Challenges and Recommendations in Assessing Potential Endocrine-Disrupting Properties of Metals in Aquatic Organisms.

New tools and refined frameworks for identifying and regulating endocrine-disrupting chemicals (EDCs) are being developed as our scientific understanding of how they work advances. Although focus has largely been on organic chemicals, the potential for metals to act as EDCs in aquatic systems is receiving increasing attention. Metal interactions with the endocrine system are complicated because some metals are essential to physiological systems, including the endocrine system, and nonessential metals can have similar physiochemical attributes that allow substitution into or interference with these systems. Consequently, elevated metal exposure could potentially cause endocrine disruption (ED) but can also cause indirect effects on the endocrine system via multiple pathways or elicit physiologically appropriate compensatory endocrine-mediated responses (endocrine modulation). These latter two effects can be confused with, but are clearly not, ED. In the present study, we provide several case studies that exemplify the challenges encountered in evaluating the endocrine-disrupting (ED) potential of metals, followed by recommendations on how to meet them. Given that metals have multiple modes of action (MOAs), we recommend that assessments use metal-specific adverse outcome pathway networks to ensure that accurate causal links are made between MOAs and effects on the endocrine system. We recommend more focus on establishing molecular initiating events for chronic metal toxicity because these are poorly understood and would reduce uncertainty regarding the potential for metals to be EDCs. Finally, more generalized MOAs such as oxidative stress could be involved in metal interactions with the endocrine system, and we suggest it may be experimentally efficient to evaluate these MOAs when ED is inferred. These experiments, however, must provide explicit linkage to the ED endpoints of interest. Environ Toxicol Chem 2023;42:2564-2579. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.