An Approach for Using In Vitro and In Silico Data to Identify Pharmaceuticals with Potential (Anti‐)Estrogenic Activity in Aquatic Vertebrates at Environmentally Relevant Concentrations

Abstract

Endocrine‐active pharmaceuticals can cause adverse reproductive and developmental effects in nontarget organisms. Aquatic vertebrates may be susceptible to the effects of such pharmaceuticals given that the structure of hormone receptors and the physiology of the endocrine system are highly conserved across vertebrates. To aid in the regulatory review of the environmental impact of drugs, we demonstrate an approach to screen and support the prioritization of pharmaceuticals based on their ability to interact with estrogen receptors (ERs) at environmentally relevant concentrations. Tox21 in vitro results from ER agonist and antagonist assays were retrieved for 1123 pharmaceuticals. In silico predictions from the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP) models were used to estimate ER agonist and antagonist activity for an additional 170 pharmaceuticals not tested in the Tox21 assay platform. The estrogenic effect ratio (EER) and anti‐estrogenic effect ratio (AEER) were calculated by comparing the activity concentration at half‐maximal response (AC50) for ER agonism and antagonism, respectively, with estimated pharmaceutical concentrations in fish tissue based on estimates of environmental exposures. A total of 73 and 127 pharmaceuticals were identified as ER agonists and antagonists, respectively. As expected, 17β‐estradiol and 17α‐ethinylestradiol displayed EERs > 1, and raloxifene and bazedoxifene acetate displayed AEERs > 1, thus indicating that these pharmaceuticals have the potential to reach fish tissue levels that exceed concentrations estimated to interact with ERs. Four pharmaceuticals displayed EERs between 0.1 and 1, and 6 displayed AEERs between 0.1 and 1. This approach may help determine the need for submission of environmental assessment data for new drug applications and support prioritization of pharmaceuticals with the potential to disrupt endocrine signaling in vertebrates. Environ Toxicol Chem 2019;38:2154–2168. © 2019 SETAC.

What Approaches Should be Used to Prioritize Pharmaceuticals and Personal Care Products for Research on Environmental and Human Health Exposure and Effects?

“…By combining the exposure predicted by ePIE with toxic potency, desvenlafaxine, loratadine, and hydrocodone were identified as priority substances in the River Ouse Basin (North Yorkshire, UK) and the Rhine River Basin (Europe; Oldenkamp et al, 2018). In addition to surface waters and the health of low trophic levels species, risk‐based methods have been used to prioritize PPCPs based on exposure via different pathways (e.g., food, water) and the hazard of PPCPs to top trophic level species (predators) and humans (Malev et al, 2020; Oldenkamp et al, 2013; Shin et al, 2015), using the pharmacokinetic data and the acceptable daily intake, respectively (Pinto et al, 2019; Zhong et al, 2022).…”

“…Furthermore, in that review, state‐of‐the‐art molecular toxicity‐based prioritization studies making use of, for example, the ToxCast database, were not discussed (see Hartman et al, 2018; Rogers et al, 2021). In addition, there have been no summaries or interpretations of several key prioritization studies employing novel screening approaches such as in vitro neuronal cytotoxicity and (anti‐)estrogenic activity published during 2018–2022 (see Pinto et al, 2019; Kan et al, 2021).…”