Assessing the exposure risk and impacts of pharmaceuticals in the environment on individuals and ecosystems

The use of human and veterinary pharmaceuticals is increasing. Over the past decade, there has been a proliferation of research into potential environmental impacts of pharmaceuticals in the environment. A Royal Society-supported seminar brought together experts from diverse scientific fields to discuss the risks posed by pharmaceuticals to wildlife. Recent analytical advances have revealed that pharmaceuticals are entering habitats via water, sewage, manure and animal carcases, and dispersing through food chains. Pharmaceuticals are designed to alter physiology at low doses and so can be particularly potent contaminants. The near extinction of Asian vultures following exposure to diclofenac is the key example where exposure to a pharmaceutical caused a population-level impact on non-target wildlife. However, more subtle changes to behaviour and physiology are rarely studied and poorly understood. Grand challenges for the future include developing more realistic exposure assessments for wildlife, assessing the impacts of mixtures of pharmaceuticals in combination with other environmental stressors and estimating the risks from pharmaceutical manufacturing and usage in developing countries. We concluded that an integration of diverse approaches is required to predict ‘unexpected’ risks; specifically, ecologically relevant, often long-term and non-lethal, consequences of pharmaceuticals in the environment for wildlife and ecosystems.     

Detection and drivers of exposure and effects of pharmaceuticals in higher vertebrates

Pharmaceuticals are highly bioactive compounds now known to be widespread environmental contaminants. However, research regarding exposure and possible effects in non-target higher vertebrate wildlife remains scarce. The fate and behaviour of most pharmaceuticals entering our environment via numerous pathways remain poorly characterized, and hence our conception and understanding of the risks posed to wild animals is equally constrained. The recent decimation of Asian vulture populations owing to a pharmaceutical (diclofenac) offers a notable example, because the exposure route (livestock carcasses) and the acute toxicity observed were completely unexpected. This case not only highlights the need for further research, but also the wider requirement for more considered and comprehensive ‘ecopharmacovigilance’. We discuss known and potential high risk sources and pathways in terrestrial and freshwater ecosystems where pharmaceutical exposure in higher vertebrate wildlife, principally birds and mammals, may occur. We examine whether approaches taken within existing surveillance schemes (that commonly target established classes of persistent or bioaccumulative contaminants) and the risk assessment approaches currently used for pesticides are relevant to pharmaceuticals, and we highlight where new approaches may be required to assess pharmaceutical-related risk.     

Female competition and aggression: interdisciplinary perspectives

This paper introduces a Theme Issue combining interdisciplinary perspectives in the study of female competition and aggression. Despite a history of being largely overlooked, evidence is now accumulating for the widespread evolutionary significance of female competition. Here, we provide a synthesis of contributions to this Theme Issue on humans and other vertebrates, and highlight directions for future research. Females compete for resources needed to survive and reproduce, and for preferred mates. Although female aggression takes diverse forms, under most circumstances relatively low-risk competitive strategies are favoured, most probably due to constraints of offspring production and care. In social species, dominance relationships and threats of punishment can resolve social conflict without resort to direct aggression, and coalitions or alliances may reduce risk of retaliation. Consistent with these trends, indirect aggression is a low cost but effective form of competition among young women. Costs are also minimized by flexibility in expression of competitive traits, with aggressive behaviour and competitive signalling tailored to social and ecological conditions. Future research on female competition and the proximate mediators of female aggression will be greatly enhanced by opportunities for interdisciplinary exchange, as evidenced by contributions to this Theme Issue.     

Our plastic age

Within the last few decades, plastics have revolutionized our daily lives. Globally we use in excess of 260 million tonnes of plastic per annum, accounting for approximately 8 per cent of world oil production. In this Theme Issue of Philosophical Transactions of the Royal Society, we describe current and future trends in usage, together with the many benefits that plastics bring to society. At the same time, we examine the environmental consequences resulting from the accumulation of waste plastic, the effects of plastic debris on wildlife and concerns for human health that arise from the production, usage and disposal of plastics. Finally, we consider some possible solutions to these problems together with the research and policy priorities necessary for their implementation.     

Sources,impacts and trends of pharmaceuticals in the marine and coastal environment

There has been a significant investment in research to define exposures and potential hazards of pharmaceuticals in freshwater and terrestrial ecosystems. A substantial number of integrated environmental risk assessments have been developed in Europe, North America and many other regions for these situations. In contrast, comparatively few empirical studies have been conducted for human and veterinary pharmaceuticals that are likely to enter coastal and marine ecosystems. This is a critical knowledge gap given the significant increase in coastal human populations around the globe and the growth of coastal megacities, together with the increasing importance of coastal aquaculture around the world. There is increasing evidence that pharmaceuticals are present and are impacting on marine and coastal environments. This paper reviews the sources, impacts and concentrations of pharmaceuticals in marine and coastal environments to identify knowledge gaps and suggests focused case studies as a priority for future research.     

Perceptual awareness and its neural basis: bridging experimental and theoretical paradigms

Understanding consciousness is a major scientific challenge of our times, and perceptual awareness is an integral part of that challenge. This Theme Issue aims to provide a timely focus on crucial insights from leading scientists on perceptual awareness and its neural basis. The issue refers to key research questions and findings in perceptual awareness research and aims to be a catalyst for further research, by bringing together the state-of-the-art. It shows how bridges are being built between empirical and theoretical research and proposes new directions for the study of multisensory awareness and the role of the states of the body therein. In this introduction, we highlight crucial problems that have characterized the development of the study of perceptual awareness. We then provide an overview of major experimental and theoretical paradigms related to perceptual awareness and its neural basis. Finally, we present an overview of the Theme Issue, with reference to the contributed articles and their relationships.     

Infectious diseases of animals and plants: an interdisciplinary approach

Animal and plant diseases pose a serious and continuing threat to food security, food safety, national economies, biodiversity and the rural environment. New challenges, including climate change, regulatory developments, changes in the geographical concentration and size of livestock holdings, and increasing trade make this an appropriate time to assess the state of knowledge about the impact that diseases have and the ways in which they are managed and controlled. In this paper, the case is explored for an interdisciplinary approach to studying the management of infectious animal and plant diseases. Reframing the key issues through incorporating both social and natural science research can provide a holistic understanding of disease and increase the policy relevance and impact of research. Finally, in setting out the papers in this Theme Issue, a picture of current and future animal and plant disease threats is presented.     

Antimicrobial Agents with Improved Clinical Efficacy versus Their Persistence in the Environment: Synthetic 4-Quinolone As an Example

There is increasing concern about the effects of pharmaceutical agents in the environment. The use of synthetic 4-quinolone compounds is rapidly increasing: newer and more complex analogues are being developed by the pharmaceutical industry to meet clinical and veterinary needs. This review aims at stimulating the need to consider the fate of pharmaceuticals in the environment as part of overall drug design and development. Currently, regulatory action is triggered if the predicted environmental concentration exceeds an arbitrarily set value, whereas in some countries, there are no regulations at all. By extension, from a clinical perspective, enviropharmacokinetics and enviropharmacodynamics are proposed to quantify the risk to organisms in the environment in a more realistic fashion that is reflective of concentrations at which hazardous effects are observable on such organisms. Such a new approach integrates our knowledge to address ecosystems and related health problems in a more holistic fashion, thus linking public health, environmental degradation, and ecology. Its success requires more collaboration in research and development of newer antibiotics, with their ultimate fate in the environment being central, to bolster the already existing aspirations of controlling the rapid emergence of resistance.     

Allelopathy as a new strategy for sustainable ecosystems development.

Natural products involved in plant-plant and plant-microorganism ecological interaction (Allelochemicals) are an important potential source for alternative agrochemicals and pharmaceuticals, in order to solve the many problems derived from inadequate culture practices and abuse of synthetic herbicides. Isolation, structural determination, bioassay techniques and applicability for these compounds in crop protection and pharmaceutical research are discussed, and future trends on Allelochemicals applications are examined. The new strategies for sustainable ecosystems controlled by allelochemicals offer a particular interest for the development of human bases in space, since these products can stimulate or inhibit plant germination and growth, and permit to develop crops with low residue amounts in water, facilitating wastewater treatment and recycling.     

Ecological effects of pharmaceuticals in aquatic systems—impacts through behavioural alterations

The study of animal behaviour is important for both ecology and ecotoxicology, yet research in these two fields is currently developing independently. Here, we synthesize the available knowledge on drug-induced behavioural alterations in fish, discuss potential ecological consequences and report results from an experiment in which we quantify both uptake and behavioural impact of a psychiatric drug on a predatory fish (Perca fluviatilis) and its invertebrate prey (Coenagrion hastulatum). We show that perch became more active while damselfly behaviour was unaffected, illustrating that behavioural effects of pharmaceuticals can differ between species. Furthermore, we demonstrate that prey consumption can be an important exposure route as on average 46% of the pharmaceutical in ingested prey accumulated in the predator. This suggests that investigations of exposure through bioconcentration, where trophic interactions and subsequent bioaccumulation of exposed individuals are ignored, underestimate exposure. Wildlife may therefore be exposed to higher levels of behaviourally altering pharmaceuticals than predictions based on commonly used exposure assays and pharmaceutical concentrations found in environmental monitoring programmes.     

药物类新污染物的微生物降解机制研究进展

环境微生物作为自然界中主要的分解者蕴含着丰富的遗传和代谢多样性,在有机污染物降解中发挥着重要作用。药物被持续不断地释放到环境中,其环境暴露、环境风险和对人体健康的潜在影响已得到广泛关注。研究药物在环境中的微生物降解过程对于药物的环境命运、药物的环境风险评估和药物污染去除技术的开发等具有重要价值。本文重点综述了目前环境中常检出药物的微生物降解途径及其分子机理,总结了目前药物微生物降解研究领域的进展,最后探讨了药物的微生物降解领域未来的研究趋势。     

Enantiomer‐Specific In Vitro Biotransformation of Select Pharmaceuticals in Rainbow Trout (Oncorhynchus mykiss)

The occurrence of pharmaceuticals in the environment represents a challenge of emerging concern. Many pharmaceuticals are chiral compounds; however, few studies have examined the relative toxicity of pharmaceutical enantiomers to wildlife. Further, our understanding of stereospecific pharmacokinetics remains largely informed by research on humans and a few well‐studied laboratory test animals, and not by studies conducted with environmentally relevant species, including fish. The objective of this study was to investigate whether rainbow trout display stereospecific in vitro metabolism of three common chiral pharmaceuticals. Metabolism by trout liver S9 fractions was evaluated using a substrate depletion approach, which provides an estimate of intrinsic hepatic clearance (CL_{IN VITRO,INT}). No biotransformation was observed for rac‐, R‐, or S‐fluoxetine. Ibuprofen, including both enantiomers and the racemic mixture, appeared to undergo slow metabolism, but the resulting substrate depletion curves did not differ significantly from those of inactive controls. Contrary to relative clearance rates in humans, S(?)‐propranolol was more rapidly cleared than the R(+)‐ enantiomer. This work demonstrates that relative clearance rates and the effects of racemic mixtures in trout could not have been predicted based on human data. Additional research describing species differences and exploring tools for species extrapolation in biomedical and environmental studies is needed. Chirality 25:763–767, 2013, © 2013 Wiley Periodicals, Inc.     

The use of rice seeds to produce human pharmaceuticals for oral therapy

Rice (Oryza sativa L.) is the major staple food consumed by half of the world's population. Rice seeds have gained recent attention as bioreactors for the production of human pharmaceuticals such as therapeutic proteins or peptides. Rice seed production platforms have many advantages over animal cell or microbe systems in terms of cost-effectiveness, scalability, safety, product stability and productivity. Rice seed-based human pharmaceuticals are expected to become innovative therapies as edible drugs. Therapeutic proteins can be sequestered within natural cellular compartments in rice seeds and protected from harsh gastrointestinal environments. This review presents the state-of-the-art on the construction of gene cassettes for accumulation of pharmaceutical proteins or peptides in rice seeds, the generation of transgenic rice plants, and challenges involved in the use of rice seeds to produce human pharmaceuticals.     

Are Pharmaceuticals with Evolutionary Conserved Molecular Drug Targets More Potent to Cause Toxic Effects in Non-Target Organisms?

The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine) and without (levonorgestrel) identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development), biochemical (RNA and DNA content) and molecular (gene expression) levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L⁻¹, respectively) followed by promethazine (1.6 and 0.18 mg L⁻¹, respectively). At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L⁻¹, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals.     

Ecosystem services and agriculture: tradeoffs and synergies

Agricultural ecosystems provide humans with food, forage, bioenergy and pharmaceuticals and are essential to human wellbeing. These systems rely on ecosystem services provided by natural ecosystems, including pollination, biological pest control, maintenance of soil structure and fertility, nutrient cycling and hydrological services. Preliminary assessments indicate that the value of these ecosystem services to agriculture is enormous and often underappreciated. Agroecosystems also produce a variety of ecosystem services, such as regulation of soil and water quality, carbon sequestration, support for biodiversity and cultural services. Depending on management practices, agriculture can also be the source of numerous disservices, including loss of wildlife habitat, nutrient runoff, sedimentation of waterways, greenhouse gas emissions, and pesticide poisoning of humans and non-target species. The tradeoffs that may occur between provisioning services and other ecosystem services and disservices should be evaluated in terms of spatial scale, temporal scale and reversibility. As more effective methods for valuing ecosystem services become available, the potential for ‘win–win’ scenarios increases. Under all scenarios, appropriate agricultural management practices are critical to realizing the benefits of ecosystem services and reducing disservices from agricultural activities.     

Community Response of Mammalian Predators and Their Prey to Motorways: Implications for Predator–Prey Dynamics

Understanding the interactions between predators and prey is essential for predicting the effects of disturbances to ecosystems. Motorways produce changes in the surrounding biotic and abiotic environment and hence have multiple impacts on wildlife. Some species are known to change their activity patterns in the proximity of motorways but the implications for the structure of food webs are unknown. This study analyzes the activity patterns of both mammalian predators and their prey species near nine motorways in attempt to clarify how motorways affect the mammalian community. Habitat structural variables were also sampled to control the effects of microhabitat on relative prey abundance. Our results revealed different activity patterns of both predators and prey near motorways that are independent of structural differences in microhabitat. Both the red fox and small mammals were found to use the zone close to the motorways more frequently, whereas lagomorphs and mustelids were less active there. These differences suggest that motorways favor the population of the predator that is most tolerant of human activity, the red fox, whose activity could have both direct and indirect effects on that of other members of the predator and prey community. On the one hand, the red fox seems to act as “top predator” and mustelids to follow a “safety match” strategy avoiding the area close to the motorway where fox is more active. On the other hand, abundances of prey species are negatively associated with the activity of their most frequent predators. This study is the first to assess how the proximity to motorways affects the activity of mammals in two levels of the food web and opens the field for research to understand the processes driving the detected patterns. Moreover, such effects at the community scale should be taken into account when evaluating the impacts of motorways on the surrounding ecosystems.