Abstract
Endocrine disrupting chemicals (EDCs) are ubiquitous in the environment and involve diverse chemical-receptor interactions that can perturb hormone signaling. The Organization for Economic Co-operation and Development has validated several EDC-receptor bioassays to detect endocrine active chemicals and has established guidelines for regulatory testing of EDCs. Focus on testing over the past decade has been initially directed to EATS modalities (estrogen, androgen, thyroid, and steroidogenesis) and validated tests for chemicals that exert effects through non-EATS modalities are less established. Due to recognition that EDCs are vast in their mechanisms of action, novel bioassays are needed to capture the full scope of activity. Here, we highlight the need for validated assays that detect non-EATS modalities and discuss major international efforts underway to develop such tools for regulatory purposes, focusing on non-EATS modalities of high concern (i.e., retinoic acid, aryl hydrocarbon receptor, peroxisome proliferator-activated receptor, and glucocorticoid signaling). Two case studies are presented with strong evidence amongst animals and human studies for non-EATS disruption and associations with wildlife and human disease. This includes metabolic syndrome and insulin signaling (case study 1) and chemicals that impact the cardiovascular system (case study 2). This is relevant as obesity and cardiovascular disease represent two of the most significant health-related crises of our time. Lastly, emerging topics related to EDCs are discussed, including recognition of crosstalk between the EATS and non-EATS axis, complex mixtures containing a variety of EDCs, adverse outcome pathways for chemicals acting through non-EATS mechanisms, and novel models for testing chemicals. Recommendations and considerations for evaluating non-EATS modalities are proposed. Moving forward, improved understanding of the non-EATS modalities will lead to integrated testing strategies that can be used in regulatory bodies to protect environmental, animal, and human health from harmful environmental chemicals.
Highlights
Endocrine disrupting chemicals (EDCs) are ubiquitous in the environment and involve diverse chemical-receptor interactions that can perturb hormone signaling
At a time when society, governments, and industry are increasingly aware of wildlife and human health concerns related to perturbations in endocrine systems, regulations for EDC continue to be fiercely debated and concepts related to dose-response-thresholds, cumulative effects, and population-level consequences are actively discussed
Three projects focus on metabolism disrupting chemicals (MDCs), which are EDCs that interfere with metabolism leading to altered energy balance
Summary
Regulation of EDCs is high on the agenda for many countries in North/South America, Asia, and European Union (Barton-Maclaren et al this issue). In 2017, the EC launched the call SC1–BHC-27-2018 ‘New testing and screening methods to identify endocrine disrupting chemicals (EDCs)’, to fill in gaps and to address the lack of validated test methods for screening non-EATS endpoints, which resulted in eight funded projects. Three projects focus on metabolism disrupting chemicals (MDCs), which are EDCs that interfere with metabolism leading to altered energy balance Such disruption in turn is associated with metabolic diseases such as obesity, type II diabetes and non-alcoholic fatty liver disease (Heindel et al, 2017; Nadal et al, 2017). All projects focus on the development of novel methodologies, ranging from in silico (QSARs, molecular docking, PBTK), to in vitro and in vivo bioassays Data from these models will be supplemented with multi-omics approaches to aid in elucidating MOA and Adverse Outcome Pathway (AOP) development. We highlight some non-EATS modalities of concern, describing examples of in vitro and in vivo assays when available, dis cussing their strengths and limitations
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