Current ecotoxicity testing needs among selected U.S. federal agencies.

U.S. regulatory and research agencies use ecotoxicity test data to assess the hazards associated with substances that may be released into the environment, including but not limited to industrial chemicals, pharmaceuticals, pesticides, food additives, and color additives. These data are used to conduct hazard assessments and evaluate potential risks to aquatic life (e.g., invertebrates, fish), birds, wildlife species, or the environment. To identify opportunities for regulatory uses of non-animal replacements for ecotoxicity tests, the needs and uses for data from tests utilizing animals must first be clarified. Accordingly, the objective of this review was to identify the ecotoxicity test data relied upon by U.S. federal agencies. The standards, test guidelines, guidance documents, and/or endpoints that are used to address each of the agencies' regulatory and research needs regarding ecotoxicity testing are described in the context of their application to decision-making. Testing and information use, needs, and/or requirements relevant to the regulatory or programmatic mandates of the agencies taking part in the Interagency Coordinating Committee on the Validation of Alternative Methods Ecotoxicology Workgroup are captured. This information will be useful for coordinating efforts to develop and implement alternative test methods to reduce, refine, or replace animal use in chemical safety evaluations.

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.

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, 17ß-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.

Risks associated with the environmental release of pharmaceuticals on the U.S. Food and Drug Administration "flush list".

A select few prescription drugs can be especially harmful and, in some cases, fatal with just one dose when not used as prescribed. Therefore, the U. S. Food and Drug Administration (FDA) recommends that expired, unwanted, or otherwise unused portions of most of these drugs be disposed of quickly through a take-back program. If such an option is not readily available, FDA recommends that they be flushed down the sink or toilet. The goal of the current investigation was to evaluate the ecological and human-health risks associated with the environmental release of the 15 active pharmaceutical ingredients (APIs) currently on the FDA "flush list". The evaluation suggests that even when highly conservative assumptions are used-including that the entire API mass supplied for clinical use is flushed, all relevant sources in addition to clinical use of the API are considered, and no metabolic loss, environmental degradation, or dilution of wastewater effluents are used in estimating environmental concentrations-most of these APIs present a negligible eco-toxicological risk, both as individual compounds and as a mixture. For a few of these APIs, additional eco-toxicological data will need to be developed. Using similar conservative assumptions for human-health risks, all 15 APIs present negligible risk through ingestion of water and fish.

Ethinyl estradiol and other human pharmaceutical estrogens in the aquatic environment: a review of recent risk assessment data.

Interest in pharmaceuticals in the environment has increased substantially in recent years. Several studies in particular have assessed human and ecological risks from human pharmaceutical estrogens, such as 17α-ethinyl estradiol (EE2). Regulatory action also has increased, with the USA and other countries developing rules to address estrogens and other pharmaceuticals in the environment. Accordingly, the Center for Drug Evaluation and Research at the US Food and Drug Administration has conducted a review and analysis of current data on the long-term ecological exposure and effects of EE2 and other estrogens. The results indicate that mean-flow long-term predicted environmental concentrations (PECs) of EE2 in approximately 99% or more of US surface water segments downstream of wastewater treatment plants are lower than a predicted no-effect concentration (PNEC) for aquatic chronic toxicity of 0.1 ng/L. Exceedances are expected to be primarily in localized, effluent-dominated water segments. The median mean-flow PEC is more than two orders of magnitude lower than this PNEC. Similar results exist for other pharmaceutical estrogens. Data also suggest that the contribution of EE2 more broadly to total estrogenic load in the environment from all sources (including other human pharmaceutical estrogens, endogenous estrogens, natural environmental estrogens, and industrial chemicals), while highly uncertain and variable, appears to be relatively low overall. Additional data and a more comprehensive approach for data collection and analysis for estrogenic substances in the environment, especially in effluent-dominated water segments in sensitive environments, would more fully characterize the risks.