title: 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 are 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 World Health Organization/International Programme on Chemical Safety definition of an endocrine disruptor, 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 endocrine disruptor. 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 that require 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 for misidentification, an objective and transparent weight-of-evidence 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 nontarget organisms. Confounding factors such as systemic toxicity, general stress, and infection can add complexity to such an evaluation and should be considered in the weight of evidence. A recommended set of questions is proffered to help guide researchers and regulators in discerning endocrine and nonendocrine responses. Although many examples provided in this study are based on ecotoxicology, the majority of the concepts and processes are applicable to both environmental and human health assessments. Integr Environ Assess Manag 2017;13:280-292. © 2016 SETAC.
authors.affiliation: Environmental and Regulatory Resources, Durham, North Carolina, USA.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Mihaich
authors.affiliation: Fraunhofer IME Applied Ecology, Schmallenberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schäfers
authors.affiliation: Center for Environmental & Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Dreier
authors.affiliation: School of the Environment & Sustainability and Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
authors.affiliation: Bayer CropScience, Research Triangle Park, North Carolina, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ortego
authors.affiliation: Japan NUS Co., Ltd., Tokyo, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kawashima
authors.affiliation: RIVM, Bilthoven, The Netherlands.
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Dang
authors.affiliation: Centre for Toxicology, School of Environmental Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Keith
authors.initials: K
authors.lastname: Solomon
mesh_terms: D054750:Ecotoxicology; D052244:Endocrine Disruptors; D004781:Environmental Exposure / Q000592:standards*; D058735:Environmental Policy; D005062:European Union; D006801:Humans; D007390:International Agencies; D018570:Risk Assessment / Q000379:methods
chemical_list: D052244:Endocrine Disruptors
keywords: Adverse outcome pathway; Endocrine disruptor; Mode of action; Weight of evidence