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.     

Antipredator phenotype in crucian carp altered by a psychoactive drug

Predator‐inducible defenses constitute a widespread form of adaptive phenotypic plasticity, and such defenses have recently been suggested linked with the neuroendocrine system. The neuroendocrine system is a target of endocrine disruptors, such as psychoactive pharmaceuticals, which are common aquatic contaminants. We hypothesized that exposure to an antidepressant pollutant, fluoxetine, influences the physiological stress response in our model species, crucian carp, affecting its behavioral and morphological responses to predation threat. We examined short‐ and long‐term effects of fluoxetine and predator exposure on behavior and morphology in crucian carp. Seventeen days of exposure to a high dose of fluoxetine (100 µg/L) resulted in a shyer phenotype, regardless of the presence/absence of a pike predator, but this effect disappeared after long‐term exposure. Fluoxetine effects on morphological plasticity were context‐dependent as a low dose (1 µg/L) only influenced crucian carp body shape in pike presence. A high dose of fluoxetine strongly influenced body shape regardless of predator treatment. Our results highlight that environmental pollution by pharmaceuticals could disrupt physiological regulation of ecologically important inducible defenses.     

The strategic role of ecological research in the design of an environmentally comprehensive plan for a new economic-development area–Meizhou Bay,China

The Government of China is planning a new economic-development area, located at Meizhou Bay on the Chinese mainland, opposite the island of Taiwan. Aspects of this development plant will be subject to an assessment of the potential environmental effects. Especially important considerations are changes in land use associated with urbanization and industrial developments, and any activities that could degrade air and water quality, with potential risks for human health, aquaculture, agriculture, and wildlife. During 1988 to 1990, we conducted studies related to meteorology, environmental geology and engineering, physical oceanography, and marine chemistry and biology.To protect culturally-important orchards of fruit trees (including litchi, orange, and tangerine) from air pollution, and aquaculture facilities for prawn and oyster from oil pollution, these toxic stressors were given priority in our eco-toxicological research, and in the planning of allowable waste discharges. To protect Meizhou Bay from eutrophication, and nutrient-loading eco-dynamic models were developed, to allow simulation of ecological changes potentially associated with nutrient-laden discharges. The results of our ecological research will play a strategic role in reconciling conflicts between economic development and environmental degradation, over both the short- and the long-term.     

Detection of Human-Derived Fecal Pollution in Environmental Waters by Use of a PCR-Based Human Polyomavirus Assay

Regulatory agencies mandate the use of fecal coliforms, Escherichia coli or Enterococcus spp., as microbial indicators of recreational water quality. These indicators of fecal pollution do not identify the specific sources of pollution and at times underestimate health risks associated with recreational water use. This study proposes the use of human polyomaviruses (HPyVs), which are widespread among human populations, as indicators of human fecal pollution. A method was developed to concentrate and extract HPyV DNA from environmental water samples and then to amplify it by nested PCR. HPyVs were detected in as little as 1 μl of sewage and were not amplified from dairy cow or pig wastes. Environmental water samples were screened for the presence of HPyVs and two additional markers of human fecal pollution: the Enterococcus faecium esp gene and the 16S rRNA gene of human-associated Bacteroides. The presence of human-specific indicators of fecal pollution was compared to fecal coliform and Enterococcus concentrations. HPyVs were detected in 19 of 20 (95%) samples containing the E. faecium esp gene and Bacteroides human markers. Weak or no correlation was observed between the presence/absence of human-associated indicators and counts of indicator bacteria. The sensitivity, specificity, and correlation with other human-associated markers suggest that the HPyV assay could be a useful predictor of human fecal pollution in environmental waters and an important component of the microbial-source-tracking “toolbox.”     

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.     

Use of pollution risk and ecosystem service values in marine management strategies in Bohai Sea,China

Different coastal areas possess different pollution risks and ecosystem service values. The management strategies in these areas also differ. With limited environmental funds available, it is necessary to conduct in-depth study of pollution risks and ecosystem service values for developing marine conservation and management strategies. This paper proposes a management method that combines marine pollution risks and ecosystem service values to identify the management priorities of different sites, which are used to determine the appropriate management strategies. The management priorities of different bays in China's Bohai Sea were determined, and management strategies were recommended. The method can be used to determine effective management strategies for oceans around the world, especially in developing countries with limited environmental protection funds.     

Medicating the environment: assessing risks of pharmaceuticals to wildlife and ecosystems

Global pharmaceutical consumption is rising with the growing and ageing human population and more intensive food production. Recent studies have revealed pharmaceutical residues in a wide range of ecosystems and organisms. Environmental concentrations are often low, but pharmaceuticals typically are designed to have biological effects at low doses, acting on physiological systems that can be evolutionarily conserved across taxa. This Theme Issue introduces the latest research investigating the risks of environmentally relevant concentrations of pharmaceuticals to vertebrate wildlife. We take a holistic, global view of environmental exposure to pharmaceuticals encompassing terrestrial, freshwater and marine ecosystems in high- and low-income countries. Based on both field and laboratory data, the evidence for and relevance of changes to physiology and behaviour, in addition to mortality and reproductive effects, are examined in terms of the population- and community-level consequences of pharmaceutical exposure on wildlife. Studies on uptake, trophic transfer and indirect effects of pharmaceuticals acting via food webs are presented. Given the logistical and ethical complexities of research in this area, several papers focus on techniques for prioritizing which compounds are most likely to harm wildlife and how modelling approaches can make predictions about the bioavailability, metabolism and toxicity of pharmaceuticals in non-target species. This Theme Issue aims to help clarify the uncertainties, highlight opportunities and inform ongoing scientific and policy debates on the impacts of pharmaceuticals in the environment.     

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.     

The spatial correlation and interaction between manufacturing agglomeration and environmental pollution

Using statistical data from 285 cities in China, this paper studies the spatial correlation and interaction between manufacturing agglomeration and environmental pollution. Using a widely used spatial correlation index, bivariate Moran's I, we first estimate the spatial correlation between manufacturing agglomeration and environmental pollution. We show that there is significant spatial correlation between them, and distinct patterns of local spatial concentration are identified. Then, we use a spatial simultaneous equations (SSE) model to analyze the interaction between manufacturing agglomeration and environmental pollution. We show that manufacturing agglomeration aggravates environmental pollution, while environmental pollution restrains manufacturing agglomeration. In addition, manufacturing agglomeration and environmental pollution in any one city can be affected by manufacturing agglomeration and environmental pollution in surrounding cities through spatial spillover. Finally, we put forward specific suggestions based on the conclusions for more sustainable development.     

Integrated assessment of the heavy metal pollution status and potential ecological risk in the Lagos Lagoon,South West,Nigeria

This study was carried out to assess the heavy metal pollution status and potential ecological risk in the Lagos lagoon, Nigeria. The concentrations of twelve heavy metals commonly associated with environmental pollution were determined in the sediments of the lagoon by Atomic Absorption Spectrophotometry (AAS) and the cold vapor method was employed for Mercury (Hg). Nonempirical risk indices and empirical Sediment Quality Guidelines (SQGs) were used to assess the ecological risk associated with heavy metal in the sediments. The nonempirical risk indices showed that Hg, Arsenic (As), and Cadmium (Cd) are the major contributors to the ecological risk associated with heavy metal pollution in the ecosystem. Comparison of heavy metal concentrations to the Screening Quick Reference Table (SQuiRT) showed that mean concentration of Cd (5.22 and 4.88 mg kg^?1 in dry and rainy seasons, respectively) exceeds the effect range low (ERL) value (1.20 mg kg^?1) in effect to biota. Industries sited around the lagoon have effluent output points in the lagoon serving as a major source of heavy metals coupled with indirect discharges from other sources. Heavy metals are nonbiodegradable, toxic and have the potential to alter ecosystem health, thus pollution sources should be effectively monitored and contained.     

Assessing Risks of Plant-Based Pharmaceuticals: II. Non-Target Organism Exposure

Plant-based pharmaceuticals potentially offer a cleaner method of producing a protein for drug manufacturing than traditional methods because plants are free of mammalian infectious agents. However, in the open environment they have the potential for intra-and inter-species gene flow, protein exposure to the public and non-target organisms, and they also have the potential to contaminate livestock feed. This study used probabilistic approaches to quantify the non-target organism risks associated with three pharmaceutical proteins produced in field-grown maize. The risk assessment for plant-based pharmaceuticals was conducted for four receptor species used as surrogates for a wider range of species. Body weights and maize consumption rates for each species were modeled from currently available information and used to calculate the exposure based on expression levels of three proteins. The acute dietary exposure for the receptor species was a single-day event in which the total maize consumption came from the recombinant maize. The non-target organism risk assessment demonstrated that risks will vary between species and between proteins, based primarily on differences in toxic endpoint and consumption rates. It also shows the utility of probabilistic, quantitative risk assessment methodologies and the importance of assessing risks from plant-based pharmaceuticals on a case-by-case basis.     

Testing hair for pharmaceuticals

More than hundred pharmaceuticals, drugs of abuse or doping agents have been reported to be detectable in human hair. This article reviews the analysis of 90 drugs and drug metabolites by chromatographic procedures, including the pretreatment steps, the extraction methods, the reported limits of detection and the measured concentrations in real human hair samples. Some progress is observed in the detection of low dose drugs, like fentanyl or flunitrazepam. The general tendency in the last years, to highly sophisticated techniques (GC–MS–NCI, HPLC–MS, GC–MS–MS) illustrates well this constant fight for sensitivity. Some new findings, based on the recent experience of the authors, are also added.     

Quantitative Cross-Species Extrapolation between Humans and Fish: The Case of the Anti-Depressant Fluoxetine

Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 µg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (H_TPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the H_TPC range, whereas no effects were observed at plasma concentrations below the H_TPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation.     

Bioaccumulation and trophic dilution of human pharmaceuticals across trophic positions of an effluent-dependent wadeable stream

Though pharmaceuticals are increasingly observed in a variety of organisms from coastal and inland aquatic systems, trophic transfer of pharmaceuticals in aquatic food webs have not been reported. In this study, bioaccumulation of select pharmaceuticals was investigated in a lower order effluent-dependent stream in central Texas, USA, using isotope dilution liquid chromatography–tandem mass spectrometry (MS). A fish plasma model, initially developed from laboratory studies, was tested to examine observed versus predicted internal dose of select pharmaceuticals. Pharmaceuticals accumulated to higher concentrations in invertebrates relative to fish; elevated concentrations of the antidepressant sertraline and its primary metabolite desmethylsertraline were observed in the Asian clam, Corbicula fluminea, and two unionid mussel species. Trophic positions were determined from stable isotopes (δ¹⁵N and δ¹³C) collected by isotope ratio-MS; a Bayesian mixing model was then used to estimate diet contributions towards top fish predators. Because diphenhydramine and carbamazepine were the only target compounds detected in all species examined, trophic magnification factors (TMFs) were derived to evaluate potential trophic transfer of both compounds. TMFs for diphenhydramine (0.38) and carbamazepine (1.17) indicated neither compound experienced trophic magnification, which suggests that inhalational and not dietary exposure represented the primary route of uptake by fish in this effluent-dependent stream.     

Air Pollution from Industry and Traffic: Perceived Risk and Affect in the Moerdijk Region,The Netherlands

The aim of the present study was to compare the perceived risks of air pollution from industry and traffic in the Moerdijk region in The Netherlands, and to identify the demographic and psychometric variables that are associated with these perceived risks. We sent out a questionnaire and risk perceptions were explored using multiple regression models. The results showed that the perceived risks of industrial air pollution were higher than for those of traffic-related air pollution. The perceived risk of industrial air pollution was associated with other variables than that of traffic. For industry, the psychometric variable affect prevailed. For traffic-related air pollution, the demographic variables age and educational level prevailed, although affect was also apparent. Which source was considered as the major source—traffic or industry—depended on a high risk perception of industrial air pollution, and not on variation in risk perception of traffic-related air pollution. These insights can be used as an impetus for the local risk management process in the Moerdijk region. We recommend that local authorities consider risk perception as one of the targets in local risk management strategies as well.     

Environmental Risk Assessment Studies of Heavy Metal Contamination in the Industrial Area of Kattedan,India—A Case Study

Kattedan is an industrial area near Hyderabad, Andhra Pradesh, India, contaminated with high concentrations of metals attributed to industrial sources (battery manufacturing, metal plating, textile and pharmaceuticals production and others). Twelve different locations in the Kattedan industrial area were assessed for concentrations of metals (Zn, Cr, Cu, Ni, Co, Pb, Hg, Cd, and As) in soils, waters, and vegetation. Application of sequential extraction technique for the soils revealed relatively high percentages of Zn, Cu, and Cr associated with mobile fractions, and correspondingly high concentrations of Zn, Cr, Cu, and Pb in forage grass samples and a high degree of bioavailability to humans. Human exposure assessment revealed high concentrations of Pb, Zn, and Cr in blood and urine samples from the residents of the study area showing a direct pathway and a potential for toxicological hazard due to heavy metal pollution.     

流域空间结构指标与药物污染水平的关系研究

流域地表特征与土地利用结构同流域水环境质量关系密切。流域空间结构指标能够表征流域空间结构特征和生态功能,主要包括流域特征指标和景观格局指数等。为探讨海湾流域生态系统结构与药物污染特征之间的关系,以浙江象山湾为研究区域,采用固相萃取、超高效液相色谱质谱联用等分析手段,研究流域水环境中药物的污染水平、分析其分布特征与流域特征指标和景观结构的关系。结果表明,象山湾22个流域共有22种药物检出,总检出浓度范围为n.d.—220.2 ng/L,主要包括林可霉素、大环内酯类、喹诺酮类、抗癫痫药物、β受体阻滞剂、抗抑郁药物,其中林可霉素、大环内酯类和抗癫痫药物的检出率高达100%,检出浓度分别为2.36—29.1 ng/L、n.d.—35.8 ng/L和n.d.—37.5 ng/L。流域地貌结构指标与水环境药物污染关系密切,其中平均坡度(MS)与药物总浓度、面积高程曲线斜率(SAEC)与β受体阻滞剂都呈显著负相关关系(P<0.01);流域景观结构也与水环境药物污染紧密相关,其中景观蔓延度指数(CONTAG)、城镇用地面积加权平均形状因子(IsSHAPE-AM)、林地最大斑块景观面积比(fLPI...     

Heavy Metal Pollution in Reef Corals of Tuticorin Coast,Southeast Coast of India

This work investigates the metal pollution documented in the skeletons of selected coral species like Acropora formosa, Montipora digitata and Porites andrewsi from the Tuticorin Coast, one of the least studied areas in the Bay of Bengal. Relating heavy metal concentrations to morphological features of skeletons, highest concentrations of all the metals (except Cu and Zn) were found in ramose or branching types of corals. Irrespective of their growth characteristics or patterns, all these species displayed higher concentrations of Pb, Ni, Mn, and Cd within the skeletal part. The study area is currently exposed to a larger degree of metal pollution (natural and anthropogenic) than even before, as a result of the increasing environmental contamination from sewage discharges, the misuse of agricultural chemicals and fertilizers, and top soil erosion. The concentrations of heavy metals obtained in the present study are compared with values from earlier works around the world. This study indicates that corals are vulnerable to the accumulation of high concentrations of heavy metals in their skeletons and therefore can serve as proxies to monitor environmental pollution.     

Bioindustrial manufacturing readiness levels (BioMRLs) as a shared framework for measuring and communicating the maturity of bioproduct manufacturing processes

Readiness level (RL) frameworks such as technology readiness levels and manufacturing readiness levels describe the status of a technology/manufacturing process on its journey from initial conception to commercial deployment. More importantly, they provide a roadmap to guide technology development and scale-up from a ‘‘totality of system’’ approach. Commercialization risks associated with too narrowly focused R&D efforts are mitigated. RLs are defined abstractly so that they can apply to diverse industries and technology sectors. However, differences between technology sectors make necessary the definition of sector specific RL frameworks. Here, we describe bioindustrial manufacturing readiness levels (BioMRLs), a classification system specific to bioindustrial manufacturing. BioMRLs will give program managers, investors, scientists, and engineers a shared vocabulary for prioritizing goals and assessing risks in the development and commercialization of a bioindustrial manufacturing process.