While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited. The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives as it was discussed in a workshop organized within the European Union partnerships HBM4EU and PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless, several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory community including the lack of quantitative information on response-response relationships and of efficient ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation of AOPs in the NGRA.

Center for Biomedical Research 28029 Madrid Spain

Centre for Arctic Health and Molecular Epidemiology Department of Public Health Aarhus University Bartholins Allé 2 8000 Aarhus Denmark

Centre for Arctic Health and Molecular Epidemiology Department of Public Health Aarhus University Bartholins Allé 2 8000 Aarhus Denmark; Greenland Centre for Health Research University of Greenland Manutooq 1 3905 Nuussuaq Greenland

Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research Leiden University Leiden Netherlands

Division of Risk Assessment Center for Biological Safety and Research National Institute of Health Sciences Kawasaki Japan

Environmental Engineering Laboratory Department of Chemical Engineering Aristotle University of Thessaloniki Thessaloniki Greece; HERACLES Research Centre on the Exposome and Health Center for Interdisciplinary Research and Innovation Thessaloniki Greece

European Commission Joint Research Centre Ispra Italy

German Federal Institute for Risk Assessment Dept Pesticides Safety Berlin Germany

Institute for Public Health and the Environment Centre for Nutrition Prevention and Health Services 3720 BA Bilthoven the Netherlands

Institute of Environmental Medicine Karolinska Institutet Nobels väg 13 Solna Sweden

Institute of Environmental Medicine Karolinska Institutet Nobels väg 13 Solna Sweden; Department of Biomedical Sciences and Veterinary Public Health Swedish University of Agricultural Sciences SE 75007 Uppsala Sweden

Institute of Medical Genetics Center for Pathobiochemistry and Genetics Medical University of Vienna 1090 Vienna Austria

Instituto de Investigación Biosanitaria 18012 Granada Spain; Department of Legal Medicine and Toxicology University of Granada School of Medicine Avda de la Investigación 11 18016 Granada Spain; Consortium for Biomedical Research in Epidemiology and Public Health CIBERESP Madrid Spain

IUF Leibniz Research Institute for Environmental Medicine Auf'm Hennekamp 50 40225 Duesseldorf Germany

KWR Water Research Institute Groningenhaven 7 3433 PE Nieuwegein the Netherlands

LABERCA Oniris INRAE Nantes France

National Institute for Public Health and the Environment Centre for Health Protection Bilthoven the Netherlands

Netherlands Organisation for Applied Scientific Research Risk Analysis for Products in Development Utrecht the Netherlands

Norwegian Institute for Water Research Norway

RECETOX Faculty of Science Masaryk University Kotlarska 2 611 37 Brno Czech Republic

Swiss Centre for Applied Human Toxicology SCAHT University of Basel Missionsstrasse 64 CH 4055 Basel Switzerland

UFZ Helmholtz Center for Environmental Research Dept Bioanalyt Ecotoxicol D 04318 Leipzig Germany

Unit Health Flemish Institute for Technological Research Boeretang 200 2400 Mol Belgium

Université Paris Cité T3S Inserm UMR S 1124 F 75006 Paris France

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Adopting Mechanistic Molecular Biology Approaches in Exposome Research for Causal Understanding