Crystal size, shape, and conformational changes drive both the disappearance and reappearance of ritonavir polymorphs in the mill.

Organic compounds can crystallize in different forms known as polymorphs. Discovery and control of polymorphism is crucial to the pharmaceutical industry since different polymorphs can have significantly different physical properties which impacts their utilization in drug delivery. Certain polymorphs have been reported to 'disappear' from the physical world, irreversibly converting to new ones. These unwanted polymorph conversions, initially prevented by slow nucleation kinetics, are eventually observed driven by significant gains in thermodynamic stabilities. The most infamous of these cases is that of the HIV drug ritonavir (RVR): Once its reluctant form was unwillingly nucleated for the first time, its desired form could no longer be produced with the same manufacturing process. Here we show that RVR's extraordinary disappearing polymorph as well as its reluctant form can be consistently produced by ball-milling under different environmental conditions. We demonstrate that the significant difference in stability between its polymorphs can be changed and reversed in the mill-a process we show is driven by crystal size as well as crystal shape and conformational effects. We also show that those effects can be controlled through careful design of milling conditions since they dictate the kinetics of crystal breakage, dissolution, and growth processes that eventually lead to steady-state crystal sizes and shapes in the mill. This work highlights the huge potential of mechanochemistry in polymorph discovery of forms initially difficult to nucleate, recovery of disappearing polymorphs, and polymorph control of complex flexible drug compounds such as RVR.

A molecularly enhanced proof of concept for targeting cocrystals at molecular scale in continuous pharmaceuticals cocrystallization.

It is impossible to optimize a process for a target drug product with the desired profile without a proper understanding of the interplay among the material attributes, the process parameters, and the attributes of the drug product. There is a particular need to bridge the micro- and mesoscale events that occur during this process. Here, we propose а molecular engineering methodology for the continuous cocrystallization process, based on Raman spectra measured experimentally with a probe and from quantum mechanical calculations. Using molecular dynamics simulations, the theoretical Raman spectra were calculated from first principles for local mixture structures under an external shear force at various temperatures. A proof of concept is developed to build the process design space from the computed data. We show that the determined process design space provides valuable insight for optimizing the cocrystallization process at the nanoscale, where experimental measurements are difficult and/or inapplicable. The results suggest that our method may be used to target cocrystallization processes at the molecular scale for improved pharmaceutical synthesis.

Pharmaceutical pollution of the world's rivers.

Environmental exposure to active pharmaceutical ingredients (APIs) can have negative effects on the health of ecosystems and humans. While numerous studies have monitored APIs in rivers, these employ different analytical methods, measure different APIs, and have ignored many of the countries of the world. This makes it difficult to quantify the scale of the problem from a global perspective. Furthermore, comparison of the existing data, generated for different studies/regions/continents, is challenging due to the vast differences between the analytical methodologies employed. Here, we present a global-scale study of API pollution in 258 of the world's rivers, representing the environmental influence of 471.4 million people across 137 geographic regions. Samples were obtained from 1,052 locations in 104 countries (representing all continents and 36 countries not previously studied for API contamination) and analyzed for 61 APIs. Highest cumulative API concentrations were observed in sub-Saharan Africa, south Asia, and South America. The most contaminated sites were in low- to middle-income countries and were associated with areas with poor wastewater and waste management infrastructure and pharmaceutical manufacturing. The most frequently detected APIs were carbamazepine, metformin, and caffeine (a compound also arising from lifestyle use), which were detected at over half of the sites monitored. Concentrations of at least one API at 25.7% of the sampling sites were greater than concentrations considered safe for aquatic organisms, or which are of concern in terms of selection for antimicrobial resistance. Therefore, pharmaceutical pollution poses a global threat to environmental and human health, as well as to delivery of the United Nations Sustainable Development Goals.

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update.

OBJECTIVE: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. METHODS: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. RESULTS: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. CONCLUSION: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.

Wastewater contaminants in a fractured bedrock aquifer and their potential use as enteric virus indicators.

Domestic wastewater is a source of persistent organic pollutants and pathogens to the aquatic environment, including groundwater aquifers. Wastewater contaminants include a variety of personal care products, pharmaceuticals, endocrine disrupters, bacteria, and viruses. Groundwater from 22 wells completed in a semi-confined to confined, fractured Silurian dolostone aquifer in southern Wellington County, Ontario, Canada, was analyzed for 14 organic wastewater contaminants (4 artificial sweeteners, 10 pharmaceuticals) as well as E. coli, total coliforms, and 6 human enteric viruses. Enteric viruses were detected in 8.6% of 116 samples, and at least one organic wastewater contaminant was detected in 82% of the wells (in order of decreasing detection frequency: acesulfame, ibuprofen, sulfamethoxazole, triclosan, carbamazepine, and saccharin). Virus indicator metrics [positive and negative predictive values (PPV, NPV), sensitivity, specificity] were calculated at the sample and well level for the organic wastewater compounds, E. coli, and total coliforms. Fecal bacteria were not good predictors of virus presence (PPV = 0%-8%). Of the potential chemical indicators, triclosan performed the best at the sample level (PPV = 50%, NPV = 100%), and ibuprofen performed the best at the well level (PPV = 60%, NPV = 67%); however, no samples had triclosan or ibuprofen concentrations above their practical quantification limits. Therefore, none of the compounds performed sufficiently well to be considered reliable for assessing the potential threat of enteric viruses in wastewater-impacted groundwater in this bedrock aquifer. Future studies need to evaluate the indicator potential of persistent organic wastewater contaminants in different types of aquifers, especially in fractured rock where heterogeneity is strong.IMPORTANCEAssessing the potential risk that human enteric viruses pose in groundwater aquifers used for potable water supply is complicated by several factors, including: (i) labor-intensive methods for the isolation and quantification of viruses in groundwater, (ii) the temporal variability of these viruses in domestic wastewater, and (iii) their potentially rapid transport in the subsurface, especially in fractured rock aquifers. Therefore, aquifer risk assessment would benefit from the identification of suitable proxy indicators of enteric viruses that are easier to analyze and less variable in wastewater sources. Traditional fecal indicators (e.g., E. coli and coliforms) are generally poor indicators of enteric viruses in groundwater. While many studies have examined the use of pharmaceutical and personal care products as tracers of domestic wastewater and fecal pollution in the environment, there is a paucity of data on the potential use of these chemical tracers as enteric virus indicators, especially in groundwater.

Advances in mass spectrometry imaging for toxicological analysis and safety evaluation of pharmaceuticals.

Safety issues caused by pharmaceuticals have frequently occurred worldwide, posing a tremendous threat to human health. As an essential part of drug development, the toxicological analysis and safety evaluation is of great significance. In addition, the risk of pharmaceuticals accumulation in the environment and the monitoring of the toxicity from natural medicines have also received ongoing concerns. Due to a lack of spatial distribution information provided by common analytical methods, analyses that provide spatial dimensions could serve as complementary safety evaluation methods for better prediction and evaluation of drug toxicity. With advances in technical solutions and software algorithms, mass spectrometry imaging (MSI) has received increasing attention as a popular analytical tool that enables the simultaneous implementation of qualitative, quantitative, and localization without complex sample pretreatment and labeling steps. In recent years, MSI has become more attractive, powerful, and sensitive and has been applied in several scientific fields that can meet the safety assessment requirements. This review aims to cover a detailed summary of the various MSI technologies utilized in the biomedical and pharmaceutical area, including technical principles, advantages, current status, and future trends. Representative applications and developments in the safety-related issues of different pharmaceuticals and natural medicines are also described to provide a reference for pharmaceutical research, improve rational clinical medicine use, and ensure public safety.

Analyzing water hyacinth plants from two South African rivers for the detection of seven pharmaceuticals and their metabolites.

Water hyacinth plants (Eichhornia crassipes Mart.) collected from two South African rivers were analyzed in order to investigate their suitability for judging the presence of pharmaceuticals in the water. Thereby, a number of drugs, including amitriptyline, atenolol, citalopram, orphenadrine, lidocaine, telmisartan, and tramadol, could be detected. Particularly for the latter substance, relatively high concentrations (more than 5000 ng g-1 dry plant material) were detected in the water plants. Subsequently, the plant extracts were also screened for drug-derived transformation products, whereby a series of phase-one metabolites could be tentatively identified.

Sequential, Electrochemical-Photochemical Synthesis of 1,2,4-Triazolo-[4,3-a]pyrazines.

1,2,4-triazolo-[4,3-a]pyrazine was prepared via a two-step electrochemical, photochemical process. First, a 5-substituted tetrazole is electrochemically coupled to 2,6-dimethoxypyrazine to yield 1,5- and 2,5- disubstituted tetrazoles. Subsequent photochemical excitation of the 2,5-disubstituted tetrazole species using an ultraviolet lamp releases nitrogen gas and produces a short-lived nitrilimine intermediate. Subsequent cyclization of the nitrilimine intermediate yields a 1,2,4-triazolo-[4,3-a]pyrazine backbone. The scope of this reaction was explored using various tetrazoles and pyrazines. Materials produced were identified using chemical analytical techniques and computationally studied for potential application as an insensitive energetic material.

Structure Elucidation of Pharmaceutically Relevant Compounds within Pyrene-based Frameworks.

Single crystal X-ray diffraction (SCXRD) is the preferred and most accurate technique for determining molecular structures. However, it can present challenges when dealing with specific small molecules and active pharmaceutical ingredients (APIs), as many do not form quality crystals without coformers or can be unstable. In this study, we introduce tetrakis(guanidinium) pyrenetetrasulfonate (G4PYR), a robust guanidinium-organosulfonate (GS) framework that efficiently encapsulates small molecules and APIs rich in functional groups. The hydrogen bonding frameworks formed by G4PYR display well-ordered structures with predictable pyrene-pyrene distances, making them ideally suited for targeting arene-based APIs with pendant groups. Successful encapsulation of various guests, including benzaldehyde, benzamide, and arenes containing multiple hydrogen bond donors and acceptors like uracil and thymine, was achieved. Furthermore, we successfully encapsulated important pharmaceutical and biologically relevant compounds, such as lidocaine, ropinirole, adenosine, thymidine, and others. Notably, we present a workflow for investigating host-guest complex formation using powder X-ray diffraction and high throughput experimentation.

Stereoselective Crystallization of Chiral Pharmaceuticals Aided by Cellulose Derivatives through Helical Pattern Matching.

Stereoselective inhibition aided by "tailor-made" polymeric additives is an efficient approach to obtain enantiopure compounds through conglomerate crystallization. The chemical and configurational match between the side groups of polymers and the molecules of undesired enantiomer is considered to be a necessary condition for successful stereoseparation. Whereas in this contribution, we present an effective resolution of chiral pharmaceuticals by using cellulose acetates as the additives, which stereoselectively reside on the specific crystal faces of one enantiomer and inhibit its crystal nucleation and growth through helical pattern and supramolecular interaction complementarity. An investigation of nimodipine serves as a case study to highlight the novelty of this strategy wherein R-crystals exhibiting an impressive enantiomeric excess value of 97 % can be attained by employing a mere 0.01 wt % cellulose acetate. Guaifenesin and phenyl lactic acid are also well-resolved by utilizing this methodology. Our work not only brings about a brand-new design strategy for "tailor-made" additives, but will also promote the further exploration of the endless potential for utilizing natural biomolecules in chiral recognition and resolution.

Validation of the imperial psychedelic predictor scale.

BACKGROUND: Access to psychedelic drugs is liberalizing, yet responses are highly unpredictable. It is therefore imperative that we improve our ability to predict the nature of the acute psychedelic experience to improve safety and optimize potential therapeutic outcomes. This study sought to validate the 'Imperial Psychedelic Predictor Scale' (IPPS), a short, widely applicable, prospective measure intended to be predictive of salient dimensions of the psychedelic experience. METHODS: Using four independent datasets in which the IPPS was completed prospectively - two online surveys of 'naturalistic' use (N = 741, N = 836) and two controlled administration datasets (N = 30, N = 28) - we conducted factor analysis, regression, and correlation analyses to assess the construct, predictive, and convergent validity of the IPPS. RESULTS: Our approach produced a 9-item scale with good internal consistency (Cronbach's α = 0.8) containing three factors: set, rapport, and intention. The IPPS was significantly predictive of 'mystical', 'challenging', and 'emotional breakthrough' experiences. In a controlled administration dataset (N = 28), multiple regression found set and rapport explaining 40% of variance in mystical experience, and simple regression found set explained 16% of variance in challenging experience. In another (N = 30), rapport was related to emotional breakthrough explaining 9% of variance. CONCLUSIONS: Together, these data suggest that the IPPS is predictive of relevant acute features of the psychedelic experience in a broad range of contexts. We hope that this brief 9-item scale will be widely adopted for improved knowledge of psychedelic preparedness in controlled settings and beyond.

Challenges and mitigation strategies associated with Burkholderia cepacia complex contamination in pharmaceutical manufacturing.

Burkholderia cepacia complex (BCC) is a Gram-negative, non-spore-forming bacterium with more than 20 opportunistic pathogenic species, most commonly found in soil and water. Due to their rapid mutation rates, these organisms are adaptable and possess high genomic plasticity. BCC can cause life-threatening infections in immunocompromised individuals, such as those with cystic fibrosis, chronic granulomatous disease, and neonates. BCC contamination is a significant concern in pharmaceutical manufacturing, frequently causing non-sterile product recalls. BCC has been found in purified water, cosmetics, household items, and even ultrasound gel used in veterinary practices. Pharmaceuticals, personal care products, and cleaning solutions have been implicated in numerous outbreaks worldwide, highlighting the risks associated with intrinsic manufacturing site contamination. Regulatory compliance, product safety, and human health protection depend on testing for BCC in pharmaceutical manufacturing. Identification challenges exist, with BCC often misidentified as other bacteria like non-lactose fermenting Escherichia coli or Pseudomonas spp., particularly in developing countries where reporting BCC in pharmaceuticals remains limited. This review comprehensively aims to address the organisms causing BCC contamination, genetic diversity, identification challenges, regulatory requirements, and mitigation strategies. Recommendations are proposed to aid pharmaceutical chemists in managing BCC-associated risks and implementing prevention strategies within manufacturing processes.

Macroalgae-derived bioactive compounds for functional food and pharmaceutical applications-a critical review.

The rising demand for global food resources, combined with an overreliance on land-based agroecosystems, poses a significant challenge for the sustainable production of food products. Macroalgae cultivation is a promising approach to mitigate impending global food insecurities due to several key factors: independence from terrestrial farming, rapid growth rates, unique biochemical makeup, and carbon capture potential. Furthermore, macroalgae are rich in vitamins, minerals, essential amino acids, polyunsaturated fatty acids and fiber, demonstrating significant potential as sustainable alternatives for enhancing dietary diversity and fulfilling nutritional requirements. This review provides an overview of the nutritional composition and functional properties of commercially cultivated macroalgae species, with emphasis on their viability as value additions to the functional food market. Furthermore, the review discusses the technological aspects of integrating macroalgae into food products, covering both innovative solutions and existing challenges. Macroalgae, beyond being nutritional powerhouses, contain a plethora of bioactive compounds with varied biological activities, including anti-diabetic, anti-cancer, cardioprotective, and neuroprotective properties, making them excellent candidates in developing novel pharmaceuticals. Thus, this review also summarizes the pharmaceutical applications of macroalgae, identifies research gaps and proposes potential strategies for incorporating macroalgae-derived bioactive compounds into therapeutic products.

Macroalgae contain diverse bioactives for food and pharmaceutical applications.Integration of macroalgae into functional foods increases its nutritional value.Surging macroalgae-based foods indicate strong commercial potential.Clinical validation is essential for macroalgae-based products' therapeutic effects.Rigorous quality control ensures safety and compliance in macroalgae applications.

Computational Modelling of the Impact of Evaporation on In-Vitro Dermal Absorption.

PURPOSE: Volatiles are common in personal care products and dermatological drugs. Determining the impact of evaporation of volatiles on skin permeation is crucial to evaluate and understand their delivery, bioavailability, efficacy and safety. We aim to develop an in-silico model to simulate the impact of evaporation on the dermal absorption of volatiles. METHOD: The evaporation of volatile permeants was modelled using vapour pressure as the main factor. This model considers evaporation as a passive diffusion process driven by the concentration gradient between the air-vehicle interface and the ambient environment. The evaporation model was then integrated with a previously published physiologically based pharmacokinetic (PBPK) model of skin permeation and compared with published in vitro permeation test data from the Cosmetics Europe ADME Task Force. RESULTS: The evaporation-PBPK model shows improved predictions when evaporation is considered. In particular, good agreement has been obtained for the distributions in the evaporative loss, and the overall percutaneous absorption. The model is further compared with published in-silico models from the Cosmetics Europe ADME Task Force where favourable results are achieved. CONCLUSION: The evaporation of volatile permeants under finite dose in vitro permeation test conditions has been successfully predicted using a mechanistic model with the intrinsic volatility parameter vapour pressure. Integrating evaporation in PBPK modelling significantly improved the prediction of dermal delivery.

Zygotic Exposure to Venlafaxine Disrupts the Circadian Locomotor Activity Behaviour in Zebrafish Larvae.

The antidepressant venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is commonly prescribed to treat major depressive disorder and is found at high concentrations in the aquatic environment. Concerns have been raised related to the health of aquatic organisms in response to this nontargeted pharmaceutical exposure. For instance, we previously demonstrated that exposure to venlafaxine perturbs neurodevelopment, leading to behavioural alterations in zebrafish (Danio rerio). We also observed disruption in serotonin expression in the pineal and raphe, regions critical in regulating circadian rhythms, leading us to hypothesize that zygotic exposure to venlafaxine disrupts the circadian locomotor rhythm in larval zebrafish. To test this, we microinjected zebrafish embryos with venlafaxine (1 or 10 ng) and recorded the locomotor activity in 5-day-old larvae over a 24-h period. Venlafaxine deposition reduced larval locomotor activity during the light phase, but not during the dark phase of the diurnal cycle. The melatonin levels were higher in the dark compared to during the light photoperiod and this was not affected by embryonic venlafaxine deposition. Venlafaxine exposure also did not affect the transcript abundance of clock genes, including clock1a, bmal2, cry1a and per2, which showed a clear day/night rhythmicity. A notable finding was that exposure to luzindole, a melatonin receptor antagonist, decreased the locomotor activity in the control group in light, whereas the activity was higher in larvae raised from the venlafaxine-deposited embryos. Overall, zygotic exposure to venlafaxine disrupts the locomotor activity of larval zebrafish fish during the day, demonstrating the capacity of antidepressants to disrupt the circadian rhythms in behaviour. Our results suggest that disruption in melatonin signalling may be playing a role in the venlafaxine impact on circadian behaviour, but further investigation is required to elucidate the possible mechanisms in larval zebrafish.

New Perspectives on the Interactions between Adsorption and Degradation of Organic Micropollutants in Granular Activated Carbon Filters.

The removal of organic micropollutants in granular activated carbon (GAC) filters can be attributed to adsorption and biological degradation. These two processes can interact with each other or proceed independently. To illustrate the differences in their interaction, three 14C-labeled organic micropollutants with varying potentials for adsorption and biodegradation were selected to study their adsorption and biodegradation in columns with adsorbing (GAC) and non-adsorbing (sand) filter media. Using 14CO2 formation as a marker for biodegradation, we demonstrated that the biodegradation of poorly adsorbing N-nitrosodimethylamine (NDMA) was more sensitive to changes in the empty bed contact time (EBCT) compared with that of moderately adsorbing diclofenac. Further, diclofenac that had adsorbed under anoxic conditions could be degraded when molecular oxygen became available, and substantial biodegradation (≥60%) of diclofenac could be achieved with a 15 min EBCT in the GAC filter. These findings suggest that the retention of micropollutants in GAC filters, by prolonging the micropollutant residence time through adsorption, can enable longer time periods for degradations than what the hydraulic retention time would allow for. For the biologically recalcitrant compound carbamazepine, differences in breakthrough between the 14C-labeled and nonradiolabeled compounds revealed a substantial retention via successive adsorption-desorption, which could pose a potential challenge in the interpretation of GAC filter performance.

Exposure Effects of Environmentally Relevant Concentrations of the Tricyclic Antidepressant Amitriptyline in Early Life Stage Zebrafish.

Antidepressants are one of the most globally prescribed classes of pharmaceuticals, and drug target conservation across phyla means that nontarget organisms may be at risk from the effects of exposure. Here, we address the knowledge gap for the effects of chronic exposure (28 days) to the tricyclic antidepressant amitriptyline (AMI) on fish, including for concentrations with environmental relevance, using zebrafish (Danio rerio) as our experimental model. AMI was found to bioconcentrate in zebrafish, was readily transformed to its major active metabolite nortriptyline, and induced a pharmacological effect (downregulation of the gene encoding the serotonin transporter; slc6a4a) at environmentally relevant concentrations (0.03 µg/L and above). Exposures to AMI at higher concentrations accelerated the hatch rate and reduced locomotor activity, the latter of which was abolished after a 14 day period of depuration. The lack of any response on the features of physiology and behavior we measured at concentrations found in the environment would indicate that AMI poses a relatively low level of risk to fish populations. The pseudopersistence and likely presence of multiple drugs acting via the same mechanism of action, however, together with a global trend for increased prescription rates, mean that this risk may be underestimated using current ecotoxicological assessment paradigms.

Pharmaceutical Pollution Alters the Structure of Freshwater Communities and Hinders Their Recovery from a Fish Predator.

Freshwater ecosystems are under threat from rising pharmaceutical pollution. While such pollutants are known to elicit biological effects on organisms, we have limited knowledge on how these effects might cascade through food-webs, disrupt ecological processes, and shape freshwater communities. In this study, we used a mesocosm experiment to explore how the community impacts of a top-order predator, the eastern mosquitofish (Gambusia holbrooki), are mediated by exposure to environmentally relevant low (measured concentration: ∼10 ng/L) and high concentrations (∼110 ng/L) of the pervasive pharmaceutical pollutant fluoxetine. We found no evidence that exposure to fluoxetine altered the consumptive effects of mosquitofish on zooplankton. However, once mosquitofish were removed from the mesocosms, zooplankton abundance recovered to a greater extent in control mesocosms compared to both low and high fluoxetine-exposed mesocosms. By the end of the experiment, this resulted in fundamental differences in community structure between the control and fluoxetine-treated mesocosms. Specifically, the control mesocosms were characterized by higher zooplankton abundances and lower algal biomass, whereas mesocosms exposed to either low or high concentrations of fluoxetine had lower zooplankton abundances and higher algal biomass. Our results suggest that fluoxetine, even at very low concentrations, can alter aquatic communities and hinder their recovery from disturbances.

Combining Advanced Analytical Methodologies to Uncover Suspect PFAS and Fluorinated Pharmaceutical Contributions to Extractable Organic Fluorine in Human Serum (Tromsø Study).

A growing number of studies have reported that routinely monitored per- and polyfluoroalkyl substances (PFAS) are not sufficient to explain the extractable organic fluorine (EOF) measured in human blood. In this study, we address this gap by screening pooled human serum collected over 3 decades (1986-2015) in Tromsø (Norway) for >5000 PFAS and >300 fluorinated pharmaceuticals. We combined multiple analytical techniques (direct infusion Fourier transform ion cyclotron resonance mass spectrometry, liquid chromatography-Orbitrap-high-resolution mass spectrometry, and total oxidizable precursors assay) in a three-step suspect screening process which aimed at unequivocal suspect identification. This approach uncovered the presence of one PFAS and eight fluorinated pharmaceuticals (including some metabolites) in human serum. While the PFAS suspect only accounted for 2-4% of the EOF, fluorinated pharmaceuticals accounted for 0-63% of the EOF, and their contribution increased in recent years. Although fluorinated pharmaceuticals often contain only 1-3 fluorine atoms, our results indicate that they can contribute significantly to the EOF. Indeed, the contribution from fluorinated pharmaceuticals allowed us to close the organofluorine mass balance in pooled serum from 2015, indicating a good understanding of organofluorine compounds in humans. However, a portion of the EOF in human serum from 1986 and 2007 still remained unexplained.

Quantitative Non-targeted Screening to Profile Micropollutants in Sewage Sludge Used for Agricultural Field Amendments.

A considerable number of micropollutants from human activities enter the wastewater network for removal. However, at the wastewater treatment plant (WWTP), some proportion of these compounds is retained in the sewage sludge (biosolids), and due to its high content of nutrients, sludge is widely applied as an agricultural fertilizer and becomes a means for the micropollutants to be introduced to the environment. Accordingly, a holistic semiquantitative nontarget screening was performed on sewage sludges from five different WWTPs using nanoflow liquid chromatography coupled to high-resolution Orbitrap mass spectrometry. Sixty-one inorganic elements were measured using inductively coupled plasma mass spectrometry. Across all sludges, the nontarget analysis workflow annotated >21,000 features with chemical structures, and after strict prioritization and filtering, 120 organic micropollutants with diverse chemical structures and applications such as pharmaceuticals, pesticides, flame retardants, and industrial and natural compounds were identified. None of the tested sludges were free from organic micropollutants. Pharmaceuticals contributed the largest share followed by pesticides and natural products. The predicted concentration of identified contaminants ranged between 0.2 and 10,881 ng/g dry matter. Through quantitative nontarget analysis, this study comprehensively demonstrated the occurrence of cocktails of micropollutants in sewage sludges.