Pharmaceuticals are known to occur widely in the environment of industrialized countries. In developing countries, more monitoring results have recently become available, but a concise picture of measured environmental concentrations (MECs) is still elusive. Through a comprehensive literature review of 1016 original publications and 150 review articles, the authors collected MECs for human and veterinary pharmaceutical substances reported worldwide in surface water, groundwater, tap/drinking water, manure, soil, and other environmental matrices in a comprehensive database. Due to the heterogeneity of the data sources, a simplified data quality assessment was conducted. The database reveals that pharmaceuticals or their transformation products have been detected in the environment of 71 countries covering all continents. These countries were then grouped into the 5 regions recognized by the United Nations (UN). In total, 631 different pharmaceutical substances were found at MECs above the detection limit of the respective analytical methods employed, revealing distinct regional patterns. Sixteen substances were detected in each of the 5 UN regions. For example, the anti-inflammatory drug diclofenac has been detected in environmental matrices in 50 countries, and concentrations found in several locations exceeded predicted no-effect concentrations. Urban wastewater seems to be the dominant emission pathway for pharmaceuticals globally, although emissions from industrial production, hospitals, agriculture, and aquaculture are important locally. The authors conclude that pharmaceuticals are a global challenge calling for multistakeholder approaches to prevent, reduce, and manage their entry into and presence in the environment, such as those being discussed under the Strategic Approach to International Chemicals Management, a UN Environment Program. Environ Toxicol Chem 2016;35:823-835. # 2015 SETAC

During the past two decades scientists, regulatory agencies and the European Commission have acknowledged pharmaceuticals to be an emerging environmental problem. In parallel, a regulatory framework for environmental risk assessment (ERA) of pharmaceutical products has been developed. Since the regulatory guidelines came into force the German Federal Agency (UBA) has been evaluating ERAs for human and veterinary pharmaceutical products before they are marketed. The results show that approximately 10% of pharmaceutical products are of note regarding their potential environmental risk. For human medicinal products, hormones, antibiotics, analgesics, antidepressants and antineoplastics indicated an environmental risk. For veterinary products, hormones, antibiotics and parasiticides were most often discussed as being environmentally relevant. These results are in good correlation with the results within the open scientific literature of prioritization approaches for pharmaceuticals in the environment. UBA results revealed that prospective approaches, such as ERA of pharmaceuticals, play an important role in minimizing problems caused by pharmaceuticals in the environment. However, the regulatory ERA framework could be improved by (i) inclusion of the environment in the risk–benefit analysis for human pharmaceuticals, (ii) improvement of risk management options, (iii) generation of data on existing pharmaceuticals, and (iv) improving the availability of ERA data. In addition, more general and integrative steps of regulation, legislation and research have been developed and are presented in this article. In order to minimize the quantity of pharmaceuticals in the environment these should aim to (i) improve the existing legislation for pharmaceuticals, (ii) prioritize pharmaceuticals in the environment and (iii) improve the availability and collection of pharmaceutical data.

The veterinary parasiticide ivermectin was selected as a case study compound within the project ERAPharm (Environmental Risk Assessment of Pharmaceuticals). Based on experimental data generated within ERAPharm and additional literature data, an environmental risk assessment (ERA) was performed mainly according to international and European guidelines. For the environmental compartments surface water, sediment, and dung, a risk was indicated at all levels of the tiered assessment approach. Only for soil was no risk indicated after the lower tier assessment. However, the use of effects data from additional 2-species and multispecies studies resulted in a risk indication for collembolans. Although previously performed ERAs for ivermectin revealed no concern for the aquatic compartment, and transient effects on dung-insect populations were not considered as relevant, the present ERA clearly demonstrates unacceptable risks for all investigated environmental compartments and hence suggests the necessity of reassessing ivermectin-containing products. Based on this case study, several gaps in the existing guidelines for ERA of pharmaceuticals were shown and improvements have been suggested. The action limit at the start of the ERA, for example, is not protective for substances such as ivermectin when used on intensively reared animals. Furthermore, initial predicted environmental concentrations (PECs) of ivermectin in soil were estimated to be lower than refined PECs, indicating that the currently used tiered approach for exposure assessment is not appropriate for substances with potential for accumulation in soil. In addition, guidance is lacking for the assessment of effects at higher tiers of the ERA, e.g., for field studies or a tiered effects assessment in the dung compartment.

The present study investigated the growth inhibition effect of the fluoroquinolone antibiotics enrofloxacin and ciprofloxacin on four photoautotrophic aquatic species: the freshwater microalga Desmodesmus subspicatus, the cyanobacterium Anabaena flos-aquae, the monocotyledonous macrophyte Lemna minor, and the dicotyledonous macrophyte Myriophyllum spicatum. Both antibiotics, which act by inhibiting the bacterial DNA gyrase, demonstrated high toxicity to A. flos-aquae and L. minor and moderate to slight toxicity to D. subspicatus and M. spicatum. The cyanobacterium was the most sensitive species with median effective concentration (EC50) values of 173 and 10.2 µg/L for enrofloxacin and ciprofloxacin, respectively. Lemna minor proved to be similarly sensitive, with EC50 values of 107 and 62.5 µg/L for enrofloxacin and ciprofloxacin, respectively. While enrofloxacin was more toxic to green algae, ciprofloxacin was more toxic to cyanobacteria. Calculated EC50s for D. subspicatus were 5,568 µg/L and >8,042 µg/L for enrofloxacin and ciprofloxacin, respectively. These data, as well as effect data from the literature, were compared with predicted and reported environmental concentrations. For two of the four species, a risk was identified at ciprofloxacin concentrations found in surface waters, sewage treatment plant influents and effluents, as well as in hospital effluents. For ciprofloxacin the results of the present study indicate a risk even at the predicted environmental concentration. In contrast, for enrofloxacin no risk was identified at predicted and measured concentrations.

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β-Adrenergic receptor blockers (β-blockers) are applied to treat high blood pressure, ischemic heart disease, and heart rhythm disturbances. Due to their widespread use and limited human metabolism, β-blockers are widely detected in sewage effluents and surface waters. β-Adrenergic receptors have been characterized in fish and other aquatic animals, so it can be expected that physiological processes regulated by these receptors in wild animals may be affected by the presence of β-blockers. Because ecotoxicological data on β-blockers are scarce, it was decided to choose the β-blocker atenolol as a case study pharmaceutical within the project ERAPharm. A starting point for the assessment of potential environmental risks was the European guideline on the environmental risk assessment of medicinal products for human use. In Phase I of the risk assessment, the initial predicted environmental concentration (PEC) of atenolol in surface water (500 ng L−1) exceeded the action limit of 10 ng L−1. Thus, a Phase II risk assessment was conducted showing acceptable risks for surface water, for groundwater, and for aquatic microorganisms. Furthermore, atenolol showed a low potential for bioaccumulation as indicated by its low lipophilicity (log KOW = 0.16), a low potential for exposure of the terrestrial compartment via sludge (log KOC = 2.17), and a low affinity for sorption to the sediment. Thus, the risk assessment according to Phase II-Tier A did not reveal any unacceptable risk for atenolol. Beyond the requirements of the guideline, additional data on effects and fate were generated within ERAPharm. A 2-generation reproduction test with the waterflea Daphnia magna resulted in the most sensitive no-observed-effect concentration (NOEC) of 1.8 mg L−1. However, even with this NOEC, a risk quotient of 0.003 was calculated, which is still well below the risk threshold limit of 1. Additional studies confirm the outcome of the environmental risk assessment according to EMEA/CHMP (2006). However, atenolol should not be considered as representative for other β-blockers, such as metoprolol, oxprenolol, and propranolol, some of which show significantly different physicochemical characteristics and varying toxicological profiles in mammalian studies.

The serotonin re-uptake inhibitor fluoxetine was selected for an environmental risk assessment, using the most recent European guideline (EMEA 2006) within the European Union (EU)-funded Environmental Risk Assessment of Pharmaceuticals (ERAPharm) project due to its environmental persistence, acute toxicity to nontarget organisms, and unique pharmacokinetics associated with a readily ionizable compound. As a widely prescribed psychotropic drug, fluoxetine is frequently detected in surface waters adjacent to urban areas because municipal wastewater effluents are the primary route of entry to aquatic environments. In Phase I of the assessment, the initial predicted environmental concentration of fluoxetine in surface water (initial PEC(SW)) reached or exceeded the action limit of 10 ng/L, when using both a default market penetration factor and prescription data for Sweden, Germany, and the United Kingdom. Consequently, a Phase II risk assessment was conducted in which green algae were identified as the most sensitive species with a NOEC of <0.6 microg/L. From this value, a predicted no effect concentration for surface waters (PNEC(SW)) of 0.012 microg/L was derived. The PEC/PNEC ratio was above the trigger value of 1 in worst-case exposure scenarios indicating a potential risk to the aquatic compartment. Similarly, risks of fluoxetine for sediment-dwelling organisms could not be excluded. No risk assessment was conducted for the terrestrial compartment due to a lack of data on effects of fluoxetine on soil organisms. The need for a separate risk assessment for the main metabolite of fluoxetine, norfluoxetine, was not conducted because of a lack of fate and effect studies. Based on published data, fluoxetine and norfluoxetine appeared to have a low to moderate bioaccumulation potential, which should be confirmed in formal studies according to OECD guidelines. Exposure assessments for fluoxetine according to the current framework rely heavily on K(OC) and K(OW) values. This approach is problematic, because fluoxetine is predominantly a cationic substance at environmental pH values. Consequently, the fate of fluoxetine (and other ionic substances) cannot be predicted using partition coefficients established for nonionic compounds. Further, published estimates for partition coefficients of fluoxetine vary, resulting in considerable uncertainties in both the exposure and environmental risk assessments of fluoxetine.