1. Application of AOPs to assist regulatory assessment of chemical risks – Case studies, needs and recommendations
- Author
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Lola Bajard, Ondrej Adamovsky, Karine Audouze, Kirsten Baken, Robert Barouki, Joost B. Beltman, Anna Beronius, Eva Cecilie Bonefeld-Jørgensen, German Cano-Sancho, Milo L. de Baat, Filippo Di Tillio, Mariana F. Fernández, Rex E. FitzGerald, Claudia Gundacker, Antonio F. Hernández, Klara Hilscherova, Spyros Karakitsios, Eliska Kuchovska, Manhai Long, Mirjam Luijten, Sanah Majid, Philip Marx-Stoelting, Vicente Mustieles, Chander K. Negi, Dimosthenis Sarigiannis, Stefan Scholz, Iva Sovadinova, Rob Stierum, Shihori Tanabe, Knut Erik Tollefsen, Annick D. van den Brand, Carolina Vogs, Maria Wielsøe, Clemens Wittwehr, and Ludek Blaha
- Subjects
Adverse outcome pathways ,New approach methodologies ,Mechanistic toxicology ,Hazard assessment ,Regulatory risk assessment ,Biomarkers of effect ,Biochemistry ,General Environmental Science - Abstract
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., European Commission 733032 857560 101057014, Ministry of Education, Youth and Sports by the RECETOX Research Infrastructure LM2018121, OP RDE project CETOCOEN Excellence CZ.02.1.01/0.0/0.0/17_043/0009632, Japan Agency for Medical Research and Development (AMED) JP21mk0101216 JP22mk0101216, Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT), Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (KAKENHI) 21K12133
- Published
- 2023
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