discuss knowledge on all matters related to chemical RA and Next Generation RA (NGRA). Chemical and Methodology leaders (CL/MLs) will follow and report on the work developed within PARC. Particular attention will be paid to increasing the amount of knowledge shared and co-created by the community. OO5-Cooperation with other programmes and initiatives will be encouraged. The identification of potential synergies, facilitation of information exchange between external projects and PARC and the establishment of collaborations and synergies with relevant scientific/regulatory/policy initiatives at national, EU and international levels will continue. OO6Communication and dissemination of knowledge produced by PARC will be performed via the website, the open access to scientific publications. The communication and dissemination strategy will be revised. SO2 - European and national RA entities and their scientific networks carry out a joint research and innovation programme to respond to the agreed priorities in chemicals RA. OO7-Work programme. The programme will be monitored and 18 new projects are starting Y4. Several on-going projects will continue to perform their testing and modelling activities to generate data and 23 projects will be extended to pursue the work implemented in the previous years. OO8-Monitoring capacity development. The HBM sampling phase will continue. The selection of the best, state-of-the-art exposure biomarkers and analytical methods will be performed according to the identified needs for implementation from Y4. The chemical analysis plan will be approved and implemented. A PARC-German External Quality Assessment Scheme (GEQUAS) Quality Assurance / Quality Control (QA/QC) programme will begin in the last quarter of Y3. A first list of qualified laboratories will be established. Add-on studies on perand polyfluoroalkyl substances (PFAS) will start. For occupational studies (health sector, e-waste), candidate laboratories for the analysis of samples for the exposure and effect biomarkers will assess their internal performance and a proficiency test will be organised by PARC in case of lack of proficiency test providers for biomarkers selected. Analysis of some samples is expected to start. For the environmental projects, the monitoring activities developed, the chemical analyses will be completed and reported according to the formats and procedures developed. The collection of existing PFAS data for the “baseline part” will be completed. OO10-To implement Findable, Accessible, Interoperable, and Reusable (FAIR) data practices, DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 16 P4.3.2.a_Y1_H01-Perinatal exposure_INRAE M1-M48 P4.3.3.a_Y1_E01-Wastewater based epidemiology_UFZ-UBATH M1-M48 P4.3.4.a_Y2_F02-Food items exposure_ANSES M13-M48 P5.1.1.a_Y1_Toxins_BfR_UNIVIE M1-M48 P5.2.1.b_Y1_MD-EDC_BfR M1-M48 P5.2.1.c_Y1_EDThDisruption_DTU M1-M48 P5.2.1.d_Y1_Immunotox_Inserm M1-M48 P5.2.1.e_Y1_DNT-ANT_UFZ_IUF_NIPH M1-M48 P5.3.1.a_Y1_SystemsToxicology_UL-LACDR M1-M48 P5.3.2.a_Y1_AOPDevelopment_Inserm M1-M48 P5.3.4.a_Y1_PBK_Kinetics_Fraunhofer M1-M48 P6.2.1.b_Y1_Aggregate_Anses M1-M48 P6.2.2.a_Y1_PBPK_INERIS_AUTH M1-M48 P6.2.3.a_Y1_RealLifeMixtures_RIVM M1-M48 P6.3.1.a_Y1_SubstanceRA_SU M1-M48 P6.3.1.a_Y1_SubstanceRA_SU_CS12_MethodOSOA_SU M1-M42 P6.3.1.b_Y1_EffectRA_BPI M1-M48 P6.3.1.b_Y1_EffectRA_BPI_CS11_GenotoxCarc_ISS M1-M48 P6.3.1.b_Y1_EffectRA_BPI_CS17_ED-in vitro_BPI M1-M48 P6.3.1.b_Y1_EffectRA_BPI_CS18_ED-classes_BPI M1-M48 P6.3.2.a_Y1_ToolsRA_SU M1-M48 P6.3.2.a_Y1_ToolsRA_SU_CS20_Y3_PESTNAM_ISS M25-M48 P6.4.1.a_Y1_OPREMIXCS1_BRUNEL_RWTH M1-M40 P6.4.1.b_Y1_MONAMMIXCS2_UFZ M1-M40 DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 17 Table 4: 23 Projects and case studies initially planned to end Y3 or Y4 that requested an extension Project ID Initial Schedule Comments Rationale for projects that have been extended P4.1.3.1.a_Y1_DerivationofHBM-GVs_UBA M1-M36 This project up to M81 has been broken down at M36 to assess what has been achieved. Request for an extension until M81 The justification for the project as such and the continuation is as follows: a consistent and comprehensible health-based interpretation of HBM results is required within the framework of PARC and beyond in order to be able to use HBM to provide meaningful policy advice on chemicals and product regulation. The derivation of further additional HBM-GVs/HBM-EECRs is associated with additional time and additional costs, which were, however, already provided for and estimated in the original planning of the project. P4.1.4.2.a_Y1_DataAnalysisHBM4EU_VITO M1-M36 Request for an extension from M37 to M48 The actions related to the initiation of the statistical analysis, the geospatial analysis and the training of the data owners took more time than anticipated. This should not affect the overall project budget. P4.2.a_Y1_ENVMonitoringPilotSurvey_INER IS_AU M1-M36 Request for a limited extension from M37 to M42 (6 months) The third part of the project (extensive collection of existing PFAS data to establish a European baseline) has been more time consuming than expected due to curation work on heterogeneous data sets. No impact on the budget. All activities will be performed as planned P4.2.b_Y2_Monitoringframe_AU_INERIS M13-M30 Request for a limited extension from M31 to M36 (6 months) The working group took more time than anticipated to align with the concept of prioritisation, to agree on common terminology, and establish a common understanding. No impact on the budget and on actions planned. P5.1.2.b_Y1_BPAalternatives_BPI_MU M1-M42 Request for a limited extension from M43 to M48 (6 months) The experimental work has started with a delay mainly due to timeconsuming procedures followed for chemicals order (centralized order for all PARC partners) and difficulties faced by several partners in hiring personnel. No impact on the budget and on the planned actions P6.1.1.c_Y1_IATA_GENTOX_Sciensano M1-M36 Request for an extension from M37 to M48 During the first year of the project, many meetings and discussions with the partners were organized to divide the work and harmonize the methodology. It resulted in some delays. A small increase in the budget (<15%) for 3 partners is required. P6.1.1.d_Y1_IATA_STOT_UL-LACDR M1-M36 Request for an extension from M37 to M48 The delay is partially related to a later start of postdocs and PhD students appointed in the project and some actions related to transcriptomics data took longer than expected. No additional budget is required. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 18 P6.2.1.a_Y1_SourcetoDose_VITO M1-M36 Request for a limited extension from M37 to M42 (6 months) The additional 6 months will allow us to finalize case studies and publications, and to integrate with 6.2.1b, which will benefit the collaboration in Y5 project on activity 6.2.1. The requested additional budget is 11 % of the initial budget. P6.3.1.b_Y1_EffectRA_BPI (M1M48)_CS10_ED-cosmetics_VUB M8-M32 Request for an extension from M33 to M43 Delays related to human resources reasons in the project lead team. The additional time required will not lead to any modification of the objectives of the project, nor will there be any change in the financial demand on PARC. P6.3.1.b_Y1_EffectRA_BPI (M1M48)_CS15_DNT_SU M1-M36 Request for an extension from M37 to M48 Modification of the objectives of the project: evaluation of a second behavioural outcome, i.e. the auditory startle reflex, in our collection of 54 guideline DNT studies. Development of graphical tools and statistical code to facilitate this. Request of Extension of budget > 15%. P6.3.2.a_Y1_ToolsRA_SU (M1M48)_CS1_CARB_SYKE M1-M36 Request for an extension from M37 to M48 Necessary to deepen the comparative analysis on PFAS regulatory thresholds in food and water after 2 years by evaluating the potential development needs of regulatory RA of PFAS and implications to RM, also considering additional regulatory frameworks and their interlinkages. No extension of budget. P6.3.2.a_Y1_ToolsRA_SU(M1M48)_CS4_SecPoisoning_INERIS M2-M38 Request for an extension from M39 to M48 Delays related to both technical and human resources reasons. Regarding technical reasons, it was planned first to use rodenticides which are recognised as bio accumulative substances. Then it was considered to align the selection of chemicals with the substances used in CS07 (covering all other environmental compartments). No extension of the budget is required. P6.3.2.a_Y1_ToolsRA_SU (M1M48)_CS7_REGPREP_EAWAG M1-M36 First proposal was to have 2 project phases: 1st phase M1-M36, 2nd phase M37-M81 As outlined in the original description of our case study, the case study was planned to have 2 phases: a first project phase on surface water and sediment and a second one on soil and air. Soil and air would be during the last 4 year. The budget was already provided for and estimated in the original planning of the case study. P6.3.2.a_Y1_ToolsRA_SU (M1M48)_CS8_OccupReproDev_KI M1-M36 Request for an extension from M37 to M48 Delays related to human resources reasons in the project lead team. Hence, to get additional time to work on analysis of findings and write up the results an extension is requested. No additional budget is requested. P6.3.2.a_Y1_ToolsRA_SU (M1M48)_CS16_UncertaintyRA_ULUND M1-M36 Request for an extension from M37 to M48 The participants have not been able to work as originally planned in the case study. No extension of budget is required. P6.4.2.b_Y1_NGRApractice_VKM_NIPH M1-M36 This project up to M81 has been broken down at M36 to assess what has been The project was originally developed for the whole 7-year PARC period. To be able to complete the different parts of the project, request for this DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 19 achieved. Request for an extension until M81 extension to be able to finalise the ongoing work in the best way. The budget included in the original 7-year proposal will remain the same. P6.4.4.a_Y1_CRNCS1_KEMI M1-M42 This project up to M81 has been broken down at M42 to assess what has been achieved. Request for an extension until M81 This project explores and develops new frameworks for risk characterisation that support system-based approaches to RAERA of chemicals (ERA). In years 4-7, PARC 6.4.4.a will continue to build collaborations, platforms, and engage stakeholders to ensure that projects “Design the right things” before “Design things right.” The budget included in the original 7-year proposal will remain the same. P6.4.4.b_Y1_PPPEXPCS2_RPTU M1-M36 This project up to M81 has been broken up into 2 phases. The first phase was planned to end M24 but was extended until M36. Request for an extension until M81 Extending the project duration will allow to realise the planned objectives in the three major areas, facilitate the improvement of the scientific basis of ERA with the aim to streamline the approval process and provide the (exposure) building blocks for the prioritization process in the RA in the EU towards a systems-based ERA of PPP. Additional budget for project management at RPTU in the amount of 48+ PMs and extension of budget for project partners for Y4-7. P6.4.4.c_Y1_PPPEFFCS3_UFZ M1-M36 This project up to M81 has been broken down at M36 to assess what has been achieved. Request for an extension until M81 This project explores and develop new frameworks for risk characterisation that support system-based approaches to RA by expanding the current ERA approaches. Continuous dialogue is needed from including regulatory risk assessors, to managers and risk manager at regulatory agencies and eventually also policy makers. The budget included in the original 7-year proposal will remain the same. P6.4.4.d_Y1_PPPBENCHCS4_UKOLD M1-M42 This project up to M81 has been broken down at M42 to assess what has been achieved. Request for an extension until M81 PARC 6.4.4.d focused on identifying products rejected under the reauthorisation procedure of 1107/2009 and scrutinised the factors that led to their rejection. A conceptual framework for benchmarking PPP ERA has been developed. The alignment with stakeholder activities coordinated by project 6.4.4.a and with other PARC projects will ensure regulatory relevance and uptake of the benchmarking results and novel methods. The budget included in the original 7-year proposal will remain the same. P6.4.4.e_Y1_PPPOSCS5_ISCIII M1-M42 This project up to M81 has been broken down at M42 to assess what has been achieved. Request for an extension until M81 The main aim of this project is moving the ERA paradigm from single chemical-crop combination to landscape-based ERA integrating landscape structures and aggregated (several crops) and combined (several pesticides) exposures into the current RA methods. The conceptual model has been already published in a high-impact scientific journal and eight case DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 20 studies, four terrestrial and four aquatic, have been selected and are ongoing. Considering the achievements, it is proposed to continue with the implementation of the case studies and the integration of the information generated through the case studies, the interaction with the other projects and through the feedback from the publication. In line with the continuation of the project through this request for extension, there is a need for confirming the budget allocation for M43 to M84. P7.2.2.a_Y1_chemicals-inenvironment_MU_VITO M1-M36 Request for a limited extension from M37 to M42 (6 months) A need to extend the duration of the metadata schema workshops has been identified by the project partners to thoroughly discuss the metadata requirements and structure for chemical occurrence data. The list of planned actions remains unchanged. No impact on the budget P7.2.2.b_Y1_HBMdatasets_VITO M1-M42 Request for a limited extension from M43 to M48 (6 months) Due to reorganisation of the project team at VITO (new project leader, people leaving and newly hired in the team), some of the actions will be prolonged with 6 months. No impact on the budget. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 21 2. Annual Work Programme Activities 2.1 Annual Work Programme 2.1.1 Structure of the Annual Work Programme The structure of the AWPY4 is based on the work packages (WP) description of transversal activities as well as more specific activities that are related to projects. 2.1.2 Timing of the different programmed activities and their components The fourth AWP will cover a duration of 12 months (M37-M48) from 1 May 2025 to 30 April 2026. All WPs will be active in Y4. 2.2 Detailed work description For all the WPs, the full description of work by projects is available in the PARC Project Portfolio in Annex II. Table 2.2.a: Annual Work Programme Activities for each set of activities WP N° WP1 Lead Beneficiary ANSES WP title Coordination and Management Part ner N° 1 1.1 1.2 1.4 2 3 3.1 4 4.2 5 6 7 8 10 10.1 11 12 13 14 15 16 17 18 20 20.6 21 22 24 25 25.2 25.4 25.6 25.7 26 26.4 27 29 29.1 30 31 32 33 34 34.5 35 35.6 35.7 35.9 36 36.2 37 50 59 61 64 Part ner shor t nam e ANSES INSERM INRAE INERIS SpF EAA AGES VITO DOMG SCIENSANO CIPH MOH-CY/SGL MU DEPA AU HB EEA THL TTL UBA BfR NCPHP UI ISS UNINA RSU NPHSL LNS RIVM TNO UL-LACDR VUA WR NIPH NIVA NIOM INSA APA SZU-SK JSI NIJZ CSIC ISCIII IISPV SEPA SU KEMI SLV AUTH GCSL BPI UKHSA UOB EPA IPHMNE PM/ part ner 1 122.7 0.5 0.4 0.4 6.7 5.1 0.3 5.9 3.3 0.6 1.1 1.1 4.7 1.5 0.4 1.2 4.0 0.1 1.5 4.8 5.9 1.8 1.5 0.7 3.0 1.2 1.0 2.5 5.0 0.3 0.3 0.4 0.4 1.2 0.2 1.3 9.4 1.0 3.1 0.5 4.5 0.4 5.2 0.3 1.1 0.3 3.2 1.0 5.6 3.0 0.3 2.0 3.0 1.2 1.0 Star t M37 End M48 1 PMs have been allocated to the Grant Signatories for the management of their affiliated entities and their role of NHCP. In some cases, the Grant Signatories do not have any PM as they do not manage any AEs and are not NHCP in PARC. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 22 Objectives The main goal of WP1 is to ensure the coordination, the strategic scientific and administrative management of PARC, including impact evaluation and the ethical issues management, in cooperation with the different governance bodies of the Partnership. The specific objectives of WP1 for year 4 are: - Task 1.1: Maintain an effective management and governance framework for the PARC consortium in compliance with the legal, ethical, financial and administrative rules and regulations and in compliance with the agreed timelines ensuring the highest quality standards; - Task 1.2: Manage the tools to ensure the Partnership’s progress and guide the PARC consortium and its activities in maintaining the course set out in the Grant Agreement, to achieve milestones and produce the agreed deliverables, within the defined budget and abiding by the highest quality standards; - Task 1.3: Maintain and update the monitoring framework for the Partnership; - Task 1.4: Ensure communication and collaboration between the Data and Ethics Protection Board (DEPB), notably composed of Ethics and Data contacts points from WP4, 5 and 7 and the PARC Consortium, and ensure that the PARC Participants follow the Ethics Charter in order to reduce and/or address ethical issues that may arise during the Partnership implementation. Description of work Task 1.1: Overall executive management and support of the Partnership Leader: ANSES (FR) Partners: All GSB members and WP co-leaders (as stated above) The activities of this task are managed by the PARC Coordination Team (CT) composed of the PARC Coordinator, the Deputy-Coordinator and the ANSES Project managers. The PARC CT ensures an efficient management of the PARC activities and associated administrative and budgetary issues. Management of the consortium and organisation of the Governance Bodies meetings: o Ensuring the respect and proper implementation of the “Terms of reference and rules of procedure” by the PARC GB and of the Consortium Agreement (CA) by the PARC GSB in compliance with the agreed timelines. o Setting the dates and organising the Governance Bodies meetings (MB, GB and GSB) to take place during the 4th year of PARC. For the GB: o Meetings of the GB are foreseen in April, September and November 2025, among them one physical meeting. The objectives will be to provide input and opinions on the PARC progression and discuss progress, indicators, relevant policy/regulatory outputs, sustainability, as well as the strategy for the AWPY5. Further to initial contact done in October 2024, representatives from Montenegro have been invited to attend the November 2024 GB meeting as observers. o Additional virtual GB meeting(s) and/or written consultation(s) (through forms, poll, and emails) may be organised on other specific topics if needed. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 23 o Ahead of each GB meeting, the coordination team will prepare working documents with the GB co-chairs for each topic planned to be addressed during the meeting. These documents are tailored to fit with the GB level of understanding needed. o Non-mandatory GB workshops will also be organised to provide the opportunity to develop further thematics of interest to the GB. For the GSB: o A meeting of the GSB will be organised end of 2025 in order to discuss and validate the AWPY5 and its associated budget. o Additional virtual GSB meeting(s) and/or written consultation(s) (through forms, poll, and emails) may be organised, if needed. For the MB: o Monthly MB meetings will be organised throughout the year, with two physical meetings, including one back-to back to a physical GB meeting. o The other MB meetings will take place online. Follow-up of the Partnership’s activities and budget: o Managing the information system (EMDESK) for the monitoring of the budget and help the financial administrators of the PARC institutions to ensure a proper and efficient use of the system. o Granting access rights to the PARC Consortium SharePoint to new individuals involved in PARC when requested in order to ensure that all individuals involved in PARC have access to internal working documents and calendar of meetings and actions to be done for the year 4 of PARC. o Assisting participants on specific administrative and financial issues. o Updating on request the Partnership handbook describing the internal requirements and specifying the common rules to be followed by all PARC Participants. Contractual documents generated by PARC activities: o Pursuing the preparation of contractual documents generated by PARC activities, when relevant: Intellectual Property Rights (IPR), Material Transfer Agreement (MTA) and Data Transfer Agreement (DTA); preparing, signing, and managing, when relevant, other PARC related agreements (e.g., confidentiality and collaboration agreements) that will arise during the 4th year. o Establishing PARC collaboration agreements with external initiatives or organisations to support synergies o Ensuring the follow-up of the collaboration agreements signed with external initiatives or organisations, especially with JRC and NORMAN, through dedicated meetings. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 24 Communication: o Updating the internal and external communication rules of the Partnership handbook, in collaboration with WP3, when relevant. o Providing articles and news items to feed the PARC website in close collaboration with the WP3. o Providing rules and repositories to the PARC Participants for internal and external communication. o Providing WP1 bulletins every 3 months in order to provide information about recent and ongoing general and WP1 processes. Task 1.2: Scientific steering and implementation of Annual Work Plans Leader: ANSES (FR) Partners: All WP co-leaders, NHCPs, NHCs, The activities of this task are managed by the PARC CT in close collaboration with the MB, GB, GSB, National Hub Coordinators (NHCs) and the CL/MLs. The MB specifically plays an active role to ensure the efficient setting up of the monitoring of the scientific progress and of the overall strategy of the Partnership, making sure that the PARC activities, resources and AWP are aligned. It also ensures the relevance of the PARC work plan with regard to external events with WP3 (projects, initiatives, EU policies linked to the PARC objectives). Scientific steering: o Moderating the MB meetings and ensuring the cross-cutting scientific links between WPs o Assisting the PARC NHCs in coordinating the NH contributions and activities in PARC o Proposing amendments of the GA or solutions / redress actions to resolve any issues, and escalating unresolvable risks or issues to the relevant boards. o Aligning work programmes to policy needs as defined by EU Agencies and partner countries. Synergies: o Ensuring the follow-up of opportunities for synergies (with WP3) (projects, initiatives, EU policies linked to the PARC objectives, National, EU and international initiatives …) Preparation and submission of AWPY5 with the Project Portfolio in Annex, Periodic Technical and Financial Report for the second period of PARC and ASRY4: o Coordinating the preparation, collection and submission to HaDEA of: o The Periodic Technical and Financial Report (PTFR) for the second period of PARC (M19-M36) in June 2025. o The AWPY5 and updated PARC Project Portfolio in Annex, in December 2025. o The ASRY4 in December 2025. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 25 The preparation of those reports will be done in close collaboration with the MB members, the Task co-leaders, the Project managers, the Task 2.1 partners, and in consultation with the relevant PARC governance bodies (see task 1.1 for the organisation of the Governance Bodies meetings). The PARC CT will organise a review meeting with HaDEA and experts involved in the review of the 2nd PTFR after its submission and assessment. Follow-up of deliverables, additional deliverables and milestones: o Ensuring respect of the different deadlines, and achievement of milestones, deliverables and additional deliverables according to the established review process. Task 1.3: Impact evaluation and Monitoring of the performance indicators of the Partnership Co-Leaders: DOMG (BE), INSA (PT) Partners: All WP co-leaders The monitoring frame and set of indicators will be further refined to ensure the key useful and impact-generating results and relevant target groups are clearly identified in order to maximise PARC’s impact and exploitation. Activities to be performed in the 4th year include: o Identifying potential barriers that could undermine the achievement of desired outcomes and impacts. o Continuing the inter-tasks meeting with WP2 – task 2.3 on sustainability –T4.1 – P4.1.5.a_Y1_SustainHBMSystem_VITO – to continue the discussion on the sustainability of PARC in support of sustainable indicators. o Finalise the definition of impact indicators and collecting information for the outcome and impact indicators in collaboration with MB, GSB and GB, NHs and stakeholders. o In close collaboration with WP3, task 3.2, continuing the development of easily interpretable indicator leaflets and communication elements on outcome and impact indicators that provide and communicate the link between the objectives, key results and (expected) impacts of PARC. o Presenting the results of the indicator framework (12 output indicators, 8 outcome indicators and 8 impact indicators) to the MB/GB and disseminating these among WPs for awareness. o Continuing the discussions with the European Environment Agency to ensure input from PARC in, and synergies with, the Chemical Strategy for Sustainability (CSS) indicator framework being developed by the EC. o Preparing and submitting D1.11 Revised list of indicators (M40). Task 1.4: Ethics framework Co-Leaders: NIJZ (SI), EHESP (FR) DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 32 EDCs not nominated Nikiforos Alygizakis Metals not nominated not nominated Pesticides and biocides not nominated not nominated PFAS Thorhallur Ingi Halldorsson Lutz Ahrens Nanomaterials Iseult Lynch Susana Loureiro Microplastics Dorte Herzke not nominated Table 6: List of nominated MLs and open vacancies for nomination Methodology Methodology Leader for Human Health Methodology Leader for the Environment Adverse Outcome Pathways (AOPs) not nominated not nominated PKB modelling Sylvia Escher Vikas Kumar Spyros Karakitsios Pre-validation of new methods Miriam Jacobs NG-ERA - Johan Axelman Romana Hornek-Gausterer Omics Martin von Bergen Josef Daniel Rasing To address the issue of the chemicals and/or methods that are missing a CL/ML, the task co-leaders are looking into a solution by approaching the activity leaders and project managers. There will be one final request for CLs/MLs after summer, with more refined criteria in the hope the missing positions can be filled in. Otherwise, a decision will need to be taken on whether to drop CLs/MLs for certain topics. Furthermore, this topic will be discussed in the MB. Task 2.3: Sustainability Co-leaders: INSERM (FR), NCPHP2 (HU) Partners: ANSES (FR), SpF (FR), EAA (AT), DOMG (BE), MU (CZ), EEA (EU), UBA (DE), BfR (DE), NIOM (PL), FMUL (PT), INSA (PT), JSI (SI), NIJZ (SI) A2.3.1 National hubs needs & peer-to-peer learning The mapping of needs of NHs is a living process. A new survey based on criteria-driven scoping documents will be created and launched in the fourth year of the Partnership to identify the new needs and expectations of the NHs based on the inputs of the NHCPs. The responses will be used to reflect on possible improvements to the progress of the development of the NHs, the way we ask questions or collect input from the NHCPs and the NHs and to the implementation of activities such 2 AMD-101057014-80: The Beneficiary ’Nemzeti Népegészségügyi Központ’ (abbreviation in Hungarian: NNK; full name in English: National Public Health Center; abbreviation in English: NPHC) was changed to ’Nemzeti Népegészségügyi és Gyógyszerészeti Központ’ (abbreviation in Hungarian: NNGYK; full name in English: National Center for Public Health and Pharmacy; abbreviation in English: NCPHP) as of 1st August 2023. The acronym NPHC was replaced by NCPHP in the WPs where they are contributors. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 33 as capacity building or sharing good practices that would support the NHs and their structuring at the national level. The peer-to-peer learning process established in the first year of the Partnership will continue to support the sustainable development of the NHs. This activity will be performed in close collaboration with WP9 ‘Building infrastructural and human capacities. The process will be coordinated and the development of the NHs will be monitored by the NHCs. Besides the annual survey, the needs of the NHs will be collected and discussed during the annual meeting. Based on the results of the 2nd and 3rd survey mapping the needs of the NHs and the needs reported by the NHCPs during the NHCP meetings, recommendations will be formulated and actions will be taken. These results, along with the recommendations and actions addressing the identified needs, will be described in D2.14. A2.3.2 Exit strategy Following the first deliverable on the exit strategy (D2.9), which includes the prioritised PARC activities to be sustainable, targeted meetings were held with the different task and WP leaders. A physical workshop on the exit strategy took place in Copenhagen in February 2025 with the involvement of T2.3 partners and MB members. The workshop was structured to focus on individual tasks and WPs before seeking broader overarching strategies, ensuring tailored solutions rather than a one-size-fits-all approach. Discussions also addressed the need for an overarching, integrated European programme to support sustainability. The following steps include continued discussions with WP leaders, European agencies, the GB, where several presentations have already been made. Once a common understanding is reached, the next phase will involve engaging with different DGs and policy makers to build an operational plan. Following these meeting, options for the exit strategy will be further elaborated and discussed with stakeholders. The following activities will be carried out in Year 4: 1. Task 2.3 partners will write an interim report summarizing discussions during and following the February 2025 Copenhagen meeting and elaborating different scenarios for the exit strategy concerning e.g. HBM, toxicology/NAMs, environmental monitoring, safe and sustainable by design, data access. The report will be discussed with the MB, the GB and the NHs. 2. The work on HBM sustainability will be carried out in close collaboration with project P4.1.5 of task 4.1. This activity will be aligned with the ongoing discussions at the EU level on the OSOA framework. 3. Different scenarios for the sustainability of toxicology activities will be discussed. Specifically, the set-up of a European Toxicology Programme inspired by the US National Toxicology programme will be discussed with EU agencies, JRC, and with EU infrastructures, in particular EIRENE. The different activities of such a programme will be determined and further discussed with the EU commission. 4. Similar approaches will be carried out for environmental monitoring, safe and sustainable by design, early warning systems and data access. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 34 5. Since PARC has been able to achieve a network of excellence in chemical risk assessment, the sustainability of a coordination framework of the activities and agencies/institutes involved in risk assessment and covering most PARC activities mentioned above, will be examined and discussed with stakeholders in Y4. We propose to call this putative framework the European Risk Assessment Programme (EURAP). 6. Following discussions with the PARC coordinators, MB and WP3, and depending on the ability of PARC partners to reach a consensus during Y4, a meeting at the EU parliament or one of the MS delegations in Brussels could be held to present PARC activities and prospects. If more internal discussions are needed, this meeting could be postponed to Y5. Deliverables: D2.11 PARCroute roadmap2 – Leader: BfR (initially planned M36, postponed M48) D2.12 Exit Strategy Plan 2 – Leader: INSERM (FR), NCPHP (HU) (M40) D2.13 2nd Mapping of Needs report – Leader: ANSES (M42) D2.14 2nd Report on national needs – Leader: NCPHP (M42) D2.15 3rd Annual CL/ML reports' coordination and submission – Leader: INSA (M45) Additional Deliverables: NA WP N° WP3 Lead Beneficiary INSA/GCSL WP title Synergies, collaborations and awareness Partne r N° 1 2 3 3.1 3.8 4 4.2 6 7 8 10 11 12 14 15 16 17 18 19 20 20.4 20.6 21 22 24 Partne r short name ANSES SpF EAA AGES UMIT VITO DOMG CIPH MOHCY/SGL MU DEPA HB EEA TTL UBA BfR NCPHP UI MOH ISS IUSS UNINA RSU NPHSL LNS PM/ partne r 1.0 0.5 4.7 2.0 2.0 1.0 2.0 1.0 1.0 2.5 1.0 1.0 13.0 1.0 2.8 0.9 14.0 1.0 1.0 1.0 1.0 0.1 1.0 1.0 2.0 Partne r N° 25 26 26.2 27 28 29 29.1 29.3 29.5 30 31 31.2 31.2 32 34 35.7 35.9 36 36.1 36.2 36.3 36.4 37 38 50 59 DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 35 Partne r short name RIVM NIPH STAMI NIOM FMUL INSA APA ENSP UAVR SZU-SK JSI NIB NIC NIJZ ISCIII KEMI SLV AUTH EFET GCSL NKUA UOC BPI FOPH UKHSA UOB PM/ partne r 1.9 1.0 4.3 1.0 4.6 36.6 3.5 3.0 2.6 1.0 1.5 3.0 1.5 5.5 2.0 1.0 1.0 10.0 5.5 19.0 10.5 3.9 2.5 1.0 2.0 1.0 Start M37 End M48 Objectives The main goal of WP3 is to boost the impact of PARC outcomes through the diffusion of the knowledge produced within the Partnership while fostering synergies and collaborations with other projects/programmes at national, EU and international levels. The specific objectives of WP3 for year 4 are: - Task 3.1: Running the International Board (IB) and Stakeholder Forum (SF), and facilitate their effective interaction with PARC’s projects, through the development of dynamic strategies and follow up actions. - Task 3.2: Continue the implementation of the communication strategy for PARC and promote its continuous improvement based on specific requirements from WPs, - Task 3.3: Continue the identification of potential synergies, facilitation of information exchange between external projects and PARC and the establishment of collaborations and synergies with relevant scientific/regulatory/policy initiatives at national, EU and international levels. Description of Programmed Activities Task 3.1: Building effective interactions Co-Leaders: EAA (AT): SF; AUTH (EL): International Board Partners: ANSES (FR), EEA (EU), UBA (DE), IUSS (IT), LNS (LU), STAMI (NO), FMUL (PT), INSA (PT), APA (PT), NIB (SI), NKUA (EL), UOC (EL), GCSL (EL) Activity 3.1.1. Running of SF In year 4 of PARC, the SF (established in year 1) will be continuing the work with the members of the SF. The SF Co-chair(s) and Task Leaders (TLs) will lead the work of members and partners to DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 36 develop and refine the strategy on information flow and of inclusion of SF members’ perceptions taking into account the respective SF groups/interests (NGOs, industry associations and other interested associations). Following the collection of priorities for the second half of PARC, a mechanism for the collection of the SF inputs, comments and suggestions on planned activities, research projects or other topics of interest will be developed. Topics of interest for the SF to be presented in the two SF meetings will be selected based on the discussions and outputs of the first three SF meetings and in close collaboration with SF Co-chair and WP Co-leaders, TLs and Project Managers (PMs). One of the annual meetings will be planned together with SF members, preferably as a physical full day meeting, allowing for in-depth exchange and discussions. SF members will be further encouraged to participate in existing PARC channels and communication tools (PARCopedia, SYNnet...), to offer them the possibility to articulate their needs and interact with the PARC consortium and other stakeholders. Partners involved: EAA, INSA, GCSL, UBA, STAMI, FMUL, APA, NIB, NKUA and UOC. SF members will be encouraged to get deeper involved and provide (industrial) data and insight on current and future activities within their organisations in the relevant section of the factsheets on potential future priorities provided by the CT (EAA, INSA, GCSL, ANSES). In addition, interactions with industry, particularly on the subjects of NAMs and of Safe and Sustainable by Design (SSbD), under WP5 and WP8 respectively, will be promoted through the SF, which has representatives of industry associations and also through other relevant stakeholders and potential synergies (collaboration with Tasks 2.2 and 3.3), based on specific consultations and participation in dedicated meetings (AUTH, ANSES). Stakeholder interests brought to the attention of Task 3.1 will be taken up, discussed and forwarded to other WPs, Tasks or projects of specific interest (all partners). Those projects of interest that are proposed by Stakeholder Forum members will be communicated to the respective fora (MB, GB, GSB) and the relevant project managers. Activity 3.1.2. Running of the International Board (IB) TLs and partners will work in close collaboration to promote the interaction between the IB members and PARC WPs. Feedback on scientific steering needs will be collected from the WPLs into a dedicated form that will be distributed in advance (two months prior the next IB meeting). A similar form will be distributed to the IB members, providing topics of key scientific interest in the field of chemicals RA, so as to enrich the list of available topics. The collected WP needs and the IB topics of key scientific interest will be discussed and prioritized by the Task 3.1.2 partners, who will decide after consultation of the MB on the topics of the forthcoming IB meetings. 4 meetings (one physical organized back-to-back with the in-person MB Meeting in mid 2025 and the other 3 online) will be organized to present the work progress and the main outcomes and to get feedback from the IB on the projects within PARC. Those meetings will also stimulate the interactions between PARC and external bodies (all partners). Particular emphasis will be put on the analysis and the provision on the future needs for PARC. Partners involved: AUTH, UBA, IUSS, LNS, STAMI, FMUL, INSA, NKUA, UOC, GCSL. Task 3.2: Communication, dissemination, and awareness DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 37 Co-Leaders: EEA (EU), NCPHP (HU) Partners: ANSES (FR), SpF (FR), EAA (AT), AGES (AT), UMIT (AT), VITO (BE), DOMG (BE), CIPH (CR), MOH-CY/SGL (CY), MU (CZ), HB (EE), TTL (FI), UBA (DE), BfR (DE), UI (IS), MOH-IL (IL), ISS (IT), UNINA (IT), RSU (LV), NPHSL (LT), LNS (LU), RIVM (NL), NIPH (NO), STAMI (NO), NIOM (PL), FMUL (PT), INSA (PT), APA (PT), ENSP (PT), UAVR (PT), SZU (SK), JSI (SI), NIB (SI), NIC (SI), NIJZ (SI), ISCIII (ES), KEMI (SE), SLV (SE), FOPH (CH), UKHSA (UK), UOB (UK), AUTH (EL), EFET (EL), NKUA (EL), UOC (EL), BPI (EL), GCSL (EL) A3.2.1 Website and social media channels The PARC website and the social media channels (LinkedIn, X, Facebook and Instagram accounts) will be maintained and updated regularly with new content, including up to date information about upcoming events, progress updates, interviews, and results (EEA, NCPHP, INSA, EFET, NKUA, NIJZ, BPI, and GCSL). New developments will be implemented on the PARC website including the visualisation of new indicators, a new section on chemicals, and interactive maps of environmental laboratories. The thematic areas will also be further developed (EEA, NCPHP). A3.2.2 Development and implementation of the communication and dissemination strategy The communication and dissemination strategy developed at the beginning of PARC will be reviewed (D3.6). Continuous dialogue will be maintained with all WP co-leaders, WP3 contact points and NHCPs to translate the latest PARC results and the agenda into communication and dissemination outputs, ensuring a coherent approach. The roadmap for the development of communication materials will be updated. New communication materials and activities, such as promoting the first research and policy briefs on the projects’ outputs provided by the different WPs, will contribute to increase PARC’s visibility, build and grow the PARC brand and engage stakeholders. The monthly Science Digest listing the latest peer-reviewed scientific PARC articles will continue to be produced, while the PARC Sampler bringing together all the latest news, interviews, science impact and much more will continue to be published twice a year. All public project deliverables produced under the project will be made available via the PARC website (UMIT, EEA, NCPHP, STAMI, FMUL, INSA, APA, ENSP, UAVR, NIB, NIJZ, EFET, NKUA, UOC and GCSL). A3.2.3 Surveys and other tools to assess stakeholders' perception and concerns Outreach activities will be carried out to raise awareness of specific target groups. New focus groups will be organized to collect more in-depth information about citizens’ perceptions and concerns about PARC-related subjects. The countries hosting focus groups will be selected in an internal call. The results of the first citizens’ survey will be further analysed and published. Communication with the scientific community and with all stakeholders, including the general public, regulators and policy makers will be done in dialogue through the different communication channels (website, social media, newsletters, PARCopedia, workshops and other events) and with the involvement of the NHs (EEA, ENSP, FMUL, GCSL, INSA, NCPHP, NIB). A3.2.4 Risk communication DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 38 The results of the survey mapping the risk perception of different stakeholders on risk communication will be published by EFET and NIJZ. A series of webinars on risk communication will be launched, tailored to a wide range of stakeholders (ENSP, FMUL, EFET, NIJZ, NIC). A.3.2.5 Monitoring of indicators Monitoring of indicators defined for the communication and dissemination activities will continue to feed into Task 1.3 by DOMG, EEA, GCSL, INSA and NCPHP. The bibliometric analysis will be updated by UOC. Indicator values will be updated on the website. Task 3.3: Networking and Synergies Co-Leaders: INSA (PT), NKUA (EL) Partners: ANSES (FR), MU (CZ), UBA (DE), FMUL (PT), APA (PT), ENSP (PT), UAVR (PT), JSI (SI), NIB (SI), NIC (SI), NIJZ (SI), EFET (EL), UOC (EL), BPI (EL), GCSL (EL) A3.3.1 Inventory of scientific activities relevant to PARC Monitor the online form created for the external partnerships, projects, networks and activities to express interest to collaborate with PARC. Update of the established database of external partnerships, projects, networks and activities that have expressed interest in collaborating with PARC (NKUA, INSA, ANSES, MU, UBA, FMUL, APA, ENSP, UAVR, JSI, NIB, NIC, NIJZ, EFET, UOC, BPI, GCSL). Contact the relevant WP/Task co-leaders to request their evaluation of the external projects/activities and to organize brainstorming sessions between researchers from PARC and from the external initiatives (NKUA, INSA). A3.3.2 Development of SYNnet strategy and roadmap for promotion of synergies Continue updating SYNnet with the information gathered in the form created to register the established synergies and work on expanding the network to include new partnerships, projects, etc. and respond to PARC demands for synergies (NKUA, INSA, ANSES, MU, UBA, FMUL, APA, ENSP, UAVR, JSI, NIB, NIC, NIJZ, EFET, UOC, BPI, GCSL). Revise and update the interaction strategy between SYNnet and WPs in order to identify and address internal needs and gaps (FMUL, APA, NKUA, GCSL, INSA, UBA). The third SYNnet Forum foreseen to take place in Y4 will be organized back-to-back with a relevant scientific event (EUROTOX 2025) to promote dialogue and knowledge sharing among scientists (NKUA, UOC, INSA, GCSL, BPI, EFET). SYNnet activities will be announced and published at the PARC website increasing the visibility of joint activities and of the external projects themselves (NKUA, INSA). Another workshop on Synergies with External Initiatives will be organized in Y4 and external activities or projects considered relevant will be invited to participate (NKUA, INSA). Development of the SYNnet dashboard for the visualization of the synergies at the website and contributing to the output and outcome indicators (NKUA, INSA, ANSES, MU, UBA, FMUL, APA, ENSP, UAVR, JSI, NIB, NIC, NIJZ, EFET, UOC, BPI, GCSL). DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 39 Deliverables: D3.6 Review of Communication and Dissemination Strategy – Leader: NCPHP (M40) Additional Deliverables: NA WP N° WP4 Lead Beneficiary UBA/SpF WP title Monitoring and exposure Part ner N° 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.9 1.10 1.11 1.12 1.13 2 3 3.4 3.5 3.6 3.9 4 4.1 4.3 4.4 4.5 4.6 4.7 5 5.2 6 7 8 8.1 8.2 8.4 Part ner shor t nam e ANSES INSERM INRAE CEA INERIS CNRS INRS ONIRIS OFB BRGM LNE CSTB EHESP SpF EAA MUI MUW UG-AT UNIVE VITO KU Leuven UH PIH OVAM ISSeP UAntwerpen SCIENSANO EV-ILVO CIPH MOH-CY/SGL MU SZU-CZ VSCHT JU PM/ part ner 51.0 12.1 44.9 6.0 15.2 1.0 13.3 18.9 0.8 7.8 0.2 4.4 16.7 71.1 5.5 24.4 2.0 2.0 6.2 48.8 11.4 2.0 5.0 3.3 31.0 21.9 11.8 0.9 1.0 28.8 51.0 12.9 7.6 0.4 Partn er N° 10.1 10.3 10.4 11.2 13.1 14 14.1 14.3 14.4 15 15.1 15.2 15.6 16.1 17 18 19 20 20.2 20.5 20.6 20.7 21 21.1 22 23 24 24.3 25 25.1 Partn er short name AU REGIONH-RH UCPH UT SYKE TTL FFA UOULU UEF UBA BfG UFZ KUM Fraunhofer-IBMT/IME NCPHP UI MOH ISS CNR-IRSA UMIL UNINA UNIPD RSU UL NHPSL LSMU LNS UniLU RIVM KWR PM/ partn er 37.1 15.0 2.9 12.5 0.8 22.4 4.2 1.1 2.0 77.7 1.3 30.3 5.2 5.0 14.0 5.2 6.0 15.4 3.0 4.5 2.1 2.0 33.0 3.0 0.3 6.2 77.9 14.8 0.1 3.2 Partne r N° 25.2 25.5 25.6 25.7 25.9 26 26.2 26.3 26.7 27 27.3 29 29.3 30 31 31.4 32 32.2 33 33.4 33.3 34 34.1 34.2 34.5 Partne r short name TNO UU-IRAS VUA WR SRU NIPH STAMI NILU UNN NIOM WULSSGGW INSA ENSP SZU-SK JSI ULFFA NIJZ NLZOH CSIC ULPGC UGR ISCIII EASP FISABIO IISPV DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 40 PM/ partne r 0.5 5.6 19.6 9.4 10.5 30.2 7.2 9.0 0.3 1.9 12.3 30.7 0.5 6.5 54.3 2.3 10.4 0.2 40.9 0.4 19.0 37.8 5.3 0.7 2.2 Partner N° 34.6 34.8 35.2 35.3 35.4 35.6 35.8 35.9 35.10 35.11 36 36.2 36.3 37 38 40 41 45 47 50 54 55 56 Partner short name INNST UPV-EHU KI ULUND ORU SU IVL SLV SLU UMU AUTH GCSL NKUA BPI FOPH UNISANTE EAWAG USI SECO UKHSA EA HSE IOM PM/ partner 1.3 7.0 3.5 13.8 9.7 8.5 19.2 1.0 11.0 2.0 31.9 1.0 10.5 16.8 1.0 5.0 20.9 6.2 0.8 3.0 1.0 6.0 1.1 Start M37 End M48 Objectives The main goal of WP4 is to monitor chemicals guided by clearly defined regulatory and policy challenges both in humans and in the environment, considering different sources, chemical fates and exposure pathways, and linking with international activities. Specifically, WP4 aims to coordinate with the WHO EHP on HMB launched in Budapest in July 2023. The specific objectives of WP4 for year 4 are: − Task 4.1: Continuation of an EU-wide general population HBM survey, continuing occupational surveys in health care sector and waste sector, developing targeted surveys (design and supporting materials), preparing and implementation of following aspects in above mentioned surveys: effect biomarkers, innovative (sampling) techniques for HBM in a tiered approach starting with state of the art analyses, update and integration of QA/QC aspects and analyses plan in the HBM surveys, evaluation of new chemical analysis methods needs, derivation of HBM guidance values (HBM-GV). − Task 4.2: Complete a first monitoring study on PFAS and endocrine disrupting chemicals (EDCs) and evaluate the process with regard to future monitoring studies. Continue a study on human exposure to organic chemicals from environmental non-food sources. Initiate an environmental monitoring study on siloxanes and transversal activities with a view to a joint T4.2-T4.3 project. − Task 4.3: Novel methodologies will be developed in a tiered approach to improve and renew current monitoring approaches, with a focus on early life stages and on early warning systems for the timely observation of the occurrence of chemicals of emerging concern along the interlinked pathways in environment, food and human matrices. The work will be covered in 4 ongoing projects (started in year 1) and 3 projects started in year 2 and 1 project starting in year 3. In year 4 a specific attention will be given to transversal activities inside WP4 to ensure that the different tasks (4.2 and 4.3) align their activities and prepare new projects considering the outcome DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 41 of the “mapping of needs” to enhance the efficient use of monitoring approaches by combining targeted analytical methods with innovative methods, such as screening and effect-based methods. The project 4.2.c is a collaboration between T4.1 and T4.2 and includes links to T4.3 and will integrate human and environmental monitoring networks. Description of Programmed Activities Task 4.1: HBM Co-Leaders: VITO (BE), ISCIII (ES) Partners: ANSES (FR), AU-PH (DK), AUTH (EL), BPI (EL), CEA (FR), CSIC (ES), EAA (AT), EHESP (FR), FFA (FI), TTL (FI), FISABIO (ES), FOPH (CH), HSE (UK), KI (SE), IMROH (HR), INRAE (FR), INRS (FR), INSA (PT), INSERM (FR), INSST (ES), IOM (UK), KUM (DE), ISS (IT), ISSeP (BE), IVL (SE), JSI (SI), KU Leuven (BE), LNS (LU), LSMU (LT), MOH-CY/SGL (CY), MOH (IL), MU (CZ), MUI (AT), MUW (AT), NIJZ (SI), NIOM (PL), NIPH (NO), NLZOH (SI), NPHSL (LT), ONIRIS (FR), UKHSA (UK), PIH (BE), REGIONH-RH (DK), RSU (LV), SRU (NL), SCIENSANO (BE), SLU (SE), SpF (FR), STAMI (NO), SZU-CZ (CZ), SZU-SK (SK), THL (FI), UAntwerpen (BE), UBA (DE), UGent (BE), UGR (ES), UH (BE), ULFFA (SI), ULPGC (ES), ULUND (SE), UMU (SE),UMIL (IT), UNINA (IT), UNIPD (IT), UNISANTE (CH), UNIVIE (AT), UNN (NO), UOULU (FI), UOC (EL), UPV/EHU (ES), USI (CH), UU-IRAS (NL), WULS-SGGW (PL), CIPH (HR), SHSO (CY), SDU (DK), Fraunhofer-IBMT (DE), UFZ (DE), NCPHP (HU), UI (IS), VSCHT (CZ), EASP (ES), SECO (CH), UCD3 (IE) A4.1.1 Design, alignment and fieldwork of HBM studies The implementation of a general population HBM survey is ongoing and will be further supported (linked to P4.1.1.2.a_Y1_GenHBMSurvey_VITO). Small-scale research components, in the general survey will be initiated they are referred to as add-ons. The topics are: i) implementation of effect biomarkers (linked to P4.1.3.3.a_Y1_RoadmapLinkingHBMhealth_SpF_VITO), ii) identify the contribution of specific environmental compartments, products to internal exposure levels (in collaboration with T4.2 - in project P4.2.c_Y3_HumanExposure_INERIS_AU), and (iii) apply innovative screening methods (Suspect screening (SS), Non targeted screening (NTS)) (in collaboration with T4.3 - in project P4.3.2.c_Y3_H03 Complementary developments_JSI/UAntwerpen). During the Y3 of PARC occupational surveys focusing on the waste management sector ( P4.1.1.4.d_Y1_OccupWaste_ENSP_TTL) (phthalates, metals, flame retardants, bisphenols) and the health care sector (P4.1.1.4.c_Y1_HealthCareSurvey_TTL_SRU) (HMPs and disinfectants) have progressed to sampling phase. Samplings performed in different countries follow the harmonised sampling procedures in accordance with the procedures for the PARC Aligned Studies. Samplings related to these studies will continue until the end of first quarter of Y4 for the waste management 3 AMD-101057014-118: The University College Dublin – PARC acronym “UCD”, PIC number 999974359 entered as new Beneficiary in PARC as of 01/10/2024 with the agreement that the ‘Environment Protection Agency’ – PARC acronym “EPA” remains the only member of the Grant Signatory Board and takes over responsibility for coordinating Ireland’s engagement in PARC in the same way as other grant signatories with AE do. The starting date for the eligibility of the costs for UCD is on 01/10/2024 and UCD specifically contributes as partner in the PARC Aligned Studies under WP4 (P4.1.1.2.a_Y1_GenHBMSurvey_VITO). DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 48 already in Y3 but continues to Y4. Chemical substance groups prioritized for analysis are cytotoxic drugs, anesthetic substances (fluranes and N2O) and disinfectants (ethanol and isopropanol). Effect Biomarkers prioritized for analysis are markers for genotoxicity (reticulocyte and PBL micronuclei), oxidative stress and inflammation. The analyses of exposure and effect markers have been shared between the partners having analytical capability. List of exposure (bio)marker analyses to be performed in the study is provided below together with laboratories performing the analysis of either their own samples or receiving samples also from other countries with no laboratory capabilities for the given (bio)marker for analysis (common analysis laboratories). Table 9: exposure biomarkers and external exposure markers analysed in P4.1.1.4.c_Y1_HealthCareSurvey_TTL_SRU and analytical laboratories Exposure group Compound Biological matrix Common analysis laboratory Partners analyzing their own samples Cytotoxic drugs Total platinum Urine ISS/IT TTL/FI, HSE/UK, RSU/LV, INRS/FR Cyclophosphamide, Isophosphamide, Methotrexate, Doxorubicine, Gemcitabin, Docetaxel, Paclitaxel, Etoposide, Cytarabine Urine SRU/NL ISS-UNINA/IT HSE/UK (cyclophosphamide/ifosfamide only) alpha-fluoro-betaalanine (FBAL) Urine INRS/FR Anaesthetic gases Parent compounds Urine (Desflurane, Isoflurane, Nitrous oxide) UMIL/IT TTL/FI, HSE/UK (not N2O), UGR/ES Exhaled air (Desflurane, Isoflurane, Sevoflurane, Nitrous oxide) TTL/FI HSE/UK Metabolites Urine (Hexafluoroisopropanol) UMIL/IT HSE/UK Disinfection products Ethanol, IPA Exhaled air SRU/NL HSE/UK (not ethanol) Cytotoxic drugs Total platinum Surface wipe MU/CZ HSE/UK Dermal wipe TTL/FI HSE/UK Air SRU/NL ISS/IT Cyclophosphamide, Isophosphamide, Methotrexate, Doxorubicine, Gemcitabin, Docetaxel, Paclitaxel, Etoposide, Cytarabine Surface wipe MU/CZ HSE/UK (cyclophosphamide/ifosfamide only) Dermal wipe TTL/FI HSE/UK (cyclophosphamide/ifosfamide only) Air SRU/NL ISS/IT Anaesthetic gases Desflurane, Isoflurane, Sevoflurane Air UMIL/IT HSE/UK DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 49 Nitrous oxide Air UMIL/IT HSE/UK Disinfection products Ethanol, IPA Air TTL/FI HSE/UK (not ethanol) In addition, effect marker analyses will be performed. The list of effect biomarkers included in the occupational healthcare study is provided in the table below with analysing laboratories. Table 10: Biomarkers of effect P4.1.1.4.c_Y1_HealthCareSurvey_TTL_SRU and analytical laboratories Exposure group Assay Biological matrix Common analysis laboratory Cytotoxic drugs exposed workers PBL Micronuclei Whole blood UGR/ES RET Micronuclei Whole blood TTL/FI Comet assay Whole blood INSA-Porto/PT Anaesthetic gases exposed workers PBL Micronuclei Whole blood UGR/ES RET Micronuclei Whole blood TTL/FI Buccal micronuclei Buccal cells TTL/FI Comet assay Whole blood INSA-Porto/PT Oxidative stress (Glutathione) Whole blood LNS/LU Inflammatory markers Plasma RSU/LV Epigenetics Whole blood UNIPD/IT - P4.1.1.4.d_Y1_OccupWaste_ENSP_TTL [M1-M48] Sampling campaigns for this study started in the beginning of Y3 of PARC. Final samplings are expected to be performed during the first quarter of PARC Y4. Samples are collected in 13 countries by: ENSP-UNL (PT), AU (DK), ISS(IT), UNIPD (IT), UMIL (IT), UNINA (IT), WULS-SGGW (PL), ULUND (SE), STAMI (NO), AUTH (EL), INSA (PT), TTL (FI), LNS (LU), MOH-CY (CY), NIOM (PL), IOM (UK), HSE (UK) and UGR (ES). The aim is to cover 40-50 companies and up to 700 workers. Analysis of samples will begin in Y3 but continue to Y4. Chemical substance groups prioritized for analysis are metals, Flame retardants, Phthalates, Bisphenols, PFAS, plasticizers. Exposure markers to be analysed in P4.1.1.4.d_Y1_OccupWaste_ENSP_TTL are listed in the following table together with laboratories performing the analysis of either their own samples or receiving samples also from other countries with no laboratory capabilities for the given (bio)marker for analysis (common analysis laboratories). Table 11: Exposure biomarkers and external exposure markers analysed in P4.1.1.4.d_Y1_OccupWaste_ENSP_TTL and analytical laboratories Chemical class Compound Biological matrix Common analysis laboratory Partners analyzing their own samples Metals Cadmium, Lead Blood TTL/FI STAMI/NO, ULUND/SE, DHP-UNINA-ISS/IT, KU Leuven/BE, UNIPD/IT, DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 50 LNS/LU, NIOM/PL, AUTH/GR, HSE/UK Cadmium, Lead, Chromium, Mercury, Cobalt, Aluminium Urine STAMI/NO, LNS/LU ULUND/SE, DHPUNINA-ISS/IT, KU Leuven/BE, UNIPD/IT, TTL/FI, AUTH/GR, NIOM/PL, HSE/UK Flame retardants Brominated Serum LNS/LU OPFRs metabolites Urine LNS/LU ULUND/SE, HSE/UK PFAS PFHxA, PFOA, PFHpA, PFNA, PFDA, PFUnDA, FDoDA, PFBS, PFHxS, PFHpS, PFOS Plasma UMIL/IT ULUND/SE Bisphenols A, F, S Urine AUTH/GR ULUND/SE Phthalates + DINCH MEP, MBzP, MiBP, MnBP, MCHP, MnPeP, MEHP, 5OHMEHP, 5oxo-MEHP, 5cx-MEPP, MnOP, OH-MiNP, cx-MiNP, OH-MiDP, cx-MiDP, DINCH Urine AUTH/GR ULUND/SE PAHs 1-hydroxypyrene Urine TTL/FI ULUND/SE Metals Cadmium, Lead, Chromium, Mercury, Cobalt, Aluminium Air STAMI/NO KU Leuven/BE, TTL/FI, ULUND/SE, LNS/LU, ISS/IT, AUTH/GR, NIOM/PL, HSE/UK Cadmium, Lead, Chromium, Mercury, Cobalt, Aluminium Settled dust LNS/LU ISS/IT Cadmium, Lead, Chromium, Mercury, Cobalt, Aluminium Dermal wipes LNS/LU, TTL/FI, KU Leuven/BE ISS/IT, AUTH/GR, HSE/UK Flame retardants PBDEs(#28,#47, #99, #100, #153, #154, #183, #209) / OPFRs (EHDPP, TBP, TPP, TBEP, TCEP, TdCPP, TEHP) Settled dust LNS/LU Effect Biomarkers prioritized for analysis are markers for genotoxicity, oxidative stress and inflammatory markers. These are analysed by the partners as described in the following table. Table 12: Biomarkers of effect in P4.1.1.4.d_Y1_OccupWaste_ENSP_TTL and analytical laboratories Biomarker Matrix Common analysis laboratory PBL micronuclei Blood INSA/LISBON-PT, TTL/FI Buccal micronuclei Buccal cells UNISANTE/CH DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 51 Frozen comet assay Blood INSA/PORTO-PT Global DNA methylation Blood KU Leuven/BE Gluthathione Blood LNS/LU Inflammatory markers Blood KU Leuven/BE A4.1.2 Laboratory analysis and quality assurance There is no project for this activity since it is a transversal activity. During Y4, work will be done in the selection of the best, state-of-the-art exposure biomarkers and analytical methods for those needs identified in the PARC HBM Targeted Studies that will be implemented in T4.1 as from Y4 (projects recently submitted for evaluation) (AU, AUTH, BPI, CEA, EHESP, FFA, FISABIO, IMROH, INSA, ISCIII, ISS, JSI, KU Leuven, KUM, LNS, LSMU, NIOM, NIPH, NPHSL, UKHSA, RSU, SRU, SpF, STAMI, SZU-SK, THL, UAntwerpen, UGR, ULFFA, ULPGC, ULUND, UMIL, UNN, UOC, UOULU, USI, VSCHT). In addition, the evaluation and selection of biomarkers will be also performed if new substances are included in the HBM studies as a result of the new activities, like the second prioritisation exercise, currently under consultation in the Governing Bodies in PARC. If new biomarkers are included in the studies, the Quality Assurance Working Group (QAWG) (AU, ISCIII, NIPH, UAntwerpen, and WR) and collaborating partners (LNS) will work in close collaboration with T9.1 and T9.3 to develop and implement the required QA/QC measures to keep ensuring the quality and comparability of the HBM data generated under T4.1. The PARC QA/QC programme will continue in year 4, two rounds of the programme are scheduled each year, and its duration will be aligned with the timeline of HBM surveys planned. The programme will adapt to new requirements both in terms of new biomarkers and concentration ranges to cover the needs of all the studies. The list of qualified laboratories that can analyse HBM samples in PARC will be updated as the results of the rounds are available. The QA/QC aspects related to the innovative sampling techniques will be evaluated and included in the add ons for the HBM surveys (ISCIII, LNS, MU, ONIRIS, UAntwerpen, UGR, UNIVIE, and UOC) as these activities are currently taking shape. The working group on reference analytical methods (ISCIII, ISS, LNS, MUI, NIPH, SCIENSANO, UAntwerpen, ULUND, UNIVIE, and UOC) will continue updating the inventory to identify strong/weak points related to the analytical methods for the selected substances and the needs to harmonise important preanalytical issues. This activity led to the design in Y3 of two activities on method development and harmonization that will continue in Y4. These two activities are: • Monitoring urinary mono-n-hexyl phthalate and its secondary metabolites. Coordinated by NIPH; partners: UAntwerpen, RegionH, ULUND, and LNS; external expert Dr. Holger Koch (Institute of the Ruhr-University Bochum, IPA). The tasks include the method development (Autum 2024 - Summer 2025, with the following activites: (a) Mapping urinary biomarkers for exposure determination of DnHexP; (b) Checking availability of standards and internal standards of the biomarkers and initiation of custom synthesis of standards if required; (c) Inclusion of biomarkers in the existing phthalate methods, validation of the methods for new biomarkers; (d) Inter-laboratory comparison between DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 52 the involved PARC partners) and the analysis of MnHexP in a subset of selected populations such as HBM4EU aligned studies 2016-2017 and PARC Aligned Studies (Summer 2025Spring/Summer 2026). • Polar PFAS in human samples. Coordinated by NIPH; partners: UAntwerpen, ISS, ULUND, and LNS. The tasks include the method development (Year 2025, with the following activites: (a) Selecting PFASs that are important to include of ultrashort and short PFAS (C1-C6); (b) Acquiring selected standards and internal standards of the biomarkers; (c) Establishment and validation of method; (d) Inter-laboratory comparison will be performed between the involved PARC partners) and the analysis of of polar PFASs in in a subset of selected populations (Year 2026; with the following activites: (a) Selection of most suitable matrix for HBM in a small pilot study, (b) Sample analysis). In Y4 the chemical analysis plan will be already implemented (LNS, MU, NIOM, RSU, SRU, SCIENSANO, SpF, THL, TTL, UAntwerpen, UBA, UGR, and ULUND). The information collected from laboratories and the progress of chemical analyses will be regularly updated. The implementation of effect biomarkers will take place under P4.1.3.3.a_Y1_RoadmapLinkingHBMhealth_SpF_VITO, and details are provided below. A4.1.3 Link exposure and health related information No transversal activities under A4.1.3, all captured in projects. Details per project: - P4.1.3.1.a_Y1_Derivation of HBM-GVs_UBA [M1-M81] (The project has been extended from M36 to M81) Health-Based HBM-GVs will be derived for a third set of prioritised substances (ANSES, AUTH, MOHIL, NIJZ, NIPH, TTL, UBA, Unisante, SECO, LNS). HBM-GVs for selected substances or their specific exposure biomarkers will be derived according to the strategy agreed under HBM4EU and described by Apel et al. (2020; https://doi.org/10.1016/j.ijheh.2020.113622). In principle, all lead experts conduct a literature search on the substance under consideration to determine the current state of toxicological/epidemiological knowledge. Depending on the data basis, the experts decide whether epidemiological data, or else a recognized external toxicity reference value respectively occupational exposure limit, or a point of departure from an experimental study together with toxicokinetic information is used to derive the HBM-GV. Thus, HBM data are only included in the derivation if studies are available that show a relationship between human internal exposure and health effects. If additional data is needed WP 5 will be involved to fill the data gaps. The substance dossiers including the derived values will afterwards be reviewed by project partners and other experts involved via the NHs. NIPH and TTL will work on mercury. It is to be examined whether and, if so, which significant published toxicological findings need to be added to the dossier in the HBM4EU Deliverable D5.12 (Deliverables – HBM4EU – science and policy for a healthy future). The findings on the toxicology of DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 53 mercury presented in the HBM4EU Deliverable D13.7 (Deliverables – HBM4EU – science and policy for a healthy future) should also be taken into account. Based on this, it should be clarified whether the provisional HBM-GVs for the general population (7 μg Hg/l urine, 3.5 μg Hg/l blood) which were derived within HBM4EU can be adopted. AUTH offered support regarding modelling work. ANSES will check whether the derivation of HBM-GV for arsenic is possible and will work on HBMGV for cis-/trans-DCCA as metabolites of various pyrethroids. A working group led by MOH-IL and involving NIPH, possibly LNS and WP 6 partners (6.2.3., case study on mixture RA) will evaluate whether/which further work is needed to reassess PFAS HBM guidance values as part of PARC. With the aim of deriving HBM-GV, UBA will work on Acetamiprid/ N-desmethyl acetamiprid and the phthalate substitute DEHA (di(2-ethylhexyl)adipate). It is planned that dossiers and reports for the abovementioned substances are included in AD4.3. - P4.1.3.1.b_Y4_Health-based-IA-GV_LNS_NCPHP [M37-M81] For a health-related interpretation of human indoor air exposures data and for effective risk management, guideline values are needed that have been derived epidemiologically or toxicologically and relate directly to the measured indoor air concentrations. Methodological harmonization and sufficient coverage of relevant substances with indoor air guideline values is lacking, in order to allow systematic and health-based evaluation of indoor air pollution by national risk assessors, public health institutes or European regulatory bodies. In the first year of the project (Y4), partners (LNS, NCPHP, UBA, VITO, TTL, EAA, MU, KI, INSA, ENSP) will review and summarize the existing initiatives and methodologies to derive health-based indoor air guideline values and a mutually agreed methodology how to derive indoor air guideline values based on toxicological and/or epidemiological data will be proposed in alignment with regulatory accepted standards to achieve harmonization. The work on an inventory of indoor air guideline values will be initiated. Existing (inter)national guideline values should be identified with main emphasis on substances prioritized in the 4.2_HumanExposure and 4.1_General Survey projects. Furthermore, criteria will be developed to prioritize substances relevant for indoor air and compiling a substance prioritisation list. Project partners will also initiate contact to other relevant (inter)national initiatives outside PARC to explore synergies in methodological harmonisation and derivation of indoor air guideline values. - P4.1.3.3.a_Y1_RoadmapLinkingHBMhealth_SpF_VITO [M1-M52] Part 1: Health Outcomes Partners involved in this part of the project: [SpF (lead), VITO (lead), BPI, IDAEA-CSIC, EAA, EHESP, Fraunhofer-IBMT, INSST, JSI, KU Leuven, LNS, NIJZ, UKHSA, RSU, TTL, UBA, UPV/EHU]. In Y4, the feasibility study will be performed to explore the link between past exposures and health effects (biological and clinical). This feasibility study will be conducted using data from existing cohorts. These cohorts must include exposure measurements as well as the evaluation of health outcomes. Additionally, biological samples, stored in biobanks, must be available for further analysis of effect biomarkers. Two partners have already expressed their interest in being involved in this DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 54 study: VITO with the 3xG cohort (Belgium) and UPV/EHU with the INMA Projet (Spain). Other partners have been contacted. After the launch of the feasibility study at the end of Y3, during the Y4 we will work on: • Selecting and defining study criteria for the measurements of exposures, health outcomes, and effect biomarkers. • Developing a data analysis approach in collaboration with A4.1.4-Data management and analysis and WP7. • Measuring the selected effect biomarkers in available biological samples, in collaboration with VITO - P4.1.3.3.an Identification of effect biomarkers. • Initiating data analysis to link past exposures, effect biomarkers, and health outcomes with participating studies. Part 2: Identification of effect biomarkers Partners involved in this part of the project: Core partners: VITO (lead), SpF, AU, AUTH, EAA, INRS, INSA, Inserm, ISCIII, JSI, LNS, MU, SECO, TTL, UGR. Additional partners: BPI, CEA, IDAEA-CSIC, KU Leuven, LSMU, NIJZ, NIOM, NLZOH, UKHSA, SRU, Sciensano, STAMI, UGent, ULPGC, UNINA, UNIPD, UOC, UOULU, USI, WULS-SGGW. In year 4, VITO will continue to lead the implementation of effect biomarkers in PARC surveys. Together with the project partners, VITO will support approved targeted studies for inclusion of effect biomarker analyses and/or health outcomes implementation. Based on the final implementation plan (submitted M22), the general survey project established an overview on which studies will measure which biomarkers of effect together with information on the tools they use for health outcome assessment. UGR will continue the selection of labs to measure the effect biomarkers, together with T4.1.2 (ISCIII) and supported by VITO. The QA/QC aspects for effect biomarker measurements and derivation of respective SOPs are organized by UGR with support of ISCIII and T9.3, as documented in "Design and implementation of a quality assurance/quality control (QA/QC) laboratory program for the implementation of effect biomarkers". In year 4, the actual QA/QC program will be initiated and will run in alignment with the requirements of the studies and the laboratories involved. A4.1.4 Data management and analysis Details for transversal activities: - Data management: the T4.1 data management team (VITO, MU, SPF, UBA, TTL, PIH) will further support all HBM related data management activities in T4.1. That is the development of the codebooks, the validation of the biomarker list, feedback and testing of the tools on data validation, calculation of derived variables and calculation of summary statistics (https://hbm.vito.be/tools), feedback on the integration of aggregated data into the European HBM dashboard and IPCHEM, definition of metadata for HBM studies and feedback on user interface for the collection of metadata, support in development of project DMP, helpdesk for data management activities. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 55 - Statistical working group: the statistical working group (VITO, UU-IRAS, MU, JSI, AU-PH, SPF, UBA, NIPH, INRAE, INSA, TTL, UH) will further elaborate the statistical analysis plan for the ongoing 4.1 projects. The statistical working group (WG) gives support and advice to research leads in performing the statistical analyses. - During Y4, statistical analyses related to targeted occupational projects P4.1.1.4.d_Y1_OccupWaste_ENSP_TTL) and P4.1.1.4.c_Y1_Occuphealthcare_TTL_SRU) are planned to be performed (during the last quarter of Y4). These will be performed following the statistical analysis plan created in T4.1.4 (TTL, INSA, INRS, STAMI, LNS). Details per project: - P4.1.4.2.a_Y1_DataAnalysisHBM4EU_VITO [M1-M48] (the project has been extended from M36 to M48) Reason for extension: For the further analyses of the HBM4EU MoM-study, the SPECIMEn study and the HBM4EU occupational studies, a delay was caused in the initiation of the statistical analysis, due to capacity issues at the involved partners’ institute. For the geospatial analysis of the HBM4EU aligned studies, it took some time to come up with the best technical solution to derive geospatial variables from the geolocation of the participants, and for the development of this tool. And now some time will be needed to allow the data owners to train themselves and implement the tool. For the exposure-effect analyses of the HBM4EU aligned studies, the approval of the data requests took longer than anticipated. Results achieved so far: For the exposure-effect analyses of the HBM4EU Aligned Studies, two manuscripts were published. For the geospatial analyses of the HBM4EU Aligned Studies, a tool was developed to retrieve geospatial variables from the geocoordinates of participants. For all the other research questions, statistical analyses were initiated. Plans year 4: The project is extended with one year, making year 4 the final year of the project and will be devoted to finalizing the statistical analyses of the data and the interpretation and discussion of the results. Scientific peer-reviewed publications will be elaborated and submitted. Results will be reported and communicated to the PARC community (AD4.11). Partners involved: AU-PH, AUTH, BPI, EASP, INRAE, INRS, INSA, ISCIII, ISSeP, JSI, LNS, LSMU, MU, NIJZ, NIPH, Sciensano, SpF, SZU-SK, TTL, UBA, UGR, UU-IRAS, VITO. A4.1.5 Preparation of a sustainable monitoring and surveillance system for Europe No transversal activities under A4.1.5, all captured in projects. Details per project: - P4.1.5.a_Y1_SustainHBMSystem_VITO [M1-M66] This project will be continued in Y4. The project's goal is the preparation of a sustainable HBM and surveillance system for Europe. Following actions are planned for Y4: DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 56 Foster interaction with international key players in HBM to exchange experiences and improve international collaboration and comparison of HBM data. Continued engagement with the PARC GB to develop a roadmap for sustainable HBM after PARC. The project is co-led by VITO and SpF. Other partners involved in the actions are FOPH, INSA, ISCIII, LNS, LSMU, MOH-CY/SGL, NIPH, UBA. This project will be run in close collaboration with WP2 and the PARC Exit Strategy. Participation in intertask meetings on sustainability (T1.3, T2.3 and P4.1.5.a_Y1_SustainHBMSystem). Organization of a workshop to share experiences on policy uptake of HBM results (HBM4EU results). Task 4.2: Environmental and multisource monitoring Co-leaders: INERIS (FR), AU (DK) Partners: ANSES (FR), BfG (DE), BRGM (FR), CNRS (FR), CNR-IRSA (IT), CSIC (ES), CSTB (FR), EA (UK), EAWAG (CH), EFET (EL), Fraunhofer-IME (DE), FISABIO (ES), INRAE (FR), INSERM (FR), ISS (IT), ISSeP (BE), IVL (SE), JSI (SI), LNS (LU), MU (CZ), NKUA (EL), OFB (FR), ONIRIS (FR), OVAM (BE), SCIENSANO (BE), SLU (SE), SYKE (FI), UAntwerpen (BE), UBA (DE), UCLM (PT), UFZ (DE), UL (LV), ULFFA (SI), UniLU (LU), VITO (BE), VSCHT (CZ), ISCIII (ES), VUA (NL), NILU (NO), UKCEH (UK), BPI (EL), NMBU (NO), SpF (FR), DCU4 (IE) The work in T4.2 will proceed in the following projects and transversal activities in Y4: - P4.2.a_Y1_ENVMonitoringPilotSurvey_INERIS_AU [M1-M42] (the project has been extended from M36 to M42) This project focuses on PFAS and EDCs with the purpose of establishing and validating environmental monitoring structures for the long-term work in T4.2. Comprehensive monitoring campaigns across air, water, soil, and biota using bioassays, target analysis, and suspect screening have been performed. The PFAS study involves baseline analyses of existing monitoring data from 10 countries and 19 case studies exploring PFAS transport, transformation, environmental factors, and source identification through fingerprinting methods. Originally planned for three years, a sixmonths extension into Y4 has been sought for the project. These six months will concentrate on the last two steps in the project, i.e. 4.2.5 Data analysis and transfer and 4.2.6 Feedback mechanism. The data analysis and transfer will be a continuation and finalization of the work started in Y3, according to a workflow for data transfer to the NORMAN database (as defined with WP7) with integrated QA/QC steps and a statistical analysis plan for the data treatment. Lessons learnt will be addressed in the feedback mechanism including all steps of the process. The collection of information has been started in Y3 and will include different perspectives, i.e. from T4.2 partners, project leaders, task coleads, WP co-leads and collaboration partners outside of WP4, as well as different topics, such as (but not limited to), i) internal organization, ii) timelines, iii) collaboration outside of T4.2, iv) technical challenges, v) expected and real outputs, vi) level of scientific progress, vii) impacts and products. 4 AMD-101057014-118: Dublin City University – PARC acronym “DCU”, PIC number 999892588 entered as new Beneficiary in PARC as of 01/10/2024 with the agreement that the ‘Environment Protection Agency’ (EPA) remains the only member of the Grant Signatory Board and takes over responsibility for coordinating Ireland’s engagement in PARC in the same way as other grant signatories with AE do. The starting date for the eligibility of the costs for DCU was on 01/10/2024 and DCU will contribude under T4.2. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 57 Partners involved: (The list of partners involved in this activity may change depending on the development of the work). SLU; BfG; NKUA; UFZ; MU; SCIENSANO; AU; INERIS; IVL; EAWAG; INRAE; SYKE; CSIC; CNR-IRSA; ONIRIS; OVAM; UAntwerp; VSCHT; INSERM; BRGM; FISABIO; UBA. The project will be concluded with a project report (R1; D4.4; M42). - P4.2.b_Y2_Monitoringframe [M12-M36] (the project has been extended from M30M36) This project has been finalized in M36. - P4.2.c_Y3_HumanExposure_INERIS_AU [M25-M72] This project has the aim to support the T4.1 project (P4.1.1.2.a_Y1_GenHBMSurvey_VITO) with personal exposure data to chemicals from environmental samples (e.g. dust, soil) and to generate knowledge of the exposure to chemicals from non-food environmental sources. As one central activity, the work in Y4 will focus on the actual monitoring activities, i.e. the collection and analysis of samples with associated QA/QC. Furthermore, the activity on 4.2.5 Data transfer and analysis will be started in parallel, as it requires close coordination with the data collection and treatment in T4.1. The activity will also build on procedures and material developed in P4.2.a_Y1 with regard to transfer of environmental data to NORMAN, adjusting them to the purpose of this project. Partners involved: AU; INERIS; LNS; CSTB; NILU; AUTh; VITO; ISCIII; UBA; UAntwerp; MOH-CY/SGL; MU; JSI; IDAEA-CSIC; ISS; ISSeP; IVL; NKUA; OVAM; RSU; UL; UniLU; UFZ; UPV/EHU; VSCHT (The list of partners needs final confirmation). Furthermore, T4.2 and T4.3 envision at least one joint project starting in Y5, related to the proposed “PARC Future Activities” that would particularly benefit from coordinated approaches involving innovative methods and environmental monitoring. One candidate topic is related to chemicals in soil in the context of the new regulatory framework foreseen in this field and has already been addressed with preliminary preparatory work in T4.3. A second topic relates to the leaching of plastic additives. For this, coordination with project 6.4.3.1 “A comprehensive review and application of databases and testing methods for substances of concern in consumer products and materials” will be pursued. Given the complexity of the field and the multi-partner organisational framework, T4.2 and T4.3 plan a joint one-year transversal activity in Y4 dedicated to the development of at least one combined project. The work will include a comprehensive mapping of research and monitoring activities recently initiated at EU and national level, to ensure complementarity of efforts and create structures for efficient information exchange. The timing of the transversal activity in Y4 will allow to build on results of the first projects in T4.2 and T4.3, including the use of newly developed strategies, techniques and materials. Partners for the transversal activities will still have to be selected. - P4.2.d_Y4_Siloxanes_AU_INERIS [M37-M60] The objective of the project is to generate environmental data for siloxanes, a chemical group of high regulatory relevance, taking into consideration that the chemical analysis of siloxanes poses several challenges. As PARC includes partners with this chemical expertise, it is the idea with this project to create a network of expert laboratories (together with WP9), address the state-of-the-art regarding DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 64 WP title Hazard Assessment Part ner N° 1 1.1 1.2 1.4 1.5 1.6 3.4 3.9 4.1 4.7 5 5.1 5.3 8 10.2 10.5 14 15.1 15.2 15.7 16 16.1 16.2 16.3 16.6 16.8 16.9 16.10 17 20 20.3 20.5 24.1 24.2 25 25.4 25.5 25.6 Part ner sho rt na me ANSES INSERM INRAE INERIS CNRS INRS MUI UNIVE KU Leuven UAntwerpen SCIENSANO UGent VUB MU DTU SDU TTL BfG UFZ UDE BfR Fraunhofer KIT IUF RPTU UKON TiHo UHC NCPHP ISS IRFM UMIL LIH LIST RIVM UL-LACDR UU-IRAS VUA PM/ part ner 78 134.0 85.6 38.2 61.0 8.6 13.9 12.8 7.3 36.0 27.3 16.8 36.5 26.5 68.1 23.6 0.5 9.5 47.9 10.3 97.6 14.2 26.9 29.0 12.0 0.5 6.8 33.6 25.9 13.5 13.8 23.1 60.0 3.0 13.7 60.4 30.7 8.0 Part ner num ber 25.7 25.8 26 26.1 26.2 26.3 26.4 26.5 26.6 27.1 27.2 29 29.3 29.5 31 31.2 31.3 31.4 31.5 33 33.2 33.4 34 34.5 35.2 35.6 35.10 35.12 36 37 46 50 54 Part ner short nam e WR WU-TOX NIPH IMR STAMI NILU NIVA NMBU NVI IEP-NRI UG-PL INSA ENSP UAVR JSI NIB NIC ULFFA MFUM CSIC UNAV UPO ISCIII IISPV KI SU SLU UU AUTH BPI UNIBAS UKHSA EA PM/ part ner 4.5 17.1 60.0 4.2 9.0 1.0 12.3 11.1 12.0 14.3 23.2 32.5 0.5 16.1 7.0 41.5 23.0 2.0 0.3 54.8 24.0 6.0 34.8 17.0 1.0 6.5 12.0 25.5 25.0 51.2 3.0 1.5 0.5 Start M37 End M48 Objectives The main goal of WP5 is to focus on Hazard Assessment (HA) for human and environmental health on three different directions: fill data gaps (task 5.1), develop and/or improve methodologies for HA to progress towards NGRA (task 5.2) and to work on AOPs, quantitative systems toxicology and physiologically based toxicokinetic (PBTK) modelling (task 5.3). The specific objectives of WP5 for year 4 are: Task 5.1: The core work in Y4 is finalizing the collection of data, beyond the one that will be processed and reported in our first “First Closing Data Gaps report” Deliverable 5.4 (M36), for human health (prioritised compounds are Bisphenol A (BPA) alternatives/analogues and Alternaria toxins and enniatins) and the environmental health (prioritised compounds are BPA alternatives, including mixtures, cyanotoxins and mycotoxins). Any outcome or need detected in our Deliverable 5.4 (M36) will be addressed in Y4. The project P5.1.1.c started in Y3, will gather the first results in Y4. Also, our first end of a WP5 project will be in this task: P5.1.2.a Natural Toxins Aqua. New: we DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 65 are in the process of welcoming the project P5.1.1.d “Leachates of Plastics” starting in Y4. Task 5.2: Advancing and refining innovative methodologies for hazard identification continues to be the aim of this task in Y4. In human health, we will continue focusing on five different endpoints and effects: immunotoxicity, non-genotoxic carcinogenicity, (developmental) neurotoxicity, endocrine disruption (with a focus on thyroid) and metabolic disruption. In environment, we will be creating NAMs in four primary areas employing i) in silico and modelling tools, ii) invertebrate animal models, iii) vertebrate models, and newly iv) complex microbial community. Regarding our transversal project initiated in Y4 and with a focus on regulatory readiness of NAMs, we will work on the points mentioned below: -Expand ReadEDtest to analyse methods for other endpoints -Independent peer-review of readiness of NAM developed in WP5 (SOPs, results of ReadEDtest…) -Support validation activities for willing partners -Writing a manuscript based on further guidance, respective deliverables and the position paper “Validation-related activities within PARC to progress new methods and approaches for hazard and risk assessment of Chemicals" in Annex II of our Deliverable D5.1; Marx-Stoelting et al., 2023,Link: here. Task 5.3: The objectives for Y4 are to keep fostering the different core or extended groups established in Y1-Y3 that are relevant for the activity of this task: omics, AOPs, bioinformatics, effect markers, PBTK, and in vivo/in vitro mode of action. We will use and update when needed our inventory and mapping established in Y1-Y3 of available knowledge, reference in vivo/human datasets, activities and models in systems biology, PBTK and AOP frameworks and prioritising additional studies. We will also continue the studies initiated in Y1-Y3 to characterise coregulated gene networks, for already published AOPs (to make them quantitative) and linking chemicals to available AOPs, linking omics data to human physiopathology, generating high quality data. New projects under revision: P5.3.1.b grOMICS (M37-M84); P5.3.4.b ResUpt (M37-M84). In Y4 two deliverables will be submitted by this task: D5.7 Systems Toxicology (and AOPs) report (M48) and D5.6 Second New PBK Models report (M48). Description of Programmed Activities Task 5.1: Toxicity testing addressing data gaps of concern Co-leaders A5.1.1: NIPH (NO), INSA (PT), Co-leader A5.1.2: BPI (EL) Participants: Activity 5.1.1: ANSES (FR), BfR (DE), BPI (EL), CNRS (FR), Fraunhofer-IBMT (DE), IMR (NO), INRAE (FR), INRS (FR), INSA (PT), INSERM (FR), ISCIII (ES), ISS (IT), LIH (LU), MUI (AT), NIB (SI), NILU (NO), NIPH (NO), NVI (NO), Sciensano (BE), SDU (DK), STAMI (NO), TTL (FI), TUB (DE), ULFFA (SI), UMIL (IT), UNAV (ES), UNIVIE (AT), WU-TOX (NL) Activity 5.1.2: BPI (EL), EAWAG (CH), IEP-NRI (PL), IISPV (ES), INERIS (FR), INRAE (FR), NIB (SI) NIVA DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 66 (NO), SDU (DK), SLU (SE), SU (SE), UAVR (PT), UFZ (DE), UG-PL (PL), UGent (BE), UU (SE), Cefas-Defra (UK), UOB (UK) A5.1.1 Closing data gaps of concern for human health We look forward to continuing the lab-based activities in year 4 and to having time to discuss and interpret the results and disseminate our findings to regulatory EU and national agencies (e.g EFSA, ECHA, EMA) to ensure regulatory uptake of the results. Results will also be shared with some institutions which showed interests in these activities (Health Canada, Ontario University and RIVM). For both projects 5.1.1a and 5.1.1.b, we are in close contact with partners within PARC, especially 5.2, 5.3 and WP6 to exchange data. For year 4 is planned the publication of the results in peer-reviewed journals, presentation of data in conferences, meetings (e.g. SETAC, WP5 annual on site meeting), and the preparation of new projects. In Year 4 the project P5.1.1.c_Y3_TG+EnnB1_ANSES “TG+ enniatin B1” will start experimental work. Details per project: - P5.1.1.a_Y1_Toxins_BfR_UNIVIE [M1-M48] (project extended from M36 to M48) The enniatins A, A1, B and B1 as well as Beauvericin have testing priority. Alternariol, Alternariol monomethylether, Altertoxin I, Altenuene, Tentoxin and Tenuazonic acid are among the prioritized compounds for the Alternaria study program. The in vitro studies agreed upon natural toxins (enniatins and Alternaria toxins) to close data gaps will include genotoxic, endocrine and immunotoxic effects, as well as other potential endpoints/target organs. In Y4 we will focus on continuing the experimental work and start followup activities based on the results of the tier 1 or tier 2 studies: - Genotoxicity/mutagenicity: SOS/umu for Alternaria toxins (+/- S9) [UNAV (ES)]; AMES assay for enniatins, as well as AOH [BfR (DE), NIB (SI)]; continuing on micronucleus assay for enniatins and Alternaria toxins [Sciensano (BE), INSA (PT)], yH2Ax assay for AOH [BfR (DE)], HPRT assay with Alternaria toxins [Fraunhofer (DE)]; comet assay will be performed if tier 1 studies indicate a need and if time and budget is available [INSA (PT)]. - Endocrine effects: H295R steroidogenesis assay (acc. OECD TG 456) on Alternaria toxins (start of activity if serum supplement Nu-serum will be delivered) [BfR], continuing work with enniatins [ISS (IT)]; agonistic and antagonistic activity of enniatins and Alternaria toxins on AR (AR STTA, acc. OECD TG 458) [BPI (EL)], agonistic and antagonistic activity of enniatins and Alternaria toxins on ER (ER STTA, acc. OECD TG 455) [INRS (PT)]; continuing work for MIE of thyroid metabolism (TPO, DIO1, NIE, DLR of TRalpha) with enniatins and Alternaria toxins [BfR (DE)]; E-screen assay [BfR (DE), BPI (EL)] and expression of estrogenic, androgenic and steroid hormone genes via qPCR [BPI (EL)] will be performed if tier 1 studies indicate a need and if time and budget is available; - Immunotoxicity: immunotoxic effects in 3D inhalation model (e.g. EpiAirway) including transcriptomics and epigenomics on Alternaria toxins [STAMI (NO)]; continuing work on THP-1-Lucia-NF-kB reporter assay on enniatins and Alternaria toxins [UNIVIE (AT)]; DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 67 continuing work on cytokine response in non-tumorigenic (HCEC-1CT) and tumorigenic (Caco-2) intestinal cells (+/- Il1ß-stimulus) with enniatins and Alternaria toxins [UNIVIE (AT)]; continuing work on TLR and Dectin reporter assay in HEK293 cells with Alternaria toxins [STAMI (NO)]; Immunotoxic effects in 3D tissue model of the human small intestine (EpiIntestinal 3D in vitro Microtissues/MatTek Life Sciences) [NVI (NO)]; Immunosuppression of enniatins and Alternaria toxins in vitro in human blood cells [NIPH (NO)]. - Other activities: In silico analyses and toxicity ranking [IMR (NO)]; Multiomics mechanistic analysis for AOP development [IMR (NO), Sciensano (BE)]; Absorption, permeability and metabolism of enniatins [ANSES (FR), NVI (NO), WU-TOX (NL)]; Effects of enniatins on human gut microbiota will be performed if time and budget is available [ISS (IT)]. Overall, the studies will provide needed in vitro data and identify critical toxicological effects of enniatins and Alternaria toxins. Experimental work started for some test substances in late Y2, and for some substances in early Y3 due to the sourcing process including the procurement process that was very time consuming. Due to the delays in obtaining the test substances, a 1-year extension of the project length has been required in Y2, therefore, the planned ending date for this project is now M48. We are in contact with the scientific officer from the feed and contaminants unit from EFSA regarding the availability of data on enniatins and beauvericin program since EFSA is searching for new data to possibly update its current opinion. We are in contact with the OECD AOP project to exchange information. The monthly online project meetings will continue as previously. [Participants: ANSES (FR), INRS (FR), Sciensano (BE), WU-TOX (NL), NIPH (NO), IMR (NO), STAMI (NO), INSA (PT), NIB (SI), UNAV (ES), BPI (EL), Fraunhofer (DE), ISS (IT), NVI (NO), TUB (DE)] - P5.1.1.b_Y1_BPA_HumTox_BfR [M1-M54] (project extended from M36 to M54) The test substances for the set of in vitro studies continue to be: BPZ, BPE, BPP, BPAP, BPPH, and BPS-MAE. Using BPA as a reference substance and for metabolism halogenated analogues as TBBPA and Pergafast 201. The aim is to fill up data gaps in the five selected endpoints and provide new mechanistic data for AOP development. Experiments are ongoing. Results will be shared with Physiologically Based Pharmacokinetic (PBPK) modelers in 5.3. We are in contact with both ECHA, RIVM and Health Canada/Ontario University to avoid duplication of efforts. Contact has been made with the EURION cluster regarding endocrine disruption studies. In Y4, all the experimental work for up to M36 would have been collected, processed, and shared in the D5.4 First Closing Data Gaps report. Any experimental work pending or any need highlighted after the report will be addressed in Y4 for each of the five endpoints. 1. Metabolism bioactivation routes and kinetics: will continue the In vitro study of the metabolic fate and bioactivation pathways of key BPA alternatives [INRAE (FR)] and isoform specific metabolism and biokinetic studies as input of PBK modelling [ISS (IT)]. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 68 2. Endocrine effects: In vitro Human H295R Steroidogenesis Assay (OECD TG 456) [ISS (IT)], Cytotoxicity of TCBPA, TBBPA; assessment of 17b-estradiol and testosterone in conditioned media of H295R cells treated with BPP, BPAP, BPS-MAE, TCBPA, TBBPA [ISS (IT)]. Effect of BPA alternatives in thyroid hormone synthesis key events using in vitro test (under consideration by EURL ECVAM that includes: I. Calculation of Inhibition/ IC50 of the Thyroid Hormone transport by MCT8 transporter in MDCKhMCT8 cells. II. Calculation of Inhibition/IC50 of the Iodide transport by NIS transporter in MDCK-hNIS cells [ISCIII (ES)]. Analysis of the data by assay calculation of EC50 for cytotoxicity of TCBPA and TBBPA - Calculation of EC50 and statistical analysis of significant Fold changes for 17b-estradiol and testosterone levels [ISS (IT), INRAE (FR), ISCIII (ES)]. 4. Developmental Neurotoxicity: For in vitro screening: tests of cellular viability following exposure to BPA, BPP, BPS-MAE and TCBPA. Cellular effects of BPA alternatives on neuronal network formation, synaptogenesis. Collection of samples for LIH for methylation studies and INRAE for studies on TH signaling. [CNRS (FR), INRAE (FR), LIH (LU)]. Other molecular and epigenetic analyses: Finalization of the analyses for exposure to BPA, BPAP, BPE and BPZ [LIH (LU)]. 5. Immunotoxicity: Identification of immune cell targets and effects of bisphenols on immune functions [UMIL (IT)]. Investigation of the relationship between bisphenols immunotoxicity and their effect on the inflammation-induced tryptophan breakdown and related immunobiochemical pathways such as inflammation-induced tryptophan breakdown (in human PBMC and/or relevant human monocyte-derived cell lines; thepreliminary information on cytotoxicity and cell viability has been shared). Investigation in a lung epithelial model will be performed in a limited set of compounds. [MUI (AT)]. Investigate the relationship between bisphenols immunotoxicity and their effect on the glucocorticoid system using THP-1 cells; Jurka cells transfected with active isoform of GRalpha and on limphoblastolid cell lines obtained from different donors to assess interindividual variability [ULFFA (SI)]. Provide new mechanistic data for AOP development, by evaluating the effects of BPA analogues on the intracellular calcium homeostasis of both resting and stimulated immune cells (on Jurka cell, ongoing for 2 compounds) [ISS (IT)]. 6. Carcinogenicity: In vitro test as foreseen in the battery of genotoxicity testing [INSA (PT), ISS (IT)], in vitro genotoxicity of BPA and BPA alternatives and relevant metabolites will be assessed on hepatic 2D and/or 3D (spheroids) cell models developed from HepG2 using micronucleus, comet and transcriptomic assays (collaboration with T5.2a) [INSA (PT), Fraunhofer (DE), NILU (NO)], nongenotoxic carcinogenicity of BPA and BPA alternatives will be assessed by Bhas 42 cell transformation assay (following OECD guidance document) [INRS (FR), INSA (PT), ISCIII (ES), TTL (FI), NILU (NO)). New Action: We welcome a new action in our project collecting data with whole organism (zebrafish). Assays are being performed in the project P5.2.1.b. Partners are joining our monthly meetings since May 2024 to exchange data and align. This is an effort to bring down silos between HumTox and Environment [Partner: UFZ (DE)]. Project Monthly meetings: every 4th Wednesday of the month all partners are meeting and two are DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 69 selected to give updates. If a partner cannot attend, a deputy is welcome and the presentation and agenda with minutes is distributed to keep all informed. We also have a committed folder in the SharePoint for these meetings presentations/agendas [Participants: ISS (IT), UMIL (IT), INRAE (FR), TTL (FI), ULFFA (SI), MUI (AT), ISCIII (ES), INRS (FR), Fraunhofer (DE), CNRS (FR), LIH (LU), NILU (NO), INSA (PT), UFZ (DE)] - P5.1.1.c_Y3_TG+ EnnB1_ANSES [M25 to M60] The purpose of this project is to fill an in vivo data gap on Enniatin B1 identified by EFSA by subcontracting a TG408 study under GLP. The tissues originating from this study will also be used for further analyses by WP5 partners, which will increase confidence in NAMs. In Y4, the 14-day dose range finding study is expected to be performed, and tissues originating from this study will be sent to WP5 partners for additional analysis. Based on the results of the 14-day study, the doses will be set for the TG 408 study, and the TG 408 study will be initiated. This is a provisional timeline at this stage. [Participants: ANSES (FR), BfR (DE), NIPH (NO), INSA (PT), INSERM (FR), NVI (NO), TUB (DE), UNAV (ES), WU-TOX (NL)] - P5.1.1.d_Y4_PlasticLeach_NIPH [M37-M81] The aim of this project is to identify the most hazardous chemicals leaching from selected plastics (both additives and non-intentionally added chemical residues) for both the environment and human health. Where relevant interactions with the CUSP cluster will be sought. Specific objectives for the first year are: 1. Preparation of leachates from plastics: Set selection criteria for plastics to be studied, justification document and discussion with stakeholders. Preparatory meeting scheduled for 14th January 2025. Kick off meeting planned for 15th May 2025, Oslo. End by June 2026, Landmark L-PlasticLeach1 Preparation of extracts completed. Lead by [NIPH, (NO)]. All partners are involved. 2. General toxicity: Utilize a range of NAMs being developed and tested in other PARC WP5 projects to test the leachates —including those for cell toxicity, genotoxicity, DNT, immunotoxicity as well as OECD-compliant assays. [INRS, (FR); IEP-NRI, (PL); UAVR, (PT), NIPH (NO, INSA (PT), KIST-Europe6 (DE), NIB (SL), BPI (GR)]. Assess ecological toxicity using aquatic and terrestrial bioindicators, including Daphnia magna and Aliivibrio fischeri. [IEP-NRI, (PL)] This action will be refined in PARC Y4 but officially starts in August 2026 Landmark L-PlasticLeach2 Start hazard testing in selected NAMs. Participants: NIPH (NO), INSA (PT), KIST-Europe* (DE), ANSES (FR), UU (NL), IEP-NRI (PL), UAVR (PT), NIB (SL), INRS (FR), NIVA (NO), WU (NL), BPI (EL). A5.1.2 Toxicity assessment addressing data gaps of concern (Environment) 6 modalities of collaboration are still under discussion DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 70 Details per project: - P5.1.2.a_Y1_NaturalToxinsAqua_Ugent [M1-M36]. This project ended in M36. - P5.1.2.b_Y1_BPAalternatives_BPI_MU [M1-M48] (this project has been extended from M42 to M48) Toxicity testing of bisphenol alternatives selected during Y1 on certain organisms has been started and will continue during Y4. It is noted that the experimental work started with a delay mainly due to time-consuming procedures followed for chemicals order (centralized order for all PARC partners) and difficulties faced by several partners in hiring personnel. Therefore 6 more months of the project's duration is requested. A list of 26 assays (OECD TG, ASTM and ISO) are being conducted by the involved partners covering a wide range of organisms (e.g., fish, aquatic invertebrates, alga, marine bacteria, earthworms, soil microorganisms, xenopus, C. elegans) and effects (e.g., acute effects, effects on reproduction and on endocrine system). In Year 4 we will mainly focus on experiments with mixtures, and testing of individual substances will be finalized. The mixtures to be tested have been selected based on the results of tests with individual substances. In addition, the mixtures have also been selected considering also the occurrence of bisphenols in different environmental compartments (i.e., surface water, soil, sediment) as revealed by reviewing the available literature data and the results from monitoring activities that will be carried out in the frame of PARC WP4. Partner UU (SE) reported problems in carrying out their originally planned experiments (effects on adipocyte development in zebrafish), and as it is taking a long time to get the ethic approvals, they propose to determine metabolic rate using Alamar blue assay adapted for zebrafish embryos (described in Renquist B. et al (2013), doi: 10.1089/zeb.2012.0841). The studies will be focusing on changes in metabolic rate in 0-4 days old zebrafish exposed to the following BPA alternatives: BPAF, BPC, BPS, TMBPA, and DAB. It is urgent to collect data on metabolic effects of BPA replacement products in early life stages since BPA is suggested to alter metabolic programming in children, which may lead to metabolic disorders at older ages. [Participants: BPI (EL), SLU (SE), IISPV (ES). SDU (DK), INERIS (FR), NIB (SI), IEP-NRI (PL), UU (SE), UG-PL (PL), UAVR (PT), EAWAG (CH), NIVA (NO), UFZ (DE), SU (SE), Cefas-Defra (UK)] - P5.1.2.c_Y4_TG+MP_ANSES [M37-M60] The start of this project will be subject to the conclusions of the PARC Helicopter document on microplastics. This project would be the second TG+ study of WP5. The objectives are twofold: filling data gaps on the bioaccumulation in fish of microplastic particles and additives, and assessing the applicability domain of in vitro bioaccumulation assessment methods, by subcontracting studies following OECD guidelines under GLP. Additionally, using tissues from the TG studies performed under GLP, nontargeted metabolomics and/or proteomics analyses will be performed to define biomarkers of exposure and to characterize possible biological pathways triggered or suppressed after the bioaccumulation of the tested plastic additives. During PARC Year 4, the objectives are: - Publishing the public tender to subcontract studies under GLP, and procurement of substances. Selection of Contact Research Organisations (CROs). DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 71 - Hold a workshop with stakeholders on selection of additives - Start of preliminary study on translocation of particles in fish to assess the particle size range for which translocation occurs and identification of influencing factors, based on partner’s budget Task 5.2: Innovative methods and tools for toxicity testing and modelling Co-leaders A5.2.1: DTU (DK), VUB (BE), Co-leader A5.2.2: MU (CZ) Participants: Activity 5.2.1: AIT (AT), ANSES (FR), BfR (DE), DTU (DK), IfADo (DE), INRAE (FR), INSA (PT), INSERM (FR), IRFM (IT), ISCIII (ES), IUF (DE), LIH (LU), LIST (LU), MU (CZ), MUI (AT), NIB (SI), NILU (NO), NIPH (NO), NMBU (NO), NCPHP (HU), RIVM (NL), SDU (DK), TiHo (DE), UAntwerpen (BE), UFZ (DE), UG-PL (PL), UDE7 (DE), RPTU (DE), UKON (DE), UL-LACDR (NL), ULFFA (SI), UNAV (ES), UOB (UK), UU (SE), UU-IRAS (NL), VUA (NL), VUB (BE), WR (NL) Activity 5.2.2: BfG (DE), BPI (EL), EAWAG (CH), IISPV (ES), INERIS (FR), MU (CZ), MUI (AT), NIB (SI), NIC (SI), NIVA (NO), SDU (DK), SLU (SE), UAntwerpen (BE), UFZ (DE), UG-PL (PL), UPO (ES), CSIC (ES), INRAE (FR) - P5.2.a_Y4_ RegNAMs _ANSES [M37-M81] In order to support some validation activities for some selected NAMs, the following actions will be taken and during PARC Y4 and are described below. These activities will be coordinated with other projects and initiatives (e.g. EU-NETVAL), JRC, to create synergies as well as WP6 and the methodology leader on validation (ML) in PARC. - Expand ReadEDTest, currently dedicated to assessing in vitro and fish embryo assays triggering endocrine disruption (https://readedtest.u-paris-sciences.fr/). By PARC WP5 partner labs involved in the development of NAMs (e.g. [INSERM (FR)]. - Asess test methods under development for other endpoints, - Organize independent peer review of NAMs developed in WP5 - Support validation activities of NAMs for willing partners. The selection will be based on regulatory relevance and therefore discussed with the EU agencies. A5.2.1 Innovative methods and tools for toxicity testing and modelling (Human Health) Details per project: - P5.2.1.a_Y1_NGTXCs_INRAE [M1-M60] The development of some tests that can identify tissue and substance specific effects related to distinct aspects of non-genotoxic carcinogenesis will need to be continued in Y4, i.e. for novel methods that are still in a rather early developmental status. For example: UL-LACDR will not only finalize biological replicate experiments with SRXN1-GFP oxidative stress response reporter 7 AMD-101057014-118: Professor Dr Kathrin Thedieck, who was the main scientific contact involved in the activities of PARC WP5 for the Austrian affiliated entity University of Innsbruck - PARC acronym “UIBK”, left the University of Innsbruck and started working for the University of Duisburg-Essen in Germany - PARC acronym “UDE”, on 01/04/2024. Consequently, UIBK withdrew from PARC on 01/04/2024 and UDE entered in PARC as affiliated entity of UBA on 01/04/2024. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 72 hepatocyte-like cells but will analyze the single cell sequencing data of mammary organoids exposed to estradiol (E2) and complement the analyses by targeted transcriptomics on liver and mammary gland progenitor cells exposed to endpoint specific controls and compounds of interest. Optionally, they will use ICAM1-GFP and FUCCI HCLs to measure the effects of compounds of interest on inflammation and cell cycle distribution and further explore if TP53 loss sensitizes liver and mammary gland progenitors to non-genotoxic carcinogens using transcriptomics and/or other readouts, such as assays that measure genomic instability. UNAV will conduct time-course experiments for oxidized chemicals that were not detected under the conditions used in Year 3 and perform the CTA and assess histone H2AX and H3 phosphorylation in a selection of compounds. The NIB team will complete the flow cytometry experiments and will perform the experiments evaluating the mRNA expression of selected genes involved in the studied pathways (proliferation, cell cycle regulation, oxidative stress response, apoptosis, epigenetic changes, DNA damage response and oncogenesis) using the same testing approach as for the first set of chemicals. RPTU will continue and finalize the testing with endpoint-specific compounds. The used intestinal cell models will be further characterized with regard to their metabolic competence and nuclear receptor expression. Furthermore, a multiplexing approach will be tested to simultaneously assess the endpoints oxidative stress, proliferation and genomic instability. However, the main focus of year 4 will be the analysis of the data obtained with the first set of reference data and at least two and up to 10 substances for each of the 5 different selected MoA (proliferation, cytotoxicity inducing regenerative proliferation, nuclear receptor activation, inflammation and changes in cellular morphology indicative for cell migration). The data will be reported in an already agreed common data template for each chemical and compiled to analyse the sensitivity and specificity of the various assays for a given Mode of Action (MoA), including a comparison of the minimal concentration needed to detect a significant effect. These analyses will facilitate the (further) development of prediction models for each assay to i.e. define thresholds that allow identification of physiological/ biological and regulatory relevant activities and to develop a complementary and predictive test battery. Additional testing / method optimization will be necessary in the course of this process. Here, the reference substances used in other tasks (5.1: BPA alternatives; mycotoxins and 5.2: Inflammation, ED-Met) might be tested to better define the applicability domain of the methods, support the other PARC projects, in particular to check if our methods/ batteries come to comparable conclusions or can support regulatory decision making in a broader (more data rich) context. [Participants: INRAE (FE), BfR (DE), ANSES (FR), INSERM (FR), NIB (SI), UL-LACDR (NL), UNAV (ES), IRFM (IT), RIVM (NL), RPTU (DE), NILU (NO), MU (CZ)] - P5.2.1.b_Y1_MD-EDC_BfR [M1-M48] In Year 4 we will continue with the development of a battery of metabolic disrupting chemicals (MDC)-specific NAMs based on human as well as non-human models. Partners will continue testing the BPA-alternatives prioritized in PARC WP5: 0-BPA, 1-BPZ, 2-BPE, 3-BPS-MAE, 4-Pergafast 201, 5-BPP, 6-BPAP, 7-TCBPA, 8-TBBPA. 1. Functional and structural characterization of Nuclear Receptor (NR and bisphenols interactions) DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 73 [INSERM (FR)] In Year 3, using reporter cell lines (Hela and U2OS), we identified several bisphenols active on CAR. In Year 4, the CAR activity of bisphenols will be further characterized, in particular by carrying out a structural study using crystallization. The effect of halogenation (bromination and chlorination) will be analysed on some of the bisphenols studied in year 3, such as BPA, BPAF, BPS and Pergafast. During preliminary experiments carried out in year 3, it was seen that halogenation increased the ability of these bisphenols to activate certain NRs such as PXR and PPARg, depending on the degree of halogenation (1 to 4 bromine or chlorine atoms). The aim of the study will be to confirm the preliminary observations and to explain them, in particular through structural studies. 2. In vitro assays for screening MBD 2.1 The Mammalian target of rapamycin (mTOR) activity is being addressed by quantitative highresolution mass spectrometry (HR-MS) and immune assays [currently University Duisburg-Essen (UDE (DE), previously IUBK (AT)]. MD screenings jointly with the partners will continue, in particular, the comparative characterization of the mTOR network response to BPA versus BPF and further MD substances. 2.2 High-throughput screening assay for phospholipidosis in human liver cells [BfR (DE)] It is planned a detailed characterization of the 3D liver model to be implemented in year 4. Subsequently, the phospholipidosis assay established in 2D will be transferres to the 3D liver model. Therefore, compounds already screened in 2D were analysed in 3D for comparison. A manuscript is intented to be published in year 4 about the phospholipidosis assay in HepaRG (2D) and the outcome of its screening (performed in Y3). 2.3 Test system for pancreatic beta cell signaling and function disruption by MDCs [BfR (DE)] The testing of additional chemicals including malathion, moncroptophos will be carried out in Y4. In addition, a review outlining substances targeting the function and signalling of beta cells will be published as well as the results of the investigation of novaluron. 2.4 Development and optimization of adipocyte models to study adipocyte differentiation and response to test chemicals [UU-IRAS (NL)] Similar to Y3, the optimization of the 96-well plate adipogenic differentiation model will continue but this time in serum free conditions using model chemicals including ROSI, MEHP, TPP, TBT, TBBPA and fludioxinil. This will allow to compare the adipogenic potential of the cells in serum free condition compared to FCS. Additionally, the optimization of an in vitro co-culture model will start to study the interaction between the endocrine and immune systems, as well as the 2D optimization and transition to 3D model. This model will be optimized testing different culture conditions and according to the serum compatibility of the models. For the co-culture model, not only the adipoginic endpoints will be considered, but some immune endpoints will be also included to elucidate the interaction of the two systems in our model. All the experiments are to be performed in triplicates with three independent replicates. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 80 utility of a placental angiogenesis assay for ED testing - P5.2.1.g_Y4_DIT-NAM_INSERM [M37-M84] Action 0, Project coordination (month 37-84) - Regular project meetings. [All partners] - Annual and periodic reporting. Lead by [NIPH (NO), INSERM (FR)] - Synergy with other PARC activities, external DIT activities. [All partners] Action (Subproject) 1. Physiological maps (month 37-84) - Literature review, based on existing animal and human data. It will also generate an updated list of DIT reference chemicals. In collaboration with the CAAT in vitro DIT initiative [All partners]. - Physiological map, resulting from the literature review, this will be a starting point for the DIT AOP task that is planned for Y5-7. The physiological map will be a living document which can be adapted when new data are available and allows contribution also from non-PARC research initiatives, first draft by M48. With contributions from partners led by [IUF, (DE)]. Action (Subproject) 2. Development of novel test battery, NAMs based on HSC or hiPSC (month 3784) adaptation of existing tests and development of novel haematopoietic stem cell and hiPSC-based models will be explored: - Combination of existing, well-characterized assays for screening and prioritisation purposes (in close collaboration with WP5.2.1d immuntoxicity NAM development activities) - HSC systems by [NCPHP (HU), LIH (LX)] - hiPSC for toxicity testing by [NIPH, (NO) WFSR, (NL)] - Other models by [MUI (AU), UMIL (IT), UFZ (DE), RIVM (NL), NMBU (NO)] - P5.2.1.h_Y4_SDHEPATOX_ANSES [M37-M60] To improve current in vitro methods for assessing chemical-induced hepatotoxicity by integrating sexual dimorphism parameters in different hepatic cell models (primary human hepatocytes, HepaRG, hepatic cells derived from multipotent stem cells (mSC) and induced pluripotent stem cells (iPSC)). The detailed actions for PARC Y4 are as follow: Action 1.1 Establishment and characterization of sexual dimorphism in in vitro hepatic models by [ANSES (FR)] Development of sexually-oriented primary human hepatocytes (PHH) (3 male and female donors) and HepaRG cell line and characterisation of their liver functionality (CYP450 activities, urea synthetises, nuclear receptor activities, metabolomics profile). HepaRG cells and PHH will be incubated with medium supplemented with male or female serum and/or hormones to induce a sexual dimorphism. Action 1.2 Characterization of general hepatic maturity (e.g. CYP and albumin expression) by [VUB (BE)]. Development of human multipotent stem cell-derived hepatic cells (mPSC-Hep) with sexspecific features and characterisation of their baseline hepatic functionality with focus on lipid metabolism. mPSc-Heps will be incubated with medium supplemented with male or female serum DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 81 and/or hormones to induce a sexual dimorphism. Action 1.3 Development of sex-specific models of the human liver based on hepatic organoids differentiated from induced pluripotent stem (iPS) cells by [BfR (DE)]. For this, hepatic organoids generated from iPS cells of male and female donors will be exposed to male or female serum and/or hormone in an attempt to elicit sex-specific cellular physiology on both the genetic and environmental level. Resulting phenotypes will be characterised based on marker expression and functional properties (e.g. CYP enzyme and drug transporter activities). A5.2.2 Innovative methods and tools for toxicity testing and modelling for Environmental Toxicology / Ecotoxicology Details per project: 5.2.2 Joint project: P5.1.2.b_Y1_BPAalternatives_BPI_MU [M1-M48] In Year 4 (M37-M48), the project will successively build on the developed strategy in the previous year to deliver new advanced methodologies. The final stage of the project, and specifically WP 5.2.2 activity, will be to finalize the method optimization and increased regulatory readiness. The obtained data from all completed assays will be disseminated through scientific publications. In addition to a scientific publication and dissemination effort, the developed methodologies will also be published as SOPs at open repositories (e.g. Zenodo). It is expected that the incoming partners in year 3, i.e. INRAE (developing methods connected with complex microbial communities and high-throughput metabolomics in aquatic periphyton) and CSIC (methods with daphnia spp. to assess cardiotoxicity, neurotoxicity, and metabolic disruption, and methods with zebrafish liver spheroid models, and behavioural endpoints in zebrafish) will also complete their work in year 4 and publish their methods. The final progress report will be published in M48 (originally planned for M42), as the project has applied for six months extension. All activities will be in the closest link with other PARC tasks: specifically, Task 5.3 for AOP development and modelling, Tasks 6.1 and 6.2 for building NAMs confidence for regulatory applications, as well as WP7 for data management and WP9 for project internal synergies as well. Year 4 will also be a time period where partners will discuss the follow-up projects that will align with PARC priorities. [Participants: BfG (DE), BPI (EL), EAWAG (CH), IISPV (ES), INERIS (FR), MU (CZ), MUI (AT), NIB (SI), NIC (SK), NIVA (NO), SDU (DK), SLU (SE), UAntwerpen (BE), UFZ (DE), UG-PL (PL), UPO (ES), CSIC (ES), INRAE (FR), CNRS (FR)] Task 5.3: Quantitative systems toxicology and development of new AOPs Co-leaders: UL-LACDR (NL), SCIENSANO (BE), INSERM (FR), Fraunhofer-ITEM (DE) Participants: Activity 5.3.1 and 5.3.3: AUTH (EL), BPI (EL), IISPV (ES), INSERM (FR), IRFM (IT), ISCIII (ES), ISS (IT), KIT (DE), MUI (AT), NIPH (NO), NCPHP (HU), Sciensano (BE), UFZ (DE), UGent (BE), UG-PL (PL), UDE (DE), UL-LACDR (NL), UMIL (IT), UNIABDN (UK), UOB (UK), WR (NL) Activity 5.3.2: ACES/SU(SE), AU (DK), AUTH (EL), BfG (DE), BPI (EL), Cefas-Defra (UK), DTU (DK), IISPV (ES), INSERM (FR), IRSN (FR), ISS (IT), KI (SE), KIT (DE), KU-Leuven (BE), LIST (LU), MUI (AT), NILU DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 82 (NO), NIPH (NO), NCPHP (HU), Sciensano (BE), SDU (DK), UAntwerpen (BE), UGent (BE), UG-PL (PL), UHC (DE), UDE (DE), UL-LACDR (NL), UMIL (IT), UNIVIE (AT), WR (NL) Activity 5.3.4: ANSES (FR), AUTH (EL), Cefas-Defra (UK), EA (UK), ETHZ (CH), Fraunhofer-ITEM (DE), IISPV (ES), INERIS (FR), INSERM (FR), ISCIII (ES), ISS (IT), NIPH (NO), NVI (NO), UFZ (DE), UHC (DE), UNIVIE (AT), WR (NL), WU-TOX (NL), UNISANTE (CH), STAMI (NO) A5.3.1 Prioritized NAM-based mechanistic hazard characterisation & A5.3.3 Translation to human pathophysiology A5.3.3 (Systems toxicology approaches for mechanism-based chemical safety assessment) were combined in a single project for coherence purposes. Details per project: - P5.3.1.a_Y1_SystemsToxicology_UL-LACDR [M1-M48] In Y4, partners will finalize the 4 identified case-studies and publish the main findings (how systems toxicology can contribute to CS1 – Read-across, CS2 – ab initio studies, CS3 – temporal responses, C4 – human translation). In particular CS1 will in Y4, evaluate the inclusion of other in vitro assays in addition to transcriptomics (e.g., ToxCast), include in the RAx study in vivo data also accessed via the OECD QSAR toolbox and ECHA database. CS2 is carrying out a comparison on how different systems toxicology approaches identify and assess hazard. In Y4 CS2 will finalize a publication comparing several interpretation methods and benchmark modelling approaches and include feedback from regulators regarding the confidence over different Benchmark Concentration (BMC) estimates. In addition, this publication will include an automated reporting system for systems toxicology data analysed with benchmark dose methods. CS3 aims to define best practices for time course experiments in systems toxicology. In Y4 the analysis including Weighted Gene Correlation networks for analysis (WGCNA)-based methods will be expanded. CS4 will continue analysis the preservation results to derive a subset of gene co-expression modules that are found to be shared by human in vivo kidney data and human in vitro proximal tubule cell lines. [Participants: UGent (BE), MUI (AT), ISCIII (ES), INSERM (FR), ISS (IT), UL-LACDR (NL), BPI (EL), KIT (DE), NCPHP (HU), WR (NL), Sciensano (BE), NIPH (NO), UNIABDN (UK), UFZ (DE), UG-PL (PL), IRFM (IT), UDE (DE), UMIL (IT), AUTh (EL), UOB (IK), IISPV (ES)] - P5.3.1.b_Y4_grOMICS_UL-LACDR [M37-M84] This project aims at proposing an operational system to incorporate HTTr and HTPP for Rax and grouping applications by including: 1) efficient reporting 2) test systems specific and robust interpretation 3) guidelines supported by case studies to merge structural and (physio)chemical (including metabolism), mode of action (from HTTr) and cellular morphology (HTPP). The actions planned for PARC Year 4 are detailed below: Action 1: To design and develop a database system to streamline reporting of HTTr and HTPP experiments and to query and navigate reporting data (M37 to M55) 1.1 Annotate current version of the OORF based on user fill in scenario. PARC M37 to M49, by [UL (NL), IISPV (ES), BfR (DE)] Action 2: To improve the interpretation framework of omics data by developing a tox-oriented, DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 83 interoperable ontology of pathways, gene sets and gene networks. (M37 to M65) 2.1 Develop test-systems specific models integrating HTTr and HTPP datasets of MCF7 and U2OS cell lines. PARC M37 to M49, by [UL (NL), INSERM (FR), UFZ (GE)], metadata support from WP7. Action 3: To propose a framework to synergistically incorporate structural, cellular morphology - based and mode of action -based similarities for read-across and grouping applications, with a particular emphasis of MIE/early KEs prediction (M37 to M81) 3.1 Collection of physiochemical properties, HTTr, HTPP and relevant in vivo ADME properties and toxicological endpoints. PARC M37 to M49, by [UL (NL), IRFM (IT), IISPV (ES), Sciensano (BE), BHAM (UK)] A5.3.2 AOP development based on integration of in vivo and in vitro data sets Details per project: - P5.3.2.a_Y1_AOPDevelopment_Inserm [M1-M48] In year 4 the core group of this project (CG) will continue to develop new innovative tools supporting AOP development, based on artificial intelligence (AI) and text mining tools, in collaboration with WP8. The CG will continue to support the work of the Specialty groups (SGs) to help them to finalize the design of new AOPs. A workshop with training is planned (to be organized by AUTh in the spring 2026 for integration of NAM/IATA/AI for AOP, as well as a topic collaborative publication. The priorities will continue using D5.3 and the inventory of available AOPs identified on AD5.5: SG1 will focus on AOPs in the fields of respiratory sensitization, immunosuppression and non-genotoxic carcinogenesis and will collaborate with P5.2.1.d and P5.2.1.a. SG2 will focus on AOPs in the fields of endocrine disruption and metabolism and will collaborate with P5.2.1.b and P5.2.1.c. SG3 will focus on AOPs in the field of Neurotoxicity (ANT and DNT) and will collaborate with P5.2.1.e. The SG1 (Immunotoxicity), SG2 (Endocrine and metabolic disruption), SG3 (Neurotoxicity) and the Effect Marker Group (EMG) are structured into subgroups corresponding to the themes of SG1, SG2 and SG3 as well as a subgroup on epigenetics. Each group meets every 6 weeks on average to monitor the progress of the work. New AOPs or improved AOPs will be submitted to the AOP-Wiki database. It has to be noted that all CG partners are also involved in the SGs so that their technical support is made easier. A following AOP activity (Y5-7) will be discussed among the partners. [Participants: SU (SE), AU (DK), AUTh (EL), BfG (DE), BPI (EL), DTU (DK), IISPV (ES), INSERM (FR), IRSN (FR), ISS (IT), KI (SE), KIT (DE), KU-Leuven (BE), LIST (LU), MUI (AT), NILU (NO), NIPH (NO), NCPHP (HU), UG-PL (PL), SDU (DK), Sciensano (BE), UAntwerpen (BE), UGent (BE), UKK/UoC (DE), UDE (DE), UL-LACDR (NL), UMIL (IT), UNIVIE (AT), WR (NL), Cefas-Defra (UK)] A5.3.4 PBK models and quantitative systems toxicology Details per project: - P5.3.4.a_Y1_PBK_Kinetics_Fraunhofer [M1-M48] From the seven case studies running in year 3, the following will continue in year 4: 01Xenobiotic metabolism in human_microbiome (planned activity: reevaluation of existing microbiomecompetent PBK models using the established optimized methodology), 06 - bioavailability of Alternaria toxins and 07bioavailability of Enniatins (the partners will finalize the acquisition of in DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 84 vitro data (clearances, fractions unbound) and in vivo (plasma) Tk data necessary to develop and validate PBK modeling using a read across approach for this family of mycotoxins for which no model (useful for RA) currently exist). In Y4 a new case (08) study will be started to develop in vitro ADME models to predict the placental uptake of compounds. In addition, case study 09 will integrate new mechanisms of metabolic disruption from P5.2.1.b_MD-ED and link them to PBK modelling. It In year 4, the case studies will spend most of the time on the integration of in vitro Absorption, Distribution, Metabolism and Excretion (ADME) data into the PBK models, the in vitro to in vivo extrapolation and the uncertainty and sensitivity analysis of the PBK models. [Participants: UNISANTE (CH), ANSES (FR), ETHZ (CH), IISPV (ES), INERIS (FR), INSERM (FR), ISCIII (ES), ISS (IT), Fraunhofer (DE), NVI (NO), UKK/UoC (DE), WR (NL), WU-TOX (NL), EA (UK), AUTh (EL), Cefas-Defra (UK), NIPH (NO), STAMI (NO), UNIVIE (AT), UDE (DE)] - P5.3.4.b_Y4_RESUPT_RIVM [M37-M84] Below the specific actions of PARC Y4 of this project are detailed. The aim is to enhance our understanding of how in vitro respiratory models can be applied to study respiratory uptake, which is crucial for evaluating the systemic toxic effects of inhaled substances. Activity 1: Data gap analysis on air liquid dosimetry, in vitro biokinetic approaches and permeability models. The aim of this activity is to collect the knowledge on transporters in respiratory epithelium, both in vitro and in vivo and mechanisms of uptake of the selected substances. This will provide the basis for choosing relevant models (including transporters) to assess respiratory uptake and relevant options for dosimetry. For novel substances, uptake mechanisms are unknown. Therefore, an approach will be developed to aid selection of a model to assess respiratory uptake. - Results will be gathered in report R-RESUPT.1 Data gap analysis on air liquid dosimetry, in vitro biokinetic approaches and permeability models, PARC M43 by [RIVM (NL), ITEM, INERIS (FR), UGPL/QSARLab, STAMI] - The selection of test chemicals will be performed and input gathered in report R-RESUPT.2 Selection of test compounds. PARC M43 by [All partners] Activity 2: Data measured for 4 model compounds on plastic binding and evaporation for in vitro biokinetic modelling. Quantitative Structure-Property Relationships (QSPR) models, along with or other in silico tools (i.e. read-across to predict kinetic for target chemicals based on similar source compounds), will be used for PBK model parameterisation. This approach will help overcome the limitations in the broader application of PBK models, which are often restricted due to gaps in chemical-specific input data. Additionally, computational techniques, such as molecular docking, will be employed to estimate parameters such as protein binding. By predicting how a compound interacts with proteins, models help in determining their bioavailability and distribution, which are the key factors affecting the transport of chemicals across biological membranes. -Results will be gathered in report R-RESUPT.3 Data measured for 4 model compounds on plastic binding and evaporation for in vitro biokinetic modelling. PARC M43 until M54 by [INERIS (), AUTH ()] Activity 3: Data measured for 4 model compounds on barrier models and integrated into PBK DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 85 models. The aim of this activity is to collect experimental data on the respiratory uptake of pesticides and reference substances, and to parameterize PBPK models with respiratory uptake data All activities mentioned above will feed Activity 4 that therefore will start at a later point of the project. Activity 4: Guidance document on dosimetry and the use of respiratory in vitro models for uptake assessment. The aim of this task is to ensure regulatory applicability of in vitro models and PBPK models for assessment of respiratory uptake. Deliverables: D5.5 2nd New approach methodologies report – Leader: BfR (initially due M36 is postponed to M48) D5.6 2nd new PBK models report – Leader: Fraunhofer-ITEM (M48) D5.7 Systems Toxicology and AOPs report – Leader: INSERM (M48) Additional Deliverables AD5.8. Study report – Leader: ANSES (M41) (linked to the project P5.1.1.c_Y3_TG+ EnnB1_ANSES (M25-M60)) WP N° WP6 Lead Beneficiary RIVM/KEMI WP title Innovation in regulatory RA Partner N° 1 1.1 1.2 1.4 1.6 1.14 1.12 1.13 3 3.1 3.4 4 4.5 4.6 4.7 5 5.1 5.3 7 8 10.1 10.2 10.3 10.4 10.5 11.2 13.1 14 14.2 15 15.2 15.5 15.7 15.8 Partner short name ANSES INSERM INRAE INERIS INRS ASNR CSTB EHESP EAA AGES MUI VITO OVAM ISSeP UAntwerpen SCIENSANO UGent VUB MOH-CY/SGL MU AU DTU REGIONH-GE UCPH SDU UT SYKE TTL Tukes UBA UFZ UOS UDE RWTH PM/par tner 75.5 9.7 8.0 10.5 3.0 3.0 1.5 4.5 1.5 13.8 1.5 30.7 0.3 13.0 11.0 47.1 6.0 4.7 1.0 52.8 11.3 19.4 23.5 6.3 3.0 18.0 4.6 8.6 1.0 29.5 33.3 5.3 19.5 6.4 Partne r N° 16.1 16.6 18 20 20.1 20.3 20.4 20.5 20.7 23 24 24.2 25 25.1 25.2 25.4 25.5 25.6 25.7 25.8 25.9 26 26.2 26.3 26.4 27 27.1 27.2 28 29 29.3 29.4 29.5 31 31.1 Partne r short name Fraunhofer-IBMT/IME RPTU UI ISS ICPS IRFM IUSS UMIL UNIPD LSMU LNS LIST RIVM KWR TNO UL-LACDR UU-IRAS VUA WR WU-TOX SRU NIPH STAMI NILU NIVA NIOM IEP-NRI UG-PL FMUL INSA ENSP UC UAVR JSI GEoZS DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 86 PM/pa rtner 4.0 31.5 1.3 19.5 7.8 6.3 6.0 3.0 1.0 2.5 5.6 2.0 57.1 2.7 9.8 8.9 22.6 14.5 3.8 3.0 8.0 19.9 17.0 2.5 16.5 19.0 25.2 15.0 4.6 12.0 6.1 5.0 7.0 1.4 7.5 Partne r N° 32 32.1 32.2 33 33.3 34 34.3 34.5 34.7 35.2 35.3 35.4 35.5 35.6 35.7 35.8 35.10 36 37 38 40 41 44 45 46 49 53 54 59 Partne r short name NIJZ OI NLZOH CSIC UGR ISCIII FINBA IISPV UCLM KI ULUND ORU RISE SU KEMI IVL SLU AUTH BPI FOPH UNISANTE EAWAG FOEN USI UNIBAS EFSA UKCEH EA UOB PM/ partne r 15.8 6.2 0.2 27.0 5.0 30.0 25.3 19.5 12.5 8.3 0.6 3.0 8.7 61.5 17.0 10.2 10.5 14.5 40.7 0.5 14.0 2.3 6.0 2.0 6.0 4.0 17.2 0.6 4.3 Start M37 End M48 Objectives The main goal of WP6 is to drive innovation in regulatory RA by strengthening its scientific basis, with implementation of NGRA as ultimate goal. The specific objectives of WP6 for year 4 are: o Task 6.1: To refine (quantitative) networks of AOPs for genotoxicity, endocrine disruption (thyroid dysfunction) and liver toxicity (liver fibrosis) To re-design, based on this work, regulatory relevant Integrated Approaches to Testing and Assessment (IATAs) for genotoxicity, endocrine disruption and liver toxicity in close collaboration with relevant stakeholders and (re-)evaluate the applicability of developed IATAs by means of dedicated case studies in an iterative way. To refine, through regulatory relevant case studies, a previously drafted workflow for the assessment of human relevance of toxicological pathways and associated NAMs, with focus on quantitative aspects. o Task 6.2: To further develop and apply innovative methods, tools and concepts to perform integrative risk and health impact assessment (HIA)s based on internal and external human exposures to single chemicals and mixtures in integrating multiple sources and routes from general and occupational environments. o Task 6.3: To continue implementation and further refinement of case studies reviewing selected methodologies and approaches for regulatory RA. o Task 6.4: To develop efficient and protective regulatory workable RA methods through in-depth analysis of collected data for mixtures, articles, NAMs and biodiversity. Description of Programmed Activities DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 87 WP6 annual workshop The joint annual WP6 workshop with WP and TL, partners, and relevant stakeholders (e.g. EU and national authorities) will be organized to discuss activities, focusing on ongoing work and proposals for developments and new case studies to ensure the regulatory relevance. The workshop will be planned together with partners from WP2 to strengthen the science-to-policy frame of the workshop. This will be reflected in the program of the workshop. Also, partners from WP2 will chair a session on how to plan for impact related to project results. The WP6 workshop will be hosted by AGES (AT) and take place on 19-21 May, 2025 (M37). In preparation for the annual WP6 workshop, webinars will be organised (in April/May 2025) where research results from all tasks in WP6 will be presented. Similar to previous years, relevant regulatory stakeholders (ECHA, EFSA, EEA, JRC, DGs) will be invited to provide feedback in a separate webinar, to present priorities and regulatory needs as well as recent and upcoming developments regarding chemical RAs. This feedback and input will be used to provide support for discussions on how WP6 can further contribute to addressing these needs and meet the regulatory challenges. Collaborations with other WPs, in particular WP2, will be continued to optimize the output [KEMI, RIVM, all WP6 partners]. Task 6.1: Integrated Approaches to Testing and Assessment of Chemicals Co-Leaders: SCIENSANO (BE), UL-LACDR (NL) Partners: AUTH (EL), BPI (EL), CEFAS-DEFRA (UK), DTU (DK), ENSP (PT), Fraunhofer-ITEM (DE), IISPV (ES), INRAE (FR), INSERM (FR), IRFM (IT), IRSN (FR), ISS (IT), KI (SE), KWR (NL), LIST (LU), MU (CZ), MUI (AT), NILU (NO), NIPH (NO), RIVM (NL), SDU (DK), STAMI (NO), UAntwerpen (BE), UGent (BE), UG-PL (PL), UKHSA (UK), UKCEH (UK), VUB (BE), WR (NL), WU-TOX (NL) A6.1.1: Development of IATAs for regulatory purposes In Y4, we will further work on the development of IATAs for genotoxicity, endocrine disruption (with focus on thyroid hormone system disruption (THSD)) and liver toxicity (with focus on liver fibrosis) for selected regulatory framework(s) and specific population groups. In Y4, AOP networks (AON), which were created based on existing AOPs and existing NAMs for each of these endpoints, will be refined and quantified, where relevant for the problem formulation at hand. The IATAs will be tested in relevant case studies; the outcomes will be reported in the final project report (genotoxicity and liver toxicity) or in the annual progress report (endocrine disruption). Additionally, we will work on further improvement and refinement of a draft workflow for human relevance assessment. Both the work on this workflow and the IATA development for genotoxicity, endocrine disruption and liver toxicity will be an iterative process consisting of various cycles of optimization, thereby taking into account the feedback from different stakeholders (A6.1.3). Details per project: - P6.1.1.a_Y1_HumanRelevance_RIVM [M1 – M36]: this project was finalised in M36 - P6.1.1.b_Y1_IATA-ED_UAntwerpen [M1 – M36]: this project was finalised in M36 - P6.1.1.c_Y1_IATA_GENTOX_Sciensano [M1 – M48; the project has been extended from M36 to M48] DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 88 IATA development for genotoxicity. In Y4, this project will continue to characterize KERs within the AON for genotoxicity based on evidence collected using the harmonized strategy. We will explore whether the qAOP for DNA alkylation leading to increases in mutations and structural and numerical chromosome aberrations developed for a reference alkylating agent can be extended to other compounds. Moreover, we will characterize the uncertainties related to genotoxicity methods. Also, we will identify the main drivers of variability. Based on all these activities, the project will design an IATA for genotoxicity. This project will also execute two case studies for genotoxicity, making use of existing as well as newly generated data. [Partners: Sciensano (BE), INRAE (FR), VUB (BE), ULLACDR (NL), WU-TOX (NL), ISS (IT), IBMT (DE), UG-PL (PL), STAMI (NO), LIST (LU), BPI (EL), IRSN (FR), RIVM (NL), KWR (NL), NILU (NO), IRFM (IT), NIPH (NO), WR (NL), MUI (AT)]. - P6.1.1.d_Y1_IATA_STOT_UL-LACDR [M1-M48; the project has been extended from M36 to M48 due to initial delays of personnel hiring and delays in experimental data generation] IATA development for liver toxicity. In Y4, we will finish execution of case studies which have been designed on the basis of the first case study, i.e., the gene expression measured at 24h following exposure to fibrosis-related chemicals in four liver cell test systems (in 2D and 3D). Given the known critical involvement of several other cell types in liver fibrosis, i.e. Kupffer cells and stellate cells, the aim is to utilize an IATA with mixed cell systems (by the involved project partners and by FDA’s organ-on-a-chip ‘Emulate’) to study and quantify late key events in the relevant AOP. qAOP development, performed in collaboration with the Horizon 2020 project RISK-HUNT3R, will be finalized in Y4, first on the basis of existing in vivo data, and subsequently on the basis of project case study data. [Partners: UL-LACDR (NL), WU-TOX (L), INSERM (FR), Ugent (BE), AUTH (EL), MU (CZ), IISPV (ES), STAMI (NO), ISS (IT), IRFM (IT), WR (NL)] - P6.1.1e_Y4_FISH-THSD_UAntwerpen [M37-M81] This project builds upon the output of the PARC T6.1 ED IATA project (P6.1.1.b_Y1_IATAED_UAntwerpen), in which AON were constructed and evaluated as a basis for developing THSD assessment strategies, and relevant methods for assessing THSD were identified and mapped to the AON. This project aims to develop and test an AON-based approach for the identification of thyroid hormone system disrupting chemicals (THSDCs) in fish. This work addresses important gaps in the currently available tools for the identification of THSDCs by integrating in silico, in vitro and in vivo fish test data for the T modality in a tiered testing approach that is aligned with the ECHA-EFSA Guidance for the identification of endocrine disruptors. Specifically, the project will provide an integrated approach for the identification of THSDCs in fish that is supported by OECD-endorsed AOPs and executed using assays that are currently under OECD and EU-NETVAL validation. The project will focus on integrating (1) the measurement of thyroid hormone levels, thyroid histopathology, eye development, swim bladder inflation and behaviour in zebrafish embryos and zebrafish larvae as additions to existing OECD Test Guidelines (TG 236 and TG 210), (2) the in vitro measurement of a selection of relevant THSD mechanisms, (3) QSAR model data. The approach will be designed in a tiered fashion that allows the implementation of a decision tree logic. A series of specific case studies will be developed and executed in collaboration with ECHA, EFSA and other stakeholders, generating new data and re-using existing data for selected chemicals that are relevant in the context of specific legislations. The project outcomes will be applicable to the REACH and Classification, Labelling and Packaging (CLP) legislations as well as the Plant Protection Products DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 89 Regulation (PPPR) and the Biocidal Products Regulation (BPR), by providing a framework for using in silico, in vitro and fish test data for THSDC identification. Based on the timelines of the OECD and EU-NETVAL validation efforts that are currently ongoing for the fish and in vitro methods that will be used in this project, it is expected that the timeline to implementation into regulatory frameworks is around 5 years. [Partners: UAntwerpen (BE), UKHSA (UK), SDU (DK), MU (CZ), CEFAS-DEFRA (UK), RIVM (NL), UG-PL (PL), IRFM (IT), VU (NL)] - P6.1.1.f_Y4_HumanRelevance_RIVM [M37-M81] This project is aimed at establishing a harmonized workflow for assessing the human relevance of AOPs and NAMs related to key events (KEs) and key event relationships (KERs). Building on previous PARC work (i.e., P6.1.1.a_Y1_HumanRelevance_RIVM), the project aims to further standardize the process for assessing human relevance. Besides improving qualitative aspects of the workflow, it will address quantitative aspects, i.e., cross-species comparisons and in vitro to in vivo extrapolations. These objectives will be achieved through case studies. In Y4, two case studies will be selected in close collaboration with ECHA and EFSA: one case study that is likely to be relevant to humans, and another case study that is likely to be less relevant to humans. For both case studies, the project team will focus on the question if and how quantitative aspects can best be addressed in the workflow. Evidence collected will be subjected to a structured weight of evidence (WoE) assessment. Where needed and feasible, we will seek support from WP7, for support on WoE assessment and uncertainty analysis. Templates (developed in the previous PARC project) for collecting and evaluating evidence will be modified where needed. During Y4, the project managers will have regular meetings with EFSA and ECHA, to discuss progress and challenges encountered. In addition, we will pro-actively work on dissemination of this PARC activity, by reaching out to other relevant stakeholders, such as the Working Group of National Co-ordinators of the OECD Test Guidelines Programme (WNT) and the Working Party on Hazard Assessment (WPHA), and through the SF (in collaboration with WP2). [Partners: AUTH (EL); RIVM (NL); ENSP (PT); BPI (EL); WU-TOX (NL); NIPH (NO); STAMI (NO); IRSN (FR); ISS (IT); IISPV (ES); LIST (LU)]. A6.1.2: Evaluation of IATAs through case studies The draft versions of the IATAs for genotoxicity, endocrine disruption (with focus on thyroid hormone synthesis disruption) and liver toxicity as well as the draft workflow for human relevance assessment developed in A6.1.1 will be evaluated through (additional) case studies. The respective case study teams will investigate the previously defined case study regulatory hypotheses with the selected relevant case study compounds. To arrive at meaningful conclusions through WoE assessments, we will closely collaborate with WP7; approaches used for WoE evaluations will be discussed upfront with regulatory agencies. For ultimate integration of the data into Quantitative in vitro / in vivo Extrapolation (QIVIVE), we will further strengthen the link with the experts and tools established in T5.3. For the latter, dedicated discussions will be organized between T6.1 and T5.3, with the aim to determine how to best organize this collaboration. Reports on the case study modeling and experimental activities will be submitted for review via the project management system under T2.1 (M48). In the IATA case studies, the lessons learned by different stakeholders DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 96 Details per project: - P6.3.1.a_Y1_SubstanceRA_SU [M1-M48] Case studies reviewing substance-specific RA depending on intended use [M1-M48]. The reviews of substance-specific assessments depending on intended use will continue through one case study. The case study is described below and will evaluate differences and similarities, and subsequent implications, across legislations. The outcomes of this project may serve as a ground for adjustments of the relevant regulations. The identification of dissimilarities in testing requirements and hazard assessments of substances depending on specific uses will offer valuable information for the implementation and potential impacts of the “One Substance One Assessment” (OSOA) approach on regulations targeting specific uses of chemicals. Further, the potential barriers and opportunities, and available methods, for harmonisation in a systematic way will be presented. [Partners involved: SU (SE), UCL (UK), SCIENSANO (BE), IRFM (IT), KI (SE)]. • CS12_MethodOSOA_SU: We are currently discussing with PARC, JRC, ECHA and EFSA what the next study focus will be. We have had a meeting with PARC, JRC and ECHA and a meeting with EFSA is planned for. We have developed a number of suggestions, which they are considering. (SU (SE), KI (SE)) • CS13_PlasticizersRA_UCL: M1-M36 (finalised). (UCL (UK), SCIENSANO (BE), IRFM (IT)). • CS14_BiocidesRA_SU: M1-M24 (finalised). (SU (SE), KI (SE)). - P6.3.1.b_Y1_EffectRA_BPI [M1-M48] Case studies reviewing effect-specific RA [M1-M48]. The reviews of effect-specific assessments will continue through six case studies. The case studies are described below and will include aspects such as sensitization and developmental neurotoxicity as well as use of non-animal methods for identification of endocrine disruption, genotoxicity, and carcinogenicity. The project will evaluate and suggest opportunities for improving and harmonising aspects of RA methodology, including in vitro short-term tests and structure-activity based methodologies. The project will analyse and discuss relevant gaps and research needs and, when relevant, propose improvements and harmonization of the testing requirements, criteria, recommendations, and best practices across EU regulations. The results will be made available to and discussed with regulatory agencies. These case studies reviewing RA methodology concerning specific priority endpoints will contribute to conclusions on the need for innovation in regulatory RA to rapidly and effectively identify chemicals with hazardous properties for human health and the environment through a more effective, accurate and harmonised across silos OSOA approach. [Partners involved: REGIONH (DK), STAMI (NO), SU (SE), IRFM (IT), UNIBAS (CH), VUB (BE), ISS (IT), NILU (NO), INSA (PT), BPI (EL), KI (SE), INSERM (FR), INERIS (FR), EAA (AT), UBA (DE), INRAE (FR), UT (EE)]. • CS9_SKINSENSIRISK_REGIONH: In Y4 the case study on successes and failures in RA of skin sensitizer will be completed. Results will be used for suggesting improvements in regulatory practices and highlight gaps of knowledge [REGIONH (DK), STAMI (NO), SU (SE), IRFM (IT), UNIBAS (CH)]. The results will be published in a peer-reviewed scientific journal and a report will be made. A Ph.D. thesis will be written and presented based on the entire project. (REGIONH (DK), STAMI (NO), SU (SE), IRFM (IT), UNIBAS (CH)). DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 97 • CS10_ED-cosmetics_VUB: In Y4 (until finalisation in M42), it is planned to finish the NGRA of octocrylene; run the 'ab initio' NGRA on systemic toxicity of the UV filter 4-methyl benzylidene campher and additionally, also perform a protective and predictive NGRA of the hair dye HCY13. When all dossiers are completed, a meeting is planned within the SCCS and with the PARC reviewers and a final report will be made available. Two publications are foreseen to be ready in that time period: one general article on the lessons learned with respect to the use of NGRA for systemic toxicity of cosmetic ingredients with ED concern and one on the specific topic of using NGRA to enrich standard safety assessment of cosmetic ingredients. (VUB (BE), INRAE (FR)). • CS11_GenotoxCarc_ISS: In Y4 the following activities will be finalized: global report on the review and comparison of regulatory practices for genotoxicity and carcinogenicity classification and assessment [ISS (IT), IRFM (IT), NILU (NO), INSA (PT)]; inventory of NAMs for genotoxicity and carcinogenicity assessment [ISS (IT), IRFM (IT), NILU (NO), INSA (PT)], including analysis of their regulatory readiness [ISS (IT), IRFM (IT), NILU (NO), INSA (PT)] and evaluation of their possible use to fill existing gaps, reduce uncertainties and improve animal welfare [ISS (IT), IRFM (IT), NILU (NO), INSA (PT)]; evaluation of selected in silico methodologies for their potential use in identifying known human carcinogens (i.e., CLP/GHS class 1A) [ISS (IT), IRFM (IT)], including application of OECD QSAR Assessment Framework (QAF) to selected cases [ISS (IT), IRFM (IT)]; FAIR-compliant table mapping relevant documentation and literature [ISS (IT) and all]. The possibility of demonstrating potential gaps and inconsistencies within or across the various regulations using real cases will be explored and, if feasible, will be showcased [ISS (IT), IRFM (IT), NILU (NO), INSA (PT)]. • CS15_DNT_SU: Y4 will be devoted to the refinement of initial ideas and models for a graphical and statistical assessment of motor activity data from 54 guideline DNT study reports, for 53 compounds of which 51 are pesticide active substances and two other substances. For a graphical analysis, focus is on displaying data that allow an intuitive understanding of effects, on total motor activity or on the (ontogeny of) habituation, on both the population mean as well as on potentially sensitive subpopulations. Regarding statistical methods, we foresee that linear mixed-effects models will be the overall method of choice because these models accommodate the experimental design. The detailed structure of the models will be tested and discussed, and recommendations will be made. We will reach out primarily to EFSA to present and discuss our approaches at an early stage, and to be able to consider their needs and opinions. A scientific manuscript is expected to be submitted in M41. R code for performing graphical and statistical analyses will be made available, likely as supporting material to the open-access publication. Work on a second behavioural outcome, the auditory startle reflex, will be initiated with the extraction of data from the same 54 guideline DNT study reports. (SU (SE)). • CS17_ED-in vitro_BPI: Y4 will be devoted to further development and implementation of reliability and relevance criteria for the evaluation of prioritised in vitro methods on estrogen, androgen, steroidogenesis, and thyroid (EATS) modalities on selected studies from the open literature. A manuscript will be submitted based on work completed in previous years and an additional manuscript will be prepared. This project has been extended and activities originally planned in Y3 will be implemented in Y4. (BPI (EL), KI (SE), INSERM (FR), INERIS DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 98 (FR), UBA (DE)). • CS18_ED-classes_BPI: Y4 will be devoted to exploring how available in vitro, in silico and readacross approaches can be used for classification (or not) of a substance under the new CLP criteria for ED, through implementation of specific examples of regulated chemicals. The outcomes will contribute to the harmonized implementation of the new CLP criteria on hazard classes for ED taking into consideration all available methods and tools. A manuscript will be submitted based on work completed in previous years on T-modality and an additional manuscript will be prepared on EAS modalities. This project has been extended and activities originally planned in Y3 will be implemented in Y4. (BPI (EL), INSERM (FR), EAA (AT), IRFM (IT), VUB (BE), UT (EE)). A6.3.2 Use of tools, criteria, and methods reviews Details per project - P6.3.2.a_Y1_ToolsRA_SU [M1-M48] Case studies reviewing tools, criteria, and methods used in regulatory RA [M1-M48]. The reviews on the use of tools, criteria, and methods in regulatory RA will continue through six case studies. The case studies are described below and include general aspects such as application of risk-based benchmarks and uncertainty analysis as well as aspects related to occupational RA and Environment RA (ERA). The project can contribute to identification of coordination needs related to RA methodology across legislations, providing support for future design of legislation on chemical RA, focusing on sustainable management of chemical risks, as well as the implementation of the OSOA approach. The project will provide regulators, legislators, and other stakeholders an in-depth understanding of the commonly used decision benchmarks and the significance of their appropriate foundation and application. The project will provide new knowledge about the practical challenges in using quantitative expressions of uncertainty in assessment, as well as pedagogical examples on how to implement quantitative expressions of uncertainty and the benefit of these in assessment and communication. The project will provide recommendations for harmonizing data gap-filling approaches in relevant EU legislations. [Partners involved: SYKE (FI), ISSeP (BE), SU (SE), STAMI (NO), UBA (DE), JSI (SI), UCL (UK), TTL (FI), KI (SE), RSU (LV), INERIS (FR), KEMI (SE), ULUND (SE), BPI (EL), LSMU (LT), EAWAG (CH), FOEN (CH), DTU (DK), UCPH (DK), UMIL (IT), UNIPD (IT), EFSA (EU)]. • CS1_CARB_SYKE: We intend to deepen our previous analysis of PFAS thresholds by evaluating the potential development needs of regulatory RA of PFAS and their implications to risk management, also considering additional regulatory frameworks and their interlinkages. This will be carried out through a literature study and stakeholder consultation. We intend to publish the results in a scientific paper. In addition, we aim at publishing a policy brief based on our results. (SYKE (FI), ISSeP (BE)). • CS2_RiskReduction_SU: M1-M36 (finalised). (SU (SE), UBA (DE), STAMI (NO), UCL (UK), JSI (SI)). • CS16_UncertaintyRA_ULUND: Collection of information on practical challenges through a questionnaire with follow up interviews will be finalised. We will make a policy brief DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 99 including justifications for expressing uncertainty quantitatively by % probability (or bounded probabilities) and how to manage uncertainty captured in scenarios or assumptions, as well as unknown unknowns. A list of examples of applications of uncertainty analysis has been created and will be expanded based on support from the community of experts. As an outreach activity and to support implementations of uncertainty analysis, sources introducing uncertainty will be listed in a publicly accessible group on PARCopedia with explanatory text and videos, together with guidance on how to express and combine quantitative expressions of uncertainty in combination with scenarios or worst-case assumptions. We will ask for and compile examples where uncertainty analysis done with quantitative expressions have been beneficial to an assessment. (ULUND (SE), KI (SE), BPI (EL), UBA (DE)). • CS19_DataGapFilling_KEMI-DTU: M13-M30 (finalised). (DTU (DK), UCPH (DK), KEMI (SE), SU (SE)). • CS7_REGPREP_EAWAG: During Y4 the results and insights of the analyis of the comparison of PPP RA under different regulations for surface water and sediment will be published. A similar comparison for soil RA will be started. (EAWAG (CH), FOEN (CH), INERIS (FR), UBA (DE)). • CS20_PESTNAM_ISS: During Y4, a critical review of the actual implementation of NAMs within EFSA’s evaluation of the approval of active substances in plant protection products in the area of human health and environmental hazard characterisation over the last 10 years will be performed and data gaps will be identified. The assessment will start with EFSA opinions, registration reports, Vol. 1 of the DAR (Addenda) and then focus on Vol. 3 for study description. The AOP concept, PBK modelling, mechanistic studies (human relevance for specific MoAs), the assessors’/EFSA’s evaluation of the reliability and acceptance of the studies, as well as the type of data (OECD TG, not yet validated, literature data) and GLP status, will be included in the data extraction. All information/data will be correlated with the data requirements in force at the time of the assessment. Potential data gaps, including regulatory or knowledge gaps (missing relevant scientific information/data), will be identified. In this context, the project team consider key involving OECD, together with EFSA, as an advisory board to the project. (ISS (IT), UMIL (IT), UNIPD (IT), BPI (EL), EFSA (EU)). • CS4_SecPoisoning_INERIS: The analysis of the main areas where harmonization is needed will continue, using examples and identifying the consequences of the lack of harmonization in the main legislations considered, i.e. chemical regulations which already have a clear framework for secondary poisoning assessment and the Water Framework Directive which also gives provisions for secondary poisoning. Further development and data collection for the substance imidacloprid, selected in collaboration with CS7, will be performed to test the hypothesis of borderline cases e.g. substances which do not meet persistent (P), bioaccumulative (B) and toxic (T) or POP criteria, but that may still cause a risk because highly exceeding one of the P or B criteria. Imidacloprid would qualify as sufficiently bioaccumulative for testing the hypothesis. The use of TK modelling to improve the definition of the trophic network, including apex species, will also continue. Stakeholder interactions will be further explored, including e.g. surveys, interviews or a dedicated workshop. (INERIS (FR). DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 100 • CS8_ OccupReproDev_KI: Y4 will focus on compiling the findings of the OEL survey (published) and the partners substance-specific reviews into a final report. Based on a literature review the report will also contain a chapter that discusses the issue of threshold vs non-threshold reproductive effects. A review regulatory status of substances with a harmonised classfication as reproductive toxicanats (1A or 1B) will be used to suggest potential prioritisation lists for consideration for OEL-setting. (KI (SE), TTL (FI), LSMU (LT), STAMI (NO), RSU (LV)). • CS3_WorkplaceRA_TTL: M1-M36 (finalised). (TTL (FI), KI (SE), JSI (SI), STAMI (NO), RSU (LV)). Task 6.4: Transposing results to regulatory RA methodologies - Co-leaders: AGES (AT), UNIBAS (CH) Partners: ANSES (FR), INERIS (FR), OFB (FR), EAA (AT), AGES (AT), MU (CZ), AU (DK), REGIONH-GR (DK), UT (EE), EFSA (EU), SYKE (FI), Tukes (FI), UBA (DE), UFZ (DE), UDE8 (DE), Fraunhofer (DE), UCPH (DK) UI (IS), ISS (IT), IRFM (IT), LSMU (LT), VUA (NL), NIPH (NO), STAMI (NO), NIVA (NO), NIOM (PL), IEP-NRI (PL), UG-PL (PL), INSA (PT), ENSP (PT), UC (PT), UAVR (PT), ISCIII (ES), UCLM (SI), RWTH9 (DE), ULUND (SE), RISE (SE), KEMI (SE), SLU (SE), NLZOH (SI) AGROSCOPE (CH), EAWAG (CH), FOEN (CH), UNIBAS (CH), BUL (UK), UKCEH (UK), UOB (UK), EA (UK), UBATH (UK) BPI (EL), DTU (DK) A6.4.1. Develop regulatory relevant approaches and methods for chemical mixtures Details per project: - P6.4.1.a_Y1_OPREMIXCS1_BRUNEL_RWTH[M1-M40] The Project has been extended until M40. The remaining period will be used to finalize the AD.6.17 Optimizing regulatory RA including the use of monitoring data and NAMs and management of chemical mixtures in Europe and prepare publication of the conducted case studies. Additionally, a meeting with stakeholders is planned, where relevant outcomes from OPREMIX and MONAMMIX Projects will be shared. The organisation of this meeting starts in the end of Y3, the meeting will take place in Y4. (Lead partner: RWTH, BUL, Participants: AGES, BPI, EAWAG, UBA, UI, NIVA, EA, ENSP, LSMU, NIOM, UAVR, KEMI, UKCEH, NLZOH). 8 AMD-101057014-118: Professor Dr Ralf Schäfer, who was involved in the activities of WP6, especially in Task 6.4 (P6.4.4.c_Y1, P6.4.4.d_Y1 and P6.4.4.e_Y1), for the German affiliated entity University of Kaiserslautern-Landau - PARC acronym “RPTU”, left the University of Kaiserslautern-Landau and started working for the University of Duisburg-Essen in Germany - PARC acronym “UDE”, on 01/07/2024. The amendment is a hand over of all the PARC activities performed by Ralf Schäfer at the University of Kaiserslautern-Landau to the University of Duisburg-Essen as of 01/07/2024 9 AMD-101057014-118: Professor Thomas Backhaus, who was the main scientific contact involved in the activities of PARC WP6 (P6.4.1.a_Y1_OPREMIXCS1_BRUNEL_UGot) for the Sweden affiliated entity University of Gothenburg - PARC acronym “UGot”, left the University of Gothenburg and started working for the RWTH Aachen University in Germany - PARC acronym “RWTH”, on 01/11/2023. Consequently, UGot withdrew from PARC on 01/11/2023 and RWTH entered in PARC as affiliated entity UBA on 01/11/2023. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 101 - P6.4.1.b_Y1_MONAMMIXCS2_UFZ [M1-M40] The project has been extended until M40. The remaining period will be used to finalize the AD6.17 Optimizing regulatory RA including the use of monitoring data and NAMs and management of chemical mixtures, which is part of the D6.18: Final report on RA and management methods for chemical mixtures across legislations (M81). Additionally, a meeting with stakeholders is planned, where relevant outcomes from OPREMIX and MONAMMIX Projects will be shared. The organisation of this meeting starts in the end of Y3, the meeting will take place in Y4. (Lead partner: UFZ, UBA Participants: AGES, BPI, UI, NLZOH, UKCEH, ENSP, UOB, NIVA, EA, EAWAG, UBATH). - P6.4.1.c_Y3_Skinsenmix_RegionH [M24-72] This project will develop new tools for RA and management of mixtures of skin sensitizers/irritants. In the second year of this project the main experiments will be initiated NAMS,3D skin cell models and in vivo/patient samples. A review of the literature regarding current knowledge and practices regarding assessment of mixture exposures for skin sensitizers will be initiated. It is foreseen to have 4 meetings, one every 3. months. For now, no changes in the budget are foreseen. (Lead partner: RegionH-DK, STAMI, participants: UCPH, AGES) - P6.4.1d_Y4_REMIX_UBA_EAWAG will be implemented in Y4 [M37-M81] This project aims to improve the assessment, regulation and management of risks due to coexposures and combined effects of multiple chemicals to the environment and human health across regulatory areas. A kick-off Workshop will be held in May 2025 (M1) where the results of the previous projects 6.4.1a_Y1_OPREMIX and 6.4.1.b_Y1_MONAMMIX will be discussed with the focus on identifying remaining open issues before the developed evidence, methods and tools can be used in regulation. In addition, regulators will be asked to communicate their current needs. Based on the workshop results followed by a landscaping exercise. The core regulatory areas of the project will be defined and specific project goals will be set. Further workshops may be organized on specific topics by the project partners. Re-mix will be guided by a regulatory core group consisting of AGES, UBA and KEMI. The regulatory core group will foster the formation of individual case studies to address the specific project goals. Case studies will involve data analyses, comparisons of different methods as well as conceptual analyses and comparisons of different regulatory options and needs and will be performed by the project partners, starting from M1 to M40. A list of already identified case studies that will start or continue under REMIX can be found in the project description. (Lead partners: UBA (DE), EAWAG (CH), Partners: AGES (AT), BPI (EL), UKCEH (UK), ENSP (PT), KEMI (SE), LMSU (LT), NILZOH (SI), NIOM (PL), NIVA (NO), UFZ (DE), UI (IS), RWTH (DE), UOB (UK), ULUND (SE), DTU (DK)) A6.4.2. Facilitate the regulatory acceptance and practical use of new methods Details per project: - P6.4.2.a_Y1_LandscapingSurv_UNIBAS [M1-M36] (finalised in M36) DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 102 - P6.4.2.b_Y1_ NGRApractice_VKM_NIPH [M37-81] This project aims to develop evidence-based tools and guidance for hazard/RA of NAMs, which will be integrated in an overall evidence-based NGRA framework across chemical sectors. The lead partner is NIPH (represented by VKM). The other partners involved in the work Y4 are BPI, ISS, and UNIBAS. The project has a scientific advisory group including 15 participants from the following institutions/organisations/projects: Karolinska Institutet, OECD, US EPA, CAAT at Johns Hopkins, EBTC at Johns Hopkins, Radboud University, EFSA, JRC, University of California San Francisco, 3Rs Management and Consulting, NIEHS, ECHA, Vrije Universiteit Brussel, University of New South Wales, and Charité – Universitätsmedizin Berlin_BIH QUEST Center, as well as observers from WP2 (BfR) and WP3 (AUTH). As reported in the table 4 of AWPY4 (PARC_D1.10_AWPY4_including_Project_Portfolio.pdf), the project was originally developed for the whole 7-year PARC period. To be able to complete the different parts of the project, an extension was requested to be able to finalise the ongoing work in the best way. The budget included in the original 7-year proposal will remain the same. Actions that will be performed year 4 - The tool for assessment of internal validity of in vitro studies: INVITES-IN A beta version of INVITES-IN will be created in the ongoing project, and the user test will also be performed as part of the ongoing project. In the period M37-M48 the user test study will be completed, the data will be analysed, and the user test publication will be prepared and submitted. In addition, the beta version of the tool will be revised, and the release version will be published. A checklist containing an overview of issues that should be reported for in vitro studies to fulfil the information need to assess the internal validity will be prepared and published. -The tool for the assessment of external validity of in vitro studies: INVITES-EX The protocol for the creation of the tool for assessment of external validity will be prepared and submitted. The creation of the tool will be started when the protocol is accepted for publication. -The cross-mapping of core systematic review and chemical RA terms The study will be finalised, and the manuscript will be prepared and submitted. For all tasks that will be performed, the “VKM team” will perform the main work and draft the publications, plan all meetings, and also have separate meetings for the different tasks. BPI, ISS and UNIBAS participates active with ideas, suggestions, and discussions, and through reading and commenting on documents, and also critical review of publications. Publications planned for 2025: - Protocol for the creation of a tool for assessment of external validity (01.10.2025) DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 103 - The INVITES-IN tool: User test study (01.10.2025) - The checklist for reporting of in vitro studies for internal validity assessment (01.10.2025) - The release version of INVITES-IN (a tool for assessment of internal validity of in vitro studies) (01.10.2025) The project team will continue having weekly meetings. The “VKM team” will have monthly meetings with the scientific advisory group. - P6.4.2.c_Y1_NAMAM_UT [M1-M36]: this project was finalized in M36 - P6.4.2.d_Y4_RegulatoryNAMs_ISS [M37-M81] This project aims to test and demonstrate how a NAM-based approach for regulatory hazard and RA of chemical substances may work and could be implemented in different regulatory frameworks and for several different regulatory purposes. In the first phase of the project an overview of related scientific and regulatory initiatives and projects (within and outside PARC) will be created, and we will establish a common ground for the work through agreeing on terminology and methods to be used in a series of case studies. Following this, case studies addressing the aspects considered of highest priority will be developed and initiated. In the CSs different steps in hazard or RA for selected endpoints will be addressed using only information from NAMs; the outcomes in terms of predictive or protective capacity will be subsequently compared to traditional (mostly animal-based) assessments as currently performed under e.g. the CLP or PPP, or will highlight new grounds on which regulatory requests for different purposes (e.g. hazard identification) should be identified. A regulatory core steering group will be established. The role of the core steering group is to e.g. coordinate the case studies, plan stakeholder interactions and engagement in order to ensure regulatory relevance of all case studies etc. ECHA and EFSA so far have expressed interest to participate in the core steering group. Partners involved: KEMI (SE); RIVM (NL); ISS (IT); BPI (EL); UNIBAS (CH); MU (CZ); KI (SE); SCIENSANO (BE); STAMI (NO), IISPV (ES), IRFM (IT), KWR (NL), UL-LACDR (NL), SU (SE), TTL (FI) - P6.4.2.e_Y4_READYAI_UNIBAS [M37-M48] Establishment of readiness criteria for Artificial Intelligence/Machine Learning (AI/ML)-based tools for supporting the RA process. This project addresses the challenges of using in silico NAMs based on ML/AI for regulatory purposes, focusing on RA and various applications like evidence management, toxicity prediction, and exposure assessment. AI/ML tools are advancing rapidly, but there’s uncertainty about their reliability in chemical regulation. In a joint effort of AI tool developers together with regulatory scientists, the project aims to establish readiness criteria and a scoring system for in silico NAMs based on ML/AI, similar to those developed for in vitro methods, to help regulatory scientists gauge their reliability, validity, reproducibility and predictivity. The project will create a readiness check questionnaire for AI/ML tools, supporting regulations across sectors and nations. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 104 The project will begin in the first year with the formation of a Core Steering Group, which will lead and oversee the initiative. A series of project meetings will follow, including a face-to-face kick-off meeting as part of the PARC WP6 workshop in 2025. These meetings aim to foster a shared understanding among all participants, especially in terms of terminology, and to outline a detailed action plan for the project. Concurrently, there will be efforts to map related initiatives and projects, both within and outside the PARC framework, ensuring alignment and the leveraging of existing work. A stakeholder meeting will be held, bringing together AI/ML tool developers and regulatory scientists to establish common ground for the project’s objectives. During Y 4 case studies that evaluate specific AI/ML-based tools, analyzing their effectiveness and relevance will be developed and initiated. Regular meetings will be organized with stakeholders from both national and international agencies to assess whether the established criteria meet the needs of the regulatory community, ensuring that the outcomes of the project are practical and beneficial. Partners involved: UNIBAS (CH); UT (EE); UG-PL (PL); UoB (UK); IRFM (IT); possibly KEMI (SE); AGES (AT); A6.4.3. Developing information transfer structures and enforcement methodology for chemicals in articles to support the transition to a circular economy The activity has an overall objective to improve chemical RA and management by more efficient use of available information structures in combination with new analytical tools. A specific focus is placed on supporting enforcement of chemicals and product legislation and the use of chemical information structures in exposure assessment and evaluation of product circularity and sustainability is also explored. Biweekly meetings with all partners will be held to monitor and discuss the progress of individual actions steering towards the overarching aim of A6.4.3. Focused working meetings will be held in between the biweekly meetings when needed. A connection with the forum for exchange of information on enforcement (ECHA forum) for enforcement has been established and the project will disseminate the results and continuously receive feed-back on the methods being developed under 6.4.3b. An internal PARC working group focusing on chemicals in products will be used to disseminate results and share data across different WPs. Dissemination will also occur via the agencies directly involved in the project (KEMI and TUKES). Details per project: - P6.4.3.a_Y1_SuProM_MU [M1-M36]: this project was finalised M36 -P6.4.3.b_Y3_ENFORCE_KEMI [M25-M72] This project will be continued during Y4. The project will evaluate the applicability of methods of chemical identification for use in the enforcement of chemical safety legislation, to fulfil crucial needs identified in project 6.4.3a. For effective enforcement rapid screening methods that cover a wide DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 105 range of restricted/SVHC substances that can be applied to a variety of sample matrices are typically needed. In evaluating methods, this project will further test to what extent databases reviewed in P6.4.3.a capture the chemical composition of articles. By developing and applying rapid analytical techniques for screening and validation the project will provide a proof-of-concept methodology that could be used in enforcement of chemicals legislation The project will have a specific focus on additives in high volume plastics and perand polyfluoroalkyl substances in articles identified as major use categories. Progress in P6.4.3.b is continuously communicated with representatives from ECHA forum to ensure that the developed methods will be relevant for enforcement purposes. Lead partner: KEMI, Participants include MU KEMI, RISE, TUKES, VUA, New partners in A6.4.3 SU and ORU. Planned Y4 of PARC: Key action 1. Based on the developed workflow and initial testing of articles and chemical products completed during Y3 a subset of 5-10 samples will be selected for a small inter laboratory comparison between RISE, SU and ÖRU. The data produced will be evaluated to determine the level of agreement between different laboratories and evaluate the readiness of the method. Together with the extensive testing of individual articles and products completed during Y3 the interlaboratory comparison will be used to assess the overall applicability of the proposed workflow for compliance testing of a broad PFAS restriction. The report delivered M54 will also provide recommendations for further validation and standardization that could be achieved by PARC to support the implementation of a broad PFAS restriction. Participants include KEMI, MU, RISE, TUKES, VUA, SU and ORU Key action 2. Method development will be continued based on the initial testing of optimal extraction procedures completed during Y3. Focus during Y4 will primarily be on generating suspect target lists for different plastic materials/product categories from relevant databases and establishing quality assurance criteria that would make suspect screening applicable to enforcement. Participants include KEMI, RISE, TUKES, VUA, ORU A6.4.4. RA to support and promote efficient overall protection of biodiversity As reported in the table 4 of AWPY4 (PARC_D1.10_AWPY4_including_Project_Portfolio.pdf), the projects 6.4.4. ae were originally planned to cover the entire length of the project, i.e. up to M81. This was due to the interdisciplinary nature of the research question and the involvement of multiple stakeholders. Working towards a paradigm shift necessitates a collaborative process in small steps. Projects a, c, d, e have been broken down at M42 to assess the project's progress as a basis for a decision to continue the projects until M81; similarly the project b has been broken up into 2 phases (i.e. a first phase was planned to end M24 but was extended until M36). The rationale for the extension of the projects is also available in the Annexes to the PDDs. The extensions requested for the PARC P6.4.4 projects (a–e) are grounded in both the need to complete originally scoped activities and the significant achievements made until M 42 (or 26 for project 6.4.4.b). The projects aim to support a transition towards systems-based environmental risk DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 112 Figure 1: High level summary of the activities planned within each of the Tasks of WP7 during Y4. The case studies in Task 7.3 are linked to the Toxicology Cluster and the Environment and HBM Projects (and their follow-up activities) and thus there is strong integration across the Data and Tools / Analyses aspects. Description of Programmed Activities Task 7.1: FAIR Data policy and implementation Co-leaders: TNO (NL), UOB (UK) Partners: ANSES (FR), BRGM (FR), VITO (BE), MU(CZ), UZIS (CZ), UBA (DE), ISS (IT), KWR (NL), ULLACDR (NL), NIVA (N), UG-PL (PL), JSI (SI), KI (SE), AUTH (EL), ISSEP (BE) Sub-contractors: GFF (NL) No project submitted for this task. A7.1.1 PARC Data Policy and Data Management Plan The first version of the PFDP was finalized (M18), although some key issues need further elaboration, including the detailed analysis of the European Open Science Cloud (EOSC) FAIR data levels, and how achievable these are for the different sub-domains of PARC. In Y3, the PFDP has been formatted into a scientific paper, which will be submitted by the end of 2024. Additional possible future content relevant to the PFDP has been proposed in the publication using Large Language Models and a semiquantitative analysis of the relevance of the different PFDP topics for different stakeholders was executed. [Partners involved: KI, UBA, KWR, UoB, VITO, TNO, NIVA]. It is foreseen that in Y4, the publication may require some additional effort, once reviewed by the journal. In collaboration with WP2 (PARCopedia) the PARC WP7 Glossary of key terms will be further updated as the various WP7 use cases produce formalised vocabularies. This, to ensure that the DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 113 various A-Zs presented in PARCopedia are fully consistent and aligned with these community developed standards that are agreed with the domain experts from across PARC WPs 4-8 and formalised via the controlled vocabularies. [Partners involved: UoB, KWR, MU]. An ongoing activity throughout Y4 will be implementation of the project-level DMPs. The initial data management sections of the PARC project proposals and implementation plans (developed in Y2) will be further elaborated, documented via the selected online DMP tool (DSW), into the final project DMPs, summarising how data have been managed, stored, archived and made FAIR. The further development of a FIP e.g., as foreseen for toxicology in Y4, will be helpful as it enables the immediate annotation of metadata etc. in the DMP. Further, the implementation of RAiDs (research activity identifier) and Protocols.IO (Protocols.io is “a secure open access platform for developing and sharing reproducible methods. Users can create, publish, and read public protocols” (https://www.protocols.io/)) and associated protocol identifiers into this environment will help the findability and foster the machine readable and actionability of completed PARC DMPs (on top of the metadata and identifier derived from DSW). The PARC protocols will also be integrated into the overall PARC exit strategy discussions. The WP7 data liaisons (see also T7.2) will support the responsible partners in the projects from the R&I WPs (e.g., represented by the Data Champion) to fill in the project specific DMPs (after training) [Partners involved: VITO, UOB, MU, UG-PL, UL-LACDR, IISPV, AUTH, TNO, ISSEP, UFZ, KI, UBA, JSI]. This work will directly feed into starting with updating and reviewing the overarching DMP (1st review of the Data Management Plan, due M42) [Partners involved: TNO, ANSES, VITO, UBA, ULLACDR, MU, ISS]. The process for monitoring of the KPI on the number of datasets FAIRified will be extended as outlined in D1.3. The approaches for tracking dataset re-use will be elaborated to support monitoring of the outcomes and impacts of the PARC FAIR efforts and the PARC Data Hub. A governance structure will be defined and implemented focussing on immediate needs and decision processes and longer-term aspects of PARC FAIR tools, resources and outputs (e.g., PARC Data Hub) sustainability, cross-domain interoperability and legacy. The governance processes will also require inputs from other WPs and the PARC coordination team, and some external organisations (such as the GFF and CoDATA representing the International Science Council who are leading the development of the Cross-Domain Implementation Framework - CDIF) as some of the decisions will have implications beyond WP7. The scope, remit and operating principles for the PARC Governance of FAIR will be elaborated and refined. A7.1.2 Communication and Training: organisation and delivery across PARC10 The dedicated training programme has been completed in Y2, led by GFF, resulting in a set of trained Data Liaisons and FAIR implementation Task group, which has led to a set of facilitators and trainers able to deliver additional training in FIP, and Metadata 4 Machines (M4M). In Y4, the participants will further develop the domain-specific FIPs for PARC, in particular on toxicology, as well as develop 10 The name of the activity was modified compared to AWPY2. The previous name in AWPY2 was: Training and organisation DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 114 tools and solutions to support the implementation of FAIR in PARC. [Partners involved: ISSeP, ULLACDR, MU, TNO, UoB with support of GFF]. The FAIR Implementation Team (see also T7.2) has implemented a process for finalising documentation and deployment (roll-out) of the tools and approaches to increase data management efficiency and facilitate data use and re-use within PARC and beyond. As tools / approaches are finalised and documented, including with WP-specific training materials, these will be rolled out to WPs / project clusters via hands-on training sessions tailored to the needs of the individual WPs / project clusters, on a rolling basis. Deployed and documented tools will also be discussed with WP2 for integration into PARCopedia, with WP8 for integration into the SSbD Toolbox and the EWS, with WP9 for integration into the PARC-wide training activities and inventories, and WP3 for communication and dissemination beyond PARC. [Partners involved, PL-UG, ISS, MU, UoB]. A7.1.3 FAIR Data Use Case Coordination For increased consistency and follow up this activity has been integrated into activity 7.2.3. Task 7.2: Data libraries Co-Leaders: MU (CZ), VITO (BE) Partners: ANSES (FR), AUTH (EL), BRGM (FR), EFSA (EU), EV-ILVO (BE), IISPV (ES), ISS (IT), ISSeP (BE), JSI (SI), KI (SE), MU (CZ), NIVA (NO), TNO(NL), UFZ (DE), UG-PL (PL), UBA (DE), UL-LACDR (NL), UNILU (LU), UOB (UK), UU (SE), UZIS (CZ), KWR (NL), WR (NL) Sub-contractors: GFF (NL) and CoDATA (FR) For Task 7.2 two projects were submitted in Y1. These projects encompass a broad and integrated approach towards two specific a priori identified domains and cut across the different activities defined under 7.2. Additional to these projects, use cases, where possible clustered for specific domains, are identified through the established horizontal links between WP7 and R&I WPs and projects, and are added on a rolling basis. Therefore, no additional project has been defined. Actions related to these additional use cases and clusters identified in Y2 and Y3 are added under the respective activities A7.2.1 to A7.2.4 as transversal activities. Details per project - P7.2.2.a_Y1_chemicals-in-environment_MU_VITO [M1-M42] (the project has been extended from M36 to M42) [Participants: MU, VITO, UFZ, BRGM, UniLU, ISSEP, JSI, ANSES, NIVA, UBA, KWR, AUTH]. The project is linked to activities under 4.2 (multiple exposure monitoring, PFAS baseline use case and ECDs) and specific activities under 6.4 such as the collection of existing exposure monitoring data on pesticides and chemicals in the articles and environment, and to some extent with A7.2.1 (the environmental component of the CRA landscaping). A 6-months extension (end date shifted from M36 to M42) of the project and related activities have been requested to allow for sufficient discussions with domain experts, feedback from stakeholders, and adequate time to finalize the project reports. In the project, the environmental (FAIR) data landscape has been mapped by identification of major databases, data platforms and FAIR enabling DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 115 and supporting resources used by the community. As part of the mapping activity, FAIR implementation profiles (FIP) of the major resources have been prepared and will serve as a basis for future development of reference FIP. Gaps have been identified and consequently, workshops with WP7 data experts and domain experts from R&I WPs were organized to develop metadata schema for (meta)data concerning occurrence of chemicals in the outdoor environment. The schema has been developed and it is currently under review by domain experts. The blue print of the dashboard for environmental data (the environmental component of PARC Data Hub) has been prepared and it is further refined. In Y4, metadata schema for data concerning chemical occurrence in the outdoor and indoor environment, and in consumer products will be discussed and further developed. Two project reports will be finalized: i) R-ENVIROdata.1: The level of FAIRness of the existing major data resources on chemicals in the environment; and ii) R-ENVIROdata.2: FAIR solutions to manage newly generated environmental data. The first report will describe the (PARC) environmental data landscape, including major databases and platforms, and their FIPs, as well as other existing FAIR enabling and supporting resources relevant for chemical occurrence data and PARC, identified gaps, resources developed in PARC, and how will these be integrated in the environmental component of PARC Data Hub. The second report will present solutions identified or developed during the project towards FAIR management of environmental (chemical occurrence) data. There will still be a need to provide support and develop solutions for FAIR management of chemical occurrence data in PARC after the project ends. Therefore, in Y4, an “environmental cluster” will be established as a set of transversal activities and will involve data experts from WP7, as well as domain experts from R&I WPs. The cluster will further develop FAIR enabling and supporting resources, and identify and manage use cases according to the needs of the PARC community. It will also contribute to further iterations of the development of PARC Data Hub, and integration with IPCHEM and COPCSD. - P7.2.2.b_Y1_HBMdatasets_VITO [M1-M48] (the project has been extended from M42 to M48) [Participants: VITO, MU, UBA, ISSeP, JSI, WR] Reason for extension: Due to reorganization of the project team at VITO (new project leader, people leaving and newly hired in the team), an extension of 6 months was requested for the P7.2.2.b_Y1_HBMdatasets_VITO project (from M42 to M48). Results achieved so far: Maintenance and improvement PEH Data Platform, development of tools for harmonisation and data validation, calculation of derived variables and summary statistics. Report on HBM data landscape and report on assessment of federated systems for privacy-preserving analysis. Finalisation of defining content for HBM metadata. Finalisation of the conceptual part of the HBM ontology work, first validated versions of vocabularies and a consolidated PARC biomarker list. Plans year 4: The WP7 HBM datasets project will build on the Y1-Y3 selection of relevant HBM datasets and linked communities, and the roadmap for FAIRification that has been developed (see table 1.4). Projects that will use these datasets include different 4.1.1 activities (HBM survey, DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 116 monitoring and occupational hazards), Activity 4.1.3 (Guidance Values) and Activity 4.1.4 (HBM Data Analysis) in WP4, several WP6 projects (A6.2.3 -real life mixturesand A6.4.1 -regulatory RA-) and the T8.2 (EWS) and T8.3 (integrative modelling network) Tasks in WP8. Online project meetings will be organised to fit the needs of the project. Table 14: Planned actions for P7.7.2.b in Y4 Parts (Schedule) Actions Participant Institution(s) (Country) 1. Transfer HBM4EU to PARC (M1 to M42) Operation of PEH data platform VITO 2. Use case management (M1 to M48) Use case working group VITO, MU, UBA, ISSEP, JSI, WR Collaboration/exchange with IPCHEM VITO Collaboration with other related data initiatives VITO, MU 3. Implementation and testing (M18 to M48) Implement use of data model, metadata schema and ontology Set up HBM data platform and services, integrating tools and pipelines for harmonization, processing and quality control of existing and newly generated datasets; 7. integration of the HBM (meta)data model in a more generic catalogues of variables 8. creation of interoperable data packages 9. Smart data aggregation and extraction 10. Automated semantic annotation 11. integration with models (WP8) 12. pipeline for sharing of data with IPCHEM (and, in future, the EEA) 13. connection to geospatial data 14. connection to environmental data 15. HBM dashboard VITO, MU, ISSEP, JSI, WR, UBA DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 117 As mentioned, domain-specific clusters have been identified in Y2 and Y3, among which data management activities on toxicology data and bioassay data, and integration of cross-domain aspects such as hydrological modelling of pollutant mobilisation of the EWS of WP8. Activities on toxicology data (e.g. the implementation of a toxicology specific FIP, formalisation of the Toxicology vocabulary and ontology, toxicology metadata standards, documentation of biological organisms (BIODA) will be further coordinated by UoB, with support from BfR (WP5) UL-LACDR TNO, and MU. Work plans drafted and embarked upon in Y2 and Y3, will flow further into Y4. Additionally, a need to establish a cross-domain cluster for NTS data has been identified, and this will be started in Y4. This activity will be coordinated by MU, with support of other partners from WP4 and will span the Toxicity and Environment Cluster activities. The work plans will be further discussed, also based on the inventory of resources and community needs carried out by WP9. A7.2.1 Mapping the PARC Data Landscape [Lead: MU, Partners involved: UOB, ISS, ISSEP, UL-LACDR, UNILU, ANSES, VITO, NIVA] A7.2.1 Identifies existing databases or repositories that may be appropriate to store newly generated data for the different CRA domains. This activity is in close collaboration with WP9, where WP7 is focused mainly on the assessment of FAIRness and sustainability, and support in FAIR management of inventories (see A7.2.2) carried out by WP9 with support of WP7, or other R&I WPs in collaboration with WP9. The landscape will be enriched further with newly identified resources resulting from specific clusters and use cases. In Y4, a major focus will include detailed assessment of the PARC data landscape for Regulatory Toxicology, Omics (sequencing data, MS NTS data, phenomics), NAMs, Mixture Toxicology and RA Modelling. [Partners involved: UoB, ISS, UL-LACDR, ANSES, MU, VITO, NIVA]. Also, the focus will be on mapping the cross-domain NTS data landscape and identifying community needs and gaps in available solutions [MU, partners from WP4]. The FAIRness of the prioritised databases/repositories’ systems, standards, and methods of operations will be assessed following application of the ‘as is’ FIPs developed by the FAIR Implementation Team (who were trained in Activity 7.1.2). [Partners involved: UOB, ISSeP, UniLU, UL-LACDR, ANSES, MU]. Their sustainability will be assessed as well. In parallel, the activities at the EC level related to the Common Platform for Data on Chemicals (CPDC) roadmap and implementation, will be further followed up and the proposed approaches followed to ensure the coherence of actions in the common European open data space. [Partners involved: MU, VITO, UFZ, UoB, UniLU, ANSES]. A7.2.2 PARC FAIR data hub [Lead: MU/VITO, Partners involved: UOB, BRGM, UFZ, WR, ISS, JSI, ISSEP, NIVA, UL-LACDR] Metadata Service – Data Catalogue of the Data Hub [Lead: MU/VITO, Partners involved: UFZ, UoB, WR, ISS, JSI] The data catalogue module of the Data Hub will be further enhanced. We must improve the server infrastructure to make it a production-grade metadata catalogue deployment (using the open source CKAN data management software -https://ckan.org/-). This will involve the second iteration of DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 118 server infrastructure to support larger volumes of dataset records and manage rich metadata descriptors. Optimization efforts will focus on complex search functionality to ensure that rich metadata descriptors do not hinder performance. Filtering criteria will also be customized to include both general filters and data type/domain-specific filters. Additionally, the metadata ingestion user interface will be further optimized to improve userfriendliness. The focus will be on ingesting datasets related to the outdoor environment, HBM indoor environments, toxicology, and consumer products. New metadata standards will also be adopted to ensure the platform stays current with regulatory and research needs. We expect the need to curate the content of the data catalogue to access individual domains and provide examples of good data management practices. Work related to progressively include the inventories on existing datasets and databases taking place in R&I WPs and in WP9. Chemical RA Dashboards [Partners involved: MU, VITO UFZ, UoB, WR, ISS, JSI] According to feedback, the existing chemical RA dashboards will receive minor updates to improve their usability and functionality. Meanwhile, new dashboards will be developed in collaboration with the key WPs: • A models’ dashboard will be developed in collaboration with WP8. • A dashboard focused on the indoor environment will be developed with WP9 and WP6. • A consumer products dashboard will also be created in collaboration with WP9 and WP6. To further support data and information exchange across the PARC project, the Data Hub will enable better integration with other WPs, notably WP2, WP8, and WP9. Based on inputs from WP9, the Data Hub will also host the results of their landscaping activities. A FAIRification toolbox component will be developed to provide the necessary tools for data providers to increase the FAIRness of their data (see 7.2.3). A tool/module to visualise FAIRness of datasets or underlying resources will be further developed. Conversion tools for interfacing towards established regulatory platforms (i.e., the CPDC, including ECHA, EFSA, EEA databases and IPCHEM) and other established domain-specific and national/local data platforms will be integrated. [Partners involved: VITO, MU, UoB, BRGM, ISSEP, NIVA, UL-LACDR]. Development of FAIR Tools [Partners involved: MU, VITO, UoB, JSI]. We plan to focus on the development of several tools aimed at enhancing the FAIRness of the data managed within the PARC Data Hub: • Metdata template generators will be built based on existing metadata schemas, vocabularies, and codebooks, allowing for the standardization of metadata creation. • Data and metadata validators will be implemented to ensure data integrity and compliance with FAIR standards. • Development and customization of SKOS vocabularies will be a priority. SKOS (Simple Knowledge Organization System) is W3C (World Wide Web Consortium) recommended standard for describing controlled vocabularies (https://www.w3.org/TR/skos-reference/). This will include tools for reference resolution and the automatic assignment of Global Unique Persistence Resolvable Identifiers (GUPRIs), ensuring that all terms are uniquely identifiable and resolvable across systems. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 119 • Tools for data and metadata enrichment. • Addiional tools will be developed to support the smooth adoption of both semantic and technical standards, facilitating broader data FAIRification efforts. Collaboration with IPCHEM and EU-Level Agencies [Partners involved: MU, VITO, UoB]. Collaboration with IPCHEM and other EU-level agencies will continue to be a priority. Ongoing meetings with the IPCHEM team will help ensure alignment with EU initiatives and maintain progress on metadata standards. Additionally, the team will actively follow and contribute to the development of emerging metadata standards, ensuring that the PARC Data Hub remains compliant and interoperable with regulatory frameworks across Europe. Feedback will be collected from the various types of data hub stakeholders to ensure a positive evolution in terms of meeting users' requirements, alignment with the wider landscape and useability. [Partners involved: MU, UoB]. The development of the Data Hub will be in close collaboration and feedback of both WP7 projects P7.2.2.a_Y1_chemicals-in-environment_MU_VITO, and P7.2.2.b_Y1_HBMdatasets_VITO and newly created clusters (toxicology, environment, other). A7.2.3 Solutions for FAIR data: development and implementation (For increased consistency in resource allocation and follow up, Task 7.1.3 has been integrated here from Y3 onwards) [Lead: VITO, Partners involved: MU, AUTH, GU-PL, IISPV, ISS, ISSeP, JSI, TNO, UBA, UL-LACDR, UOB, WR, NIVA, EV-ILVO, UG-PL, UFZ] Use case and cluster identification [Partners involved: VITO, MU, AUTH, GU-PL, IISPV, ISSeP, JSI, TNO, UBA, UL-LACDR, UOB, WR, NIVA, EV-ILVO] The communication channels and decision structures are now in place for WP7 to be made aware of the needs of PARC projects and regulatory stakeholders and be able to prioritise them into priority data domains (clusters) or use cases. Several of these have been identified, represent ongoing work and are mentioned in other sections of this document, others are in the process of being integrated in one of the FAIR or Semantic teams. This process of identification, triage and selection will continue in Y4. The Data Liaisons have also started an awareness initiative in Y3 on FAIR data and good Research Data Management that will possibly bring more use case candidates to the surface. Development and implementation of solutions Bottlenecks for data reuse and synergies with existing data platforms have been identified. FAIR Implementation Profiles and associated roadmaps and machine-actionable metadata have been or are being developed in close collaboration between domain experts from the R&I WPs, WP7 Data Liaisons and the FAIR Implementation Team in use case or cluster-based working groups (facilitated by the Facilitators and Trainers who have been trained and certified as part of T7.1.2 by the Go FAIR Foundation, and who constitute the FAIR Implementation Team). In Y4 this will be further developed for toxicology and bioassays A FAIRification methodology was developed that builds upon and goes beyond the GFF Three-Point FAIRification Framework (3PFF) and this is now being implemented as both a technical data structure and a set of tools to facilitate interaction with the data, starting from the well-known DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 120 domains in P7.2.2.a_Y1 (environmental data) and P7.2.2.b_Y1 (HBM data) and then expanding to domains where similar needs present themselves (toxicology, bioassays). Generic artefacts, solutions and tools developed in the projects P7.2.2.a_Y1 and P7.2.2.b_Y1 (such as lists of variables, chemical identifiers, (meta)data validation tools, tools for harmonisation, conversion between standards, semantic annotation, FAIR publication, …) will be repurposed for other domains. Domain-specific FAIR enabling resources (such as metadata schema, data templates, harmonisation standards, data reporting interfaces) will further be elaborated and implemented. This approach allows systematic co-creation of domain-, use-case or project-specific roadmaps for development and implementation of FAIR metadata and data based on the current level of maturity of the specific case (e.g., RA is further advanced than NAMs). One generic functionality, for domains that have adopted the PARC FAIRification methodology, that we will develop in Y4 is a standardised and automated approach to creating FAIR (meta)data packages. In terms of the development of domain-specific resources, we will follow the demand, available expertise and FAIR Steering Team prioritisation, but expect that exposure data and model metadata, NTS data and health guidance values will be among the topics addressed in Y4. In addition, we intend to explicitly concentrate on the data and model interoperability aspects of CRA research and contribute with our FAIR (meta)data formats to the technical implementation of interoperability between data and models in the PARC Integrative Model Network (T8.3) and the EWS (T8.2) Framework. Apart from P7.2.2.a_Y1 and P7.2.2.b_Y1, clusters and use cases selected in Y1 and Y2 are supported further in implementing their workflows, i.e., • making available scientific data sources for (re)use in regulatory RA, i.e., development and implementation of user-friendly tools (interfaces) to make occurrence and hazard data available in formats supported by the CPDC (i.e., IPCHEM (meta)data formats (see P7.2.2.a and P7.2.2.b), IUCLID, OECD Harmonised templates, EFSA templates, national templates, …); [Partners involved: ISS, UL-LACDR, NIVA, MU]. • addressing domain-specific data needs and related workplans and actions identified in Y2 that address the management of hazard and toxicological data that span across WP5 and WP6 and require cross-WP alignment (coordinated by UoB, with support from BfR (WP5) and ULLACDR). These include: • Regulatory toxicology (EFSA, ECHA) where endpoints are well-defined: refinement of existing harmonised templates; [Partners involved: ISS, UL-LACDR, UOB, WR, MU, NIVA]. • Updating of metadata, and development of new templates for novel in vitro endpoints and approaches as developed for NAMs (aligned with OECD requirements for validation of methods) [Partners involved ISS, UL-LACDR, UoB, NIVA, MU, KWR, TNO] In particular for in vitro methods applicable to SSbD. This will involve the development of a toxicology FIP. • Development of a community standard for documentation of toxicological study systems (animals, organisms, organoids, cell culture systems etc.) and accompanying DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 121 sampling protocols, formalised via a European Committe for Standardization (CEN) Workshop Agreement or other appropriate means [Partners involved: UOB, MU, ULLACDR, TNO, NIVA] • Collaboration with the FAIR AOP cluster on FAIRification of the AOP Framework to support (i.e., development of FAIR Implementation Profile and FAIR Enabling Resources) to support the development of the new “AOP-Wiki 3.0” and AOP-related terms and concepts; [Partners involved: IISPV, UOB, UG-PL, ISS, MU, NIVA] • Workflows for documentation and FAIRification of omics / systems toxicology modelling data to support its integration into RA; this will be done in collaboration with the ASPIS cluster (https://aspis-cluster.eu/) and the ELIXIR Toxicology Community implementation project (https://elixireurope.org/communities/toxicology). [Partners involved: INSERM, UoB, KI, ULLACDR, IISPV, NIVA, TNO]. • Further elaboration of the workflow, templates and data repository for ecotoxicological data for broad use by the PARC community and beyond, and testing in dedicated use cases [Partners involved: NIVA, UoB, members of FIT] • Metadata for MS NTS data, analytical workflows and data processing (cross-WP effort in collaboration with EMBL) [Partners involved: MU, additional partners to be confirmed during Y3]. • Implementation of Protocols.IO (Protocols.io is “a secure open access platform for developing and sharing reproducible methods. Users can create, publish, and read public protocols” (https://www.protocols.io/)) for documentation of PARC data generation protocols, to increase findability (discovery), re-usability and overall FAIRness of the workflows and protocols underpinning PARC datasets. Analysis of Protocols.IO as a FAIR Enabling Resource is underway in Y3, and is included as a critical element of the PARC Toxicology FIP, with applicability to Environment (and potentially HBM) datasets also. As noted earlier, integration as a PARC Data Hub workflow to is also envisaged. Training and support for all PARC partners on use and implementation of their protocols will be provided via WP7 in collaboration with the Protocols.IO team. • Continued work on use cases on FAIR elements common to many projects: finetune and improve tools for metadata management, for schema-based validation of harmonised templates, for semantic annotation, taking into account new domains and use cases; [Partners involved: VITO, MU, additional T7.2 partners to be confirmed]. • Further elaboration and implementation/selection of a tool for automated FAIR assessment [Partners involved: MU, UoB, VITO]. • Depending on concrete workplans defined in Y3 and the progress in the respective WP8 Tasks, develop and implement workflows and tools to facilitate data availability and interoperability for tools developed in T8.1 - Safe and Sustainable by Design; T8.2 - Early Warning Systems and T8.3 - Integrative Modelling Network. [Partners involved: AUTH, WR, other WP7 partners to be determined during Y3]. At the Annual meeting for WP7, it was agreed to spec out two additional cross-domain / cross-WP case studies as follows: • Integration of hydrological data for predicting pollutant movements (hotspots, hot moments) and the impacts of droughts, floods and these rivers/river basins, together DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 128 recommend promising methods for further evaluation and refinement if needed. [Partners involved: KWR, WR, NIVA]. Following three use cases are currently implemented and will continue in Y4. Use case 1: Assessment of uncertainty in PBK models of PFAS exposure in humans and reverse dosimetry (uncertainty in PFAS exposure) (Lead: MU, Partners involved: IISPV, WR) The aim of the case study is to assess uncertainty through all workflow of when comparing results of a PBK model for internal exposure and a dietary model for external exposure to PFASs. The PBK model is used for a reverse dosimetry, modelling daily intake from known blood PFASs concentration whereas food frequencies, portion sizes and PFASs concentrations in different food items and drinking water over the European countries are used to estimate daily intake from external sources. Uncertainty in all inputs is quantified and advanced methods for sensitivity and uncertainty propagation are used to quantify the uncertainty in daily intakes estimated by both models. In past 2 years of the case study (Y2 and Y3), 4 PFASs were selected for the case study (PFOA, PFOS, PFNA, FHxS), the PBK model for the first subpopulation (teenagers) was selected (RIVM model) in collaboration with T6.2.2, the external exposure (dietary) model was constructed and data from European food were collected (over 7,400 records). The parametrization of the selected model will be finished in collaboration with T6.2.2 in Y3 and estimates of uncertainty of all the parameters will be suggested and discussed among the case study partners. Before the end of Y3 also the final version of a review of the uncertainty and sensitivity treatment methods will be finalized. Planned activities for Y4 consist of a comparison of different methods of the uncertainty propagation within the external exposure model and a comparison of results of the PBK model reverse dosimetry with the results of the external exposure model for teenagers. Further, a thorough comparison of results of the reverse dosimetry with the results of external exposure modelling, including their uncertainties, distributions and discussion of the results will happen. First of the two suggested scientific papers should be submitted during the Y4. In the following year, a similar workflow will be realized for other subpopulations (adults and potentially also poregnant women) and the second suggested paper will be submitted. Use case 2: From Bioassay Response to Risk Uncertainty (Lead: KWR, Partners involved: IISPV, NIVA), First three years of work has been completed and results has been published in a scientific article ((https://doi.org/10.1016/j.envint.2024.108733). Second phase of this work will continue in year 4 and in collaboration with WP4. Bioassays in water or food quality monitoring can measure effects induced by chemical mixtures. Such chemicals, that induce bioassay responses, have different levels of toxicity for different human or other organisms’ endpoints. This means that there is uncertainty in interpretation of the possible risks associated with a measured effect in a bioassay. Although a derived trigger value can pinpoint a response at which risk is low, information on risk magnitude and uncertainty in it is good to have at any bioassay response. The case will showcase a method to quantify these risks and uncertainties. Use case 3 Control Coefficient analysis of PBPK model (Lead: IISPV, Partners involved: TBD): Sensitivity coefficients quantify the effects of (small) changes in any parameter on any dependent variable, whereas a control coefficient quantifies the DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 129 extent to which a catalytic/biochemical process determines a system variable. The scoping study of this use case started in year 3 to develop the system biology approach that is called Metabolic Control Analysis (MCA) for PBPK and investigate the control coefficients that are most relevant for a toxicokinetic system. Application of this methodology to selected PBPK models will continue in Y 4. Use case 3: Enhancing Hazard Prediction with Cell Painting and Conformal Prediction (Hazard_cellpainting_uncertainty, Lead Partner: UU (ola Spujth, Partners: IISPV): AI models are emerging as important components when assessing hazard and risk of chemicals. With this case study, we focus on the data-rich and yet inexpensive in vitro assay Cell Painting and aim to demonstrate the value of using conformal predictions to deliver prediction intervals instead of point predictions as output of AI models. This has the potential to improve the reliability and interpretability in chemical hazard assessments. In this case study, we integrate Cell Painting assays with conformal prediction methods to improve hazard prediction in AI modeling. Cell Painting is a high-content imaging technique that captures comprehensive morphological profiles of cells exposed to various compounds. By leveraging these rich phenotypic datasets, we train machine learning models to predict toxicological outcomes of new chemical entities. To address the inherent uncertainty in AI predictions, we employ conformal prediction—a statistical framework that provides confidence measures for individual predictions. This combination allows us to generate not only accurate hazard predictions but also quantifiable uncertainty estimates, enhancing the trustworthiness of the AI model. The case study is linked to and based on data generated in PARC 5.2.1b and T5.2.1e. AI model sharing and discovery is linked to PARC T8.3. Use case 4: Benchmark dose (BMD) Modeling of Omics Data: understanding and harnessing uncertainties (BMD_uncertainty_modelling, Lead: UL-LACDR ; Partners involved: ANSES) BMD modeling is a key tool in toxicological RA, providing estimates of doses that elicit a predefined biological response. In this case study, we focus on omics-based BMD modeling, where highdimensional transcriptomics data is used to predict dose-response relationships. However, the variability between different gene sets can introduce uncertainty in BMD estimates, complicating their use in regulatory decision-making. To address this uncertainty, we are planning: 1) to focus on a network-centric modelling approach rather than gene set approach, 2) to integrate omics data with advanced ML approaches. By utilizing models such as Random Forests, BNNs, and Gaussian Process Regression (GPR), we aim to enhance the accuracy and reliability of BMD estimates while providing uncertainty quantification for each prediction. These approaches (network-centric modelling and ML techniques) allow us to account for the inherent variability in gene sets, improving model robustness. In this case study, we leverage gene expression data generated using the human breast cancer cell line (MCF7) and available via the CompTox and EPA reference datasets (https://comptox.epa.gov/dashboard/), along with their respective weighted correlation network analysis derived models, to train ML algorithms.The combination of high-content omics data and probabilistic ML approaches enables us to generate not only precise benchmark dose (BMD) estimates but also confidence intervals for each prediction. This enhances the interpretability of the DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 130 results and provides regulators with a clearer understanding of the uncertainties involved in omicsbased BMD modelling. By addressing the variability and uncertainty in transcriptomics-based BMD estimates, this case study demonstrates the potential for more accurate and transparent toxicological assessments, ultimately improving the integration of omics data in regulatory frameworks. There has been some delay in the progression of this case study due to hiring, now solved for Y4. A7.3.3 Novel computational methods for integrating and extracting knowledge from non-structured data Details per project: - P7.3.3.a_Y3_ ALT-IST_IISPV [M1-M60] After completing the scoping study for methodologies, tool development, and applicability domains, tool development began in Year 2, resulting in a prototype that will continue to be refined in Year 4. This year, the tool will be implemented in ongoing case studies, specifically WP 5.3 (immunosuppression and adult neurotoxicity), as well as in new case studies currently under discussion including in WP6 and WP8. During testing of the tool prototype with specific use cases, several limitations were identified. In response, a more advanced information extraction and text mining system will be developed to meet the requirements of AOP development. The case studies initiated in Year 3 will continue in the coming years, providing further insights to optimize the text mining system and clarify requirements. Additionally, the writing of scientific articles, and presentations at scientific congresses and SFs will continue in Year 4. [Partners involved: IISPV (ES), UoB (UK), ANSES (FR), INSERM (FR), JSI (SI), AUTH (EL), MU (CZ), UL-LACDR (NL), KI (SE), NIVA (NO)] Specific actions for year 4 include: - Drafting a whitepaper outlining a comprehensive pipeline for integrating additional data into text mining evidence, focusing on ensuring relevance and meeting the required evidence level for regulatory use. This pipeline will be designed to accommodate diverse data types, such as multi-omics and imaging, while maintaining alignment with regulatory standards. Key enhancements will include advanced meta-data filtering to prioritize high-quality, regulatoryrelevant data and reduce redundancy. A version control system will also be incorporated, allowing periodic updates and re-indexing of evidence to reflect the latest scientific findings. Additionally, tools will be harmonized to ensure smooth integration with standardized reporting frameworks, such as OECD templates for multi-omics data. The white paper will also propose customization options for specific regulatory domains, ensuring that the pipeline meets the unique evidence-level standards required for areas like toxicogenomics and RA. [Participant: UL-LACDR, IISPV] - Text mining framework will further be optimized to make it scalable for a wider usability by the community. Addition of meta-data filtering to reduce redundant results. Integration of index versioning system to allow periodic indexing of information. Further, harmonization DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 131 and integration of developed tools into a single platform and customization for the domain specific requirement [Participants: IISPV, UoB] - Planning of a harmonised FAIR evidence representation started in Year3 will transition to implementation phase in year 4 where ontology-based framework will be developed to represent an event information. [Participants: UOB/IISPV] - Development of hybrid text mining approach integrating ML and grammatical syntax parsing techniques for relation extraction [Participants: UOB/IISPV] - Systematic evaluation of methods for deriving binary and typed relationships between biomedical / toxicological entities based on transactional occurrence data will continue in year 4. [Participants: UOB/IISPV] - Building a consistent data exchange schema according to FAIR principle and mapping of diverse data sources to build the knowledge graphs started in year 3, will continue to the implementation phase in Year 4. [Participants: UOB/IISPV] - Development of FAIR AOP planned in year 3 will shift to implementation phase in Y4 by adopting a new bottom-up approach using nanopublications. Use case 2 (Partners involved: UL-LACDR). Gene expression data is characterized by some accepted ontologies at the gene/protein level (e.g., NCBI Gene, UniProt) and some at the pathway or functional levels (e.g., Gene Ontology, WikiPathways, ..). However, both levels are at the moment sub-optimal to inform RA as they are either too detailed and not informative (gene level) or redundant and not pertinent to the toxicological experiments (pathway and functional level). Gene co-expression networks defined on the basis of exposure-derived experiments represent a good starting point to obtain data that is fitting the RA domain and that achieve data dimensionality reduction, however the annotation of such co-expression networks is at the moment not standardized but expert-based and time consuming. In Y3 we will develop an automated ontology naming application, including additional data sources for genes or gene sets. These would include compound modulation and pathology information, using existing datasets (e.g., DisGeNET) and text mining on literature and clinical trials. The to-be-developed FAIR (connection to 7.2.4) ontology will be tailored for RA use and will link to the information sources used (provenance). The ontology terms with knowledge on the function of individual genes and interactions between genes/proteins within modules can then be compared to existing literature and data repositories using text mining tools. A7.3.4 Identify additional needs in PARC for innovative analyses and promising evolutions in the data science landscape, and translate them in use cases for evaluation The objective of this activity is to identify emerging needs in PARC for innovative analyses on one hand, and promising innovative techniques on the other hand. For the annual plan year 4, scoping and testing of new methods will continue. Based on this implementation planning will be executed with the steps mentioned below with collaborating partners. Use case 1 (7.3.4.a): Pharmacophore modelling using machine learning for screening Blood Brain Barrier (BBB) permeation of xenobiotics [Partners involved: IISPV, UFZ, JSI]: This use case aims to investigate the effectiveness of different fingerprints generated based on pharmacophore modelling in deciphering the BBB permeation of xenobiotics. With pharmacophore modelling, this study will explore the influence of the P-gp protein in the transportation process. Scoping and testing with limited data sources have been completed and the work is published DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 132 (https://doi.org/10.3390/ijerph192013471). There is some delay with new data collection and work will continue in year 3 and 4 with specific focus on identifies chemical groups in the PARC. To achieve this objective, the use case will perform the following activities: • The collection of chemical data from reviewed literature sources and databases, followed by a filtering and standardization process to obtain a stabilized 3D structure. • A scaffold of the collected data will be generated to analyze the distribution of the core structure of the chemical responsible for permeability. • Stabilization and hydration of the protein retrieved from the protein data bank (PDB) will be undertaken, for docking purposes. • Different methods will be explored to generate pharmacophore fingerprints including receptor-based and ligand-based methods. The residue-based pharmacophore will be generated by docking the P-gp substrates and extracting the most common residues involved in the interaction. Whereas, the interaction-type pharmacophore will be generated using the docked chemical molecules, which will further be processed with the proLIF library to generate a 9-bit fingerprint and Rdkit. • The generated fingerprint and classical fingerprint will then be trained on a classical algorithm, such as Support Vector Machine (SVM), RF (Random Forest), and naïve Bayes, for comparison. New generation of ML method like graph model will also be implemented for methodological comparison. This use case has been developed in consultation with WP5 and WP8 and activity will be complemented with BBB experimental data generated in Task 5.3.4a (P5.3.4.a_Y1_PBK_Kinetics_Fraunhofer) and the computational tools for early warning system in Task 8.2. Use case 2 (7.3.4.b): Scoping study of AI&ML-driven computational NAMs for use in NGRA [Partners involved: UFZ, JSI, IISPV]: Activity 7.3.4 will also collaborate with A6.4.3 with a selected project P6.4.2.c_Y1_ NAMAM_UT: AI&ML-driven computational NAMs for use in NGRA lead by UT (EE) and work on landscaping and readiness of NAMs based on advanced AI&ML approaches for use in chemical RA. This activity is a collaborative activity between two WPs and WP7.3 will support and provide input to the planned activity of A6.4.2. Here the focus is on the documentation of the data feeding into these models, and of the predictions coming out, and how to ensure transparency of these and their FAIRness. Use Case 3 (7.3.4.c): AI-based Methods to Predict Biochemical Parameters such as Fraction Unbound in Plasma (IISPV, UG-PL): This use case focuses on developing ML and deep learning (DL) models to predict the fraction unbound (fu) in plasma based on critical structural features of chemicals. The fraction unbound (fu) is a key biochemical parameter in the development and analysis of PBPK models, providing insight into the portion of a xenobiotic that binds to plasma proteins. This binding affects how much of the chemical remains in circulation to exert its biological effects. Accurate prediction of fu is essential as it influences chemical interactions across different tissues, impacting drug efficacy and safety profiles. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 133 To achieve this, it is crucial to explore and understand the chemical structures that determine plasma protein binding. In vitro data for fu is available from various chemical databases such as ChEMBL and DrugBank, offering a solid foundation for model training. Objectives: The aim of this use case is to build predictive models by utilizing machine learning and deep learning approaches to better understand how structural features influence fu values. Specifically, the activities will include: • Data Retrieval: Gather in vitro fu data from publicly available chemical databases like ChEMBL, DrugBank, and relevant literature. • Data Cleaning and Validation: Cross-validate fu data from different sources, checking for discrepancies, and rectify any inconsistencies to ensure data quality and accuracy for model training. • Feature Extraction: Calculate structural features of chemicals using conventional cheminformatics descriptors (via tools such as RDKit and Mordred). Additionally, generate graph-based embeddings to capture more nuanced structural information of the molecules, providing an enhanced feature set for model training. Additionaly, development of evolutionary algorithms and ML techniques (i.e. genetic algorithms, SHAP) to extract the most relevant features affecting the modeled variable (fu), which will have the direct impact on the overall models’ predictive abilities and stability. • Machine Learning Model Development: Train predictive models for fu using conventional machine learning regression algorithms like Random Forest, XGBoost, and Support Vector Machines (SVM). The input features will be based on cheminformatics descriptors and graph embeddings, providing a robust representation of the chemical structures. The descriptors will be computed on several levels of theory, i.e., at the level of quantum chemical calculations, simple representational identifiers (like SMILES, empirical formulas), with an aim to determine which level of theory is required to develop meaningfull structurerelationship models. • Deep Learning Approach: We will evaluate deep learning approaches by developing advanced neural network models and its variants such as graph neural networks (GNN) and using pretrained models andcompare the performance and accuracy of deep learning models against conventional machine learning methods to determine the most effective approach. Outcome: By leveraging both traditional machine learning and cutting-edge deep learning techniques, this use case aims to deliver highly accurate models for predicting the fraction unbound (fu) in plasma. These predictions will provide valuable insights into the role of structural features in chemical-protein interactions, improving PBPK model development and aiding drug discovery efforts. Use Case 4 (7.3.4.d): Read-Across Through Transcriptomics Data (IISPV, UG-PL, UoB) DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 134 This use case focuses on employing and integrating two distinct approaches—structural similarity analysis and MoA—to perform Read-Across of chemical compounds. The aim is to benchmark these methods, validate them, and establish a standardized pipeline for Read-Across in NAMs for RA. A. Structural Similarity Analysis: This approach involves clustering chemicals based on their structural representation using cheminformatics tools. The chemical structures are characterized by molecular fingerprints, which serve as input for clustering algorithms. Key activities include: • Clustering: Apply various clustering techniques such as K-means and hierarchical clustering to group chemicals based on structural similarity. Development of novel implementation of fuzzification algorithms (soft clustering) in terms of similarity analysis, which will be particularly useful in the context of read-across analyses and their justification for the domain expert, leveraging the idea of probability of existing of one chemical structure to several groups at once. The implementation will be followed with development of an interactive tool for this purpose. • AI-Based Structural Similarity: Use advanced AI methods, such as graph-based models, to generate molecular embeddings that capture complex structural information. These embeddings will be used to cluster chemicals in a more nuanced way, potentially revealing deeper structural relationships. B. Mode of Action (MoA): This approach leverages transcriptomics data to group chemicals based on their biological effects, particularly their impact on gene expression profiles. The steps involved in this approach include: • Transcriptomics Data Processing: Implement a bioinformatics pipeline for handling transcriptomics data. Key tasks include quality control (e.g., removing adapter contamination and filtering out low-read data) and processing the data for alignment and mapping to a reference transcriptome. • Gene Expression Analysis: Quantify gene expression levels and perform differential gene expression analysis to identify changes in gene activity upon exposure to different chemicals. • Functional Enrichment and Pathway Analysis: Conduct functional enrichment analysis to identify the key biological pathways and molecular mechanisms affected by chemical exposure. These pathways may be linked to AOPs, offering insight into the MoA. • Toxicophore Modeling: Develop toxicophore models by mapping the structural features of chemicals to their interaction with targeted proteins involved in AOPs. This will help elucidate the relationship between chemical structure and molecular activity. Integration of Approaches and Benchmarking: Integration: Combine the results from structural similarity analysis and mode of action clustering to perform an integrated Read-Across of chemical compounds. This dual approach helps to consider both structural and biological effects in the assessment. Benchmarking and Validation: Benchmark the performance of different clustering and AI models to identify the most effective approaches for Read-Across. The validation process ensures that the results are reliable and can be used to develop a standardized pipeline for Read-Across in NAMs. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 135 Outcome: This use case aims to provide a validated and standardized pipeline for performing ReadAcross based on both chemical structure and transcriptomics data. By comparing different methods, it will identify the most accurate and reliable approaches, facilitating improved chemical RA within the framework of NAMs. This use case is strongly in alignment with the running CS1 in the P5.3.1.a_Y1_SystemsToxicology_UL-LACDR, and with the new submitted P5.3.1.a_Y4_grOMICS_ULLACDR. Deliverables D7.5 1st review of the Data Management Plan (DMP) – Leader: TNO (M42) Additional Deliverables: NA WP N° WP8 Lead Beneficiary AUTH/UNINA WP title Concepts and toolboxes Partner N° 1.1 4 4.6 8 12 14 14.5 15 20.4 25 Partner short name INSERM VITO ISSeP MU EEA TTL TAU UBA IUSS RIVM PM/ partner 0.2 3.0 0.5 21.6 3.8 5.0 6.0 4.6 19.0 12.0 Partner N° 25.4 26.4 29.2 31.3 34.6 35.8 35.11 36 36.3 52 Partner short name UL-LACDR NIVA DGS NIC INSST IVL UMU AUTH NKUA Cefas-Defra PM/ partner 1.9 1.0 1.0 7.0 2.0 7.5 15.2 73.0 7.5 0.7 Start M37 End M48 DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 136 Objectives The overall goal of WP8 is to support the development and consolidation of concepts and tools for chemical RA, also considering Safe and Sustainable by Design (SSbD) chemicals and materials and their operationalisation. The specific objectives of WP8 for year 4 are: o Task 8.1: Further improve the functionalities of the V1.0 of the SSbD toolbox and assess its applicability through new case studies o Task 8.2: Further develop the PARC computational EWS and the validation framework to support the EWS based on the completion of the identification framework o Task 8.3: Implement case studies to advance the development of the PARC model network, based on an updated conceptual framework and inventory of models and tools, and deliver an enhanced version of the initial beta of the PARC model network Description of Programmed Activities Task 8.1: Safe and sustainable by design (SSbD) Co-Leaders: RIVM (NL), EMPA (CH), AUTH (EL) Partners: INERIS (FR), BNN (AT), MU (CZ), DTU (DK), SYKE (FI), TTL (FI), UBA (DE), ISS (IT), IRFM (IT), IUSS (IT), UNINA (IT), NILU (NO), NMBU (NO), UG-PL (PL), FMUL (PT), NIC (SI), INSST (ES), IVL (SE), BUL (UK), Cefas-Defra (UK), TAU (Fl) A8.1.1. Translate EC SSbD criteria & methodology towards operationalisation The work plan in year 4 includes the activities below: Continuing and deepening the interaction with industry and (internal/external) PARC experts 1. Scaling-up PARC internal and external expert involvement Here we will expand and deepen the existing efforts and activities focused on involving experts from PARC, and external scientists from academia and industry. Safe-and-Sustainable-by-Design (SSbD) requires complex risk and sustainability assessments and decision-making processes within an innovation context. The JRC Methodological Guidance has detailed the development of a “Scoping analysis” step that sets the goal and scope for the whole SSbD assessment and redesign process. We found in the company interviews and several references that in the actual industrial context, such a scoping step occurs within a multidisciplinary team of experts where available information is used to “scope” the assessment and redesign problem, use information, tools and expert judgement to arrive at the best available conclusions for the innovation stage. By performing the scoping analysis within a team-based context, we can address the limited availability of information at early innovation stages. This scoping process is at the core of the SSbD problem definition and defines for a large part the steps that need to be taken to do a full SSbD assessment. Performing SSbD starts with a good scoping exercise, that is identifying the SSbD question at hand, identifying and defining the system boundaries, identification of the lifecycle and the involved stakeholders, finding hotspots and prioritize SSbD topics, gathering basic information, making an information assessment, etc. Building a scoping approach has two important aims. First of all, to learn from current practices in early screening. We set out to learn from experts how they deal with read-across approaches, how to prioritize and determine hotspots, how to include and deal with expert judgement. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 137 Focus will be on the applied reasoning and the principles the reasoning is based upon. Thus, enhanced interaction with specialist will also add to the wider detailed understanding of the SSbD-approach. Activities proposed included: 1. Developing an approach that enables a process to perform an SSbD assessment in a multidisciplinary team. This approach can be seen as a fictive role-play as of an innovation team within a company (serious game/workshop/designathon). 2. Organising (PARC) internal development/test workshops make use of a specific case in point. As the scoping approach will utilise a specific case study (chemical/product/process), this work will be performed in collaboration with 8.1.3. 3. Investigate the possibility of testing the approach in a company or value chain environment. 4. Translate the results to requirements for the toolbox. 2. Continued interaction with other EU projects (HE 2023-24), and expansion of the overview of SSbD to knowledge developed in previous (and terminated) EU projects Aim is to analyse the knowledge development and examine and establish links to operationalization of SSbD (8.1.1), the toolbox (8.1.2), case studies (8.1.3), Knowledge and education platform (8.1.4). Activities included: 1. Drafting overview and subsequent analyses of relevant projects. 2. Active information exchange with running SSbD relevant projects (e.g. meetings, regular presentations at regular PARC SSbD meetings) (RIVM, IVL, AUTH). 3. Development of a NAM-SSbD relevant knowledge base Several developments in chemical RA are of crucial importance for SSbD. NGRA is a paradigm that can be useful for the operational development of SSbD. Additionally, in-vitro NAMs play a role in NGRA and potentially in SSbD as well. Activities included: 1. Analyses and exploration of the SSbD and NGRA concepts to identify similarities and potential connections. 2. Development of insight in the current (in-vitro) NAMs and the way they can be used in the context of SSbD. 3. (Outline of) an scientific article (RIVM). 4. Completing the analysis on links between chemical regulation and SSbD. We will finalise the current paper that we are working on (RIVM, EEA, UBA, JRC, AUTH, BNN, EMPA, UNINA) • Continued discussion and interaction with industry (RIVM, AUTH, EMPA, IVL, Unina, IUSS). A two-way communication with potential users through software development ensures that the innovation context and user needs are accurately captured, while garnering wider acceptance for SSbD framework and toolbox. Through implementing a bespoke interview and focus group approach, we have arrived DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 144 Big Data Analytics (AUTH, IRFM, NKUA, UMU, INSERM). The framework will include suitable models for predicting exposure and hazard AUTH, NKUA, IISPV, UMU). It will also include the automatic retrieval of exposure from high-resolution mass spectrometry data that will be achieved through API link with Digital Sample Freezing Platform (NKUA, SLU, AUTH, UMU). Moreover, efforts will be put towards the early detection of signals. A key source of information for early detection of potentially emerging chemicals is patent data. Methodologies to collect and analyze patent data will be tested and developed (UMU). The activity also aims at reading and translating chemical structure information embedded in patent data to function in fate and hazard model platforms (UMU). Another activity is the design of a new predictive model based on a methodology previously developed by INSERM, which has been experimentally validated. This method is to be updated and adjusted for the use in EWS, such as prediction of putative effects of chemicals on human health. In Y4, INSERM aims to develop a prototype. The framework and individual model components of the computational framework of the EWS will be tested and further developed using case studies (all partners). These are planned to apply data from the experimental case studies of WP8.2 but also using data from 4.2 or literature data. Further improvements of the existing components for chemical RA in the context of EWS will continue by translating the needs of the identification framework (AUTH, NKUA, UMU), as well as from the experience gained from the previous and ongoing case studies within Task 8.2. Case studies will enable testing of the pilot system and further improvement (AUTH, NKUA, UMU, AU, SLU). Additional efforts for integrating models developed in other work packages of PARC including WP6 and methods to include NTS data (NKUA, AU, SLU) steamed from WP4. Additional input for the needs of the computational platform will come from stakeholder input and requests and the respective interaction forum will continue to operate (UMU, IVL), so as to align with current and coming legislation to ensure the applicability of the EWS and that the output can be effectively used. This will be evaluated using the output of pilot studies (IVL). The stakeholder questionnaire that was devised during Y3 will be sent out and the results evaluated to ensure that the EWS is aligned with the stakeholders' needs and the decided EU EWS (IVL, EFET, AUTH, OVAM, SLU, SEPA). Work with continue with guidance for the evaluation of signals within the EWS (IVL, AUTH, UBA, NKUA, AU). Task 8.3 Integrative models Co-Leaders: WR (NL), AUTH (EL) Partners: ANSES (FR), INERIS (FR), ISSeP (BE), MU (CZ), DTU (DK), SYKE (FI), TTL (FI), IRFM (IT), IUSS (IT), UL-LACDR (NL), WU-TOX (NL), NIVA (NO), NMBU (NO), NIC (SI), IISPV (ES), INSST (ES), UU (SE), UOC (EL) A.8.3.1: Design, implementation and application of the PARC integrative model network In year 4 development of the model network will concentrate on two key actions as detailed in D8.3 and AD8.4 to implement user-friendly and transparent (PARC) workflows for integrative RA. First, the general framework for integrating models in workflows will be applied and evaluated (AUTH, WR, IISPV, UU, NIVA, MU). Second, model improvements and connections between models will be developed or refined, addressing specific case study needs (AUTH, WR, ANSES, INERIS, ISSeP, MU, DTU, SYKE, TTL, IRFM, IUSS, UL-LACDR, WU-TOX, NIVA, NMBU, NIC, IISPV, INSST, UU, UOC). On-line meetings foreseen in Y4: bi-weekly core group meetings (AUTH, WR), 4-6 x T8.3 plenary meetings possibly one in person (all partners), bilateral meetings between partners. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 145 More specifically, the first action involves applying the general framework for model integration to case studies (WR, AUTH, ANSES, NIVA, IISPV, UU). This approach will outline for each case study the key entities for model linkage, map and align relevant data and modeling tools, and identify options for connecting these into workflows. The framework will be updated iteratively to address any identified gaps. Additionally, the development of a framework for FAIR PBK modeling will continue (WR, INERIS, IISPV, AUTH, NIVA). The evaluation and enhancement of the generic framework will incorporate (user) requirements from various PARC WPs (main links: T6.2 (and its connection with EFSA), WP7, T8.1), and the Task 8.3 case study on bisphenols (see below). Input on (future) PARC model network requirements will also follow from collaboration with WP2 (AUTH). The inventory of models/tools within the PARC model network will be updated based on these developments. This will be achieved by direct participation in T8.3 (ANSES, INERIS, ISSeP, MU, DTU, SYKE, TTL, IRFM, IUSS, UL-LACDR, WU-TOX, NIVA, NMBU, NIC, IISPV, INSST, UU, UOC) or by links with other PARC projects (AUTH, WR, ANSES, VITO). A first prototype for a general interface / access point to the model network via the inventory will be developed (AUTH, WR). Additionally, integration of the model inventory with the PARC data hub from WP7 will continue to be explored (MU, WR). The development of the PARC integrative model network will continue through the implementation and refinement of workflows in the case studies. The case studies guide the implementation of the necessary model improvements and links and validation of the model network. Human and environmental-relevant workflows will connect models across various domains, including aggregate and cumulative exposure assessment (WR, AUTH, ANSES, NIVA), HBM analysis (AUTH, WR, MU, ANSES), development and use of PBK models (AUTH, WR, INERIS, IISPV, IUSS, ANSES, MU, NIVA), QSAR models (IRFM), hazard characterization (IUSS, UL-LACDR, IRFM, WR, NIVA), RA (WR, AUTH, NIVA), EBD (WR, ANSES, VITO), and uncertainty analysis (MU, WR, IISPV, NIVA). In this process model platforms such as INTEGRA (AUTH), MCRA (WR), RSExpo (ANSES), VEGAHUB (IRFM) and STOP (NIVA) will be further refined and interconnected with other tools (and each other) to enhance coverage of important regulatory domains in chemical RA. Additionally, model harmonization efforts (in association with WP7) will be evaluated and updated. The main case studies currently in view are the bisphenols case study in this activity (lead from T8.3: AUTH), case studies in T6.2 (lead from T8.3: WR), T6.4.2 on Environmental exposure, hazard and RA (NIVA), the VEGA-MCRA case study (lead by IRFM), and a case study on uncertainty in PFAS exposure modeling from T7.3.2 (lead from T8.3: MU). Efforts for harmonization of the workflows within these case studies will be initiated. The case study on human integrative RA supporting T6.2 will continue (T8.3 lead: WR; partners: ANSES, INERIS, VITO). The workflow for HBM-based mixture RA in MCRA will be refined based on methodological developments and requirements in T6.2.3 (real-life mixtures) and will support assessing mixtures of PFASs, pesticides and metals by T6.2.3 users. Depending on T6.2.3 developments, integration of environmental monitoring data (T4.2) will be explored (WR, VITO). Connections will be made between the HBM-based mixture RA workflow and those developed in T6.2.1 and T6.2.2, for example to compare modelled (external) exposures to HBM measurements (WR, ANSES, VITO). Integration of FAIR PBK models in MCRA will be improved, and PBK models selected in T6.2 will be linked (WR, ANSES, VITO, INERIS). Work linked to T6.2.1 will focus on maintaining and improving MCRA’s connections to other models for aggregating exposures (WR, ANSES, VITO), considering data import or complete model DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 146 integration options (WR). Models from the RSExpo tool (ANSES) are being evaluated for integration (WR, ANSES), with a proof-of-principle for PFOA and Cadmium planned (ANSES). Additionally, linking to project 6.2.1.a, integration of source-to-dose models in the network will be explored (VITO, WR). Linking EBD methods to MCRA will be extended in collaboration with T6.2.4 (WR, ANSES, VITO). Finally, presentation of results to external stakeholders, such as through a dashboard, will be explored (WR, ANSES). The case study of bisphenols (BPA and BPA alternatives) in A.8.3.1 will continue in Y4 (T8.3 lead: AUTH) with the collection of relevant data started in Y2 (AUTH). Additional data outside PARC and HBM4EU will also be included in order expand the chemical space of bisphenols, as well as alternative (AUTH, IUSS, UoC). Exposure reconstruction is also under further development, so as to improve the respective algorithm available in the INTEGRA model, which is part of the PARC model network (AUTH). Significant efforts will also focus on developing modules to integrate NAMs, facilitating the use of read-across approaches in collaboration with T5.3.1, as well as incorporating quantitative AOPs (qAOPs) to model toxicodynamics, linking MIEs to downstream key events (AUTH, UL-LACDR, WU-TOX, IUSS, NIVA). The case study on uncertainty in PFAS exposure modeling from T7.3.2 will conclude in Y4, with finalization of all related activities (MU, WR). The development of uncertainty assessment methods for the case study will continue, followed by the integration of uncertainty analysis and implementation of the workflow into MCRA, accompanied by relevant guidance. This guidance should have the potential for broader application across various PBK models and compounds. Optionally, the PFAS PBPK model and PFAS occurrence dataset could also be incorporated into MCRA. In the final phase, the case study will expand the uncertainty analysis to encompass broader model networks, investigating how uncertainty propagates between domains and how this can be quantified and assessed throughout the data flow across domains (MU). The process already started with the development of a review that outlines uncertainty analysis approaches across model network domains. Based on this document, a comprehensive strategy and guidance for uncertainty analysis across domains—focusing on uncertainty propagation in workflows involving multiple linked models—will be developed. The VEGA-MCRA case study will continue in Y4 with the goal to perform a cumulative RA on CAGs (IRFM, WR). VEGA supports the hazard identification, covering a wide range of (eco)toxicological endpoints. New models will be applied to improve the assessment of the endocrine disruptors. We will also identify a AOP network applicable for this case study (IRFM). The integrated environmental case study for cumulative RA will continue in Y4, in T5.2, T6.4.2, T7.2 and T7.3 (NIVA), exploiting data-rich exposure data sets from selected national monitoring programs (T6.4.2), developing multi-species hazard assessments predictions (T5.2 and T6.4.2) from available (eco)toxicity sets (Ecotox db, Toxcast, available predicted no-effect concentration and environmental quality standard threshold values etc.), expanding QSAR estimates to a broader set of (eco)toxicological endpoints (IRFM), incorporating AOP/quantitative AOP information (T5.2), exploring uncertainty analysis (T7.3, NIVA), incorporating ecological-relevant PBPK models (NIVA) and supporting better linkage between human and environmental models for aggregate exposure pathways (NIVA, WR). We will initiate a new case study (AI-SERVE) for FAIR serving of resource-demanding AI models based on SciLifeLab Serve (Lead: UU), jointly with uncertainty modeling (T7.3) and demonstrated on image-based in vitro data for NAM generated in T5.2.1e (DNT) and T5.2.1b (MD). Serving of PBPK models will be explored. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 147 Deliverables: D8.5 1st Report on the testing and operability, uptake and impact of the PARC EWS – Leader: INSERM initially planned M36 was postponed M48. This will be included in the next amendment of the GA. D8.7 Advancing SSbD Implementation: Uptake, Testing and Integration of the PARC Toolbox through Case Studies, Stakeholder Engagement and Knowledge Sharing – Leader: EMPA (M48) (Given the feedback from HADEA—which highlights the need to better reflect the richness and breadth of WP8 activities beyond just the testing of the toolbox—a more comprehensive and representative title for Deliverable D8.7 has been proposed. This will be included in the next amendment of the GA Additional Deliverables: NA WP N° WP9 Lead Beneficiary ISCIII/MU WP title Building infrastructural and human capacities Partner N° 1 1.1 1.2 1.4 1.7 1.10 1.11 2 3.8 3.9 4.6 5 6.1 8 8.2 10.1 14.4 15 17 20.3 21 22 Partner short name ANSES INSERM INRAE INERIS ONIRIS BRGM LNE SpF UMIT UNIVIE ISSeP SCIENSANO IMROH MU VSCHT AU UEF UBA NCPHP IRFM RSU NPHSL PM/partner 0.9 3.0 2.2 0.1 1.4 3.8 3.6 3.0 1.0 4.6 3.7 5.1 1.0 44.3 3.9 5.0 1.0 3.1 3.0 0.4 0.4 8.9 Partner N° 24 25.7 26 26.2 26.7 28 29 29.3 29.5 30 30.1 31 31.4 32 33 34 34.2 34.4 35.2 36 36.2 37 50 Partner short name LNS WR NIPH STAMI UNN FMUL INSA ENSP UAVR SZU-SK UK JSI UL FFA NIJZ CSIC ISCIII FISABIO FNS KI AUTH GCSL BPI UKHSA PM/partne r 8.2 6.0 1.9 5.1 1.1 4.5 16.5 3.0 2.8 1.3 1.2 3.3 1.0 2.5 17.8 31.4 2.0 3.2 2.0 3.2 3.1 3.7 1.0 Start M37 End M48 Objectives The overall goal of WP9 is to further develop human capacities and existing and new infrastructures related to laboratory and monitoring networks including reference laboratories, join activities and exposure monitoring networks and databases. The specific objectives of WP9 for year 4 are: Task 9.1: Laboratory networking DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 148 o Collaborate with T7.2 and T9.2 on developing the interactive platform presenting catalogues of laboratories and other relevant information collected in T9.1 and 9.2 o Keep the catalogues created on exposure laboratories up to date o Extend the catalogues to include additional laboratory networks (Y4 priority fields: soil and sediment, food and feed, (eco)toxicological and articles/consumer products, and finish the ongoing air and water) o Detect needs for laboratory network strengthening and promotion o Define tools to promote and coordinate laboratory networks and start with their implementation o Include the information of laboratories from air and water on the laboratory interactive map on the PARC website. o Include the information of laboratories from different fields on the laboratory network dashboard within the PARC data Hub Task 9.2: Building exposure monitoring capacities o Collaborate with T7.2 and T9.1 on developing the interactive platform presenting catalogues of HBM studies, cohorts, environmental projects, networks and other relevant information collected in T9.1 and 9.2 o Continue with the inventory of environmental contamination resources (Y3 priority: water and sediment monitoring networks and projects, indoor studies and consumer products data) o Collaborate with relevant WPs and Tasks to collect information on and outcomes of the ongoing surveys o In collaboration with T7.2 and relevant WPs contribute to the development of the harmonised templates for future surveys o Interact with other WPs to identify the needs for future catalogues (toxicology, models etc.). Task 9.3: Joint activities – harmonisation o Disseminate guidances drafted in M36 (D9.4) to WP4 and WP5 o Collect feedback from WP4 and WP5 on 9.3 QA/QC guidances, their implementation, and needs for chemicals prioritized in second half of PARC o Align with and review project-specific WP4 and WP5 QA/QC activities Task 9.4: Training o In collaboration with training (scientific) coordinators, implement PARC training plan for Y4, as defined in AD9.1. o Provide the necessary logistical support to organizers of local training events. o Update PARC website to feature information on (external) existing training of potential interest to partners and stakeholders. Description of Programmed Activities Task 9.1: Laboratory networking DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 149 Leader: ISCIII (ES) A9.1.1 Identify existing laboratory networks, draw up and maintain up-to-date and active a database of the laboratory networks Partners: CSIC, SZU-SK, ANSES, AU, BPI, BRGM, FISABIO, FMUL, INERIS, INSA, ISCIII, LNE, MU, NIPH, NPHSL, SCIENSANO, STAMI, FINIBIC11, VSCHT, GCSL, RSU, UK, ONIRIS To update the networks already created (HBM, air and water) with new laboratories or updated information of those already included, or to collect data from any laboratory interested in joining the PARC networks, a communication channel is established through the PARC website. The search of laboratories working on the domain articles/consumer products started during Y3 in collaboration with WP6 will continue during Y4 and the catalogue will be created. Due to the low rate of response from water laboratories, the work to create this network was extended more than planned, trying to reach new laboratories in different ways (including the creation of a specific Water Working Group). In consequence, the work on the fields soil and sediment and food and feed, previously planned for Y3, has been postponed to Y4. The first catalogues will be available by M42. During Y4, the new strategies defined to expand the networks and to include new laboratories which started to be implemented in Y3 (including publications on social media, announcements in relevant conferences and congresses and contacts with the already existing networks) will continue. These have already proven effective but further evaluation will continue being carried out in order to identify measures that can increase the interest of laboratories. During Y3, the work on the identification of (eco)toxicological European resources started in collaboration with Task 9.2, using a survey. The obtained information on the laboratories working in this field and their capacities will be analyzed during Y4, and these results will be included in the two tools (interactive map and dashboard) on an ongoing basis. The information collected from the HBM laboratory network (including name, contact, country, substances and matrices analyzed) was translated into an interactive map in May 2024, developed by Task 3.2 and hosted on the PARC website. During the rest of Y3 the information and visualization was polished. The work to include new networks in the map has been foreseen for Y4, starting with air laboratory network and following with water field. A9.1.2 Promote the development of new laboratory networks and support their consolidation Partners: leaded by FISABIO with collaboration from INERIS, AU, BRGM, FMUL, INSA, ISCIII, MU, NPHSL, LNS, NIPH, SCIENSANO, ISSeP, FNS, VSCHT, GCSL, NMBU The list of criteria to identify the level of development, experience, extension, etc. of the networks was created during Y3, which will allow us to identify the weak points that need to be improved/developed to achieve better interaction among laboratories. During Y4, these points/criteria will be applied to the laboratory networks created, to establish their different level of development. The list will serve as a living document and will be updated alongside the gradual 11 AMD-101057014-118: The Spanish affiliated entity Fundación Profesor Novoa Santos - PARC acronym “FNS”, has changed its name to Fundación Pública Galega de Investigación Biomédica INIBIC (FINIBIC) as of 06/05/2024. The list of affiliated entities must be updated accordingly. The acronym FNS must be replaced by FINIBIC in the WP9 where they are contributors DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 150 creation of the networks. The analysis of the alternatives to the sustainability of the networks (out of research projects) will continue during Y4. A9.1.3 Facilitate the coordination and linkage of existing and new laboratory networks Partners: leaded by CSIC with collaboration from INERIS, BRGM, FMUL, INSA, LNE, MU, LNS, STAMI, ISCIII, ISSeP, FINIBIC, VSCHT, GCSL, NMBU Initial strategies and tools to achieve the coordination and linkage of the networks were defined during Y2 and Y3, however due to the process of laboratory network creation was longer than expected, no activities of coordination have been yet carried out. During Y4, the first activities will be implemented. A9.1.4 Develop an interactive tool (dashboard) to show the capacities of the laboratory networks The concept and design of the dashboard was established in Y2 in collaboration with Task 3.2, Task 7.2 and all the Task 9.1 partners. The PARC Data Hub is under development together with Task 7.2 and Task 9.2 and will show, during Y4, the information on the laboratory networks, including the laboratories integrating each network and their analytical capacities, among other information. This will be a very useful tool for users to search and find laboratories of interest by country, matrices or chemical substances analyzed, sample quantity, quantification limit, etc. The HBM laboratory network will be the first implemented on the dashboard. For the upcoming years, the dashboard will be continuously fed with updated information and new laboratory networks. Task 9.2: Building exposure monitoring capacities Leader: MU (CZ) A9.2.1 Mapping of exposure monitoring capacities Partners: ANSES, Inserm, Oniris, LNE, SpF, ISSeP, Sciensano, IMROH, MU, VSCHT, AU, NCPHP, NPHSL, LNS, UU-IRAS, STAMI, FMUL, INSA, ENSP, SZU-SK, CSIC, ISCIII, AUTH, BPI, GCSL Mapping of the existing biomonitoring and environmental exposure monitoring networks initiated in the first three years in close collaboration with WP 4.1 and 4.2 will continue in Y4 with indoor exposure mapping. Together with Task 7.2 and Task 9.1, first prototype of PARC Data Hub will be developed, drawing from the experience with the Power Bi tool presenting the outcomes of ongoing surveys. Specific attention will be paid to the harmonisation of parameters (such as biomarkers) collected across various surveys. Surveys mapping capacities (networks, projects, databases) on toxicology resources, initiated in Y3 will be further developed and updated. First visualisations of consumer product databases will be developed, in cooperation with WP6. A9.2.2 Strengthening of exposure monitoring capacities Partners: ANSES, LNE, SpF, ISSeP, Sciensano, IMROH, MU, VSCHT, AU, LNS, UU-IRAS, FMUL, INSA, ENSP, JSI, CSIC, ISCIII, GCSL DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 151 Joint development and update of PARC Data Hub with Task 9.1, Task 7.2 and relevant WP4 partners will provide new tools not only for presenting data on existing biomonitoring and environmental monitoring networks, laboratories and databases but for assessment of gaps and future needs. This will provide a base for better targeting of research initiatives in WP4 but also for setting priorities and development of surveys in other WPs. Task 9.3: Joint activities – harmonisation Leader: WR (NL) Partners: UNIVIE (AT), SCIENSANO (BE), MU (CZ), VSCHT (CZ), UBA (DE), RegionH (DK), AU (DK), CSIC (ES), ISCIII (ES), FINIBIC (ES), INRAE (FR), ANSES (FR), BRGM (FR), INERIS (FR), LNE (FR), ONIRIS (FR), BPI (GR), GCSL (GR), LNS (LU), NIPH (NO), UNN (NO), STAMI (NO), NMBU (NO), INSA (PT), JSI (SI), NLZOH (SI) Transversal activity: Towards harmonised QA/QC in laboratory testing This activity focuses on quantitative chemical analysis methods and toxicity assays. Suspectand non-target screening and bioanalytical assays are dealt with in T4.3. In Y1-3 inventories on existing QA/QC regarding sampling, chemical analysis, and toxicity testing/toxicokinetics studies were done. Subsequently, five working groups (see below) drafted the first guidance documents with minimum requirements on various QA/QC parameters focussing on sample types and substances/techniques prioritised/used in WP4 and WP5 in the first half of PARC. In Y4 the guidance documents will be disseminated in WP4 and WP5, through the relevant taskand project leaders, through PARC internal laboratory contact lists, and to the wider community/stakeholders via the PARC website and/or PARCopedia. Online meetings will be held for project leads and people responsible for QA/QC in WP4 and WP5 to discuss the guidances for their implementation, and to collect feedback and needs. This will be used to initiate revision and extension of the guidance documents. Further 9.3 online meetings foreseen in Y4: core group (WG co-leads) 2-3x, WG meetings (4-10 per WG), and T9.3 plenary 1-2x, of which one in person. Working groups and contributors: WG-1: Overarching QA/QC working group on Sampling. Includes: fit-for-purpose sampling, passive sampling, pretreatment, storage/stability, artifacts, uncertainty. Lead: AU, LNE. Partners: ANSESLSAI PCPPA, ONIRIS, INERIS, BRGM, LNE, Sciensano, MU, AU, LNS, STAMI, NMBU, UNN, INSA, JSI, CSIC, ISCIII, FINIBIC, BPI. WG-2: Overarching QA/QC working group on Performance criteria chemical analysis. Includes: limit of detection and quantification (LOD/LOQ), identification, trueness/precision criteria, calibration, validation, batch control, measurement uncertainty. Lead: MU. Partners: ANSES, INRAE, ONIRIS, INERIS, BRGM, LNE, UNIVIE, Sciensano, MU, VSCHT, RegionH, UBA, LNS, WR, NIPH, STAMI, NMBU, UNN, INSA, JSI, BPI, GCSL. WG-3: Overarching QA/QC working group on Assessment of interlab comparability chemical analysis. Includes: (evaluation of) protocols for proficiency testing (PT/ICI/EQUAS), small-scale interlab comparisons, catalogue for PT providers, catalogue (C)RMs. Lead: ANSES, LNE. Partners: DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 152 ANSES, ONIRIS, INERIS, BRGM, LNE, Sciensano, MU, VSCHT, UBA, LNS, WR, NIPH, INSA, JSI, CSIC, ISCIII, BPI, GCSL. WG-4: Overarching QA/QC working group on Reporting and acceptability of results from chemical analysis. Includes: reporting requirements, normalisation or results, acceptability of lab data, criteria for qualification of labs. Lead: ONIRIS, LNS. Partners: ANSES, INRAE, ONIRIS, INERIS, BRGM, LNE, UNIVIE, Sciensano, MU, VSCHT, AU, UBA, LNS, WR, NIPH, NMBU, INSA, JSI, CSIC, BPI, GCSL. WG-5: QA/QC EDA, moved from T9.3 to T4.3 WG-6: Overarching QA/QC working group on Toxicity testing & kinetic studies. Includes: in vivo and in vitro test systems (novel approach methods, NAMs), reporting. Lead: NIPH, STAMI. Partners: ANSES, INERIS, Sciensano, LNS, WR, NIPH, STAMI, NMBU, INSA, FINIBIC. Task 9.4: Training Leader: INSA (PT) Partners: ANSES (FR), INRAE (FR), ONIRIS (FR), BRGM (FR), LNE (FR), UMIT (AT), Sciensano (BE), MU (CZ), VSCHT (CZ), IRFM (IT), RSU (LV), NPHSL (LT), LNS (LU), STAMI (NO), NMBU (NO), ENSP (PT), UAVR (PT), JSI (SI), ULFFA (SI), NIJZ (SI), CSIC (ES), ISCIII (ES), FINIBIC (ES), IMM-KI (SE), BPI (GR), GCSL (GR), UEF (FI) In order to achieve a flexible and dynamic training plan, adjusted to PARC progress and stakeholder needs, by Y4, Task 9.4 will again request to NHCs the distribution of 2nd training needs online survey (refined on the basis of the results obtained in the 1st survey) to all NH members (PARC and beyond). Data obtained will be thoroughly analysed by partners under the coordination of NPHSL (LT) and INSA (PT) and used to build the 2nd PARC Training Plan (AD9.2, to be submitted by M42, Oct 2025), that will cover M43 to M66 (Nov 2025 to Oct 2027). Up to October 2025, Task 9.4 will continue the implementation of the 1st PARC training plan (AD9.1), developed to cover the topics identified by partners and stakeholders. This includes two in-person training courses (1. New approach methodologies; and 2. AOPs and IATAs) carried out under the scientific coordination of MU, CZ and KI, SE, respectively, and aimed at both PARC partners and stakeholders The local organizers of training events to be carried out under PARC will receive support from Task 9.4 members, covering dissemination, registration, preparation and distribution of certificates, preparation, distribution of training evaluation surveys, and training evaluation assessment (activity coordinated by NIJZ, SI).Task 9.4 partners will also develop additional highquality e-learning materials on topics identified for non-formal learning, upon partner availability and potential synergies emerging under SYNET to ensure continuous innovation. To foster on the job training, Task 9.4 partners will continue to encourage staff exchange amongst PARC partners. A close follow-up of this activity will be carried out to ensure proper dissemination of the initiative, and new strategies will be implemented in case of need. In parallel, task partners will continue to work on the identification of external training (outside PARC), namely events and online resources on relevant topics under the coordination of UAVR (PT); all events/materials found relevant will be indicated on PARC website. DELIVERABLE D1.10 P-A-R-C HORIZION-HLTH-2021-ENVLTH-03 CONTRACT N. 101057014 153 A summary of all training activities carried out from M30 to M42 will be presented and discussed in D9.9, Report on training activities M30 to M42, to be submitted by M45. Deliverables: D9.9: Report on training events Y3, initially due M36 is modified in “Report on training activities M30 to M42” and is postponed to M45 (leader: INSA) in order to describe all activities from M30 to M42 (end of PARC 1st training plan). This modification will be included in the next amendment of the GA D9.10: Report on training events Y4, initially due M48 is cancelled. This will be included in the next amendment of the GA. Additional Deliverables: AD9.2: Training plan, version 2 - Leader: INSA (M42) Table 2.2.b: AWP Set of Activities Activity No Activity Title Lead Participant No Short name of lead participant PersonMonths Start Month End month 1 Coordination and management 1 ANSES 239.0 37 48 2 A common science-policy agenda 3/12 EAA/EEA 190.5 37 48 3 Synergies, collaborations and awareness 29/36.2 INSA/GCSL 189.9 37 48 4 Monitoring and exposure 15/2 UBA/SpF 1 461.7 37 48 5 Hazard Assessment 16/1 BfR/ANSES 1 769.0 37 48 6 Innovation in regulatory RA 25/35.7 RIVM/KEMI 1 241.3 37 48 7 FAIR Data 4/59 VITO/UOB 310.4 37 48 8 Concepts and toolboxes 36/20.6 AUTH/UNINA 194.0 37 48 9 Building infrastructural and human capacities 34/8 ISCIII/MU 229.0 37 48 TOTAL 5 824.8 PARC – ANNEX I AWPY4 – page 255 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.10 AWPY4 including PARC Project Portfolio MTM (SE), SLU (SE), UAntwerpen (BE), JSI (SI), KWR (NL), UniLU (LU), VUA (NL), ISS (SP), INERIS (FR), BfG (DE), UL-FFA (SI), BRGM (FR), WULS-SGGW (PL), JU (CZ), MU (CZ), INRAE (FR), OFB (FR), UL (PL), VITO (BE) Schedule: Starting date: 01/05/2022 (M1) Expected ending date: 30/04/2026 (M48) Costs Expected PM for the fourth year of the project: 9 PM Expected ODC for the fourth year of the project: 1 625 € P4.3.3.b_Y2_EO2-Sentinel animals_ONIRIS Project Title Proof-of-concept of innovative sampling and HRMS based / EDA screening methods for exploring chemicals of emerging concern in sentinel animal species Project Acronym (15 letters max) Sentinel animals Project Manager Ronan CARIOU [email protected] ONIRIS FR Deputy Project manager Gaud DERVILLY [email protected] ONIRIS FR Expected starting date PARC (Month number) 13 Expected duration 48 PARC Workpackage number P4 PARC Task/Activity/Subactivity: 4.3.3 Project Id P4.3.3.b_Y2_E02-Sentinel animals_ONIRIS Status: Implementation Summary of the project: Capturing the complex real chemical exposure of human and/or in the environment requires new conceptual frameworks and innovative methodological approaches: SS/NTS based on HRMS coupled to EDA are a promising trend developed within PARC T4.3 in that purpose. Within the One Health concept, animal sentinel species can serve as a source of useful information with respect to both human exposure to chemical hazards through the food chain and ecotoxicological considerations related to the environment. Species with bioaccumulation capacities especially appears of interest for SS/NTS screening of chemicals based on higher concentration levels than those observed in human biological matrices. Selected species will cover marine and terrestrial environments. Candidate species are marine mammals, molluscs, gulls, pigeons, raptors and bees. The sample sourcing of such sentinel species also stands as less laborious compared to human matrices, especially if already available in a specimen bank. The aim of this project is to develop and conduct a proof-of-concept permitting to assess then relevance of animal sentinel species upon applying those innovative methods, as complementary to conventional and targeted approaches. It will feed the EWS on CEC, the end-users being the food and environment policy makers. Main expected outputs of the project: ∙ Documented advantages/limitations of innovative approaches compared to conventional ones ∙ Scientifically supported prioritisation of some animal species for short term implementation ∙ Paved way for further developments/improvements needed for long term implementation ∙ Documentation of real-life mixtures associated to environmental health and human food chain PARC – ANNEX I AWPY4 – page 256 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.10 AWPY4 including PARC Project Portfolio ∙ Prioritization of further targeted developments focused on particular exposure markers evidenced ∙ Contribution to feed EWS through an established link between tasks 4.3 and 8.2 ∙ General food law and environment policy makers aware of the main findings Outcomes and impacts expected on end-users and stakeholders: The proposed project appears as a pre-required methodological development activity, expected to provide eventually a list of exposure markers pinpointing potential CEC. This perspective should benefit a number of end-users including laboratories aiming to implement those new analytical approaches (capacity building), as well as actors aiming to build and use EWSs for which the expected new exposure data generation capabilities will represent a significant input. Policies related to the human food chain are a first target. It includes the general food law (Reg 178/2002), as well as the recently revised official control regulation (Reg 2017/625) and other regulations for business operators (Reg183/2005 Reg 852/2004, Reg 853/2004). For example, EFSA recently noted in its opinion on PFASs (doi: 10.2903/j.efsa.2020.6223) that a representative set of occurrence data are still lacking for many foods and, therefore, recommended to gather such data for a wide range PFASs in a broad range of widely consumed foods. Consequently, it is advised in the Commission Recommendation 2022/1431 that Member States should also consider testing for the presence in food of emerging PFASs, in addition to the 4+18 cited. Policies related to the environmental aspects are another target. It includes the Marine Strategy Framework Directive (Dir 2008/56/EC) in which Qualitative descriptors for determining good environmental status n°8 and n°9 deal with contaminants giving rise to pollution or concern for human consumption. Such approach is also about to be extended to terrestrial environments according to a current proposal for a Nature Restoration Law. Key words: Sentinel species, human food chain, environmental health, innovative methods, suspect screening, nontargeted screening, effect-directed analysis, real-life mixtures, emerging chemicals Link to the PARC DoA: The project responds to the PARC OOs OO3, OO5, OO7, OO8 and OO12. Conventional sampling and targeted quantitative analytical methods are already available to support environmental, food and human monitoring, RA/RM decisions. However, these approaches sometimes suffer from a lack of sensitivity to characterize lowest exposed populations, face some limitations for largescale implementation, and only capture a limited number of a priori known and selected markers of exposure. Developing a proof-of-concept for illustrating the capacities of SS/NTS/EDA approaches in the particular case of sentinel animal species is directly connected to task 4.3 DoA, in particular with regard to fostering collaboration of environmental, food safety and HBM communities. Links within PARC (WPs/Tasks/Activities/Projects) (between 2-8 lines): WP4: 4.1: Check Human internal exposure to highlighted exposure markers 4.2/4.2.2/P4.2.a_Y1_ENVMonitoringPilotSurvey_INERIS_AU: Mutualized resources 4.3/4.3.1/P4.3.1.a_Y1_T01_Concept Paper_MU: Alignment of objectives / purposes of SS/NTS/EDA 4.3/4.3.1/P4.3.1.b_Y1_T02_QA/QC Issues_WR: Ensure quality of the generated data 4.3/4.3.1/P4.3.1.c_Y1_T03_Early Warning System_SLU: Ensure useful output for EWS 4.3/4.3.1/P4.3.1.d_Y1_T04_Data Processing Worflow_EHESP: Support annotation of generated data WP6: Potential use of some of the generated new exposure data from SS/NTS/EDA for mixture modelling WP7: Definition of specific requirements for SS/NTS/EDA data management (retrospective use, repository…) WP8: Potential use of some of the generated new exposure data from SS/NTS/EDA for EWS Links outside PARC: Tight connexions with the NORMAN network and LIFE APEX consortium for taking advantage of existing PARC – ANNEX I AWPY4 – page 257 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.10 AWPY4 including PARC Project Portfolio tools developed for monitoring the environment and top food chain biota, respectively. It includes sample handling, QA/QC procedures and highly visible data repositories. There will be discussion with biodiversa + on possible collaboration. Key PARC Deliverables (or Additional Deliverables) and Milestones to which the project contributes D4.14. Final report on the application of new exposure assessment approaches (i.e. from sampling to data interpretation) to support regulatory needs (i.e. lessons learnt and conclusions/perspective for sustainable follow-up) (M81). Partners list: ONIRIS (FR), ANSES (FR), AU (DK), BfR (DE), EAWAG (CH), CSIC (SP), INRAE (FR), JSI (SI), JU (CZ), OFB (FR), ORU-MTM (SE), SU (SE), UFZ (DE), UG-AT (AT), VUA (NL). Schedule: Starting date: 01/05/2023 (M13) Expected ending date: 30/04/2027 (M60) Costs Expected PM for the third year of the project : 36 PM Expected ODC for the third year of the project : 74 479 € A4.3.4 Food samples based proof-of-concepts – 1 PROJECT P4.3.4.a_Y2_F02Food items exposure _ANSES Project Title Complementary developments regarding the application of HRMS based/EDA screening methods on food samples Project Acronym (15 letters max) F02-Food items exposure Project Manager Julien Parinet [email protected] ANSES France Deputy Project manager Sophie Mompelat [email protected] ANSES France Expected starting date PARC (Month number) 13 Expected duration 36 PARC Workpackage number 4 PARC Task/Activity/Subactivity: 4.3.4 Project Id P4.3.4.a_Y2_F02Food items exposure_ANSES Status: Implementation Summary of the project: Innovative approaches such as SS/NTS based on HRMS, and EDA combined with HRMS, represent a revolution in the field of monitoring chemicals present or potentially present in food, allowing to cover a much larger chemical range than the approaches used until now (low resolution) in the regulatory field. However, the application of these innovative approaches in food is still limited. In addition, the performances of SS/NTS/EDA approaches need to be better assessed in order to be adapted to a regulatory context and harmonisation. This project aims to develop and to qualitatively and quantitatively compare various analytical strategies and workflows (from food sample preparation to data acquisition and data processing) in order to identify their complementarities or overlap in terms of captured exposure markers (known, emerging and unknown chemicals) in food. A preliminary step will consist in the selection of specific food items related to particular risk situations for both general and particularly vulnerable populations (e.g. infant food), as highlighted by EFSA as a major issue for RA. The aim of this project is to develop and conduct a proof-of-concept permitting to assess the relevance of the implementation of such PARC – ANNEX I AWPY4 – page 258 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.10 AWPY4 including PARC Project Portfolio developed screening methods as part of the monitoring and control plans. This would allow to identify original contaminant mixtures from field data. The longitudinal follow-up of the data generated by these means would also allow highlighting both emergences (unregulated substances) and misuses (regulated substances). It will feed and help to structure the EWS on CEC, the end-users being the food policy makers. Main expected outputs of the project: ▪ Characterization of advantages/limitations of innovative approaches compared to conventional ones through the evaluation of the chemical coverage potential of different SS/NTS/EDA methods ▪ Qualitative and quantitative assessment of the performances of the developed SS/NTS/EDA methods in order to implement one or more methods that will cover the largest possible chemical range and thus limit the failure to detect hazardous substances potentially present in a sample ▪ Definition of the needs for further developments/improvements for long-term implementation ▪ Generation of FAIR data to support the monitoring of real-life mixtures, and especially to support the exposure assessment of vulnerable population groups (e.g. children) ▪ Contribution to feed EWS through an established link between tasks 4.3 and 8.2 ▪ Awareness of general food law policy makers regarding key findings of the project and the data generated Outcomes and impacts expected on end-users and stakeholders: By providing a clearer picture of the complementarity and performances of the methods compared in this project, the project should open the door to the integration of new innovative methods and tools needed for a more exhaustive monitoring for end-users, including the laboratories in charge of implementing control methods. Actors from the EWSs will also benefit from the innovative methods capabilities to generate external exposure data. The production of field data through the application of these new tools will allow risk assessors and risk managers to have a broader view of the real-life chemical mixtures to which consumers are exposed. This will provide scientific data for guiding further toxicological studies and hence support the paradigm shift in RA of these chemical mixtures. Policies related to the human food chain are a first target. It includes the general food law (Reg 178/2002), and official control regulation (Reg 2017/625) as well as specific food laws such as Regulation (EC) No 1881/2006, Regulation (EC) No 396/2005, Regulation (EC) No 1935/2004. Key words: Monitoring, food, innovative methods, suspect screening, non-targeted screening, effect-directed analysis, real-life mixtures, emerging chemicals Link to the PARC DoA: The project responds to the PARC OOs OO1, OO2, OO3, OO4, OO6, OO8, OO10, OO11 and OO13. Food monitoring is supported by the use of targeted analytical methods focusing on a selection of a relatively limited number of chemicals, compared to the number and diversity of chemicals constantly appearing on the market. The development of new and innovative analytical approaches is needed to support and renew the monitoring of the actual complex chemical mixtures in food to which consumers are exposed. The improvement and provision of new methods and tools is therefore a prerequisite to meet the need, formulated by European agencies (including EFSA) and in the EC Roadmap for the CSS, for a paradigm shift in exposure/RA and the establishment of an EWS. This project aims to contribute to the fulfilment of these needs as expressed in the PARC's objectives and DoA. Links within PARC (WPs/Tasks/Activities/Projects): WP4: 4.3/4.3.1/P4.3.1.a_Y1_T01_Concept Paper_MU: Alignment of objectives / purposes of SS/NTS/EDA 4.3/4.3.1/P4.3.1.b_Y1_T02_QA/QC Issues_WR: Ensure quality of the generated data 4.3/4.3.1/P4.3.1.c_Y1_T03_Early Warning System_SLU: Ensure useful output for EWS 4.3/4.3.1/P4.3.1.d_Y1_T04_Data Processing Worflow_EHESP: Support annotation of generated data 4.3/4.3.1/P4.3.2.b_Y2_E02_Sentinel animals_ONIRIS: Mutualized resources / harmonization PARC – ANNEX I AWPY4 – page 259 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.10 AWPY4 including PARC Project Portfolio WP6: Potential use of some of the generated new exposure data from SS/NTS/EDA for mixture modelling WP7: Definition of specific requirements for SS/NTS/EDA data management (retrospective use, repository…) WP8: Potential use of some of the generated new exposure data from SS/NTS/EDA for EWS WP9: Contribution to harmonised QA/QC and training for SS/NTS/EDA approaches Links outside PARC: In order to carry out the project, it would be preferable to capitalize on the projects already initiated by the partners in the margin of PARC. As such, there will be links between this task and French TDS3, ANR AlimOmic, PhD Emergexpo, PhDs and other projects conducted by the contributing partners. Key PARC Deliverables (or Additional Deliverables) and Milestones to which the project contributes D4.10. 3rd Proof-of-concept assessing the usefulness of innovative (self-) sampling combined with integrated suspect/NTS/EDA approaches (M60) Partners list: ANSES (FR), INRAE (FR), VUA (NL), BfG (DE), CEA (FR), CNRS (FR), EAWAG (CH), CSIC (SP), ISS (IT), JSI (SI), MUI (AT), Oniris (FR), SLU (SE), UAntwerpen (BE), UL-FFA (SL), VSCHT (CZ), WR (NL), WULS (PL), EV-ILVO (BEL), GCSL (GR). Schedule: Starting date: 01/05/2023 (M13) Expected ending date: 30/04/2026 (M48) Costs Expected PM for the third year of the project : 44 PM Expected ODC for the third year of the project : 262 119 € PARC – ANNEX I AWPY4 – page 260 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.10 AWPY4 including PARC Project Portfolio WP5 Hazard Assessment - 20 PROJECTS The overall goal of WP5 is to overcome the major challenges in hazard assessment (HA) for human and environmental health. The specific objectives are: a) to close data gaps identified by key stakeholders; b) to improve the current hazard characterisation paradigm by establishing comprehensive testing strategies, thereby promoting the availability and applicability of NAMs in RA; c) to contribute to the improvement of mechanistic understanding of toxicity by analysing all available data and applying systems toxicology approaches and taking into account AOPs and to improve modelling approaches such as PBPK modelling. The work envisaged is divided into three tasks: T5.1, T5.2 and T5.3 Fig 7: WP5 contribution: Hazard assessment T5.1 Toxicity testing addressing data gaps of concern 6 PROJECTS This task aims to investigate and close existing data gaps through toxicity testing. The following groups of substances have been selected for the first round of testing: natural toxins, in particular the mycotoxins enniatins and those derived from Alternaria -their presence in food products is of concern-, as well as alternatives to Bisphenol A (BPA). Activities on toxins will address existing data gaps left open by regulatory data requirements, such as toxicokinetics data or comprehensive studies like the Extended OneGeneration Reproductive Toxicity study (OECD 2018a). The latter study is also envisaged for other groups of substances of concern, which may include synthetic contaminants such as BPA alternatives/analogues not assessed by industry for authorisation or PFAS (perand polyfluoroalkyl substances). A5.1.1 Closing data gaps of concern for human health – 4 PROJECTS P5.1.1.a_Y1_Toxins_BfR_UNIVIE Project Title Hazard identification and hazard characterisation of the mycotoxins enniatins and Alternaria toxins in order to close data gaps and improve risk assessment for human health Project Acronym (15 letters max) Toxins Project Manager Doris Marko [email protected].at UNIVIE Austria Project manager Anne-Cathrin Behr BfR Germany PARC – ANNEX I AWPY4 – page 261 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.10 AWPY4 including PARC Project Portfolio [email protected] Expected starting date PARC (Month number) 1 Expected duration 48* PARC Workpackage number 5 PARC Task/Activity/Su b-activity: 5.1.1 Project Id P5.1.1.a_Y1_Toxins_BfR_UNIVIE *The project has been extended from M36 to M48 Status: Implementation Summary of the project Natural toxins have no manufacturer or supplier that is responsible for providing hazard data. Due to climate changes, the human exposure to natural toxins will likely increase and regulatory agencies have asked for more hazard data to improve the RA. This will ultimately result in recommendations on which natural toxins should be closely monitored in food feed and food products (Regulation (EC) No 1881/2006) in order to prevent adverse human health effects and setting maximum levels in food and feed based on knowledge. For example, EFSA’s Contaminants in the Food Chain (CONTAM) Panel stated that there might be a health concern regarding chronic exposure to the natural toxin enniatins however there is insufficient data to assess the risk on chronic exposure 4 . Also, in the case of another natural toxins Alternaria, the scientific Panel was not able to conduct a systematic RA due to the lack of data. Additionally, for both enniatins and Alternaria toxins major data gaps were identified in toxicity data in a recent report from the Norwegian Scientific Committee for Food and the Environment (VKM et al., 2019) 5 . All the above-mentioned underlines that further research, in terms of hazard identification and characterization, is required for both toxins: enniatins and Alternaria. This project initially focuses on these two emerging mycotoxins, with pressing regulatory need for more specific hazard data: i.e., enniatins and Alternaria toxins. Preferably, the studies will be performed according to OECD test guidelines (TGs), but in some cases no guidelines are available to address the specific endpoints and NAMs will be employed. Main expected outputs of the project The study will provide urgently needed in vitro data and identify critical toxicological effects of enniatins and Alternaria toxins. The data is necessary for subsequent in vivo studies which are required to establish HBGVs and to perform an appropriate RA and provide an efficient consumer protection. Outcomes and impacts expected for end-users and stakeholders This project will generate toxicological data (mainly focusing on hazard identification and characterization), aiming at incorporating it in RA performed in EU Agencies to set HBGVs that could therefore trigger the establishment of maximal levels in food in the context of Regulation (EC) No 1881/2006. Key words: Natural toxins, Alternaria toxins, enniatins, mycotoxins, genotoxicity, endocrine effects, immunotoxicology, in vitro, in silico Link to the PARC DoA The project responds to the PARC OOs OO3, OO4, OO5, OO6, OO7, OO10 and OO11. 4 EFSA CONTAM, Scientific Opinion on the risks to human and animal health related to the presence of beauvericin and enniatins in food and feed, EFSA Journal, 2014. 12(8): 3802 5 VKM, Inger-Lise Steffensen, Christiane Kruse Fæste, Trine Husøy, Helle Katrine Knutsen, Gro Haarklou Mathisen, Robin Ørnsrud, Angelika Agdestein, Johanna Bodin, Edel Elvevoll, Dag O. Hessen, Merete Hofshagen, Åshild Krogdahl, Asbjørn Magne Nilsen, Trond Rafoss, Taran Skjerdal, Gaute Velle, Yngvild Wasteson, Gro-Ingunn Hemre, Vigdis Vandvik, Jan Alexander (2019). Ranking of substances for monitoring in foods, drinks and dietary supplements - based on risk and knowledge gaps. Scientific Opinion of the Scientific Steering Committee of the Norwegian Scientific Committee for Food and Environment. VKM report 2019:13, ISBN: 978-82-8259-329-8, ISSN: 2535-4019. Available at https://vkm.no/ PARC – ANNEX I AWPY4 – page 262 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.10 AWPY4 including PARC Project Portfolio The project was designed in order to fill data gaps regarding the main representatives of emerging mycotoxins groups of enniatins and Alternaria toxins as defined by EFSA. The results are needed to identify critical toxicological effects for subsequent in vivo studies which are needed to establish HBGVs and to perform an appropriate RA and provide an efficient consumer protection. A working group was formed in which specialists on Alternaria and enniatins were combined with specialists in genotoxic, endocrine effects and immunotoxicological endpoints in order to design and deliver a program of studies. Review papers are in progress to summarise the existing data. Frequent meetings were held in order to share as much relevant information as possible. The long-term objective is to establish a European network of scientists interested and having experience in studying natural toxins. Links within PARC (WPs/Tasks/Activities/Projects) • WP4: Human exposure to the mycotoxins will be monitored in WP4. Analytical support in measuring the test items in test media is needed in order to support PBPK and in vitro - in vivo extrapolation (IVIVE) modelling. • WP5: T5.2 and T5.3: The test items will also be studied in selected NAMs in T5.2 (Cf. project on immunotoxicology P5.2.1.d). Data that will be generated on kinetics and toxicity will be used in task 5.3 in order to improve and expand existing models (AOP and Physiologically Based Kinetic (PBK)). • WP6: Hazard data generated will be used in WP6 to build Integrative Approaches for testing and Assessments (IATAs). Since most mycotoxins will be present in food and feed as mixtures, selected mixtures will also be tested. Relative Potency Factors could therefore be derived where possible and will provide important support for the assessments of risks of mixtures. • WP7: T7.3: data and text mining, data provision, DMP Links outside PARC • HBM4EU • EFSAlink to the Scientific Committee and Emerging Risks Unit European Food Safety Autority, Parma, Italy • OECD project Using AOP to address combined exposures to chemicals with relevant effectbiomarkers. 2022-2025 Key PARC Deliverables and Milestones to which the project contributes D5.1: 1st NAMs Report (delivered) D5.3: 1st new AOPs Report (delivered) D5.4: 1st Closing data Gaps Report (M36) D5.11. 2nd closing data gaps report (M54) Partners List: BfR (Germany), UNIVIE (Austria), BPI (Greece), IBMT (Germany), IMR (Norway), INRS (France), ANSES (France), INSA (Portugal), NIB (Slovenia), NIPH (Norway), Sciensano (Belgium), STAMI (Norway), UNAV (Spain), NVI (Norway), WU-TOX (Netherlands), ISS (Italy), NVI (Norway) Schedule: Starting date: 01/05/2022 (M1) Expected ending date: 30/04/2026 (M48) Costs Expected PM for the fourth year of the project: 87 PM Expected ODC for the fourth year of the project: 170 401 € PARC – ANNEX I AWPY4 – page 263 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.10 AWPY4 including PARC Project Portfolio P5.1.1.b_Y1_BPA_HumTox_BfR Project Title Hazard assessment of bisphenol A alternatives to close data gaps of concern for human health and improve their risk assessment Project Acronym (15 letters max) BPA_HumTox Project Manager Kiara Aiello [email protected] BfR Germany Deputy Project manager 1. Endocrine Disruptors: Sabrina Tait and Catherine Viguié 2.Developmental Neurotoxicity:Sakina Mhaouty-Kodja 3. Immunotoxicity: Emanuela Corsini 4. Carcinogenicity: Maria Jaoa Silva 5. Metabolism: Daniel Zalko and Emma Di Consiglio 1. ISS INRAE 2.CNRS 3.UMIL 4.INSA 5.INRAE, ISS Italy France France Italy Portugal France, Italy Expected starting date PARC (Month number) 1 Expected duration 54* PARC Workpackage number 5 PARC Task/Activity/Subactivity: 5.1.1 Project Id P5.1.1.b_Y1_HumanTox_BfR *The project has been extended from M36 to M54 Status: Implementation Summary of the project Due to the restrictions on the use of BPA in consumer products, which is the most widely used and studied bisphenol, a number of BPA substitutes have emerged. For most BPA alternatives, information on potential effects on relevant endpoints for human health is either missing or too limited for a sound HA/characterization. BPA alternatives are already being found in humans and the environment and have raised concerns in a regulatory context. With the upcoming restrictions on BPA, BPA’s alternatives’ tonnages and frequencies of use are expected to severely increase in the coming years. Therefore, this project aims to fill the identified data gaps, and providing a complete data set for at least four relevant BPA alternatives. The selected alternatives were identified in an ad hoc Workshop together with ECHA and EFSA, following a tiered approached (Details on the prioritization basis can be found at AD5.1, Deliverables page | Parc (eu-parc.eu)). We will fill the knowledge gaps on human health on the following five toxicological endpoints: 1. EDs; 2. Developmental Neurotoxicity (DNT); 3. Immunotoxicity; 4. Non-genotoxic Carcinogenicity; 5. Metabolism (biotransformation, potential bioactivation pathways, toxicokinetics). This project will also contribute to the identification of molecular biomarkers to develop a method to rapidly predict the possible effects of BPA alternatives. The identification of molecular biomarkers enables the determination of the mechanism(s) through which BPA alternatives act; identifying the key steps of their modes of action will be a key driver in the synergy between Work Package 5 and 6 regarding the improvement/production of AOP. Main expected outputs of the project Fill the identified data gaps on human health and provide a complete data set for at least four relevant BPA alternatives on the five toxicological endpoints stated previously. PARC – ANNEX I AWPY4 – page 264 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.10 AWPY4 including PARC Project Portfolio The data obtained will provide modelers with input for PBPK and QIVIVE models and/or AOP development as well as a trigger for further higher-tier investigations. Furthermore, the results to be obtained in this project will provide risk assessors with screening-level information that feeds mainly into the HA component of RA. Our project´s data will help to decide if specific BPA alternatives are potential regrettable substitution if e.g., their ED potential is higher than that of BPA. In that sense, the data will be supporting information for regulatory processes. This will contribute significantly to the enhanced protection of public health and requirements for safe food, consumer products and drinking water. Outcomes and impacts expected for end-users and stakeholders The Project will provide in vitro data on a set of toxicological endpoints for BPA alternatives that have not been assessed by the industry, to support assessors in conducting an adequate RA and implementing CLP classifications. With this project we will address the concern of the general population regarding this kind of substances, contributing to the production of safe products, such as plastic bottles, food cans and cash receipts, therefore minimizing the risk of adverse effects for end users. Key words: BPA analogues, risk assessment, endocrine disruptors, developmental neurotoxicity, immunotoxicity, metabolism, kinetics, in vitro methods, cognitive impairment, carcinogenicity Link to the PARC DoA The project responds to the PARC OOs OO3, OO4, OO5, OO6, OO7, OO10 and OO11. A significant contribution to the PARC project will be made, providing useful data regarding BPA alternatives for both general awareness as well as for the needs of regulatory bodies. The data will provide also input for modellers working in PARC to build an experimental strategy relying only on NAMs. A working group was formed in which specialists on BPA alternatives were combined with specialists in genotoxic and non-genotoxic carcinogenesis, endocrine disruption, developmental neurotoxicology, and immunotoxicologyical endpoints in order to deliver a program of studies. Frequent meetings were held in order to share as much relevant information as possible. A Workshop between WP/T leaders, project partners, EFSA and ECHA was organized to build a list of priority BPA alternatives for study (AD5.1), considering the regulatoty gaps and needs. Links within PARC (WPs/Tasks/Activities/Projects) • WP4: Elucidation of the structure of yet unknown metabolites of BPA alternatives that may be used as potential biomarkers of exposure and related effect biomarkers • WP5; Task 5.1, Task 5.2 and Task 5.3: - Task 5.2 Human Tox: we are working together with P5.2.1.e to fill up BPA alt data gaps using the stablished developmental neurotoxicity in vitro test battery (DNT IVB). Other WP5 project working with BPA alternatives in Task 5.1 and 5.2 Environment is P5.1.2.b joint project with A5.2.2. - We will share with projects in WP5 working with BPA Alt. the information regarding the production of major BPA alternatives metabolites for toxicological screening, notably as regards their potential to activate Nuclear Receptors (NR); Characterization of bioactivation pathways mechanistically involved in the onset of endpoints such as immune-toxicity and genotoxicity. - Mechanistic data generated will be used in the development of AOPs (e.g., DNT endpoint in A5.2.3.2) - We are also working closely with PBPK modelers in A5.3.4 to share the data produced (Km, Vmax, hepatic clearance) • WP6: Hazard data is expected to feed into IATA building. Potency factors will be derived for the assessment of mixture effects. • WP7: Task 7.3: data and text mining, data provision, DMP PARC – ANNEX I AWPY4 – page 271 PARC — HORIZON-HLTH-2021-ENVHLTH-03 Contract No. 101057014 D1.10 AWPY4 including PARC Project Portfolio Ondřej Adamovský ([email protected]) Deputy Project manager Katerina Kyriakopoulou ([email protected]) Benaki Phytopathological Institute (BPI) Greece Expected starting date PARC (Month number) 1 Expected duration 48* PARC Workpackage number 5 PARC Task/Activity/Sub -activity: 5.1.2 5.2.2 Project Id P5.1.2.b_Y1_BPAalternatives_BPI_MU *The project has been extended from M42 to M48 Status: Implementation Summary of the project The concerns regarding the potential adverse effects of BPA and tight restrictions of BPA in many countries has led to the development of alternative chemicals (e.g., bisphenol Z (BPZ), bisphenol E (BPE), bisphenol P (BPP), bisphenol AP (BPAP), bisphenol B (BPB), bisphenol C (BPC), bisphenol S (BPS), bisphenol F (BPF), bisphenol AF (BPAF)) resulting in emerging environmental contaminants found worldwide in various environmental components including water, sediment, sludge, soil, indoor dust and air. In addition, the use of BPA alternatives will be increased in the following years, since the use of BPA should be significantly reduced based on the upcoming EFSA scientific opinion in which EFSA has re-evaluated the risks form BPA in food and propose a lower tolerable daily intake (TDI) than the one previously set. Regarding their properties most bisphenols are characterized as toxic (or very toxic) to aquatic organisms, have been shown to exhibit adverse effects on the endocrine, reproduction, metabolism and immune system in different species and some of them are persistent, mobile or bioaccumulative and are characterized as persistent, bioaccumulative and toxic (PBT)/very persistent and very bioaccumulative (vPvB) or Persistent, mobile and toxic (PMT)/very persistent and very mobile (vPvM). In parallel, BPA alternatives are molecules regulated under REACH and their chemical safety assessment is carried out at different levels of comprehensiveness according to the specific data requirements based on the tonnage levels in which the substance is produced. These data are not always adequate to assess the potential adverse effects of BPA alternatives not only on human health but also on non-mammalian species, also considering the widespread use of many bisphenols and the possibility of exposure in the environment. Finally, the current regulatory RA focuses on single chemicals, widely disregarding potential adverse effects of mixtures of BPA alternatives on different organisms, especially after long-term exposure to environmentally realistic concentrations. Consequently, the assessment of combined effects of BPA alternatives and chemicals in general is recognized as one of the major needs in chemical RA and this need has been highlighted in the CSS, in the European Green Deal and in PARC / HBM4EU prioritization survey. Therefore, this project aims to fill the data gaps concerning the BPA alternatives (activities i and ii) and will serve as a platform for development of NAMs (activities iii-v). Main expected outputs of the project The specific aims and the relevant expected outputs of this project are the following: • Investigation of the potential adverse effects (e.g., apical endpoints such as mortality, effects related to the anticipated mode of action (MoA) or molecular initiation events (MIE), effects on reproduction, effects on endocrine system) of certain individual substances and “real-life” mixtures of BPA alternatives on nonmammalian organisms belonging to different taxa (activity i and ii) • Development of in silico and modelling tools for HA of BPA alternatives to ultimately support grouping of substances and read-across (RAx) approaches based on NAMs (activity iii). [Document text truncated for crawler view.]