Pharmaceuticals in the environment: An introduction to the <i>ET&amp;C</i> special issue

It has now been more than 15 yr since the defining articles by Daughton and Ternes 1 and Halling-Sørensen 2 identified pharmaceuticals in the environment as an important issue. Subsequently, a study by Kolpin et al. 3 confirmed the widespread presence of pharmaceuticals in freshwater ecosystems, leading to intensive research in that field. Since then, numerous studies have reported the presence of pharmaceuticals in environmental matrices that were directly or indirectly receiving wastewater discharges (human pharmaceuticals) and animal wastes (veterinary pharmaceuticals) 4. The ability to detect pharmaceuticals in environmental matrices at increasingly lower sub–parts per billion concentrations drove this development to a large extent, making risk assessment of environmentally realistic exposure scenarios all the more challenging. In addition to having diverse physicochemical properties, pharmaceuticals as a class of compounds are designed to have a broad range of therapeutic modes of action. Given the conservation of biological receptors across species, it was expected that the presence of pharmaceuticals in environmental matrices might have adverse ecotoxicological implications 1, 5. Indeed, this was demonstrated in the mid 2000s through predictable 6 and unpredictable 7 exposures and subsequent devastating effects on fish and birds. Other studies showing such dramatic ecotoxicological implications for pharmaceuticals, however, have been much less prevalent than those merely measuring their presence and, to a lesser extent, their fate in the environment. Pharmaceuticals have clear health, economic and societal benefits, and restricting their use to avoid environmental risks is not desirable. Their responsible use, however, not only is attractive to reduce environmental impacts but also helps improve healthcare outcomes and costs 8. Unlike other contaminant classes (such as personal care products), pharmaceuticals are well-studied compounds and have substantial available data on their fate and effects in mammalian systems, which can be used to better understand their environmental hazards and risks 9-11. In 2009, a decade after the first publications highlighted pharmaceuticals in the environment as an issue for environmental research, assessment, and management, Environmental Toxicology and Chemistry (ET&C) published a special issue on the topic to distill the main findings from a decade of intense and growing scientific interest. It was apparent from that special issue that research interest in this area was becoming more refined. Following an increasing number of reports demonstrating the widespread contamination of freshwater systems with pharmaceuticals, their bioavailability was demonstrated in freshwater fish 12, along with the recognition that this could have consequences for ecologically significant effects on behavior 13 and development 14. At the same time, challenges in the ecotoxicological assessment of metabolites and mixtures were identified 15, 16. Furthermore, the issue of perceived potency was addressed in numerous papers with respect to endocrine active pharmaceuticals, cytotoxic pharmaceuticals, and selective serotonin re-uptake inhibitors 13, 14, 17-19. The fate of pharmaceuticals in compartments other than freshwater, the use of readily available pharmacological data, and the potential consequences of the effects of antibiotics on bacterial communities also received some attention 20, 21. The likely global presence of pharmaceuticals beyond the traditionally scrutinized environments in North America and Europe was also highlighted 20, 22. Based on the contributions to that first ET&C special issue on pharmaceuticals in the environment, recommendations for future work focused on the prioritization of pharmaceuticals for environmental assessment to enable better use of limited resources 23. Establishing the importance of environmental processes that determine their ultimate fate in the environment, how this affects exposure assessments, and the implications on bioavailability in a range of environmental compartments were considered critical for a predictive understanding. With respect to effects assessment, it was recommended that the knowledge generated during the registration process of pharmaceuticals should be used for improving decisions related to environmental hazards and risks. The importance of understanding the mode of action of a pharmaceutical in nontarget organisms also was highlighted. Seven years after that first ET&C special issue, it is obvious that scientific interest in the issue of pharmaceuticals in the environment is still strong, measured, for example, in the sheer quantity of peer-reviewed publications and meeting abstracts. The number of contributions submitted to the present special issue is also indicative of the ongoing research interest in the topic. In this context, it is worth noting that SETAC's Pharmaceuticals Advisory Group (PAG) did not preselect the content of the present special issue, and thus the special issue represents a true reflection of the current work in the field. Prioritization strategies is one area that has received considerable attention in the present special issue and elsewhere in the literature, with a number of articles proposing risk-based approaches, taking into account not only anticipated exposure levels but also the relative potency of the compounds 24-29. Despite some differences in the composition of prioritization lists, the represented pharmaceutical classes overlap and include antibiotics, selective serotonin reuptake inhibitors (SSRIs), antidepressants, endocrine active pharmaceuticals, and nonsteroidal anti-inflammatory drugs. Although the presence of pharmaceuticals in the environment used in such prioritization strategies can be predicted based largely on their usage volumes, it is critical to ensure that social and cultural factors also are taken into account, as they can greatly influence both temporal and geographical variability 30. In the absence of environmental exposure or effects assessments, Berninger et al. 31 outline how available mammalian pharmacological data can be used to rank the likely hazards of pharmaceuticals to fish. This highlights the value of pre-existing data, an important distinction from other environmental contaminants 9, 11. However, using such information for predicting relevant effects in nontarget organisms in the environment remains problematic. Numerous studies in the present special issue focused on SSRIs, which target the well-conserved neurotransmitter serotonin in humans, all highlighting the potential for their effects at low concentrations 32-35. Exposure of fish to SSRI mixtures was demonstrated to influence the levels of serotonin in the brain, with potential behavioral consequences 34. The reasons for observed effects in invertebrates are less clear, with nonmonotonic dose–response relationships, large interspecies variability, and serotonin-independent effects apparent 32. Other less predictable effects of SSRIs include a decrease in the expression of microRNA, which is usually related to endocrine function 35, and an increase in T lymphocyte production in fish 33. Furthermore, the bioavailability of ionizable pharmaceuticals, such as SSRIs. is likely to be variable in a range of environments and organisms 32, 36, adding even more complexity to their environmental assessment. Additionally, it has long been recognized that the assessment of mixture effects is critical for a realistic assessment of pharmaceuticals in the environment. This also presents a major challenge for ecotoxicologists because of inherent complexities in study design and interpretation 37. Pharmaceuticals have well-defined interactions when used as therapeutic mixtures within the relatively stable internal environment of mammals, and this knowledge could be explored further to improve the understanding of mixture toxicity in nontarget organisms 37. In contrast to the known and comparatively stable mixture composition found in target organisms, wastewater contains highly variable loads of pharmaceuticals, whose effects are further modified by fluctuating water quality parameters. This was highlighted by a number of ecotoxicological studies in the present special issue in which nonmonotonic dose–response and temporal variations in endpoint values occurred 33, 34, 38. When Brodin et al. 39 demonstrated that exposure to a single concentration of a benzodiazepine increases activity and reduces sociality in fish, the effects of pharmaceuticals on behavioral traits attracted widespread scientific attention. Two studies in the present special issue noted reduced feeding rates and aggression in fish following exposure to mixtures of SSRIs, opioids, and benzodiazepine 33, 34, although the implications of such changes in behavior at different levels of biological organization remain to be fully understood. Such integrative ecotoxicological approaches hold much promise for characterizing the environmental risks of pharmaceuticals, despite their inherent variability. More work is needed, however, to correlate physiological responses to population-level effects 23. The complex patterns often found in ecotoxicological data for pharmaceuticals reflects not only the physiological and ecological complexity of exposed organisms and communities but also the temporal variability of pharmaceutical concentrations and the fluctuating physicochemical properties of the receiving environments, both of which affect the bioavailable fractions of pharmaceuticals and the overall risk to exposed organisms 40. Research focus previously has been on freshwater systems, and marine ecosystems have been identified here as being underrepresented and requiring further investigation 41. This is particularly important in coastal environments, where human impacts are pronounced and dynamic, in terms of daily physicochemical cycles; the use of innovative methods for examining bioavailability and potential risks to marine organisms is therefore highly desirable 40, 42. In addition, the terrestrial environment increasingly is receiving attention, especially with respect to crop exposure through wastewater and biosolids application. Other terrestrial pathways, however, such as inputs of veterinary medicines 43 or landfill leachates 44, still receive comparatively little attention. As our understanding of the geographic and temporal variability of pharmaceuticals in the environment increases, the assessment of pharmaceuticals thought to be already well-characterized continues to evolve. For example, environmental quality standards accepted by some jurisdictions for carbamazepine, a commonly encountered antiepileptic pharmaceutical, are likely to be exceeded in several exposure scenarios 45. Elucidating the role of environmental processes for causing antimicrobial resistance might also warrant increased attention in the future, particularly because antibiotics are commonly detected in various ecosystems. For example, sulfamethoxazole is ubiquitous in aquatic urban environments throughout the United States, confirming previous studies 46, 47, but its impact on antimicrobial resistance is largely unknown 48. So far, SETAC as a society has not been engaged much in research on antimicrobial resistance, but our members' collective skills in environmental chemistry, ecotoxicology, and environmental sciences make us well placed to provide important contributions to this critical global issue in the future. Given their importance and widespread use in human society, pharmaceuticals are expected to occur globally, yet only a fraction of the pharmaceuticals on the market are monitored. More strategic monitoring programs are required 30, 47, 49, adequately considering pharmacology (e.g., pharmacokinetics, therapeutic potency), geography (e.g., urban density, healthcare or manufacturing facilities, hydrology, environments receiving discharges), societal factors (e.g., use preferences, prevalence of disease, social acceptance), and economic factors (e.g., wealth, healthcare access, subsidies). Such activities will be critical for an effective use of resources and an improved understanding of the risks of pharmaceuticals in environmentally realistic settings 50. Using such information is especially critical as awareness of the global nature of pharmaceuticals in the environment gains increased recognition even in the absence of monitoring information 51. Innovative approaches for identifying the most likely compounds to be present in the environment are needed to enable the effective design of monitoring programs. This is especially pertinent to jurisdictions where previous assumptions may be tenuous because, for example, prescription data is not readily available, therapeutic dosing does not follow indicated uses in human and veterinary applications, and different discharge pathways into the environment may exist 50, 52. As wealth and population increase in regions of low- to medium-income nations in Asia, Africa, and the Americas, pharmaceutical use and entry into the environment also will increase 50. This is caused by the globalization not only of markets for therapeutic use but also of manufacturing facilities, with the need for managing not only environmental but also relevant social risks 53, 54. The expertise of SETAC members will be critical in providing sound scientific advice to policymakers, regulatory bodies, and industry to enable them to make the most effective decisions, based on environmental risks, economic limitations, and societies' expectations. We hope that the studies in the present special issue will make a contribution toward providing new understanding and more refined approaches, thus stimulating further interest relating to the assessment of pharmaceuticals in the environment. We also hope that future special issues relating to pharmaceuticals in the environment will be forthcoming in ET&C, building on the work highlighted in the present issue as well as research priorities identified elsewhere 4. The multidisciplinary and global nature of SETAC is ideally suited to inform regional and global understanding of environmental risks of pharmaceuticals—through engagement not only with regulators and industry but increasingly with human health professionals, environmental engineers, social scientists, nongovernment organizations, economists, and others—to enable socially relevant, economically viable, and technically effective management of pharmaceuticals in the environment. Mike Williams CSIRO Land and Water South Australia, Australia Thomas Backhaus Department of Biological and Environmental Sciences University of Gothenburg Gothenburg, Sweden Craig Bowe Department of Science Ohio University Ironton, OH, USA Kyungho Choi School of Public Health Seoul National University Seoul, Republic of Korea Kristin Connors Oak Ridge Institute for Science and Education Oak Ridge, TN, USA Silke Hickmann Environmental Risk Assessment of Pharmaceuticals German Environment Agency Dessau-Roßlau, Germany Wesley Hunter Center for Veterinary Medicine US Food and Drug Administration Rockville, MD, USA Rai Kookana CSIRO Land and Water South Australia, Australia Ruth Marfil-Vega American Water Belleville, IL, USA Tim Verslycke Gradient Cambridge, MA, USA We would like to acknowledge the vast contributions not included in the present special issue that other groups have made to this area of research. Specifically, we would like to highlight the great contributions to this area of research made by M. Schultz (Wooster University, Wooster, OH, USA), who tragically died before she could submit her intended paper to the present special issue. The body of research she published has given us a great insight into the presence and fate of pharmaceuticals (particularly SSRIs), and her substantive and creative contributions will be sorely missed.

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