Development of a Set of AOP Network-Supported IATAs for Thyroid Hormone System Disruption

The Partnership for the Assessment of Risks from Chemicals (PARC) is a research and innovation programme funded by Horizon Europe, bringing together nearly 200 partners from 28 countries as well as EU agencies to support next-generation chemical risk assessment and risk management incorporating both human health and the environment in a "One Health" approach.
One of the activities in this context is the development of integrated approaches for testing and assessment (IATAs) for endocrine disruption (Task 6.1.1). The PARC endocrine disruption IATA development process is closely aligned with work on adverse outcome pathway (AOP) development for endocrine and metabolic disruption (Task 5.3.2) to ensure that the methods that are considered for inclusion in the IATAs are supported by key event descriptions of well-developed AOPs.
Thyroid hormone system disruption (THSD) has been identified as one of the priority areas for IATA and AOP development in PARC. Effects on the hypothalamic-pituitary-thyroid axis are considered low-hanging fruit because of the relatively large number of AOPs available or under development for this system, and the ongoing efforts to assess and validate in vitro assays for the assessment of THSD conducted at the JRC, the OECD Thyroid Disruption Methods Expert Group, the US Environmental Protection Agency, and within the EURION project cluster under the Horizon 2020 programme.
We present an update on the joint work of developing AOPs and IATAs for THSD in Tasks 5.3.2 and 6.1.1 of PARC. An existing cross-species AOP network for THSD consisting of 50 AOPs taken from the AOP-Wiki, initiated by 13 molecular initiating events and leading to 9 adverse outcomes, provided a starting point. Data and knowledge gaps were identified based on this inventory of available AOPs. Pivotal key events relevant to THSD were identified, and the associated methods were evaluated in terms of data interpretation, available prediction models, test method readiness, and performance. These methods were then mapped to the AOP network, and priorities for further AOP development were determined as a function of IATA development priorities. A set of conceptual IATAs was subsequently outlined, addressing adverse effects that are relevant to either human or environmental health. These IATAs will be further developed and refined in the future in close collaboration with relevant stakeholders, and evaluated through dedicated case studies.