The prevalence of pharmaceutical residues like diltiazem in environments raises concerns over their potential threat to non-target organisms. While the immune system poses as a potential target, little is known about the immunotoxicity of diltiazem to aquatic species such as bivalve molluscs. In this study, the binding affinity of diltiazem to the calcium channels of several aquatic species was evaluated by molecular docking. Taking blood clam as a representative, the impacts of diltiazem on Ca2+-homeostasis and immune parameters were also assessed. Our results illustrated diltiazem exhibit a high binding affinity to calcium channels of representative aquatic species. Moreover, Ca2+-homeostasis in the haemocytes of blood clam was significantly disrupted by 4-week exposure to diltiazem. Additionally, apart from exhibiting significantly lower survival rates upon pathogenic challenge, diltiazem-exposed blood clams also suffered markedly impaired immune-related hematic parameters and lower levels of immune factors. Furthermore, diltiazem exposure generally altered the expression of key Ca2+-homeostasis and immune-related genes. Collectively, our data suggest that diltiazem at environmentally relevant concentrations could severely undermine the immunity of blood clam by disrupting Ca2+-homeostasis. Given the high binding affinities of diltiazem to calcium channels of diverse aquatic species and the critical role of Ca2+-homeostasis, the far-reaching impacts of diltiazem pollution on non-target aquatic species warrant closer attention and monitoring.

Antidepressants are increasingly detected in aquatic environments due to their incomplete removal in wastewater treatment, raising significant concerns about their ecological impacts. This review focuses on the three most widely used classes of antidepressants-tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). It systematically explores their physicochemical properties and how these properties influence their environmental fate, including sorption, mobility, and bioaccumulation in aquatic ecosystems. The sublethal effects of these antidepressants on aquatic organisms, particularly their impacts on behavior, reproduction, and development, are critically analyzed, highlighting potential threats to biodiversity and ecological stability. Key knowledge gaps are identified, including the long-term impacts of chronic low-dose exposure, the role of bioactive metabolites, and the combined toxicity of antidepressants with other contaminants. The review underscores the importance of advanced wastewater treatment technologies, environmentally mindful prescribing practices, and public awareness campaigns as essential measures to mitigate these risks. By addressing these challenges, this study aims to inform future research and guide sustainable environmental management strategies.

Few studies exist that focus on contaminants of emerging concern (CECs) in transitional and coastal waterbodies. This study presents chemical profiling of two protected marine harbours on the South coast of the UK sampled in 2022. Across 21 sites, 105 unique compounds were detected (0.05 ng L-1 --1798 ng L-1, median: 11 ng L-1) in water samples and biota, including 67 pharmaceuticals, 29 pesticides and nine recreational drugs. There were significant differences between campaigns with increased chemical numbers and concentrations that coincided with increased rainfall and combined sewer overflow (CSO) discharges. The comparison with CSO discharges revealed that they were an important source for loading of specific chemicals with concentrations increasing for some cases by three-orders of magnitude. High relative risks were estimated for sites sampled during recorded CSO discharges for five compounds with risk quotients (RQs) ranging from 1.1 up to 9.3, with the highest risk from the neonicotinoid, imidacloprid. To understand the exposure in biota, six species; one macroalgae (Fucus vesiculosus) and five fauna (Hediste diversicolor, Patella vulgate, Crassostrea gigas, Carcinus maenas, Echinogammarus marinus) were analysed (n = 5/species) at a CSO-impacted site. Between eight to 18 compounds were detected with Fucus vesiculosus (seaweed) showing the highest accumulation with mean cumulative burdens reaching up to 343 ± 71 ng g-1. Surface water contamination did not correlate with body burdens. Overall, the work highlights the complexity of the chemical space present in a transitional waterbody showing dynamic contamination patterns that are further influenced by tide, rainfall and salinity. CSOs demonstrated an important but compound specific role for CEC input and pulsing into receiving waters.

This study provides the first quantitative data on the presence of 17 pharmaceuticals and personal care products (PPCPs) from various therapeutical classes in surface seawater from Kongsfjorden (KF, Svalbard Archipelago, Norway, 79°00'N, 11°40'E), collected over five summers (2018-2022). The PPCPs (ciprofloxacin-CIP, enrofloxacin-ENR, amoxicillin-AMX, erythromycin-ERY, sulfamethoxazole-SMX, N4-acetylsulfamethoxazole-N4-SMX, carbamazepine-CBZ, diclofenac-DCF, ibuprofen-IBU, acetylsalicylic acid-ASP, paracetamol-PAR, caffeine-CFF, triclosan-TCL, N,N-diethyl-meta-toluamide-DEET, estrone-E1, 17β-estradiol-E2 and 17α-ethinyl estradiol-EE2) were also analysed in sewage from the wastewater treatment plant, serving Ny-Ålesund, located on KF's southern shore. Samples were processed using solid phase extraction and liquid chromatography with high-resolution mass-spectrometry. An environmental risk assessment (ERA) was conducted to evaluate ecological and antimicrobial resistance (AMR) risks and the cumulative risk from the chemical mixture. PPCPs detected in sewage were also found in seawater, with the highest concentrations in sewage for CFF (151.9 ± 8.7 ng/L) and ASP (122.5 ± 9.4 ng/L). In seawater, the main contributors were ASP (39.2 ± 12.9 ng/L) and EE2 (32.5 ± 11.9 ng/L), suggesting influences from local emissions, fjord circulation, and broader oceanic and atmospheric transport. The ERA identified CIP, DCF, IBU, CFF, TCL, E1, E2 and EE2 as potentially harmful to the Arctic marine ecosystem. When evaluated as a mixture, all compounds contributed additively to the overall risk. The AMR risk from the antibiotic ciprofloxacin was found to be low. These findings emphasize the need for enhanced monitoring of PPCPs and comprehensive ERAs of chemical mixtures to guide management strategies and protect sensitive Arctic ecosystems.

Endocrine-disrupting contaminants (EDCs) are frequently monitored in environments because of their biological impacts on wildlife and humans. We conducted a systematic review using Web of Science to identify global research trends for EDC environmental sampling. Specifically, we aim to better understand geographic variation in (1) the compartment that EDCs were sampled in the environment; (2) the types of EDC sampled; and (3) the taxa that are sampled. A total of 9140 papers were found, of which 2554 were included in our review. The number of studies sampling EDCs varied between continents, with majority of research occurring in Europe, Asia, and North America. Although economy and access to technology will contribute to the number of articles published, we found the current output of research showed distinct disparities in sampling methods. Across all continents, water was the most frequently sampled compartment to determine EDC concentrations (sampled in 50-75% of studies). Wildlife was sampled far less often in studies across all continents, comprising 30% of studies at most. Pharmaceuticals were the most commonly studied chemical group, and fish were the most commonly sampled taxonomic group. Although far fewer studies sampled for EDCs in wildlife compared with abiotic compartments, these studies provide valuable information on the potential consequences of environmental EDC exposure and link environmental surveillance of EDCs with lab-measured organism-level effects. Studies that sampled only the water matrix for EDCs may be doing so as a proxy despite the large knowledge gaps on how environmental EDCs affect wildlife at varying concentrations.

Most drugs excreted in urine are not filtered by wastewater treatment plants and end up in aquatic systems. At concentrations measured in waters, toxic effects on species have been described. Second, most of the drug consumption is attributable to primary care prescriptions. We thus present here, an ecotoxicity classification of the most sold drugs in primary care in Switzerland. Three datasets were combined: (1) surveyed ecotoxic drugs by the Swiss National Surface Water Quality Monitoring Programme and its European equivalent, (2) the top 50 drugs by sale in primary care in Switzerland, and (3) active pharmaceutical ingredient (API) concentrations in Lake Geneva and the rivers of the canton of Vaud between 2017 and 2022. We classified APIs into five categories from the safest to the least safe: (1) APIs found in concentrations (C) <10× their environmental quality standard (EQS·10-1), (2) EQS·10-1 < C < EQS and not listed by the Swiss or the EU Watch List, (3) EQS·10-1 < C < EQS and listed, (4) C > EQS and not listed, and (5) C > EQS and listed. We obtained full ecotoxicological data for 35 APIs. Fifteen APIs were designated as safe (category (1):paracetamol, tramadol, amisulpride, citalopram, mirtazapine, metformin, gabapentin, lamotrigine, primidone, candesartan, irbesartan, atenolol, hydrochlorothiazide, ofloxacin, sulfadiazine), eleven as intermediately safe, and nine were of concern (azithromycin, ciprofloxacin, clarithromycin, sulfamethoxazole, carbamazepine, diclofenac, ibuprofen, iomeprol, iopromide). Full data were available for only one-third of the drugs most sold in primary care. Where data do exist, we observed significant differences in environmental impact among the same class of drugs. Our classification could therefore help guide doctors to adopt more eco-friendly prescriptions.

In this review, several factors have been collected from previous studies on emerging pharmaceutical pollutant adsorption to explain and describe the mechanisms and determine the reactions involved: X-ray Photoelectron Spectroscopy (XPS), Fourier Transform Infrared Spectroscopy (FTIR), and the Boehm titration are the most used characterization techniques to determine activated carbons' surface functional groups. Some studies have confirmed that the specific surface area and the pore structure are not more important than the functional groups present in the adsorbent surface to explain the amount of adsorption obtained and to describe correctly the interaction between the adsorbent-adsorbate. After the analysis of several studies, we concluded that to have good adsorption, it is necessary to choose the right treatment with the right activating agent to obtain the appropriate functions that will enhance the adsorption process. In addition, the functions that can react with the pharmaceutical pollutants are the oxygenated functions such as hydroxyl function, carboxylic function, and carbonyl function.

Pharmaceutical active compounds (PhACs) and microplastics (MPs) have been detected in different marine compartments from coastal areas, raising concerns due to their simultaneous discharge through wastewater treatment plants (WWTPs) and the role of MPs as vectors of pollutants for marine organisms. This study investigates the biochemical effects of citalopram (CIT) and bezafibrate (BEZ) on the mussel Mytilus galloprovincialis, at environmentally relevant concentrations, and their co-exposure with high-density polyethylene (HDPE) MPs. MPs accumulated in gills and digestive glands during exposure, but they were rapidly eliminated after depuration, except for a small fraction of the smallest MPs in gills. This study evaluated the biological effects in gills and digestive gland, and confirmed CIT induced oxidative stress in both tissues, exacerbated by the presence of MPs. BEZ, despite not being detected at high concentrations in the mussel tissues, activated an antioxidant response in gills and increasing the transcription of the genes Se-gpx and gst-pi in digestive gland. Both PhACs impaired the cholinergic pathway long-term, even after the depuration period, as indicated by decreased AChE levels in the gills, suggesting potential neurotoxic effects after prolonged exposure. Consequently, adverse effects were provoked by both PhACs with (CIT) and without (BEZ) significant bioaccumulation capacity.

Sertraline is one of the most widely prescribed antidepressants, worldwide detected in rivers, thus raising concern about its ecotoxicology. However, there is knowledge gap on its pharmacokinetics and pharmacodynamics in freshwater bivalves. Comparative biology can help to gain in understanding and improve our ability to assess ecotoxicological risks in a wide range of species. This study investigated the kinetic-based bioconcentration and depuration of sertraline by two freshwater bivalve species, Dreissena polymorpha (zebra mussel, ZM) and Dreissena rostriformis bugensis (quagga mussel, QM), and (2) its biological effects depending on the exposure duration and frequency. Several biomarkers related to known sertraline side effects in human were followed. Results document a higher body burden in QM than in ZM. The steady-stage was not reached after 5 days of exposure. Bivalves were unable to depurate sertraline in 5 days in clean water. Findings provide evidence that environmentally relevant concentration of sertraline can disturb the physiology of Dreissena species, but not in the same way. QM was found to be more sensitive to sertraline than ZM, experiencing oxidative stress and lipid disorder. Intermittent exposure also led to biochemical changes in the two species, requiring further study.

Pharmaceuticals have been acknowledged as an important contaminant of emerging concern with the potential to cause adverse effects in exposed fauna. Most research has focused on temperate freshwater systems; therefore, there is a pressing need to quantify pharmaceutical exposure in subtropical coastal marine systems. This study investigated the prevalence of pharmaceutical exposure to bonefish (Albula vulpes) in subtropical South Florida, USA, and evaluated the relative risk of detected concentrations to elicit pharmacological effects. The influence of sampling region, season (within or outside spawning season), and bonefish length on pharmaceutical assemblage, detection frequency, and risk was assessed. Both spatial (multiple regions) and temporal (spawning season) components were considered in order to incorporate bonefish biology biological in our exploration of pharmaceutical exposure and potential risk of effect. To quantify risk of pharmacological effects, concentrations were compared to a 1/3 threshold of the human therapeutic plasma concentration (HTPC). In total, 53 different pharmaceuticals were detected with an average of 7.1 pharmaceuticals per bonefish and 52.3 % had at least one pharmaceutical exceeding the 1/3 HTPC threshold. The presence of pharmaceutical cocktails at concentrations capable of eliciting pharmacological effects is of particular concern considering the potential for unknown interactions. For exposure and risk of pharmacological effect, region and season were significant, while bonefish length was not. Pharmaceutical exposure and risk were highest in the most remote sampling region. Results establish pharmaceuticals' widespread prevalence in subtropical coastal marine ecosystems, exposure and risk to biota, and the necessity to examine marine systems.

A field study on the occurrence and distribution of forty-three pharmaceutically active compounds (PhACs) in water and fish samples from anthropogenically impacted section of the Sava River (Croatia) was performed to estimate the importance of bioaccumulation for the environmental risk assessment of PhACs. The study was performed using a highly specific LC-MS/MS method, tailored to include the most prominent PhACs from different therapeutic categories as well as their major metabolites and/or transformation products (TPs). The results revealed a widespread occurrence of PhAC residues both in water and fish samples with a large spatial variability reflecting the distance from the dominant wastewater discharges. The most prominent PhAC categories in less polluted upstream part of the river were common psychostimulants caffeine and cotinine, therapeutic opioids and cardiovascular drugs, while in the river section affected by the local municipal and industrial wastewater inputs, antibiotic drugs became clearly predominant, especially in fish tissue samples. The apparent bioconcentration factors (BCFs) of investigated PhACs varied over several orders of magnitude, from 0.02 ± 0.01 L kg-1 for O-desmethyl tramadol in fish muscle to 784 ± 260 L kg-1 for terbinafine in fish liver, indicating rather large differences in their bioconcentration potential and affinity to different tissues, with the tissue-specific BCFs increasing in the following order: muscle < gills < gonads < heart < liver < kidneys. The bioconcentration potential of most of the PhACs included in this study was only low to moderate however moderately high BCFs of certain PhACs (e.g. sertraline, terbinafine, loratadine, diazepam and azithromycin) in some tissues should be taken into consideration when assessing their potential environmental risks. Moreover, it was shown that BCFs could be strongly affected by biotransformation in fish. Risk prioritization based on risk quotient (RQ) and ToxPi index, revealed antibiotics, in particular azithromycin, and therapeutic psychoactive substances as the most hazardous pharmaceutical contaminants in the Sava River.

Pharmaceuticals in aquatic environments pose threats to aquatic organisms because of their continuous release and potential accumulation. Monitoring methods for these contaminants are inadequate, with targeted analyses falling short in assessing water quality's impact on biota. The present study advocates for integrated strategies combining suspect and targeted chemical analyses with molecular biomarker approaches to better understand the risks posed by complex chemical mixtures to nontarget organisms. The research aimed to integrate chemical analysis and transcriptome changes in fathead minnows to prioritize contaminants, assess their effects, and apply this strategy in Wascana Creek, Canada. Analysis revealed higher pharmaceutical concentrations downstream of a wastewater-treatment plant, with clozapine being the most abundant in fathead minnows, showing notable bioavailability from water and sediment sources. Considering the importance of bioaccumulation factor and biota-sediment accumulation factor in risk assessment, these coefficients were calculated based on field data collected during spring, summer, and fall seasons in 2021. Bioaccumulation was classified as very bioaccumulative with values >5000 L kg-1, suggesting the ability of pharmaceuticals to accumulate in aquatic organisms. The study highlighted the intricate relationship between nutrient availability, water quality, and key pathways affected by pharmaceuticals, personal care products, and rubber components. Prioritization of these chemicals was done through suspect analysis, supported by identifying perturbed pathways (specifically signaling and cellular processes) using transcriptomic analysis in exposed fish. This strategy not only aids in environmental risk assessment but also serves as a practical model for other watersheds, streamlining risk-assessment processes to identify environmental hazards and work toward reducing risks from contaminants of emerging concern. Environ Toxicol Chem 2024;43:2252-2273. © 2024 SETAC.

Globally, pharmaceuticals and personal care products (PPCPs) are detected in surface waters receiving wastewater, yet their presence in biota, remain largely understudied. To address this, we conducted a study that measured 46 PPCPs in spot water samples and fish caught up- and downstream from wastewater treatment plants (WWTPs) in Victoria, Australia. We sampled 15 sites located along four waterways following a 3-site design: WWTP-discharge('hotspot'), 'upstream'(∼2 km) and 'downstream'(∼2 km). Spot water and fish were also sampled at reference sites >100 km from WWTP discharge (n = 3). Additionally, spot water samples were taken from WWTP effluent outflows (n = 3). From each locality, we analysed 3-12 fish (n = 131 total). In waterways, passive samplers (POCIS; ∼28d, n = 19 PPCPs) were also deployed. Individual fish (axial muscle) and water were analysed with LC-MS-MS. We found that PPCP concentrations in environmental surface water ranged from<0.02-0.97 μg/L. In WWTP effluent, the range was <0.02-1.4 μg/L. Of the 46 PPCPs analysed, 12 were detected in spot water samples and five in fish. In water, the highest concentration detected was for antidepressant venlafaxine (3 μg/L). The most frequently detected PPCPs: venlafaxine (54.9%), metoprolol (41.2%), propranolol (29.4%), carbamazepine (29.4%), caffeine (17.6%) and sulfamethoxazole (17.6%). Out of 131 fish analysed, 35 fish had detectable levels of PPCPs in the muscle tissue. The highest muscle concentrations were: venlafaxine (150 μg/kg, redfin perch), and sertraline (100 μg/kg, eel). Bioaccumulation factors ranged from 104 to 341L/kg for venlafaxine in redfins, 21-1,260L/kg for carbamazepine in redfins and eels, and 367-3,333L/kg for sertraline in eels. Based on our human health risk calculations for venlafaxine, carbamazepine, sertraline, triclosan, and caffeine, consumption of fish does not pose a significant risk to human health. Despite this, most of the detected PPCPs in surface waters exceeded 10 ng/L trigger value, which has led to further investigations by EPA. Our study highlights the need for using multiple lines of evidence for estimating risks of PPCPs.

Pharmaceuticals (PhACs) are increasingly detected in aquatic ecosystems, yet their effects on biota remain largely unknown. The environmentally relevant concentrations of many PhACs may not result in individual-level responses, like mortality or growth inhibition, traditional toxicity endpoints. However, this doesn't imply the absence of negative effects on biota. Metabolomics offers a more sensitive approach, detecting responses at molecular and cellular levels and providing mechanistic understanding of adverse effects. We evaluated bioaccumulation and metabolic alterations in a benthic ostracod, Heterocypris incongruens, exposed to a mixture of five PhACs (carbamazepine, tiapride, tolperisone, propranolol and amlodipine) at environmentally relevant concentrations for 7 days using liquid chromatography coupled with mass spectrometry. The selection of PhACs was based, among other factors, on risk quotient values determined using toxicological data available in the literature and concentrations of PhACs quantified in our previous research in the sediments of the Odra River estuary. This represents a novel approach to PhACs selection for metabolomic studies that considers strictly quantitative data. Amlodipine and tolperisone exhibited the highest bioaccumulation. Significant impacts were observed in Alanine, aspartate and glutamate metabolism, Starch and sucrose metabolism, Arginine biosynthesis, Histidine metabolism, Tryptophan metabolism, Glycerophospholipid metabolism, and Glutathione metabolism pathways. Most of the below-individual-level responses were likely nonspecific and related to dysregulation in energy metabolism and oxidative stress response. Additionally, some pharmaceutical-specific responses were also observed. Therefore, untargeted metabolomics can be used to detect metabolic changes resulting from environmentally relevant concentrations of PhACs in aquatic ecosystems and to understand their underlying mechanism.

Chemical pollution is a threat to coral reefs. To preserve them, it is crucial to monitor novel contaminants and assess the related risks. The occurrence of active pharmaceutical ingredients (APIs) in coral reefs has been poorly investigated until now. Under this light, we tested the use of the marine sponge Cf. Hyrtios as bio-monitors and conducted a pilot study in the Faafu Atoll (Maldives). Analyses were carried out by in vivo solid-phase microextraction (SPME) and liquid chromatography (LC) electrospray ionization (ESI) tandem mass spectrometry (MS/MS). Twelve APIs were selected for method optimization. Limits of quantitation (LOQs) were in the 0.6 and 2.5 ng/g range, accuracy between 86.5 % and 104.7 %, and precision between 3.0 % and 14.9 %. All the sponges located in the inner reefs resulted contaminated with at least one API. Gabapentin and Carbamazepine displayed the highest detection rates, while Ketoprofen had the highest concentration (up to 15.7 ng/g).

Pharmaceutical uptake involves processes that vary across aquatic systems and biota. However, single studies examining multiple environmental compartments, microhabitats, biota, and exposure pathways in mesoconsumer fish are sparse. We investigated the pharmaceutical burden in bonefish (Albula vulpes), pathways of exposure, and estimated exposure to a human daily dose. To evaluate exposure pathways, the number and composition of pharmaceuticals across compartments and the bioconcentration in prey and bonefish were assessed. To evaluate bioaccumulation, we proposed the use of a field-derived bioaccumulation factor (fBAF), due to variability inherent to natural systems. Exposure to a human daily dose was based on bonefish daily energetic requirements and consumption rates using pharmaceutical concentrations in prey. Pharmaceutical number and concentration were highest in prey, followed by bonefish, water and sediment. Fifteen pharmaceuticals were detected in common among bonefish, prey, and water; all of which bioconcentrated in prey and bonefish, and four bioaccumulated in bonefish. The composition of detected pharmaceuticals was compartment specific, and prey were most similar to bonefish. Bonefish were exposed to a maximum of 1.2 % of a human daily dose via prey consumption. Results highlight the need for multicompartment assessments of exposure and consideration of prey along with water as a pathway of exposure.

The escalating levels of hazardous pharmaceutical contaminants, specifically nonsteroidal anti-inflammatory drugs (NSAIDs), in groundwater reservoir surfaces and surface waterway systems have prompted substantial scientific interest regarding their potential deleterious effects on both aquatic ecosystems and human health. Extraction of those pollutants from wastewater is quite challenging. Hence, the development of economic, sustainable, and scalable techniques for capturing and removing those pollutants is crucial to ensure water safety. Herein, we demonstrate a physicochemically stable, reusable, porous Hf(IV)-based cationic metal-organic framework (MOF), namely, 1'@MeCl for the aqueous phase adsorption-based removal of NSAIDs (diclofenac, naproxen, ibuprofen) from the wastewater environment. The highly positively charged surface of the 1'@MeCl MOF enables it to selectively extract more than 99% of diclofenac, naproxen, and ibuprofen contaminants within less than 30 s. With fast adsorption kinetics, very high adsorption capacities (Qe) were achieved at neutral pH for diclofenac (482.9 mg/g), naproxen (295.9 mg/g), and ibuprofen (219.5 mg/g). Moreover, the influence of changes in pH and coexisting anions on the adsorption property of the 1'@MeCl MOF was studied. Furthermore, the adsorption efficiency of 1'@MeCl in different real water environments was ensured by performing diclofenac, naproxen, and ibuprofen adsorption from tap, river, and lake water. Moreover, a 1'@MeCl-anchored cellulose acetate-chitosan membrane was developed successfully to demonstrate the membrane-based extraction of diclofenac, naproxen, and ibuprofen from contaminated water. Furthermore, a molecular-level mechanistic study was performed through experimental and computational study to propose the plausible adsorption mechanisms for diclofenac, naproxen, and ibuprofen over the surface of 1'@MeCl.

The presence of contaminants of emerging concern in aquatic ecosystems represents an ever-increasing environmental problem. Aquatic biota is exposed to these contaminants, which can be absorbed and distributed to their organs. This study focused on the assessment, distribution, and ecological risk of 32 CECs in a Spanish river impacted by effluents from a wastewater treatment plant, analyzing the organs and plasma of common carp. Environmental concentrations in water and sediment were examined at sites upstream and downstream of the wastewater treatment plant. The two downstream sites showed 15 times higher total concentrations (12.4 μg L-1 and 30.1 μg L-1) than the two upstream sites (2.08 μg L-1 and 1.66 μg L-1). Half of the CECs were detected in fish organs, with amantadine having the highest concentrations in the kidney (158 ng g-1 w.w.) and liver (93 ng g-1 w.w.), followed by terbutryn, diazepam, and bisphenol F in the brain (50.2, 3.82 and 1.18 ng g-1 w.w.). The experimental bioaccumulation factors per organ were compared with the bioconcentration factors predicted by a physiologically based pharmacokinetic model, obtaining differences of one to two logarithmic units for most compounds. Risk quotients indicated a low risk for 38 % of the contaminants. However, caffeine and terbutryn showed an elevated risk for fish. The mixed risk quotient revealed a medium risk for most of the samples in the three environmental compartments: surface water, sediment, and fish.

Drugs do not disappear once they have been excreted. In fact, 992 active principles have already been measured in the different environmental matrices. A recent study led by scientists from the University of York has studied the presence of drugs in the rivers of more than 100 different countries, showing that environmental contamination by pharmaceuticals is a global issue and that, concentrations found are frequently harmful to the environment. In this work, we have tried to briefly expose the problem of environmental contamination with medicines, but above all, we have tried to address the possible solutions, with a perspective from the field of hospital pharmacy. This is a very complex matter (a wicked problem), since it involves multiple stakeholders with different visions and interests regarding medicines. In order to find solutions, we will probably need to act at all steps of the drug's life cycle. Until now, health professionals have been part of the problem. It is time for us to be part of the solution.

Drugs do not disappear once they have been excreted. In fact, 992 active principles have already been measured in the different environmental matrices. A recent study led by scientists from the University of York has studied the presence of drugs in the rivers of more than 100 different countries, showing that environmental contamination by pharmaceuticals is a global issue and that, concentrations found are frequently harmful to the environment. In this work, we have tried to briefly expose the problem of environmental contamination with medicines, but above all, we have tried to address the possible solutions, with a perspective from the field of hospital pharmacy. This is a very complex matter (a wicked problem), since it involves multiple stakeholders with different visions and interests regarding medicines. In order to find solutions, we will probably need to act at all steps of the drug's life cycle. Until now, health professionals have been part of the problem. It is time for us to be part of the solution.

Ecosystems are negatively impacted by pharmaceutical-contaminated water in different ways. In this work, a new biosorbent obtained by immobilizing Lactococcus lactis in a calcium alginate matrix was developed for the removal of pharmaceuticals from aqueous solutions. Ethacridine lactate (EL) was selected as the target drug. Lactococcus Lactis biomass was chosen for the biosorbent synthesis for two reasons: (i) the microbial biomass used in the food industry allows the development of a low-cost biosorbent from available and renewable materials, and (ii) there is no literature mentioning the use of Lactococcus Lactis biomass immobilized in natural polymers as a biosorbent for the removal of pharmaceuticals. The characterization of the synthesized biosorbent named 5% LLA was performed by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) analysis. Additionally, particle size and the point of zero charge were established. Batch biosorption investigations showed that using 5% LLA at an initial pH of 3.0 and a biosorbent dose of 2 g/L resulted in up to 80% EL removal efficiency for all EL initial concentrations (20-60 mg/L). Four equilibrium isotherms, given in the order of Redlich-Peterson > Freundlich > Hill > Temkin, are particularly relevant for describing the experimental data for EL biosorption on the 5% LLA biosorbent using correlation coefficient values. Kinetic parameters were determined using kinetic models such as pseudo-first-order, pseudo-second-order, Elovich, Avrami and Weber-Morris. The pseudo-second-order kinetics model provides the greatest fit among the evaluated equations, with correlation coefficients greater than 0.99. According to the study's findings, the developed biocomposite is a potentially useful material for the removal of pharmaceuticals from aqueous matrices.

Meropenem is a potent carbapenem antibiotic frequently used in medical settings. Several studies have confirmed the pervasive presence of these antibiotics in wastewater treatment plants and aquatic environments. However, the effects of these substances on non-target organisms, such as plants, have not been adequately monitored. Thus, this study aimed to assess the short-term impact of meropenem on the growth, photosynthesis, chlorophyll content, and enzyme activity of the macrophyte plant Lemna minor. The methods involved exposing the plant to meropenem under controlled conditions and assessing physiological and biochemical parameters to determine the impact on photosynthetic activity and oxidative stress. These analyses included growth rate, antioxidant enzyme activity, and photosynthetic capacity. The findings suggest that the growth rate of Lemna minor remained unaffected by meropenem at concentrations <200000 μgL-1. However, plants exposed to concentrations >20 μgL-1showed physiological alterations, such as decreased net photosynthesis rate (17%) and chlorophyll concentration (57%), compared to the control group. For acute toxicity assays, the calculated EC50 7-day and EC20 7-day were 1135 μgL-1and 33 μgL-1, respectively. In addition, in most treatments tested, meropenem caused an increase in the superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX) activity as a defense mechanism against oxidative stress. Our results suggest that meropenem affects photosynthetic processes and induces oxidative stress in the macrophyte plant Lemna minor. Further studies are needed to assess the physiological and metabolic interactions between antibiotics and primary producers at different long-term trophic levels.

In recent years, contaminants of emerging concern have been reported in several environmental matrices due to advances in analytical methodologies. These anthropogenic micropollutants are detected at residual levels, representing an ecotoxicological threat to aquatic ecosystems. In particular, the pharmacotherapeutic group of non-steroidal anti-inflammatories (NSAIDs) is one of the most prescribed and used, as well as one of the most frequently detected in the aquatic environment. Bivalves have several benefits as a foodstuff, and also as an environment bioindicator species. Therefore, they are regarded as an ideal tool to assess this issue from both ecotoxicological and food safety perspectives. Thus, the control of these residues in bivalves is extremely important to safeguard environmental health, also ensuring food safety and public health. This paper aims to review NSAIDs in bivalves, observing their consumption, physicochemical characteristics, and mechanisms of action; their environmental occurrence in the aquatic environment and aquatic biota; and their effects on the ecosystem and the existent legal framework. A review of the analytical methodologies for the determination of NSAIDs in bivalves is also presented.

Uptake and elimination kinetics, bioconcentration factors (BCFs), and metabolic transformation of 20 different pharmaceutically active compounds (PhACs), covering a wide range of therapeutic categories and physico-chemical properties, were studied using zebrafish (Danio rerio). The fish were exposed to the mixture of the selected PhACs at environmentally relevant concentrations similar to 10 µg L-1. The experiments were performed in semi-static conditions and comprised a 7-day uptake period followed by a 7-day depuration period. Most of the PhACs reached a concentration plateau within the 7-day uptake-phase which was followed by an efficient depuration, with the observed uptake (ku) and depuration rate constants (kd,) ranging between 0.002 and 3.752 L kg-1 h-1, and 0.010 to 0.217 h-1, respectively. The investigated PhACs showed low to moderate BCFs. The highest BCFs of 47.8, 28.6 and 47.6 L kg-1 were determined for sertraline, diazepam and desloratadine, respectively. A high contribution of metabolic products to the total internal concentration was observed for some PhACs such as codeine (69%), sulfamethoxazole (51%) and verapamil (87%), which has to be taken into account when assessing the bioconcentration potential. Moreover, most of the metabolites exhibited significantly longer half-lives in zebrafish than their parent compounds and affected the overall depuration kinetics.

At present the information regarding the occurrence of human pharmaceuticals (PhaCs) in coral reefs and their potential impacts on the associated fauna is limited. To optimize the collection of data in these delicate environments, we employed a solid-phase microextraction (bioSPME) and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) procedure that enabled in vivo determinations in soft corals. Specifically, we researched the antibiotics Ofloxacin Sulfamethoxazole and Clarithromycin, the anti-inflammatory Diclofenac Propyphenazone Ketoprofen and Amisulpride, the neuroactive compounds Gabapentin-lactam, the beta-blocker Metoprolol and the antiepileptic Carbamazepine. Reproducibility was between 2.1% and 9.9% and method detection limits LODs) were between 0.2 and 1.6 ng/g and LOQs between 0.8 and 5.4 mg/g. The method was then applied to establish a baseline for the occurrence of these compounds in the Maldivian archipelago. Colonies of Sarcophyton sp. and Sinularia sp. were sampled along an inner-outer reef transect. Five of the ten targeted PhaCs were identified, and 40% of the surveyed coral colonies showed the occurrence of at least one of the selected compounds. The highest concentrations were found inside the atoll rim. Oxoflacin (9.5 ± 3.9 ng/g) and Ketoprofen (4.5 ± 2.3 ng/g) were the compounds with the highest average concentrations. Outside the atoll rim, only one sample showed contamination levels above the detection limit. No significant differences were highlighted among the two surveyed soft coral species, both in terms of average concentrations and bioconcentration factors (BCFs).

The investigation of pharmaceuticals as emerging contaminants in marine biota has been insufficient. In this study, we examined the presence of 51 pharmaceuticals in edible oysters along the coasts of the East and South China Seas. Only nine pharmaceuticals were detected. The mean concentrations of all measured pharmaceuticals in oysters per site ranged from 0.804 to 15.1 ng g-1 of dry weight, with antihistamines being the most common. Brompheniramine and promethazine were identified in biota samples for the first time. Although no significant health risks to humans were identified through consumption of oysters, 100-1000 times higher health risks were observed for wildlife like water birds, seasnails, and starfishes. Specifically, sea snails that primarily feed on oysters were found to be at risk of exposure to ciprofloxacin, brompheniramine, and promethazine. These high risks could be attributed to the monotonous diet habits and relatively limited food sources of these organisms. Furthermore, taking chirality into consideration, chlorpheniramine in the oysters was enriched by the S-enantiomer, with a relative potency 1.1-1.3 times higher when chlorpheniramine was considered as a racemate. Overall, this study highlights the prevalence of antihistamines in seafood and underscores the importance of studying enantioselectivities of pharmaceuticals in health risk assessments.

Pharmaceuticals are recognised as environmental contaminants of emerging concern (CECs) due to their increasing presence in the aquatic environment, along with high bioactivity linked to their therapeutic use. Therefore, information on environmental levels is urgently required. This study examined the presence of a range of common pharmaceuticals in oysters and mussels intended for human consumption from England and Wales using stable isotope dilution tandem mass spectrometry. A range of compounds were detected in bivalve tissue, with the Selective Serotonin Reuptake Inhibitor antidepressant sertraline being most abundant, reaching a maximum concentration of 22.1 ng/g wet weight shellfish tissue. Levels of all pharmaceuticals showed seasonal and geographical patterns. A dietary risk assessment revealed that the levels of pharmaceuticals identified in bivalve molluscs represent a clear hazard, but not a risk for the consumer. This study highlights the requirement for further monitoring of the presence of pharmaceuticals and other CECs in bivalve molluscs.

Water and industries are intangible units of the globe that are always set to meet the population's demand. The global population depends on one-third of freshwater increasing the demand. The increase in population along with urbanization has polluted the fresh water resources. The pharmaceutical industry is marked as an emerging contaminant of water pollution. The most common type of pharmaceutical drugs that are detected in the environment includes antibiotics, analgesics, NSAIDs, and pain-relieving drugs. These drugs alter the food chain of the organisms causing chaos mainly in the marine ecosystem. Pharmaceutical drugs are found only in shallow amounts (ng/mg) they have a huge impact on the living system. The consumption of water contaminated with pharmaceutical ingredients can disrupt reproduction, hormonal imbalance, cancer, and respiratory problems. Various methods are used to remove these chemicals from the environment. In this review, we mainly focused on the emerging hybrid technologies and their significance in the effective treatment of pharmaceutical wastewater. This review paper primarily elaborates on the merits and demerits of existing conventional technologies helpful in developing integrated technologies for the modern era of pharmaceutical effluent treatment. This review paper further in detail discusses the various strategies of eco-friendly bioremediation techniques namely biostimulation, bioaugmentation, bacterial degradation, mycoremediation, phytoremediation, and others for the ultimate removal of pharmaceutical contaminants in wastewater. The review makes clear that targeted and hybrid solutions are what the world will require in the future to get rid of these pharmacological prints.

Pharmaceuticals are receiving increasing attention as emerging contaminants in the aquatic environment. Herein, we investigated the occurrence of 11 antidepressants, 6 antihistamines and 4 metabolites in treated wastewater effluents, rivers, stormwater, and seawater in Hong Kong, with special focus on chirality. The average levels of ∑pharmaceuticals ranged from 0.525 to 1070 ng/L in all samples and the total annual mass load of target pharmaceuticals in the marine environment of Hong Kong was 756 kg/y. Antihistamines accounted for >80 % of ∑pharmaceuticals, with diphenhydramine and fexofenadine being predominant. The occurrence and enantiomeric profiles of brompheniramine and promethazine sulfoxide were reported in global natural waters for the first time. Among chiral pharmaceuticals, mirtazapine and fexofenadine exhibited R-preference, while others mostly exhibited S-preference, implying that the ecological risks derived from achiral data for chiral pharmaceuticals may be biased. The joint probabilistic risk assessment of fluoxetine revealed that R-fluoxetine and rac-fluoxetine presented different ecological risks from that of S-fluoxetine; Such assessment also revealed that target pharmaceuticals posed only minimal to low risks, except that diphenhydramine posed an intermediate risk. As estimated, 10 % aquatic species will be affected when the environmental level of diphenhydramine exceeds 7.40 ng/L, which was seen in 46.9 % samples. Collectively, this study highlights further investigations on the enantioselectivity of chiral pharmaceuticals, particularly on environmental behavior and ecotoxicity using local aquatic species as target organisms.

Although pharmaceuticals are increasingly detected in abiotic matrices in the Arctic, the accumulation of drugs in the resident biota and trophic transfer have not been yet examined. This study investigated the behaviour of several pharmaceuticals in the rocky-bottom, macrobenthic food web in the coastal zone of Isfjorden (western Spitsbergen) using stable isotope analyses (SIA) coupled with liquid chromatography-mass spectrometry (LC-MS/MS). Across 16 macroalgal and invertebrate species the highest average concentration was measured for ciprofloxacin (CIP) (on average 60.3 ng g-1 dw) followed by paracetamol (PCT) (51.3 ng g-1 dw) and nicotine (NIC) (37.8 ng g-1 dw). The biomagnification potential was assessed for six target compounds of 13 analytes detected that were quantified with a frequency > 50 % in biological samples. The trophic magnification factor (TMF) ranged between 0.3 and 2.8, and was significant for NIC and CIP. TMF < 1.0 for NIC (0.3; confidence interval, CI 0.1-0.5) indicated that the compound does not accumulate with trophic position. The dilution of pharmaceutical residues in the food web may result from limited intake with dietary route, poor assimilation efficiency and high biotransformation rates in benthic invertebrates. TMF for CIP (2.8, CI 1.2-6.4) suggests trophic magnification, a phenomenon observed previously for several antibiotics in freshwater food webs. Trophic transfer therefore plays a role in controlling concentration of CIP in the Arctic benthic communities and should be considered in environmental risk assessment. Biomagnification potential of diclofenac (DIC; 0.9, CI 0.5-1.7), carbamazepine (CBZ; 0.4, CI 0.1-2.1), caffeine (CAF; 0.9, CI 0.5-1.9) and PCT (1.3, CI 0.7-2.7) was not evident due to large 95 % confidence of their TMFs. This study provides the first evidence of drug bioaccumulation in the Arctic food web and indicates that behaviour of pharmaceuticals varies among target compounds.

Fabrication of a metal-organic framework-based photocatalyst has been gaining much interest due to its higher surface area and reasonable band gap, enhancing its photocatalytic activity. This study attempted a facile synthesis of the hybrid photocatalyst UiO-66 doped with graphitic carbon nitride (GCN) by a simple solvothermal method. This composite minimized the drawback related to photogenerated charge transfer and recombination and helped the absorption of visible light. The material was investigated by using various instrumental techniques. In this work, ciprofloxacin (CIP), a fluoroquinolone drug, was chosen as a target micropollutant, and a photodegradation experiment was carried out by using UiO-66, GCN, and UiO-66/GCN under a visible light source, which exhibited 81.85, 69.48, and 93.60% of degradation, respectively. Finally, liquid chromatography mass spectrometry analysis and theoretical computation were carried out to identify the CIP degradation mechanism, and T.E.S.T. software was used to investigate the toxicity of the intermediate products. Apart from photocatalytic activity, the prepared material was also tested for its antibacterial properties against Staphylococcus aureus and Escherichia coli.

Environmental risk assessment of chemical contaminants requires prioritizing of substances taken up by biota as it is a starting point for potential adverse effects. Although knowledge about the occurrence of known chemical pollutants in aquatic organisms has significantly improved during the last decade, there is still a poor understanding for a broad range of more polar compounds. To tackle this issue, we proposed an approach that identifies bioaccumulative and biomagnifiable polar chemicals using liquid chromatography coupled with electrospray ionization to high resolution tandem mass spectrometry (LC-HRMS/MS) and combine it with trend analysis using hierarchical clustering. As a proof-of-concept, this approach was implemented on various organisms and compartments (sediment, litter leaves, periphytic biofilm, invertebrates and fish) collected from a small urban river. HRMS/MS data measured via data-independent acquisition mode were retrospectively analysed using two analytical strategies: (1) retrospective target and (2) suspect/non-target screening. In the retrospective target analysis, 56 of 361 substances spanning a broad range of contaminant classes were detected (i.e. 26 in fish, 18 in macroinvertebrates, 28 in leaves, 29 in periphyton and 32 in sediments, with only 7 common to all compartments), among which 49 could be quantified using reference standards. The suspect screening approach based on two suspect lists (in-house, Norman SusDat) led to the confirmation of 5 compounds with standards (three xenobiotics at level 1 and two lipids at level 2) and tentative identification of seven industrial or natural chemicals at level 2 and 3 through a mass spectra library match. Overall, this proof-of-concept study provided a more comprehensive picture of the exposure of biota to emerging contaminants (i.e., the internal chemical exposome) and potential bioaccumulation or biomagnification of polar compounds along the trophic chain.

Computer-aided (in silico) prediction has shown good potential to support the environmental risk assessment (ERA) of pharmaceutical emerging contaminants (PECs), allowing low-cost, animal-free, high-throughput screening of multiple potential risks posed by a wide variety of pharmaceuticals in the environment based on insufficient toxicity data. This review provided recent insights regarding the application of in silico approaches in prediction for environmental risks of PECs. Based on the review of 20 included articles from 8 countries published since 2018, we found that the researchers' interest and concern in this research topic were sharply aroused since 2021. Recently, in silico approaches have been widely used for the prediction of bioaccumulation and biodegradability, lethal endpoints, developmental toxicity, mutagenicity, other eco-toxicological effects such as ototoxicity and hematological toxicity, and human health hazards of exposure to PECs. Particular attention has been given to the simultaneous discernment of multiple environmental risks and health effects of PECs based on mechanistic data of pharmaceuticals using advanced bioinformatic methods such as transcriptomic analysis and network pharmacology prediction. In silico software platforms and databases used in the included studies were diversified, and there is currently no standardized and accepted in silico model for ERA of PECs. Date suggested that in silico prediction of the environmental risks posed by PECs is still in its infancy. Considerable critical challenges need to be addressed, including consideration of environmental exposure concentration for PECs, interactions among mixtures of PECs and other contaminants coexisting in environments, and development of in silico models specific to ERA of PECs.

Psychotropic drugs (PDs) and their bioactive metabolites often persist in aquatic environments due to their typical physical properties, which made them resistant to removal by traditional wastewater treatment plants (WWTPs). Consequently, such drugs and/or their metabolites are frequently detected in both aquatic environments and organisms. Even at low concentrations, these drugs can exhibit toxic effects on non-target organisms including bony fish (zebrafish (Danio rerio) and fathead minnows) and bivalves (freshwater mussels and clams). This narrative review focuses on the quintessential representatives of three different categories of PDs-antiepileptics, antidepressants, and antipsychotics. The data regarding their concentrations occurring in the environment, patterns of distribution, the degree of enrichment in various tissues of aquatic organisms, and the toxicological effects on them are summarized. The toxicological assessments of these drugs included the evaluation of their effects on the reproductive, embryonic development, oxidative stress-related, neurobehavioral, and genetic functions in various experimental models. However, the mechanisms underlying the toxicity of PDs to aquatic organisms and their potential health risks to humans remain unclear. Most studies have focused on the effects caused by acute short-term exposure due to limitations in the experimental conditions, thus making it necessary to investigate the chronic toxic effects at concentrations that are in coherence with those occurring in the environment. Additionally, this review aims to raise awareness and stimulate further research efforts by highlighting the gaps in the understanding of the mechanisms behind PD-induced toxicity and potential health risks. Ultimately, the study underscores the importance of developing advanced remediation methods for the removal of PDs in WWTPs and encourages a broader discussion on mitigating their environmental impacts.

Environmental pollution is a growing threat to natural ecosystems and one of the world's most pressing concerns. The increasing worldwide use of pharmaceuticals has elevated their status as significant emerging contaminants. Pharmaceuticals enter aquatic environments through multiple pathways related to anthropogenic activity. Their high consumption, insufficient waste treatment, and the incapacity of organisms to completely metabolize them contribute to their accumulation in aquatic environments, posing a threat to all life forms. Various analytical methods have been used to quantify pharmaceuticals. Biotechnology advancements based on next-generation sequencing (NGS) techniques, like eDNA metabarcoding, have enabled the development of new methods for assessing and monitoring the ecotoxicological effects of pharmaceuticals. eDNA metabarcoding is a valuable biomonitoring tool for pharmaceutical pollution because it (a) provides an efficient method to assess and predict pollution status, (b) identifies pollution sources, (c) tracks changes in pharmaceutical pollution levels over time, (d) assesses the ecological impact of pharmaceutical pollution, (e) helps prioritize cleanup and mitigation efforts, and (f) offers insights into the diversity and composition of microbial and other bioindicator communities. This review highlights the issue of aquatic pharmaceutical pollution while emphasizing the importance of using modern NGS-based biomonitoring actions to assess its environmental effects more consistently and effectively.

Pharmaceutical pollutants are a group of emerging contaminants frequently found in water streams. In this study, the composite chitosan beads with incorporated molecularly imprinted polymers (monoliths or microparticles) and iron(III) hydroxide were fabricated to remove ibuprofen from aqueous solutions. The adsorptive properties were investigated in different conditions to evaluate the influence of solution pH, adsorbent dose, ibuprofen initial concentration, adsorption time, and temperature. The highest adsorption capacity (79.41 mg g-1), about twice as large as that for the chitosan beads without polymers (39.42 mg g-1), was obtained for the ones containing monoliths imprinted with ibuprofen. The theoretical maximum adsorption capacity of 103.93 mg g-1 was obtained based on the experiments in optimal pH 5. The adsorption of ibuprofen on the hybrid hydrogel beads followed the Freundlich isotherm and pseudo-second-order kinetic models. The process was found as endothermic and thermodynamically spontaneous. The adsorbent with a molecularly imprinted polymer retained its selectivity in the presence of other molecules. The imprinted cavities, chitosan functional groups, and iron hydroxide were presumably responsible for interactions with ibuprofen molecules. Additionally, the effectiveness of the adsorbent did not change significantly in real water samples and remained at a satisfactory level for up to four desorption-adsorption cycles.

Ibuprofen (IBP) is an anti-inflammatory drug found in aquatic environments, potentially toxic for the biota. We exposed the test fish C. decemmaculatus to two environmentally relevant concentrations (50 and 100 μg IBP/L) for 4 and 12 d and evaluated the effect on some biomarkers. Micronucleus test, nuclear abnormality test and comet assay indicated cyto-genotoxicity at both concentrations and exposure periods. Oxidative stress and biochemical biomarkers were not affected, excepting muscle AChE activity for 4 d. Muscle metabolic biomarkers showed significant decrease in ETS, lipid and protein content, while carbohydrate content was not affected. The CEA index increased at the lower IBP concentration for 4 and 12 d, possibly due to changes in body energy reserves. A full-factorial GLM performed to assess the effects of IBP and exposure times showed that the metabolic and genotoxicity biomarkers were the most sensitive to IBP toxicity, mainly at 50 μg IBP/L for 4 d.

Bisoprolol and ketoprofen are widely used pharmaceuticals in medical treatment hence these substances are occurring in wastewaters and in water environment. This research investigated the toxic effects of bisoprolol and ketoprofen on two microalgae taxa, Chlorella vulgaris and Desmodesmus armatus. The results showed that both drugs inhibited the growth of the species tested and induced a decrease in chlorophyll a content compared to controls. Ketoprofen turned out to be harmful to algae as the half maximal effective concentration (EC50) values (14 days) were 37.69 mg L-1 for C. vulgaris and 40.93 mg L-1 for D. armatus. On the other hand, for bisoprolol, the EC50 values were greater than the established NOEC, 100 mg L-1. Bisoprolol and ketoprofen induced oxidative stress in the tested microorganisms, as indicated by changes in the activities of antioxidant enzymes. Exposure to 100 mg L-1 of drugs significantly increased the activity of catalase, peroxidase and superoxide dismutase. Fluorescence microscopy showed that both medicaments changed the cells' morphology. There was atrophy of chlorophyll in the cells, moreover, dying multinuclear cells and cells without nuclei were observed. In addition, there were atrophic cells, namely cells that lacked nuclei and chlorophyll. Profile area analyses showed that bisoprolol and ketoprofen treated C. vulgaris cells were approximately 4 and 2 times greater compared to control ones. Our experimental findings highlight the ecotoxicological threats for aquatic primary producers from bisoprolol and ketoprofen and provide insight into the characteristics of their death.

Environmental risks of human pharmaceutical products should be made transparent and mitigated as far as possible. We propose to apply a risk mitigation scheme to the marketing authorisation of human medicinal products which is pragmatic and tailored, and thus will not increase the burden to regulators and industry too much. This scheme takes into account increasing knowledge and accuracy of the environmental risk estimates, applying preliminary risk mitigation when risks are determined based on model estimates, and definitive, more strict and far-reaching risk mitigation when risks are based on actual measured environmental concentrations. Risk mitigation measures should be designed to be effective, proportional, easy to implement, and in line with current (other) legislation, as well as not being a burden to the patient/health care professionals. Furthermore, individual risk mitigation measures are proposed for products showing environmental risks, while general risk mitigation measures can be applied to all products to reduce the overall burden of pharmaceuticals in the environment. In order to effectively mitigate risk, linking marketing authorisation legislation to environmental legislation is essential.

Ketoprofen, a bicyclic non-steroidal anti-inflammatory drug commonly used in human and veterinary medicine, has recently been cited as an environmental contaminant that raises concerns for ecological well-being. It poses a growing threat due to its racemic mixture, enantiomers, and transformation products, which have ecotoxicological effects on various organisms, including invertebrates, vertebrates, plants, and microorganisms. Furthermore, ketoprofen is bioaccumulated and biomagnified throughout the food chain, threatening the ecosystem function. Surprisingly, despite these concerns, ketoprofen is not currently considered a priority substance. While targeted eco-pharmacovigilance for ketoprofen has been proposed, data on ketoprofen as a pharmaceutical contaminant are limited and incomplete. This review aims to provide a comprehensive summary of the most recent findings (from 2017 to March 2023) regarding the global distribution of ketoprofen in the environment, its ecotoxicity towards aquatic animals and plants, and available removal methods. Special emphasis is placed on understanding how ketoprofen affects microorganisms that play a pivotal role in Earth's ecosystems. The review broadly covers various approaches to ketoprofen biodegradation, including whole-cell fungal and bacterial systems as well as enzyme biocatalysts. Additionally, it explores the potential of adsorption by algae and phytoremediation for removing ketoprofen. This review will be of interest to a wide range of readers, including ecologists, microbiologists, policymakers, and those concerned about pharmaceutical pollution.

One of the flagship actions of the Pharmaceutical Strategy for Europe is to address environmental challenges associated with pharmaceutical use. This includes strengthening the Environmental Risk Assessment (ERA) at marketing authorisation (MA) of pharmaceuticals, and revision of the pharmaceutical legislation where needed. The overall aim of an ERA should be to enable comprehensive and effective identification and management of environmental risks of pharmaceuticals without affecting the availability of pharmaceuticals to patients. As experts in the evaluation of ERAs of human medicinal products submitted by pharmaceutical industries (Applicants), we have summarized the current status of the ERA and suggest legislative changes to improve environmental protection without affecting availability. Six regulatory goals were defined and discussed, including possible ways forward: 1) mandatory ERAs in accordance to the EMA guideline at the time of the MA, 2) enforcement of risk mitigation measures including re-evaluation of the ERA, 3) facilitated exchange of environmental data between pharmaceutical and environmental legislations, 4) substance-based assessments, 5) transparency of data, and 6) a catching-up procedure for active pharmaceutical ingredients that lack an ERA. These legislative proposals can be considered as prerequisites for a harmonised assessment and effective management of environmental risks and hazards of human pharmaceuticals.

Pharmaceuticals are a ubiquitous group of emerging pollutants of considerable importance due to their biological potency and potential to elicit effects in wildlife and humans. Pharmaceuticals have been quantified in terrestrial, marine, fresh, and transitional waters, as well as the fauna and macro-flora that inhabit them. Pharmaceuticals can enter water ways through different human and veterinary pathways with traditional wastewater treatment, unable to completely remove pharmaceuticals, discharging often unknown quantities to aquatic ecosystems. However, there is a paucity of available information regarding the effects of pharmaceuticals on species at the base of aquatic food webs, especially on phytoplankton, with research typically focussing on fish and aquatic invertebrates. Diatoms are one of the main classes of phytoplankton and are some of the most abundant and important organisms in aquatic systems. As primary producers, diatoms generate ∼40 % of the world's oxygen and are a vital food source for primary consumers. Diatoms can also be used for bioremediation of polluted water bodies but perhaps are best known as bio-indicators for water quality studies. However, this keystone, non-target group is often ignored during ecotoxicological studies to assess the effects of pollutants of concern. Observed effects of pharmaceuticals on diatoms have the potential to be used as an indicator of pharmaceutical-induced impacts on higher trophic level organisms and wider ecosystem effects. The aim of this review is to present a synthesis of research on pharmaceutical exposure to diatoms, considering ecotoxicity, bioremediation and the role of diatoms as bio-indicators. We highlight significant omissions and knowledge gaps which need addressing to realise the potential role of diatoms in future risk assessment approaches and help evaluate the impacts of pharmaceuticals in the aquatic environment at local and global scales.

Ciprofloxacin (CIP) is an antibiotic commonly used in human and veterinary medicine. It is present in the aquatic environment, but we still know very little about its effect on non-targeted organisms. This study aimed to evaluate the effects of long-term exposure to environmental CIP concentrations (1, 10, and 100 μg.L^-1) in males and females of Rhamdia quelen. After 28 days of exposure, we collected the blood for the analysis of hematological and genotoxic biomarkers. Additionally, we measured 17 β-estradiol and 11 keto-testosterone levels. After the euthanasia, we collected the brain and the hypothalamus to analyze acetylcholinesterase (AChE) activity and neurotransmitters, respectively. The liver and gonads were assessed for biochemical, genotoxic, and histopathological biomarkers. At 100 μg.L^-1 CIP, we observed genotoxicity in the blood, nuclear morphological changes, apoptosis, leukopenia, and a reduction of AChE in the brain. In the liver was observed oxidative stress and apoptosis. At 10 μg.L^-1 CIP, leukopenia, morphological changes, and apoptosis were presented in the blood and a reduction of AChE in the brain. Apoptosis, leukocyte infiltration, steatosis, and necrosis occurred in the liver. Even at the lowest concentration (1 μg.L^-1), adverse effects such as erythrocyte and liver genotoxicity, hepatocyte apoptosis, oxidative stress, and a decrease in somatic indexes were observed. The results showed the importance of monitoring CIP concentrations in the aquatic environment that cause sublethal effects on fish.

In this work, a wide-scope liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantitative determination of environmental levels of multiclass drugs and their metabolites in water and fish samples was developed. The method allowed the reliable determination of 44 drugs, covering a rather wide range of chemistries and physicochemical characteristics. In order to obtain a reliable and robust analytical protocol, different combinations of extraction and cleanup techniques were systematically examined. Aqueous samples were extracted using a simple Oasis HLB SPE enrichment protocol with pH-optimized sample percolation (pH 3). The extraction of cryo-homogenized biota samples was performed using double extraction with MeOH basified with 0.5% NH₃, which allowed high extraction recoveries for all target analytes. The problem of the coextracted lipid matrix, which is known to be the key obstacle for reliable biota analysis, was systematically examined in a series of model cleanup experiments. A combination of cryo-precipitation, filtration, and HLB SPE cleanup was proposed as a protocol, which allowed reliable and robust analysis of all target compounds at low ng/g levels. At the final conditions, the method which was validated at three concentration levels showed high extraction recoveries (68-97%), acceptable matrix effects (12 to -32%), accuracies (81-129%), and reproducibilities (3-32%) for all analytes. The developed method was used to determine drug concentrations in river water and in feral freshwater fish, including whole fish and muscle tissue, from the Sava River (Croatia), in order to estimate their corresponding bioaccumulation potential. With respect to bioaccumulation potential in whole fish and fish muscle, the most relevant drugs were lisinopril, sertraline, terbinafine, torsemide, diazepam, desloratadine, and loratadine with estimated bioaccumulation factors ranging from 20 to 838 and from 1 to 431, respectively.