Defining the data gap: what do we know about environmental exposure, hazards and risks of pharmaceuticals in the European aquatic environment?

Active pharmaceutical ingredients (APIs) and their transformation products inevitably enter waterways where they might cause adverse effects to aquatic organisms. Identifying the potential risks of APIs in the environment is therefore a goal and current strategic direction of environmental management described in the EU Strategic Approach to Pharmaceuticals in the Environment and the Green Deal. This is challenged by a paucity of monitoring and ecotoxicity data to adequately describe risks. In this study we analyze measured environmental concentrations (MECs) of APIs from 5933 sites in 25 European countries as documented in the EMPODAT database or collected by the German Environment Agency for the time period between 1997 to 2020. These data were compared with empirical data on the ecotoxicity of APIs from the U.S. EPA ECOTOX database. Although 1763 uniquely identifiable APIs are registered with the European Medicines Agency (EMA) for sale in the European Economic Area (EEA), only 312 (17.7%) of these are included in publicly available monitoring data, and only 36 (1.8%) compounds have sufficient ecotoxicological data to perform an EMA-compliant ERA. Among the 27 compounds with sufficient exposure and hazard data to conduct a single substance risk assessment according to EMA guidelines, four compounds (14.8%) had a median risk quotient (RQ) > 1. Endocrine disruptors had the highest median RQ, with 7.0 and 5.6 for 17α-ethinyl-estradiol and 17β-estradiol respectively. A comparison of in-silico and empirical data for 72 APIs demonstrated the high protectiveness of the current EMA guidelines, with predicted environmental concentrations (PECs) exceeding median MECs in 98.6% of cases, with a 100-fold median increase. This study describes the data shortfalls hindering an accurate assessment of the risk posed to European waterways by APIs, and identifies 68 APIs for prioritized inclusion in monitoring programs, and 66 APIs requiring ecotoxicity testing to fill current data gaps. Highlights 1763 medicines are EMA-approved for sale in the EEA The data gap is 1201 APIs (68%) that have no ecotoxicity or public monitoring data Only 27 APIs (1.5%) have sufficient empirical data for risk assessment. ERA using 23 years of EU monitoring data shows four compounds with a median RQ > 1 Data gap APIs prioritized for monitoring programs (68) and ecotoxicity testing (66)