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Trenbolone acetate is widely used in some parts of the world for its desirable anabolic effects on livestock. Several metabolites of the acetate, including 17β-trenbolone, have been detected at low nanograms per liter concentrations in surface waters associated with animal feedlots. The 17β-trenbolone isomer can affect androgen receptor signaling pathways in various vertebrate species at comparatively low concentrations/doses. The present article provides a comprehensive review and synthesis of the existing literature concerning exposure to and biological effects of 17β-trenbolone, with an emphasis on potential risks to aquatic animals. In vitro studies indicate that, although 17β-trenbolone can activate several nuclear hormone receptors, its highest affinity is for the androgen receptor in all vertebrate taxa examined, including fish. Exposure of fish to nanograms per liter water concentrations of 17β-trenbolone can cause changes in endocrine function in the short term, and adverse apical effects in longer exposures during development and reproduction. Impacts on endocrine function typically are indicative of inappropriate androgen receptor signaling, such as changes in sex steroid metabolism, impacts on gonadal stage, and masculinization of females. Exposure of fish to 17β-trenbolone during sexual differentiation in early development can greatly skew sex ratios, whereas adult exposures can adversely impact fertility and fecundity. To fully assess ecosystem-level risks, additional research is warranted to address uncertainties as to the degree/breadth of environmental exposures and potential population-level effects of 17β-trenbolone in sensitive species. Environ Toxicol Chem 2018;37:2064-2078. Published 2018 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

In this paper existing regulatory frameworks and test systems for assessing potential endocrine-active chemicals are described, and associated challenges discussed, along with proposed approaches to address these challenges. Regulatory frameworks vary somewhat across geographies, but all basically evaluate whether a chemical possesses endocrine activity and whether this activity can result in adverse outcomes either to humans or the environment. Current test systems include in silico, in vitro and in vivo techniques focused on detecting potential endocrine activity, and in vivo tests that collect apical data to detect possible adverse effects. These test systems are currently designed to robustly assess endocrine activity and/or adverse effects in the estrogen, androgen, and thyroid hormone signaling pathways; however, there are some limitations of current test systems for evaluating endocrine hazard and risk. These limitations include a lack of certainty regarding: 1) adequately sensitive species and life-stages, 2) mechanistic endpoints that are diagnostic for endocrine pathways of concern, and 3) the linkage between mechanistic responses and apical, adverse outcomes. Furthermore, some existing test methods are resource intensive in regard to time, cost, and use of animals. However, based on recent experiences, there are opportunities to improve approaches to, and guidance for existing test methods, and reduce uncertainty. For example, in vitro high throughput screening could be used to prioritize chemicals for testing and provide insights as to the most appropriate assay(s) for characterizing hazard and risk. Other recommendations include adding endpoints for elucidating connections between mechanistic effects and adverse outcomes, identifying potentially sensitive taxa for which test methods currently do not exist, and addressing key endocrine pathways of possible concern in addition to those associated with estrogen, androgen and thyroid signaling. This article is protected by copyright. All rights reserved.

To assess the hazards and risks of possible endocrine active chemicals (EACs) there is a need for robust, validated test methods that detect perturbation of endocrine pathways of concern and provide insights reliable information as to assess to potential adverse effects on apical endpoints. One issue of significant concern to for current EACS screening/testing programs involves resources in regard such as to cost, time, trained personnel, and animal use. This is especially problematic when considering the number of chemicals that some regulatory authorities need to assess. One way to address this challenge is to prioritize chemicals for possible in vivo testing using in vitro high throughput (HTP) assays focused on a suite of endocrine molecular initiating events (MIEs) of concern. Additional challenges associated with the design and conduct of in vivo EAC screening and testing include selection of appropriate species (i.e., sensitive and amenable to laboratory testing), endpoints and life-stages. A component of this involves experience gained using existing tests to determine, for example, those that have been shown to be exceptionally sensitive to perturbation of a given MIE of concern. However, there is the opportunity for strategic use of HTP data and/or early screening level information to help guide the selection of existing assays that can further evaluate a given EAC modality. Further challenges for EAC screening and testing involve guidance and optimization in several areas, such as concentration setting, statistical power to detect biologically significant adverse effects, delivery and analytical measurement of test substances, availability of technical expertise, and study interpretation, including linking mechanistic and apical effects. Some of these areas can be addressed by the lessons learned and best practices developed through recent experiences conducting EAC screening/testing. Additionally, the collective assessment of EAC screening and testing data (e.g. compilation of historical control data) can be leveraged to refine test designs and performance criteria to maximize the power and utility of EAC screening/testing. Finally, a number of recommendations are provided for longer term research to address areas of uncertainty, including identifying potentially sensitive species for which test methods currently do not exist (e.g., invertebrates) and key endocrine pathways in addition to estrogen, androgen and thyroid signalling.Katherine Coady, Ronald Biever, Nancy Denslow, Melanie Gross, Patrick Guiney, Henrik Holbech, Natalie Karouna-Renier, Ioanna Katsiadaki, Henry Krueger, Steven Levine, Gerd Maack, Mike Williams, Jeffrey Wolf, Gerald Ankley