Toward an AOP Network-Based Tiered Testing Strategy for the Assessment of Thyroid Hormone Disruption

Abstract

A growing number of environmental pollutants are known to adversely affect the thyroid hormone system, and major gaps have been identified in the tools available for the identification, and the hazard and risk assessment of these thyroid hormone disrupting chemicals. We provide an example of how the adverse outcome pathway (AOP) framework and associated data generation can address current testing challenges in the context of fish early-life stage tests, and fish tests in general. We demonstrate how a suite of assays covering essential biological processes involved in the underlying toxicological pathways can be implemented in a tiered screening and testing approach for thyroid hormone disruption, using the levels of assessment of the OECD's Conceptual Framework for the Testing and Assessment of Endocrine Disrupting Chemicals as a guide.

A Multidimensional Matrix Model for Predicting the Effects of Male‐Biased Sex Ratios on Fish Populations

“…However, bridging the gap from results of these mechanistic assays to determination of whether changes in basic endocrine function in fact cause adverse effects in individuals and populations has been challenging (Matthiessen et al, 2017). The focus of the AOP concept on assessing and depicting causal linkages in responses across biological levels of organization provides a logical basis for making the key connection between changes in HPG/T axis function and impacts meaningful to risk assessment (e.g., Browne et al, 2017; Coady et al, 2017; Knapen et al, 2020; McCardle et al, 2020). But, even within the context of the AOP framework, linking changes in individuals to population status remains a vexing problem and one that, apart from a few notable efforts (e.g., Kidd et al, 2007), has not been addressed for EACs based on experimental data.…”

“…While changes at these biological levels of organization can be highly diagnostic of perturbation of specific pathways, there remains the challenge of translating them into potential adverse effects meaningful to risk assessors/managers. The adverse outcome pathway (AOP) framework (Ankley et al, 2010) seeks to establish transparent, causal linkages between responses at different levels of organization and, hence, has been proposed as a basis for utilizing data from pathway‐based EAC assays for higher‐level risk assessments (Browne et al, 2017; Coady et al, 2017; Knapen et al, 2020; McCardle et al, 2020). One of the challenges in developing AOPs relevant to assessment of EAC risk(s) has been establishing linkages between changes in apical responses in individuals and potential impacts on populations.…”

Emerging concepts and opportunities for endocrine disruptor screening of the non-EATS modalities

“…Although a relatively new concept, several qAOPs have already been proposed for both EATS and non-EATS. For EATS modalities, qAOPs have been developed for reproductive impairment in fish via aromatase inhibition, altered swimming performance in fish via inhibition of thyroid hormone synthesis/degradation, and diverse adverse outcomes (AOs) involved in reproduction and development in vertebrates via activation of ERα ( Knapen et al, 2020 ). For non-EATS modalities, qAOPs concerning immunosuppression and decreased egg production in fish because of GR signaling have been developed ( Margiotta-Casaluci et al, 2016 ), as well as early life stage mortality in birds and fishes via AhR ( Doering et al, 2018 ), and liver steatosis in humans via PPARα ( Perkins et al, 2019 ), among others.…”

From Causal Networks to Adverse Outcome Pathways: A Developmental Neurotoxicity Case Study

“…On top, several helper tools for AOP development and visualization have been made available to the community (e.g., http://datasciburgoon.github.io/aopxplorer ). The AOPs in the AOP-wiki have been useful resources for quite diverse toxicological studies, e.g., to find chemicals likely to activate the AOPs ( Jeong et al, 2019 ), to evaluate the hazard associated with specific chemicals and chemical groups ( Carvaillo et al, 2019 ; Negi et al, 2021 ), to develop assays for in vitro assessment of mixture toxicity ( Pistollato et al, 2020 ), to develop a new tiered testing approach for thyroid hormone disruptors ( Knapen et al, 2020 ), to find the mechanisms of nanomaterial toxicity ( Murugadoss et al, 2021 ) and to develop quantitative AOPs, mathematical models that can be used directly in chemical risk assessment ( Margiotta-Casaluci et al, 2016 ; Doering et al, 2018 ; Perkins et al, 2019 ; Burgoon et al, 2020 ; Lillicrap et al, 2020 ).…”