US EPA

3974257 

Journal Article 

Evaluating chemicals for thyroid disruption: Opportunities and challenges with in vitro testing and adverse outcome pathway approaches 

Noyes, PD; Paul-Friedman, KP; Haselman, JT; Barone Jr., S; Crofton, KM; Gilbert, ME; Hornung, MW; Laws, SC; Simmons, SO; Stoker, TE; Tietge, JE; Degitz, SJ 

2019 

Yes 

Environmental Health Perspectives
ISSN: 0091-6765
EISSN: 1552-9924 

National Institute of Environmental Health Sciences 

127 

9 

95001 

English 

31487205 

10.1289/EHP5297 

WOS:000488971900009 

https://www.ncbi.nlm.nih.gov/pubmed/31487205
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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. 

Adverse outcome pathway, computational toxicology, EDSP, endocrine disruptor, high-throughput screening, thyroid hormone, thyroid disruption