New approach methods to improve human health risk assessment of thyroid hormone system disruption–a PARC project

Frontiers in Toxicology

Toxicology

Timo Hamers¹  Majorie Van Duursen¹  Kim Heikamp²  Michael Oelgeschlaeger³  Kostja Renko³  Lars Dahmen³  Vera Rogiers⁴  Yoni Baert⁴  Tamara Vanhaecke⁴  Lorna Marchandise⁴  Henrik Holbech⁵  Jane E. Morthorst⁵  Ana I. Cañas-Portilla⁶  Monica Torres-Ruiz⁶  Antonio De La Vieja⁶  Patricia Iglesias-Hernandez⁶  Ana C. V. E. Nissen⁷  Eva Bay Wedebye⁷  Nikolai Georgiev Nikolov⁷  Mette H. Stub⁸  Terje Svingen⁸  Louise Ramhøj⁸  Marta Axelstad⁸  Gerrit Schüürmann⁹  Frédéric Chalmel^1,10  Bertrand Evrard^1,10  Evelyn Stinckens^1,11  Lucia Vergauwen^1,11  Ann-Cathrin Haigis^1,11  Dries Knapen^1,11 

[1]Amsterdam Institute for Life and Environment (A-LIFE), Vrije Universiteit Amsterdam, Amsterdam, Netherlands

[2]Amsterdam Institute for Life and Environment (A-LIFE), Vrije Universiteit Amsterdam, Amsterdam, Netherlands

[3]Centre for Health Protection (GZB), National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands

[4]Department Experimental Toxicology and ZEBET, German Centre for the Protection of Laboratory Animals (Bf3R), German Federal Institute for Risk Assessment (BfR), Berlin, Germany

[5]Department In Vitro Toxicology and Dermato-cosmetology (IVTD), Vrije Universiteit Brussel, Jette, Belgium

[6]Department of Biology, University of Southern Denmark, Odense, Denmark

[7]Environmental Toxicology Unit from National Center for Environmental Health (CNSA), Endocrine Tumor Unit from UFIEC, Instituto de Salud Carlos III (ISCIII), Madrid, Spain

[8]Group for Chemical Risk Assessment and GMO, National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark

[9]Research Group for Molecular and Reproductive Toxicology, National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark

[10]UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Leipzig, Germany

[11]Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), Rennes, France

[12]Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Wilrijk, Belgium

关键词: PARC;    endocrine disruption;    thyroid disruption;    non-animal test methods;    regulatory toxicology;    adverse outcome pathways;    chemicals;   

DOI  :  10.3389/ftox.2023.1189303

 received in 2023-03-18, accepted in 2023-05-05,  发布年份 2023

来源: Frontiers

【 摘 要 】

Current test strategies to identify thyroid hormone (TH) system disruptors are inadequate for conducting robust chemical risk assessment required for regulation. The tests rely heavily on histopathological changes in rodent thyroid glands or measuring changes in systemic TH levels, but they lack specific new approach methodologies (NAMs) that can adequately detect TH-mediated effects. Such alternative test methods are needed to infer a causal relationship between molecular initiating events and adverse outcomes such as perturbed brain development. Although some NAMs that are relevant for TH system disruption are available–and are currently in the process of regulatory validation–there is still a need to develop more extensive alternative test batteries to cover the range of potential key events along the causal pathway between initial chemical disruption and adverse outcomes in humans. This project, funded under the Partnership for the Assessment of Risk from Chemicals (PARC) initiative, aims to facilitate the development of NAMs that are specific for TH system disruption by characterizing in vivo mechanisms of action that can be targeted by in embryo/in vitro/in silico/in chemico testing strategies. We will develop and improve human-relevant in vitro test systems to capture effects on important areas of the TH system. Furthermore, we will elaborate on important species differences in TH system disruption by incorporating non-mammalian vertebrate test species alongside classical laboratory rat species and human-derived in vitro assays.

【 授权许可】

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Copyright © 2023 Ramhøj, Axelstad, Baert, Cañas-Portilla, Chalmel, Dahmen, De La Vieja, Evrard, Haigis, Hamers, Heikamp, Holbech, Iglesias-Hernandez, Knapen, Marchandise, Morthorst, Nikolov, Nissen, Oelgeschlaeger, Renko, Rogiers, Schüürmann, Stinckens, Stub, Torres-Ruiz, Van Duursen, Vanhaecke, Vergauwen, Wedebye and Svingen.