Current limitations and recommendations to improve testing for the environmental assessment of endocrine active substances
Authors: Coady Katherine K , Biever Ronald C , Denslow Nancy D , Gross Melanie , Guiney Patrick D , Holbech Henrik , Karouna-Renier Natalie K , Katsiadaki Ioanna , Krueger Hank , Levine Steven L , Maack Gerd , Williams Mike , Wolf Jeffrey C , Ankley Gerald T 
Published: December 2016

Abstract

In the present study, existing regulatory frameworks and test systems for assessing potential endocrine active chemicals are described, and associated challenges are 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 to 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 with 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 to 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 assays 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. Integr Environ Assess Manag 2017;13:302–316. © 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)

Key Points
The present study is an up-to-date review of the major challenges and potential solutions associated with environmental endocrine testing and assessment. The present study recommends leveraging in silico, in vitro, as well as high-throughput data to the extent possible to prioritize and inform environmental endocrine testing programs. Practical suggestions are made in the present study to guide environmental endocrine testing and improve sensitivity in regard to species, life-stage, and endpoint selection and measurement. Key gaps in endocrine knowledge and assessment techniques are highlighted, with recommendations for future research.