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Psychoactive drugs are frequently detected in the aquatic environment. The evolutionary conservation of the molecular targets of these drugs in fish suggests that they may elicit mode of action–mediated effects in fish as they do in humans, and the key open question is at what exposure concentrations these effects might occur. In the present study, the authors investigated the uptake and tissue distribution of the benzodiazepine oxazepam in the fathead minnow (Pimephales promelas) after 28 d of waterborne exposure to 0.8 μg L−1, 4.7 μg L−1, and 30.6 μg L−1. Successively, they explored the relationship between the internal concentrations of oxazepam and the effects on fish exploratory behavior quantified by performing 2 types of behavioral tests, the novel tank diving test and the shelter-seeking test. The highest internal concentrations of oxazepam were found in brain, followed by plasma and liver, whereas muscle presented the lowest values. Average concentrations measured in the plasma of fish from the 3 exposure groups were, respectively, 8.7 ± 5.7 μg L−1, 30.3 ± 16.1 μg L−1, and 98.8 ± 72.9 μg L−1. Significant correlations between plasma and tissue concentrations of oxazepam were found in all 3 groups. Exposure of fish to 30.6 µg L−1 in water produced plasma concentrations within or just below the human therapeutic plasma concentration (HTPC) range in many individuals. Statistically significant behavioral effects in the novel tank diving test were observed in fish exposed to 4.7 μg L−1. In this group, plasma concentrations of oxazepam were approximately one-third of the lowest HTPC value. No significant effects were observed in fish exposed to the lowest and highest concentrations. The significance of these results is discussed in the context of the species-specific behavior of fathead minnow and existing knowledge of oxazepam pharmacology. Environ Toxicol Chem 2016;35:2782–2790. © 2016 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. © 2016 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. ; The present study was funded by Brunel University(London, UK), the Spanish Ministry of Economy and Competitivenessthrough the project WATER-Fate (CTM2012-38314-C0201), and theEuropean Union through the European Regional Development Fund. Thepresent study was partly supported by the Economy and KnowledgeDepartment of the Catalan government (Consolidated Research Group 2014SGR 291-ICRA). S. Rodriguez-Mozaz acknowledges Ramon y Cajalresearch fellowship RYC-2014-16707 from the Spanish Ministry ofEconomy and Competitiveness. ; Peer reviewed

This paper presents 10 recommendations for improving the European Medicines Agency's guidance for environmental risk assessment of human pharmaceutical products. The recommendations are based on up-to-date, available science in combination with experiences from other chemical frameworks such as the REACH-legislation for industrial chemicals. The recommendations concern: expanding the scope of the current guideline; requirements to assess the risk for development of antibiotic resistance; jointly performed assessments; refinement of the test proposal; mixture toxicity assessments on active pharmaceutical ingredients with similar modes of action; use of all available ecotoxicity studies; mandatory reviews; increased transparency; inclusion of emission data from production; and a risk management option. We believe that implementation of our recommendations would strengthen the protection of the environment and be beneficial to society. Legislation and guidance documents need to be updated at regular intervals in order to incorporate new knowledge from the scientific community. This is particularly important for regulatory documents concerning pharmaceuticals in the environment since this is a research field that has been growing substantially in the last decades.

The EDEN project is an interdisciplinary effort conceived to address key issues that have hampered sound hazard and risk assessment for endocrine disrupting chemicals (EDCs) in the European Union. It has adopted an approach that fully integrates human, wildlife, exposures, mechanisms and low-dose/mixture evaluations. The project was structured into four interlocking themes focusing on EDC mixture exposures, mechanisms of action and novel endpoints, effects on male reproductive health and the evaluation of low-dose and mixture effects of EDCs. For the first time, the simultaneous occurrence of nearly 150 different EDCs in human and wildlife tissues was measured. These studies revealed that numerous EDCs occur together in humans, yet differences in the levels of individual EDCs in specimens from boys with cryptorchidism and from women suffering from breast cancer and their respective controls did not become apparent. It appears that the likelihood of developing any of the above conditions cannot be attributed to any individual chemical at relevant exposure levels. However, there are signs that simultaneous exposure to many different EDCs may play a cumulative role in these disease processes. This means that efforts to develop biomarkers of cumulative EDC exposure should be re-doubled. In contrast, symptoms of endocrine disruption in fish could be explained largely in terms of exposure to estrogenic chemicals, but the possible role of antiandrogenic chemicals in disrupting sexual development in fish requires urgent attention. Fish caught in certain Dutch rivers exceeded the EU permissible levels for polychlorinated dioxins and furans. Considerable progress has been made in establishing relevant modes of action of EDCs and in assessing new endpoints. The screening for EDCs, with its focus on steroid receptor interactions, has not kept up with the progress made in understanding rapid cellular signalling events that occur in the wake of receptor activation. In the interest of avoiding overlooking endocrine active agents it is necessary to expand screening tools to capture rapid signalling events. Substantial progress has been also achieved in characterising the role of the aromatase system in fish as a target of EDCs and the consequences of steroid synthesis disruption on sexual differentiation, reproduction as well as non-reproductive processes such as neurodifferentiation. Extensive investigations of the role of certain phthalates in disrupting male sexual development have revealed delays in germ cell differentiation and other molecular effects as key events underlying the induction of the testicular dysgenesis syndrome. The role of the InsL3 protein in promoting male sexual development proved to be more complex than thought previously. Although the development and validation of an assay for the measurement of InsL3 blood levels was successful, the differences in blood InsL3 levels in normal and cryptorchid boys were too small to exploit InsL3 as a biomarker indicative of disruption of testis descent. The hypothalamic pituitary unit proved to be exquisitely sensitive to the effects of several EDCs, and the effects may account for precocious sexual development observed after early EDC exposure. EDEN has advanced the study of endocrine disruption in fish with activities including the development of microarrays for assessing endocrine disruption in zebrafish and establishing sensitive screening tools for endocrine disruption in fish. The development of a transgenic fish model for the detection of EDC effects proved to be technically too demanding to be completed in time, but efforts continue to complete this project after conclusion of EDEN. An in vivo model in fish (the three-spined stickleback) for the detection of antiandrogenic EDC was developed as a complement to the Hershberger assay. Male reproductive health in Denmark and Finland showed a worrying declining trend. For the first time, it could be established that the same is true for young men in Germany. It is of concern that semen quality among young Germans is similar to the values found in young Danes, a group previously thought to show the lowest semen quality in Europe. Foetal exposure to smoking has been identified as one reason for these effects. Observations of a declining total natural conception rate among the young Danish cohorts imply that the current poor semen quality has an impact on the population fertility in the future – a situation which will be difficult to reverse in the short term. The current and projected widespread use of assisted reproductive technologies may be a sign of such an emerging public health problem which also adds to the load of medical costs in young population. It is of vital importance to continue surveillance of semen quality and all efforts should be made to identify the factors that may cause harm in order to prevent further deterioration. Extensive low-dose studies with EDCs have shown that the conventional estimation of no-observed-adverse-effect-levels (NOAEL), with their reliance on hypothesis testing methods is inadequate for capturing low-dose effects of EDCs. Whenever possible, regression-based approaches with benchmark dose limits should replace NOAEL as the basis for establishing acceptable human exposure levels. A framework was developed to combine the strengths of both methodologies by making considerations of statistical detection limits and statistical power the starting point of testing procedures. Implementation of this framework will require a significant change in toxicological testing practice. Determinants of additivity for EDC mixtures have been characterised and are now well understood for combinations of similarly acting EDCs. Experimental studies have produced evidence that EDCs of relatively low potency and at low exposure levels can still work together to produce significant combination effects when they are present in sufficient numbers. The perceived low potency of many EDCs alone is uninformative in anticipating possible risks stemming from these chemicals. Where EDCs act in concert with endogenous hormones, significant additional effects may result under certain circumstances. Uncertainty still exists in relation to the likelihood of synergistic mixture effects, and concerted efforts should be made to fill this gap. Another source of uncertainty that will hamper sound EDC mixture risk assessment is incomplete knowledge about the identity of EDCs, their exposure levels and number. This issue can only be resolved through the development of dedicated exposure assessment strategies that take account of cumulative exposures. Despite these uncertainties, knowledge about determinants and factors that govern the joint action of similarly acting EDCs is now sufficiently advanced to come to pragmatic risk assessment approaches that take mixture effects into consideration. A modus operandi for EDC mixtures was developed which includes the use of dose addition (including the toxic equivalency factor approach) to arrive at a "mixture no-observed-adverse-effect-level" (MNOAEL) for endpoints relevant to endocrine disruption. These are then combined with a safety factor to arrive at estimates of tolerable human exposure. "Data-poor" situations may require estimation of a crude MNOAEL by dividing individual NOAEL of certain prototype chemicals by the anticipated number of relevant similarly acting chemicals. ; European Commission, FP5 "Quality of Life and Management of Living Resources": Contract No. QLK4-CT2002-00603.