Environmental exposure to active pharmaceutical ingredients (APIs) can have negative effects on the health of ecosystems and humans. While numerous studies have monitored APIs in rivers, these employ different analytical methods, measure different APIs, and have ignored many of the countries of the world. This makes it difficult to quantify the scale of the problem from a global perspective. Furthermore, comparison of the existing data, generated for different studies/regions/continents, is challenging due to the vast differences between the analytical methodologies employed. Here, we present a global-scale study of API pollution in 258 of the world’s rivers, representing the environmental influence of 471.4 million people across 137 geographic regions. Samples were obtained from 1,052 locations in 104 countries (representing all continents and 36 countries not previously studied for API contamination) and analyzed for 61 APIs. Highest cumulative API concentrations were observed in sub-Saharan Africa, south Asia, and South America. The most contaminated sites were in low- to middle-income countries and were associated with areas with poor wastewater and waste management infrastructure and pharmaceutical manufacturing. The most frequently detected APIs were carbamazepine, metformin, and caffeine (a compound also arising from lifestyle use), which were detected at over half of the sites monitored. Concentrations of at least one API at 25.7% of the sampling sites were greater than concentrations considered safe for aquatic organisms, or which are of concern in terms of selection for antimicrobial resistance. Therefore, pharmaceutical pollution poses a global threat to environmental and human health, as well as to delivery of the United Nations Sustainable Development Goals.

This study used a geographic based water model to predict the environmental concentrations of 9 three pharmaceuticals 17-ethinylestradiol (EE2), 17-estradiol (E2) and diclofenac throughout 10 European rivers. The work was prompted by the proposal of the European Community 11 (COM(2011)876) to consider these chemicals as candidates for future control via environmental 12 quality standards (EQS). National drug consumption information, excretion, national water use, and 13 sewage removal rates, were used to derive per capita sewage effluent values for the European 14 countries . For E2, excretion rates of the natural hormone and national demographics were also 15 included. Incorporating this information into the GWAVA model allowed water concentrations 16 throughout Europe's rivers to be predicted. The mean concentration from the expected sewage 17 discharge scenario indicated that 12% by length of Europe's rivers would reach concentrations 18 greater than the proposed 0.035 ng/L EQS for EE2. For several countries, between a quarter and a 19 third of their total river length would fail such an EE2 EQS. For E2, just over 1% by length of rivers 20 would reach concentrations greater than the 0.4 ng/L proposed EQS, whilst just over 2% by length of 21 rivers would reach concentrations greater than the proposed EQS of 100 ng/L for diclofenac. 22 Key words 23Ethinylestradiol, estradiol, diclofenac, river water, model, prediction, environmental quality 24 standard, Europe 25 2 Introduction 26

Environmental risk assessment of pharmaceuticals requires the determination of their environmental exposure concentrations. Existing exposure modeling approaches are often computationally demanding, require extensive data collection and processing efforts, have a limited spatial resolution, and have undergone limited evaluation against monitoring data. Here, we present ePiE (exposure to Pharmaceuticals in the Environment), a spatially explicit model calculating concentrations of active pharmaceutical ingredients (APIs) in surface waters across Europe at ∼1 km resolution. ePiE strikes a balance between generating data on exposure at high spatial resolution while having limited computational and data requirements. Comparison of model predictions with measured concentrations of a diverse set of 35 APIs in the river Ouse (UK) and Rhine basins (North West Europe), showed around 95% were within an order of magnitude. Improved predictions were obtained for the river Ouse basin (95% within a factor of 6; 55% within a factor of 2), where reliable consumption data were available and the monitoring study design was coherent with the model outputs. Application of ePiE in a prioritisation exercise for the Ouse basin identified metformin, gabapentin, and acetaminophen as priority when based on predicted exposure concentrations. After incorporation of toxic potency, this changed to desvenlafaxine, loratadine, and hydrocodone.

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This paper presents a screening tool for the location-specific prioritization of human pharmaceutical emissions in Europe, based on risk quotients for the aquatic environment and human health. The tool provides direction towards either monitoring activities or additional research. Its application is illustrated for a set of 11 human antibiotics and 7 antineoplastics. Risk quotients for the aquatic environment were highest for levofloxacin, doxycycline and ciprofloxacin, located in Northern Italy (Milan region; particularly levofloxacin) and other densely populated areas in Europe (e.g. London, Krakow and the Ruhr area). Risk quotients for human health not only depend on pharmaceutical and location, but also on behavioral characteristics, such as consumption patterns. Infants in eastern Spain that consume locally produced food and conventionally treated drinking water were predicted to run the highest risks. A limited comparison with measured concentrations in surface water showed that predicted and measured concentrations are approximately within one order of magnitude.