Challenges in assigning endocrine-specific modes of action: Recommendations for researchers and regulators

Abstract

As regulatory programs evaluate substances for their endocrine disrupting properties, careful study design and data interpretation is needed to distinguish between responses that are truly endocrine-specific and those that are not. This is particularly important in regulatory environments where criteria are under development to identify endocrine disrupting properties to enable hazard-based regulation. Irrespective of these processes, most jurisdictions use the WHO/IPCS definition of an endocrine disruptor (ED), requiring that a substance is demonstrated to cause a change in endocrine function that consequently leads to an adverse effect in an intact organism. Such a definition is broad, and at its most cautious, might capture many general mechanisms that would not specifically denote an ED. In addition, endocrine responses may be adaptive in nature, designed to maintain homeostasis rather than induce an irreversible adverse effect. The likelihood of indirect effects is increased in (eco)toxicological studies requiring the use of maximum tolerated concentrations or doses, which must produce some adverse effect. The misidentification of indirect effects as truly endocrine mediated has serious consequences for prompting animal- and resource-intensive testing and regulatory consequences. To minimize the risk of misidentification, an objective and transparent weight of evidence (WoE) procedure based on biological plausibility, essentiality, and empirical evidence of key events in an adverse outcome pathway is recommended to describe the modes of action that may be involved in toxic responses in non-target organisms. Confounding factors such as systemic toxicity, general stress, and infection can add complexity to such an evaluation and should be considered in the WoE. A recommended set of questions are proffered to help guide researchers and regulators in discerning endocrine and non-endocrine responses. While many examples provided in this paper are based on ecotoxicology, the majority of the concepts and processes are applicable to both environmental and human health assessments

Recommended approaches to the scientific evaluation of ecotoxicological hazards and risks of endocrine-active substances

“…Finally, issues were identified that aid in distinguishing between endocrineversus nonendocrine-specific responses. These crosscutting issues are broadly outlined below and discussed in detail in the associated companion papers (Coady et al this issue; Marty et al this issue; Mihaich et al this issue; Parrott et al this issue). …”

“…The use of an AOP approach to assemble the lines of evidence that lead to an adverse effect helps to put into context the various mechanisms that may be responsible. This approach was used to examine 3 of the case study substances, EE2, propiconazole, and 17β-trenbolone (Supplemental Data S1, S3, and S5; Mihaich et al this issue). …”

“…It should be noted that the flow chart is intended for use in situations where a substance has already been clearly identified as an EDS, and therefore decisions about whether or not to initiate ecotoxicological risk assessment need to be made. The issues underpinning these decisions have been discussed more fully in the section entitled Cross-Cutting Issues Relevant to the Evaluation of Hazards and Risks of EAS/EDS, and at length in the accompanying papers (Coady et al this issue; Marty et al this issue; Mihaich et al this issue; Parrott et al this issue). …”

“…Several areas where further research is needed were identified at the workshop, and the main points are highlighted here; for more detail, see the companion papers in this series (Coady et al this issue; Marty et al this issue; Mihaich et al this issue; Parrott et al this issue). Many of these areas involve the need for fundamental biological research, but there is also a need for the development of new testing methods.…”

A critical review of the environmental occurrence and potential effects in aquatic vertebrates of the potent androgen receptor agonist 17β‐trenbolone

“…In early 2016, the Society of Environmental Toxicology and Chemistry (SETAC) sponsored an international Pellston workshop focused on hazard‐ versus risk‐based approaches for the ecological assessment of endocrine‐active chemicals (Matthiessen et al ). For this comparative evaluation, workshop participants focused on several facets of endocrine‐active chemical assessments, including linkage of mechanistic data indicative of altered endocrine function to adverse outcomes (Mihaich et al ), limitations and proposed improvements in current screening and testing approaches (Coady et al ), attributes of endocrine‐active chemicals that might complicate test interpretation and prediction of hazard/risk (Parrott et al ), and population‐level effects of endocrine‐active chemicals (Marty et al ). To support and illustrate these analyses, relatively extensive literature reviews were conducted for 6 well‐established endocrine‐active chemicals that affect different pathways, endpoints, and/or species, including an estrogen receptor agonist (17α‐ethinylestradiol), a sex steroid synthesis inhibitor (propiconazole), a compound associated with the induction of intersex in invertebrates (tributyltin), a thyroid‐active substance (perchlorate), and chemicals that interact with the vertebrate androgen receptor as an antagonist (vinclozolin) or an agonist (17β‐trenbolone; Matthiessen et al ).…”