Citation:

Noyes, Pamela, K. Friedman, P. Browne, Jonathan Haselman, M. Gilbert, M. Hornung, Stanley Barone, K. Crofton, S. Laws, T. Stoker, S. Simmons, J. Tietge, AND S. Degitz. Evaluating chemicals for thyroid disruption: opportunities and challenges with in vitro testing and adverse outcome pathway approaches. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 127(9):095001, (2019). https://doi.org/10.1289/EHP5297

Impact/Purpose:

Thyroid hormones (TH) are essential modulators of vertebrate development and numerous physiological processes. The complexity of the thyroid system makes chemical safety evaluations of thyroid-related endpoints a challenging task. To increase chemical safety screening efficiency and reduce vertebrate animal testing, progress has been made recently to develop in vitro high throughput screening (HTS) assays that identify chemical interactions with molecular targets of the thyroid system. Applications of in vitro HTS to inform interpretations of thyroid toxicity continues to be complicated by a lack of quantitative linkages between measurements at macromolecular levels of biological organization (e.g., receptor, cellular) and downstream endpoints and adverse effects traditionally used in hazard assessment (e.g., developmental neurotoxicity). As a result, regulatory test guidelines and decision making to evaluate chemicals for potential thyroid-related effects and associated outcomes continue to rely on data derived from in vivo animal studies. The thyroid adverse outcome pathway (AOP) network presented serves as the foundation to organize and evaluate thyroid data in a research context, identify gaps in existing assays, examine the evidence for causality between key events (KEs) in AOPs, and define quantitative KE relationships linking pairs of KEs. At present, use of in vitro HTS beyond screening and prioritization for thyroid bioactivity continues to be challenged by the complexity of potential TH-related adverse outcomes and continuing limited knowledge of mechanistic processes controlling such responses. Despite the unknowns, for regulatory applications the thyroid AOP network lays out the necessary biological structure to contextualize and incorporate information from NAMs to supplement and support predictive modeling and hazard evaluations for large numbers of previously untested chemicals.

Description:

Background: Extensive clinical and experimental research documents the potential for chemical disruption of thyroid hormone (TH) signaling through multiple molecular targets. Perturbation of TH signaling can lead to abnormal brain development, cognitive impairments, and other adverse outcomes in humans and wildlife. To increase chemical safety screening efficiency and reduce vertebrate animal testing, in vitro assays that identify chemical interactions with molecular targets of the thyroid system have been developed and implemented. Objectives: We present an adverse outcome pathway (AOP) network to link data derived from in vitro assays that measure chemical interactions with thyroid molecular targets to downstream events and adverse outcomes traditionally derived from in vivo testing. We examine the role of new in vitro technologies, in the context of the AOP network, in facilitating consideration of several important regulatory and biological challenges in characterizing chemicals that exert effects through a thyroid mechanism. Discussion: There is a substantial body of knowledge describing chemical effects on molecular and physiological regulation of TH signaling and associated adverse outcomes. Until recently, few alternative nonanimal assays were available to interrogate chemical effects on TH signaling. With the development of these new tools, screening large libraries of chemicals for interactions with molecular targets of the thyroid is now possible. Measuring early chemical interactions with targets in the thyroid pathway provides a means of linking adverse outcomes, which may be influenced by many biological processes, to a thyroid mechanism. However, the use of in vitro assays beyond chemical screening is complicated by continuing limits in our knowledge of TH signaling in important life stages and tissues, such as during fetal brain development. Nonetheless, the thyroid AOP network provides an ideal tool for defining causal linkages of a chemical exerting thyroid-dependent effects and identifying research needs to quantify these effects in support of regulatory decision making.

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