Pharmaceuticals and Personal Care Products in the Environment: What Progress Has Been Made in Addressing the Big Research Questions?

Pharmaceuticals and personal care products (PPCPs) include numerous chemical classes to prevent or treat human and animal disease or improve the quality of daily life of humans. During the life cycles of these products, it is inevitable that they will be released to the natural environment. It is, therefore, not surprising that a wide range of ingredients used in PPCPs has been detected widely in surface waters, soils, sediments, and groundwaters across the world (Aus der Beek et al., 2016; Wilkinson et al., 2022). Pharmaceuticals and many personal care products are biologically active compounds that are designed to interact with specific pathways and processes in targets in humans and animals. Concerns have therefore been raised about the potential effects of PPCPs in the environment on public health, biodiversity, and ecosystem services. Since the late 1990s, a substantial amount of work has been done to determine the occurrence, fate, effects, and risks of PPCPs in the environment. Recognizing the concerns around PPCPs in the environment and the value in providing some focus for research in the area, in 2011 the Pharmaceutical Advisory Group of the Society of Environmental Toxicology and Chemistry (SETAC) initiated a horizon scanning exercise to identify the top research questions related to pharmaceuticals in the environment. The hope then was that the results of the exercise would help in informing the design, coordination, and implementation of future environmental research programs on PPCPs and thus provide a better understanding of the potential and relative risks of these substances in the natural environment, allowing us to more effectively control and manage these risks. The exercise employed a "key question" approach where research questions were Initially solicited from academic, government, and business communities around the world. A list of 101 questions was then discussed at an international expert workshop, and a top-20 list was developed, with these questions falling into seven categories: (1) prioritization of substances for assessment, (2) pathways of exposure, (3) bioavailability and uptake, (4) effects characterization, (5) risk and relative risk, (6) antibiotic resistance, and (7) risk management. Following the workshop these questions were ranked by importance. In 2012, the results of this exercise were published in a review paper in Environmental Health Perspectives entitled "Pharmaceuticals and Personal Care Products in the Environment: What Are the Big Questions" (Boxall et al., 2012). Since publication, this paper has had significant impact on the research community, being cited over 1000 times. The exercise also provided a foundation for the broader SETAC Global Horizon Scanning Exercise, which identified priority research questions around sustainable environmental quality in North America, Asia, Australasia, Europe, and Latin America. The questions from this exercise have been published in a series of papers covering each of the geographical regions (Gaw et al., 2019; Fairbrother et al., 2019; Furley et al., 2018; Leung et al., 2020; van den Brink et al., 2018). As 2022 was the 10th anniversary of the Environmental Health Perspectives publication, we felt that it would be timely to review the state of the science around the questions identified in the PPCP 20 questions paper and to look forward to the next 10 years. This special issue has therefore been developed where leading researchers from around the world were invited to give their perspectives on the current level of knowledge around the different questions identified in the 2012 paper and to identify new research questions related to each topic area that are a priority for research over the next decade. In developing their manuscripts, authors were asked to consider the topic area of the question from multiple perspectives—scientific, regulatory, technical—and to go well beyond their own work. We asked that the papers give an authoritative and up-to-date understanding of the subject matter relating to the question. This special issue, therefore, provides an overview of the current state of the science around 14 of the 20 key questions (Table 1) and a forward-looking synthesis on research priorities for the coming years. Pharmaceuticals and Personal Care Products in the Aquatic Environment: How Can Regions at Risk Be Identified in the Future? Taken together, the papers in the special issue show that significant progress has been made since 2012 in developing our understanding of the inputs, occurrence, fate, effects, and risks of PPCPs in the environment and of advancing approaches to characterize and manage PPCP risks. In terms of prioritization, a range of exposure-, hazard-, and risk-based approaches have been developed and applied to identify PPCPs of most concern in the environment (Mo et al., 2024). These approaches have now been applied to a wide range of geographies, giving us an insight into which PPCPs are of most concern in different regions of the world (Mo et al., 2024). We now have a much improved understanding of the uptake of PPCPs into organisms. Progress here has been made on the development of models to estimate the uptake of ionizable PPCPs into invertebrates, fish, earthworms, and plants (Carter et al., 2024). These developments have been supported by developments in in vitro testing methodologies and increasing access to machine learning modeling methodologies, such as artificial neural networks (Carter et al., 2024). Significant progress has been made in the development of methods to extrapolate from effects of PPCPs in humans to effects in the natural environment. For pharmaceuticals, we have now moved from the evaluation of single-drug targets in organisms to an understanding of the conservation of all know drug targets in a wide range of species (Margiotta-Casaluci et al., 2024). Alongside this, there have been major advances in the development of adverse outcome pathways (AOPs) for PPCPs from different molecular initiation events, providing us with a much stronger foundation for extrapolating molecular-level effects to effects on whole organisms (Brooks et al., 2024; Margiotta-Casaluci et al., 2024). The experimental effects testing area has seen the development of a range of new approach methodologies aimed at reducing the use of whole-animal tests, including approaches for bioaccumulation, weight-of-evidence approaches, and omics-based applications (Langan et al., 2024). The last decade has also seen an increase in the amount of data on the ecotoxicological interactions of mixtures of pharmaceuticals, including mixture effects at the molecular level; and this has helped us to evaluate mixture toxicity models for estimating the effects of pharmaceutical mixtures (Kidd et al., 2024). Significant developments in methodologies for effects-directed analyses, including increasing access to high-resolution mass spectrometry for nontargeted analysis, means that we are now much better placed to identify drivers of toxicity in complex and undefined mixtures (Kidd et al., 2024). Increasing availability of openly available software systems, such as ECODrug, SeqAPASS, MAPPFAST, AOPwiki, and sources of toxicity ecotoxicity data (e.g., REACH dossiers, ToxCast), means that the research community is much better placed to understand the effects of PPCPs on aquatic and terrestrial organisms (Ankley et al., 2024; Margiotta-Casaluci et al., 2024) and to advance the precision of environmental assessments (Brooks et al., 2024). In the past decade, the number of PPCPs monitored in the environment has risen, and there has been increasing access to data on the occurrence of PPCPs across the globe (Wilkinson et al., 2024). Alongside this improvement, there have been significant developments in exposure modeling approaches, such as ePiE, PhATE, STREAM-EU, and GLOBAL-FATE, which provide exposure predictions at much finer scales than before (Wilkinson et al., 2024). This progress has allowed risks of PPCPs to be assessed more broadly and supported the identification of the drivers of risks in different regions of the world (Wilkinson et al., 2024). In terms of risks to terrestrial wildlife, we have an improved understanding for select PPCP classes, such as the nonsteroidal inflammatory drugs, euthanasia products, veterinary parasiticides, and estrogens, with the focus being on avian species (Bean et al., 2024). It is still questionable, however, as to whether we really have an understanding yet of the real impacts of PPCPs in the environment (Sumpter et al., 2024). For example, an evaluation of the results of current prospective risk-assessment approaches with effects data for real systems indicated that true exposure and impacts of PPCPs might still be underestimated using current regulatory risk-assessment approaches (Oldenkamp et al., 2024). Increasing concerns over the links between antimicrobial resistance (AMR) and human health have resulted in a wealth of work on the impacts of chemicals, particularly antibiotics, on resistance selection. We now have a much improved understanding of the mechanisms of selection and drivers of AMR in the environment (Manaia et al., 2024). The last decade has seen an increase in the volume of laboratory-derived data on minimal selective concentrations, concentrations shown to promote horizontal gene transfer, and the development of new methodologies to derive predicted-no-effect concentrations (PNECs) for resistance (Manaia et al., 2024; Stanton et al., 2024). The evidence that environmental exposure to PPCPs is contributing to the AMR crisis is now much stronger, with comparisons of monitoring data with PNECs indicating risks of selection in some regions, associations being found between the occurrence of PPCPs in the environment and resistance selection and human acquisition of resistance being demonstrated from some environmental settings (Stanton et al., 2024). Alongside the advances in understanding exposure, effects and risks, the risk-management landscape is now very different from 2012. Concerns over PPCP exposure in the environment are now much higher up the policy agenda, with pharmaceutical pollution now being recognized as an issue by organizations such as the United Nations Environment Programme and the World Health Organization. The European Union has recently adopted a strategic approach to pharmaceuticals in the environment (Helwig et al., 2024). Work on risk management has begun to consider the whole life cycle and to approach the problem from a one health perspective with a much wider range of strategies to manage risk being considered/explored, including better health promotion to reduce pharmaceutical use, green chemistry to design less harmful pharmaceuticals and to produce medicines with lower pollution profiles, changes in prescription practices, and improved waste and wastewater management and treatment (Helwig et al., 2024). Despite the many advances in our understanding of the impacts of PPCPs on the natural environment and how to manage them, there are still significant gaps in our knowledge; and all of the special issue papers highlight areas where more work is needed. Many of the papers stress the need for broadening the research to include a much wider range of geographical areas (Oldenkamp et al., 2024; Wilkinson et al., 2024), chemicals and chemical classes (Ankley et al., 2024; Carter et al., 2024), and species and life stages (Brooks et al., 2024). On the effects side, approaches for extrapolating from molecular-level interactions to higher levels of organization need to become more quantitative, including broader taxonomic domains of applicability (Brooks et al., 2024); and more focus needs to be placed on the functional endpoints that really matter for pollution prevention and the protection of biodiversity and ecosystem services (Brooks et al., 2024; Margiotta-Casaluci et al., 2024). Work on mixtures needs to move away from considering effects following short-term exposures of single species to considering effects of chronic exposure on food webs (Kidd et al., 2024). It is impossible to study everything, so to deliver all of this will require a more systematic approach to generate the necessary in vitro and in vivo data to support these analyses (Ankley et al., 2024; Kidd et al., 2024). Improved access to data for a range of stakeholders would help facilitate a better understanding of the environmental risks of PPCPs (Oldenkamp et al., 2024). More focus is needed on underrepresented geographies that are likely vulnerable to PPCP impacts (Oldenkamp et al., 2024). Exposure modeling efforts also need to move toward working at finer temporal resolutions and to include factors such as pH that will modify the impacts of PPCPs (Carter et al., 2024; Wilkinson et al., 2024). More use needs to be made of effects-based approaches (e.g., batteries of in vitro and in vivo methods) and in-field ecological monitoring (Oldenkamp et al., 2024). Work needs to continue to understand the role the environment plays in the risk of AMR to human health (Manaia et al., 2024). We also need to widen the work to consider the impacts of a range of non-antibiotic contaminants on levels of resistance in the environment and start to consider potential mixture interactions and risks from an AMR perspective (Manaia et al., 2024; Stanton et al., 2024). While major strides have been made in the management of the risks of PPCPs, policy in the area needs to become much stronger so that solutions are implemented more rapidly and equitably around the world. Human health needs to be better integrated into the management process, and a move to a one health approach could be highly beneficial here (Helwig et al., 2024). Work on PPCPs in the coming decade will benefit from a wide range of "new" methodologies that are introduced in papers in the special issue. These include citizen science to monitor PPCPs (Wilkinson et al., 2024); non-invasive monitoring tools for monitoring uptake into and effects on organisms (Bean et al., 2024); new approach methodologies that minimize the use of animals (Ankley et al., 2024; Bean et al., 2024; Langan et al., 2024); genetic modification methods, such as clustered, regularly interspaced short palindromic repeats, coupled with new imaging methods (Margiotta-Casaluci et al., 2024); omics methods (Brooks et al., 2024; Manaia et al., 2024); high-throughput experimental testing methods—for example, high-throughput absorption, distribution, metabolism, and excretion tests (ADME; Kidd et al., 2024; Margiotta-Casaluci et al., 2024); machine learning approaches (Carter et al., 2024; Margiotta-Casaluci et al., 2024); and other advanced modeling methods such as Bayesian physiologically based pharmacokinetic models, population-based ADME simulators, hidden Markov models, and population ecology and bioenergetic tools (Brooks et al., 2024; Manaia et al., 2024; Margiotta-Casaluci et al., 2024). The big questions identified by Boxall et al. (2012) provided fodder for a wave of international research on PPCPs in the environment. As demonstrated by the synthesis articles in this special issue, subsequent advances have been palpable, with tools and approaches developed to understand PPCPs also contributing to an improved understanding of other anthropogenic contaminants and natural toxins in environmental matrices. While the science has moved on considerably in the past decade, because of some of the knowledge gaps identified above, Sumpter et al. (2024) point out that we are still unable to answer the most important question of 2012: How important are PPCPs relative to other chemicals and nonchemical stressors in terms of biological impacts in the natural environment? This is despite the fact that over 18,000 documents are now available on the occurrence, effects, and risks of PPCPs in the environment (Sumpter et al., 2024). It would be depressing if, in 2032, we are in a similar situation. Moving forward, the research community needs to take a much more hypothesis-driven approach to address the knowledge gaps preventing us from answering this question. We hope that this special issue and the new research questions identified here (Table 2) will provide the research community with some direction and focus to this important endeavor to improve the sustainability of healthcare and personal care products. How do we prioritize pharmaceuticals for geographical regions with limited monitoring and usage data? In addition to apical endpoints, how can ecotoxicological responses such as molecular levels be utilized for PPCP prioritization? How can we include microbial communities in PPCP prioritization? Which types of species that are vulnerable to PPCPs are not considered during current prioritization approaches? What are the partitioning and sorption behaviors of strongly ionizing chemicals among species? How does membrane permeability of ions influence bioaccumulation of PPCPs? To what extent are salts and associated complexes with PPCPs influencing bioaccumulation? How do biotransformation and other elimination processes vary within and among species? Are bioaccumulation modeling efforts currently focused on chemicals and species with key data gaps and risk profiles? What are the key sources of uncertainty for PPCP bioaccumulation modeling? Can we generate a knowledge map for the functional conservation of drug targets? What is the best way to extract knowledge on comparative biology and make it usable for environmental toxicology applications? What is the quantitative relationship between subapical adverse endpoints and apical effects across species? Can we use modeling approaches to overcome the experimental (and resource) limitations of using model laboratory organisms? Can we develop a scalable battery of new approach methodologies for the characterization of uptake, pharmacokinetics, and pharmacodynamics of chemicals in fish species? How can the quantity, taxonomic/species coverage, quality, and annotation of sequences improve to expand information available for comparative studies using bioinformatics and other omics approaches? What are the molecular targets of specific chemical classes, and are these targets conserved across species used in and reflected by endpoints employed during regulatory ecotoxicology testing? How can we better take advantage of combined approaches considering molecular target sequence similarity and protein structural knowledge to inform functional predictions for species extrapolation in chemical safety assessments? Which molecular targets have a quantitative relationship between evolutionary conservation and species sensitivity? What vulnerable species co-occur with contaminants in specific locations at concentrations above adverse effect thresholds that are anticipated based on cross-species extrapolation approaches? How can advances in eco-exposomics and precision exposure science accelerate development of precision ecotoxicology and its applications to improve the practice of environmental science and engineering? What are the criteria that would drive the adoption of alternative methods, model systems, and bioinformatics approaches for regulatory decision-making regarding cross-species extrapolation? How can we develop and implement a systematic approach to collect in vitro bioactivity and in vivo effects data for a greater diversity of PPCPs and taxa? How can the number of AOPs (including qAOPs) relevant to predicting the effects of PPCPs be expanded? What is needed in terms of additional knowledgebases and computational tools to efficiently conduct hazard/risk assessments for the ecological effects of PPCPs? To which API mixtures are aquatic populations and communities exposed—focusing on understanding patterns of coexposure and global exposure dynamics? Which aquatic populations and communities are most sensitive to which type of API mixture(s), considering both direct and indirect effects? How can new approach methodologies, in particular "omics," be used to assess hazards and risks of API mixtures? Which mixtures might cause synergistic/interactive toxicities of APIs under environmentally realistic conditions? What is necessary to evolve the discussion and mutual understanding between developers and end users (industry/regulatory agencies) on when and how to further methods/approaches as new science or regulatory change emerges? How can potential divergence of environmental no-observed-effect concentrations be better assessed? Can variability between taxa and attributable to multiple environmental modifiers like chemical mixture effects, abiotic stressors including climate change, and biotic stressors like variable food webs be incorporated? How can knowledge about the uncertainties of traditional tests for environmental protection be better used to define benchmark criteria for the scientific and regulatory acceptance of new approach methodologies data? How can socioeconomic and geophysical "risk factors" for environmental exposure to PPCPs be used to prioritize monitoring in regions where PPCPs pose the greatest risk to environmental and human health? What effects will climate change have on the risks associated with PPCP exposure via the environment? Where will these effects be most significant? Can public engagement in science produce a robust and reliable identification of the risks associated with PPCP exposure to humans and the environment in regions not typically studied by the scientists or where analytical capacity is limited? How can novel analytical techniques and in silico modeling be used to make the study of PPCPs and their geographical risk gradients more accessible, accurate, and "green"/sustainable? How can good-quality ecotoxicity data required for the risk assessment of pharmaceuticals become easily findable, accessible, interoperable, and reusable for the global scientific, regulatory, and general public? How can regulatory frameworks for environmental risk assessment and management of pharmaceuticals be made fit for purpose in developing regions of the world? How can effect-based and ecological approaches be integrated into regulatory risk-assessment practice? To what extent are pharmaceuticals in the environment affecting populations and the diversity of reptiles, amphibians, and mammals? How are mixtures of antibiotics and other antimicrobials contributing to the presence of antimicrobial resistance in aquatic environments? What are the MSCs of nonantibiotic PPCPs? What are the in situ MSCs of PPCPs in the environment, and do these align with laboratory-derived MSCs? What are the effects of PPCP mixtures on selection and horizontal gene transfer in the environment? Does transmission from various underresearched natural environments result in a human health outcome? How can the issue of pharmaceuticals in the environment be integrated in a wider discussion on public and ecological health, in particular in the planetary health context? What synergies can be found between improving public health, providing value-based health and care, and reducing pharmaceuticals in the environment, acknowledging the global societal complexities of these issues? What further drivers can be put in place, in a range of global contexts, to aid the integration of the transformative changes that are achievable through cleaner environments and health promotion into strategies on pharmaceuticals in the environment? The authors declare no conflict of interest. Alistair B. A. Boxall, Bryan W. Brooks: Conceptualization; Writing—original draft; Writing—review & editing. There are no data used in this article, which is an introduction to a special issue of the journal.