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Current limitations and recommendations to improve testing for the environmental assessment of endocrine active substances
Citation:
Coady, K., R. Biever, N. Denslow, M. Gross, P. Guiney, H. Holbech, N. Karouna-Renier, I. Katsiadaki, H. Krueger, S. Levine, G. Maack, M. Williams, J. Wolf, AND G. Ankley. Current limitations and recommendations to improve testing for the environmental assessment of endocrine active substances. Integrated Environmental Assessment and Management. Allen Press, Inc., Lawrence, KS, 13(2):302-316, (2017).
Impact/Purpose:
There has been substantial scientific advancement in the development and implementation of testing, hazard and risk assessment approaches to evaluate potential adverse effects though an endocrine mechanism. In particular, existing test systems and frameworks that have been developed for assessing potential interaction with the estrogen, androgen, and thyroid pathways are relatively comprehensive for identifying and assessing endocrine effects. However, there are now opportunities to retrospectively examine the lessons learned from the recent implementation of these efforts to improve the reliability and relevance of endocrine assessments. Priority areas for improving endocrine screening and testing described in this paper include: • Leveraging information to the extent possible from high through-put screening assays to prioritize and inform testing programs, • Using experience with existing assays as a basis for modifying approaches to optimize resource use, • Developing additional approaches to address species sensitivity, sensitive life-stages, and critical endpoints to improve the predictive ability to detect an adverse effect at the population level, and • Identifying gaps that can be addressed by research to improve testing paradigms.
Description:
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 organizations, 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 hormonal 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 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 assay(s) for characterizing hazard and risk. High throughput screening conducted with cytotoxicity endpoints could also inform endpoint interpretation (e.g., identification of endocrine vs. non-endocrine mediated toxicity). Other recommendations include improvements to current test guidelines including adding endpoints for elucidating the connection between mechanistic effects and adverse outcomes. Finally, there are a number of recommendations for longer term research efforts to address areas of uncertainty, including potentially sensitive taxa for which test methods currently do not exist and key endocrine pathways of possible concern in addition to those associated with estrogen, androgen and thyroid signalling.
