Residues of pharmaceuticals in the environment can cause significant ecotoxicological issues but they also pose an imminent risk for human health e.g. by pollution of water resources used for food and drinking water production. Many active substances of pharmaceuticals for human use and their metabolites have been identified in the environment worldwide. To maintain water quality a variety of approaches during a pharmaceutical lifecycle are urgently needed, spanning actions from development, production over dispensing to end-of-pipe advanced wastewater treatments. In this paper, we report about a recently developed eco-directed pharmaceutical prescribing concept for Germany capable to trigger a significant beginning-of-the-pipe effect. The proposed system aims to balance therapeutical needs and environmental impacts by including ecotoxicological information and classification into pharmaceutical and medical decision making within the praxis of prescribing and dispensing medicines. We reviewed relevant existing eco-directed classification systems from Sweden, Finland, and Scotland. Based on these three different systems, we propose a practical environmental information, classification and dissemination system tailored to the German healthcare system, which combines positions from stakeholders including those responsible for regulation and health related data. Our results can be highly relevant to approaches aiming to establish similar systems in further countries. We identified the database ChemInfo hosted by the German Environment Agency as the central information system, for collecting environmental information from market authorisation processes. Our novel traffic light classification system is based on the hazard and risk outcomes of the environmental risk assessment and presents for the first time a European wide applicable environmental classification, capable of ranking pharmaceuticals within an indication group and identifying substances of concern to support decision making.The classification system will label all pharmaceuticals, recently added to the EU list of priority substances within the Water Framework Directive, in red. Finally, we identified eight dissemination systems through which this information and classification can be included into decision making.

Abstract Environmental Threshold Concentrations (ETCs), such as the Predicted No Effect Concentrations (PNECs) and European Environmental Quality Standards (EQSs), represent the concentration of a chemical in an environmental compartment at or below which no adverse effects are expected. While multiple ETCs may exist for a given substance across regulatory frameworks and scientific literature, selecting the most useful value can be challenging. Even when only one ETC exists, its usefulness must be evaluated. This paper addresses this challenge by providing a systematic and stepwise framework for selecting and interpreting ETCs, with a focus on human pharmaceuticals and European regulatory frameworks. However, the ideas behind this may be applied more broadly. The proposed approach begins by defining the context of the assessment and the associated protection goals. It then requires a systematic evaluation of all available ETCs, regarding their relevance and reliability. This includes the use of the most appropriate methodology and underlying data, as well as newly published information. It also considers overall uncertainties, the need to address chronic or short-term peak exposures, and whether the ETCs have been independently reviewed. We apply the framework to metoprolol to demonstrate its usefulness in ensuring that ETCs used in environmental assessments and management decisions are robust and fit for purpose.

The One Health concept strongly brings into focus the important connections for human and ecosystem health. However, the incorporation of behavior method guidelines in risk assessment and regulation/policy is not equal between human and ecological disciplines. A survey was conducted on the perceptions and role of behavioral (eco)toxicology in the protection of human and ecosystem health. Those surveyed include scientists working in the field of environmental toxicology and behavioral ecology, representing industry, government, nongovernment organizations, and academia/research centers. The respondents (N = 166) agreed that contaminants "can impact" and "are impacting" wildlife (97% and 77%) and humans (84% and 62%, respectively). Overall respondents believed behavioral experiments to be repeatable (60%), reliable (61%), and relevant (84%), although those not studying behavior (43%) were more cautious in their answers. Respondents were more likely to be neutral when asked whether behavioral endpoints are more sensitive (43%), but they agreed (80%) that behavioral endpoints provide important alternative information to standard endpoints. The largest group disagreed (42%) with the statement that behavioral endpoints are currently used in risk assessment but agreed that they were essential (55%). The majority of respondents disagreed (63%) that we understood the risks of contaminants to human and ecosystem health, but they agreed (68%) that regulatory authorities should consider behavioral endpoints. When answers were compared among sectors (academia, government, or industry), industry scientists were more likely to be negative or neutral in their responses to the application of behavioral toxicology. We discuss how these data could be used to support our understanding of and confidence in the effects of contaminants on human and ecosystem health.

Behavioural analysis has been attracting significant attention as a broad indicator of sub-lethal toxicity and has secured a place as an important subdiscipline in ecotoxicology. Among the most notable characteristics of behavioural research, compared to other established approaches in sub-lethal ecotoxicology (e.g. reproductive and developmental bioassays), are the wide range of study designs being used and the diversity of endpoints considered. At the same time, environmental hazard and risk assessment, which underpins regulatory decisions to protect the environment from potentially harmful chemicals, often recommends that ecotoxicological data be produced following accepted and validated test guidelines. These guidelines typically do not address behavioural changes, meaning that these, often sensitive, effects are not represented in hazard and risk assessments. Here, we propose a new tool, the EthoCRED evaluation method, for assessing the relevance and reliability of behavioural ecotoxicity data, which considers the unique requirements and challenges encountered in this field. This method and accompanying reporting recommendations are designed to serve as an extension of the "Criteria for Reporting and Evaluating Ecotoxicity Data (CRED)" project. As such, EthoCRED can both accommodate the wide array of experimental design approaches seen in behavioural ecotoxicology, and could be readily implemented into regulatory frameworks as deemed appropriate by policy makers of different jurisdictions to allow better integration of knowledge gained from behavioural testing into environmental protection. Furthermore, through our reporting recommendations, we aim to improve the reporting of behavioural studies in the peer-reviewed literature, and thereby increase their usefulness to inform chemical regulation.

Leverett et al. commented on the Environmental quality standard (EQS) for diclofenac derived under the European Water Framework Directive [Leverett et al. (2021) Environ Sci Eur 33: 133 https://doi.org/10.1186/s12302-021-00574-z]. They postulated that the derivation of the EQS value for diclofenac is not conducted according to the EQS Technical Guidance, but rather using data of poor reliability and relevance. Consequently, the authors suggested using their alternative derived value instead. It is to be noted that the process for the EQS derivation for diclofenac is still ongoing and not finalized, and that as a consequence, any critical analysis is very premature. In general, within the current European Commission process, EQS values proposals are derived by expert groups led by the Joint Research Centre. In the specific case for diclofenac, Leverett et al. have also been actively involved as experts. This response to Leverett et al. (2021) aims to clarify the reasoning behind the proposal from a scientific point of view and to express our concern for the lack of transparency of their position in the statement of competing interests. Indeed, the authors did not disclose their participation in the expert group for deriving the diclofenac EQS value, nor that they have direct and indirect ties to a company that markets diclofenac in Europe, Glaxo Smith & Kline plc (GSK). This amounts to a significant conflict of interest and leads to disinformation to the reader.

The European Union intends to implement a horizontal and coherent approach for the identification of endocrine disruptors (ED) across all relevant legislations, based on the broadly accepted definition given by the World Health Organisation in its International Programme on Chemical Safety. With regard to this, the European Commission is currently undertaking a “fitness-check” across all relevant European legal frameworks to analyze whether ED are adequately addressed in each regulation and to propose measures to close identified gaps. However, different regulatory approaches exist in different parts of European legislation for substances identified as ED. The pesticides applied in agriculture (i.e., plant-protection products (PPPs)) and biocides regulations contain a similar provision requiring ED identification through scientific criteria, but the approach differs slightly between the two pieces of legislation. For PPPs, substances with particularly hazardous properties are excluded from market authorization. This includes also intended ED in invertebrates, despite the fact that these substances provide a relatively specific toxicity and, therefore, typically a rather low toxicity for vertebrate taxa. For biocides, intended ED in invertebrates are excluded from these exclusion or “cut-off criteria.” The European Regulation for the Registration, Evaluation, Authorization and Restriction of Chemicals’ legislation specifically mentions ED as substances that can be identified as Substances of Very High Concern, if they are of equivalent level of concern when compared with carcinogenic, mutagenic, or toxic for reproduction; persistent, bioaccumulative, and toxic; or very persistent and very bioaccumulative substances. The use and import of ED in products and articles can also be restricted, if a concern for human health and/or the environment is identified. In contrast, all pharmaceuticals, including ED, are assessed based on risk. However, the risk assessment should reflect the specific mode of action of the substance tested. Consequently, the most sensitive taxa should be tested, and the test should cover the most sensitive life stage and the most sensitive endpoint.

Environmental Toxicology and ChemistryVolume 41, Issue 3 p. 541-543 Introduction Pharmaceuticals in the Environment: Just One Stressor Among Others or Indicators for the Global Human Influence on Ecosystems? Gerd Maack, Corresponding Author Gerd Maack gerd.maack@uba.de German Environment Agency, Dessau-Roßlau, Germany Address correspondence to gerd.maack@uba.deSearch for more papers by this authorMike Williams, Mike Williams Commonwealth Scientific and Industrial Research Organisation Land and Water, Adelaide, South Australia, AustraliaSearch for more papers by this authorThomas Backhaus, Thomas Backhaus University of Gothenburg, Gothenburg, SwedenSearch for more papers by this authorLaura Carter, Laura Carter University of Leeds, Leeds, UKSearch for more papers by this authorSigrun Kullik, Sigrun Kullik Canadian Food Inspection Agency, Ottawa, Ontario, CanadaSearch for more papers by this authorDean Leverett, Dean Leverett WCA Environment, Faringdon, UKSearch for more papers by this authorFabiana L. Lo Nostro, Fabiana L. Lo Nostro Universidad de Buenos Aires and Consejo Nacional de Investigaciones Cientificas y Técnicas, Ciudad Autónoma de Buenos Aires, ArgentinaSearch for more papers by this authorJ. Brett Sallach, J. Brett Sallach University of York, York, UKSearch for more papers by this authorJane Staveley, Jane Staveley Exponent, Cary, North Carolina, USASearch for more papers by this authorChris Van den Eede, Chris Van den Eede Zoetis, Zaventum, BelgiumSearch for more papers by this author Gerd Maack, Corresponding Author Gerd Maack gerd.maack@uba.de German Environment Agency, Dessau-Roßlau, Germany Address correspondence to gerd.maack@uba.deSearch for more papers by this authorMike Williams, Mike Williams Commonwealth Scientific and Industrial Research Organisation Land and Water, Adelaide, South Australia, AustraliaSearch for more papers by this authorThomas Backhaus, Thomas Backhaus University of Gothenburg, Gothenburg, SwedenSearch for more papers by this authorLaura Carter, Laura Carter University of Leeds, Leeds, UKSearch for more papers by this authorSigrun Kullik, Sigrun Kullik Canadian Food Inspection Agency, Ottawa, Ontario, CanadaSearch for more papers by this authorDean Leverett, Dean Leverett WCA Environment, Faringdon, UKSearch for more papers by this authorFabiana L. Lo Nostro, Fabiana L. Lo Nostro Universidad de Buenos Aires and Consejo Nacional de Investigaciones Cientificas y Técnicas, Ciudad Autónoma de Buenos Aires, ArgentinaSearch for more papers by this authorJ. Brett Sallach, J. Brett Sallach University of York, York, UKSearch for more papers by this authorJane Staveley, Jane Staveley Exponent, Cary, North Carolina, USASearch for more papers by this authorChris Van den Eede, Chris Van den Eede Zoetis, Zaventum, BelgiumSearch for more papers by this author First published: 22 November 2021 https://doi.org/10.1002/etc.5256Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume41, Issue3March 2022Pages 541-543 This article also appears in:Pharmaceuticals in the Environment: Advances in Exposure, Hazard and Risk Assessment RelatedInformation

For decades, we have known that chemicals affect human and wildlife behavior. Moreover, due to recent technological and computational advances, scientists are now increasingly aware that a wide variety of contaminants and other environmental stressors adversely affect organismal behavior and subsequent ecological outcomes in terrestrial and aquatic ecosystems. There is also a groundswell of concern that regulatory ecotoxicology does not adequately consider behavior, primarily due to a lack of standardized toxicity methods. This has, in turn, led to the exclusion of many behavioral ecotoxicology studies from chemical risk assessments. To improve understanding of the challenges and opportunities for behavioral ecotoxicology within regulatory toxicology/risk assessment, a unique workshop with international representatives from the fields of behavioral ecology, ecotoxicology, regulatory (eco)toxicology, neurotoxicology, test standardization, and risk assessment resulted in the formation of consensus perspectives and recommendations, which promise to serve as a roadmap to advance interfaces among the basic and translational sciences, and regulatory practices.

Interest in behavioural ecotoxicology is growing, partly due to technological and computational advances in recording behaviours but also because of improvements of detection capacity facilitating reporting effects at environmentally relevant concentrations. The peer-reviewed literature now contains studies investigating the effects of chemicals, including pesticides and pharmaceuticals, on migration, dispersal, aggression, sociability, reproduction, feeding and anti-predator behaviours in vertebrates and invertebrates. To understand how behavioural studies could be used in regulatory decision-making we: (1) assessed the legal obstacles to using behavioural endpoints in EU chemicals regulation; (2) analysed the known cases of use of behavioural endpoints in EU chemicals regulation; and (3) provided examples of behavioural endpoints of relevance for population level effects. We conclude that the only legal obstacle to the use of behavioural endpoints in EU chemicals regulation is whether an endpoint is considered to be relevant at the population level or not. We also conclude that ecotoxicity studies investigating behavioural endpoints are occasionally used in the EU chemicals regulation, and underscore that behavioural endpoints can be relevant at the population level. To improve the current use of behavioural studies in regulatory decision-making contribution from all relevant stakeholders is required. We have the following recommendations: (1) researchers should conduct robust, well-designed and transparent studies that emphasize the relevance of the study for regulation of chemicals; (2) editors and scientific journals should promote detailed, reliable and clearly reported studies; (3) regulatory agencies and the chemical industry need to embrace new behavioural endpoints of relevance at the population level.

• 9 recommendations digest recent developments in regulatory environmental risk assessment. • Efforts are necessary to make the translation of ecotoxicology into regulatory decisions more open and transparent. • They require concerted and sustained action from a variety of sectors and stakeholders. • Better evidence will lead to better decisions, sustainable innovation and a healthier environment.

The release of endocrine active substances (EAS) into the environment can have effects on the aquatic community. Due to a very direct route of exposure and the similarity of the endocrine systems in vertebrates, fish are in the main focus of environmental science and research. The release of human and veterinary pharmaceuticals is steadily increasing. Moreover, the progress in drug development results in the design of new and more specific acting and potent molecules. There are already several known substances, which act at very low concentration levels and finally cause adverse effects in aquatic organisms. The regulation of pharmaceuticals considers the impact on the environment. However, the standard Environmental Risk Assessment (ERA) procedure is not able to cover all Mode of Actions (MoA). Beside others, EAS need a tailored risk assessment strategy. Currently, only for estrogen, androgen and aromatase inhibitors, MoA tailored ERA strategies are available. A current project of the German Environment Agency (UBA) aims to develop tailored risk assessment strategies for the groups of progestins and glucocorticoids. Effects on aquatic vertebrates, invertebrates and sediment dwellers will be recorded within this project, and should build a database for developing this adapted assessment strategy. For fish, a Zebrafish extended one generation reproduction test (ZEOGRT) was conducted, as the endpoints in this test can address all potential and relevant MoA. Here, we present first results of the project, for which dienogest was chosen as a model substance for progestins.

Trenbolone acetate is widely used in some parts of the world for its desirable anabolic effects on livestock. Several metabolites of the acetate, including 17β‐trenbolone, have been detected at low nanograms per liter concentrations in surface waters associated with animal feedlots. The 17β‐trenbolone isomer can affect androgen receptor signaling pathways in various vertebrate species at comparatively low concentrations/doses. The present article provides a comprehensive review and synthesis of the existing literature concerning exposure to and biological effects of 17β‐trenbolone, with an emphasis on potential risks to aquatic animals. In vitro studies indicate that, although 17β‐trenbolone can activate several nuclear hormone receptors, its highest affinity is for the androgen receptor in all vertebrate taxa examined, including fish. Exposure of fish to nanograms per liter water concentrations of 17β‐trenbolone can cause changes in endocrine function in the short term, and adverse apical effects in longer exposures during development and reproduction. Impacts on endocrine function typically are indicative of inappropriate androgen receptor signaling, such as changes in sex steroid metabolism, impacts on gonadal stage, and masculinization of females. Exposure of fish to 17β‐trenbolone during sexual differentiation in early development can greatly skew sex ratios, whereas adult exposures can adversely impact fertility and fecundity. To fully assess ecosystem‐level risks, additional research is warranted to address uncertainties as to the degree/breadth of environmental exposures and potential population‐level effects of 17β‐trenbolone in sensitive species. Environ Toxicol Chem 2018;37:2064–2078. Published 2018 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

In the present study, existing regulatory frameworks and test systems for assessing potential endocrine active chemicals are described, and associated challenges are discussed, along with proposed approaches to address these challenges. Regulatory frameworks vary somewhat across geographies, but all basically evaluate whether a chemical possesses endocrine activity and whether this activity can result in adverse outcomes either to humans or to the environment. Current test systems include in silico, in vitro, and in vivo techniques focused on detecting potential endocrine activity, and in vivo tests that collect apical data to detect possible adverse effects. These test systems are currently designed to robustly assess endocrine activity and/or adverse effects in the estrogen, androgen, and thyroid hormone signaling pathways; however, there are some limitations of current test systems for evaluating endocrine hazard and risk. These limitations include a lack of certainty regarding: 1) adequately sensitive species and life stages; 2) mechanistic endpoints that are diagnostic for endocrine pathways of concern; and 3) the linkage between mechanistic responses and apical, adverse outcomes. Furthermore, some existing test methods are resource intensive with regard to time, cost, and use of animals. However, based on recent experiences, there are opportunities to improve approaches to and guidance for existing test methods and to reduce uncertainty. For example, in vitro high‐throughput screening could be used to prioritize chemicals for testing and provide insights as to the most appropriate assays for characterizing hazard and risk. Other recommendations include adding endpoints for elucidating connections between mechanistic effects and adverse outcomes, identifying potentially sensitive taxa for which test methods currently do not exist, and addressing key endocrine pathways of possible concern in addition to those associated with estrogen, androgen, and thyroid signaling. Integr Environ Assess Manag 2017;13:302–316. © 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)

Agencies responsible for environmental protection are tasked with developing regulatory guidance that is based on the best available scientific evidence. Histopathology is a common endpoint in toxicologic bioassays; however, because of the subjective nature of this endpoint, and the advanced level of specialized training required for its effective utilization, the reliability of histopathology data can be inconsistent. Consequently, mechanisms for evaluating such data on a case‐by‐case basis are needed. The purposes of the present review are to describe a methodology that can be used to evaluate the credibility of histopathology findings and to discuss the results of such assessments as applied to real‐world data collected from the scientific literature. A key outcome of these efforts was the finding that only 54% of the studies examined contained histopathology data that were considered to be either highly credible or credible, whereas data in 46% of those studies were of equivocal, dubious, or no credibility. In addition, the results indicated that the quality of the data examined tended to decline during the past 15 yr. The ultimate goals of the present review are to draw attention to reliability issues that can affect histopathology results, provide recommendations to improve the quality of this endpoint, and suggest an approach for the expeditious and judicious use of histopathology data in the weight‐of‐evidence determinations required for hazard and/or risk assessment. This exercise was conducted initially as part of a SETAC Pellston Workshop™ entitled “Environmental Hazard and Risk Assessment Approaches for Endocrine‐Active Chemicals (EHRA): Developing Technical Guidance Based on Case Studies to Support Decision Making” that was held in Pensacola, Florida (USA) from 31 January to 5 February 2016. Environ Toxicol Chem 2017;36:601–611. © 2016 SETAC

A SETAC Pellston Workshop (R) Environmental Hazard and Risk Assessment Approaches for Endocrine-Active Substances (EHRA) was held in February 2016 in Pensacola, Florida, USA. The primary objective of the workshop was to provide advice, based on current scientific understanding, to regulators and policy makers; the aim being to make considered, informed decisions on whether to select an ecotoxicological hazard- or a risk-based approach for regulating a given endocrine-disrupting substance (EDS) under review. The workshop additionally considered recent developments in the identification of EDS. Case studies were undertaken on 6 endocrine-active substances (EAS-not necessarily proven EDS, but substances known to interact directly with the endocrine system) that are representative of a range of perturbations of the endocrine system and considered to be data rich in relevant information at multiple biological levels of organization for 1 or more ecologically relevant taxa. The substances selected were 17-ethinylestradiol, perchlorate, propiconazole, 17-trenbolone, tributyltin, and vinclozolin. The 6 case studies were not comprehensive safety evaluations but provided foundations for clarifying key issues and procedures that should be considered when assessing the ecotoxicological hazards and risks of EAS and EDS. The workshop also highlighted areas of scientific uncertainty, and made specific recommendations for research and methods-development to resolve some of the identified issues. The present paper provides broad guidance for scientists in regulatory authorities, industry, and academia on issues likely to arise during the ecotoxicological hazard and risk assessment of EAS and EDS. The primary conclusion of this paper, and of the SETAC Pellston Workshop on which it is based, is that if data on environmental exposure, effects on sensitive species and life-stages, delayed effects, and effects at low concentrations are robust, initiating environmental risk assessment of EDS is scientifically sound and sufficiently reliable and protective of the environment. In the absence of such data, assessment on the basis of hazard is scientifically justified until such time as relevant new information is available. Integr Environ Assess Manag 2017;13:267-279. (C) 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)

Ecological risk assessments and risk management decisions are only as sound as the underlying information and processes to integrate them. It is important to develop transparent and reproducible procedures a priori to integrate often-heterogeneous evidence. Current weight-of-evidence (WoE) approaches for effects or hazard assessment tend to conflate aspects of the assessment of the quality of the data with the strength of the body of evidence as a whole. We take forward recent developments in the critical appraisal of the reliability and relevance of individual ecotoxicological studies as part of the effect or hazard assessment of prospective risk assessments and propose a streamlined WoE approach. The aim is to avoid overlap and double accounting of criteria used in reliability and relevance with that used in current WoE methods. The protection goals, problem formulation, and evaluation process need to be clarified at the outset. The data are first integrated according to lines of evidence (LoEs), typically mechanistic insights (e.g., cellular, subcellular, genomic), in vivo experiments, and higher-tiered field or observational studies. Data are then plotted on the basis of both relevance and reliability scores or categories. This graphical approach provides a means to visually assess and communicate the credibility (reliability and relevance of available individual studies), quantity, diversity, and consistency of the evidence. In addition, the external coherence of the body of evidence needs to be considered. The final step in the process is to derive an expression of the confidence in the conclusions of integrating the information considering these 5 aspects in the context of remaining uncertainties. We suggest that this streamlined approach to WoE for the effects or hazard characterization should facilitate reproducible and transparent assessments of data across different regulatory requirements. Integr Environ Assess Manag 2017;13:573-579. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).