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Veröffentlichung Prospective environmental risk assessment of mixtures in wastewater(2018) Coors, Anja; Vollmar, Pia; Sacher, Frank; Hassold, Enken; Polleichtner, Christian; Gildemeister, Daniela; Kühnen, UteThe aquatic environment is continually exposed to a complex mixture of chemicals, whereby effluents of wastewater treatment plants (WWTPs) are one key source. The aim of the present study was to investigate whether environmental risk assessments (ERAs) addressing individual substances are sufficiently protective for such coincidental mixtures. Based on a literature review of chemicals reported to occur in municipal WWTP effluents and mode-of-action considerations, four different types of mixtures were composed containing human pharmaceuticals, pesticides, and chemicals regulated under REACH. The experimentally determined chronic aquatic toxicity of these mixtures towards primary producers and the invertebrate Daphnia magna could be adequately predicted by the concept of concentration addition, with up to 5-fold overestimation and less than 3-fold underestimation of mixture toxicity. Effluents of a municipal WWTP had no impact on the predictability of mixture toxicity and showed no adverse effects on the test organisms. Predictive ERAs for the individual mixture components based on here derived predicted no effect concentrations (PNECs) and median measured concentrations in WWTP effluents (MCeff) indicated no unacceptable risk for any of the individual chemicals, while MCeff/PNEC summation indicated a possible risk for multi-component mixtures. However, a refined mixture assessment based on the sum of toxic units at species level indicated no unacceptable risks, and allowed for a safety margin of more than factor 10, not taking into account any dilution of WWTP effluents by surface waters. Individual substances, namely climbazole, fenofibric acid and fluoxetine, were dominating the risks of the investigated mixtures, while added risk due to the mixture was found to be low with the risk quotient being increased by less than factor 2. Yet, uncertainty remains regarding chronic mixture toxicity in fish, which was not included in the present study. The number and identity of substances composing environmental mixtures such as WWTP effluents is typically unknown. Therefore, a mixture assessment factor is discussed as an option for a prospective ERA of mixtures of unknown composition. © 2018 Elsevier Ltd. All rights reserved.Veröffentlichung Environmental fate and effects assessment of human pharmaceuticals: lessons learnt from regulatory data(2021) Gildemeister, Daniela; Hein, Arne; Schröder, Patrick; Bachmann, Jean; Schwarz, SimonHuman pharmaceuticals are extensively studied and assessed before marketing approval. Since 2006, this also includes an assessment of environmental risks. In the European Union, this is based on the guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00 corr 2), which is currently under revision. For Germany, the German Environment Agency (UBA) is tasked with the evaluation of environmental risks of human pharmaceuticals. Applicants seeking approval of medicinal products need to submit fate and effect data, in case predicted environmental concentrations (PECs) exceed 10 ng/L in surface waters, or the substance is of specific concern through its mode of action or physico-chemical characteristics. Over the last decade, this regulatory work resulted in an internal agency database containing effect data on approximately 300 active pharmaceutical ingredients (APIs). A considerable part of this data is currently not publicly available due to property rights held by the respective applicants. The database was evaluated to draw conclusions on how the current assessment approach may be improved. The evaluation of aquatic effect data shows considerable variation in ecotoxic effect concentrations, but supports the current use of 10 ng/L as PEC action limit. For endocrine-active substances and antibiotics, a clear sensitivity profile was observed, which allows a more targeted assessment in the future. The conclusions drawn from terrestrial effect data are less clear, as the database itself is biased because information is only available for substances with high sorption. Further adaptations of the terrestrial assessment strategy, including action triggers, appear necessary. Fate data show a high persistence of many APIs: approximately 43% of all APIs are classified as very persistent; 12% of these show DT50 values in a range where abiotic or biotic degradation is not expected. Overall, the evaluation has shown that improvements of the current guideline are possible. © The Author(s) 2021Veröffentlichung Improving the regulatory environmental risk assessment of human pharmaceuticals: Required changes in the new legislation(2023) Gildemeister, Daniela; Moermond, Caroline T.A.; Berg, CeciliaOne of the flagship actions of the Pharmaceutical Strategy for Europe is to address environmental challenges associated with pharmaceutical use. This includes strengthening the Environmental Risk Assessment (ERA) at marketing authorisation (MA) of pharmaceuticals, and revision of the pharmaceutical legislation where needed. The overall aim of an ERA should be to enable comprehensive and effective identification and management of environmental risks of pharmaceuticals without affecting the availability of pharmaceuticals to patients. As experts in the evaluation of ERAs of human medicinal products submitted by pharmaceutical industries (Applicants), we have summarized the current status of the ERA and suggest legislative changes to improve environmental protection without affecting availability. Six regulatory goals were defined and discussed, including possible ways forward: 1) mandatory ERAs in accordance to the EMA guideline at the time of the MA, 2) enforcement of risk mitigation measures including re-evaluation of the ERA, 3) facilitated exchange of environmental data between pharmaceutical and environmental legislations, 4) substance-based assessments, 5) transparency of data, and 6) a catching-up procedure for active pharmaceutical ingredients that lack an ERA. These legislative proposals can be considered as prerequisites for a harmonised assessment and effective management of environmental risks and hazards of human pharmaceuticals. © 2023 The Authors.Veröffentlichung Proposal for regulatory risk mitigation measures for human pharmaceutical residues in the environment(2023) Moermond, Caroline T.A.; Berg, Cecilia; Bergstrom, Ulrika; Gildemeister, DanielaEnvironmental risks of human pharmaceutical products should be made transparent and mitigated as far as possible. We propose to apply a risk mitigation scheme to the marketing authorisation of human medicinal products which is pragmatic and tailored, and thus will not increase the burden to regulators and industry too much. This scheme takes into account increasing knowledge and accuracy of the environmental risk estimates, applying preliminary risk mitigation when risks are determined based on model estimates, and definitive, more strict and far-reaching risk mitigation when risks are based on actual measured environmental concentrations. Risk mitigation measures should be designed to be effective, proportional, easy to implement, and in line with current (other) legislation, as well as not being a burden to the patient/health care professionals. Furthermore, individual risk mitigation measures are proposed for products showing environmental risks, while general risk mitigation measures can be applied to all products to reduce the overall burden of pharmaceuticals in the environment. In order to effectively mitigate risk, linking marketing authorisation legislation to environmental legislation is essential. © 2023 The Authors