Unveiling intricate transformation pathways of emerging contaminants during wastewater treatment processes through simplified network analysis.

As the key stage for purifying wastewater, elimination of emerging contaminants (ECs) is found to be fairly low in wastewater treatment plants (WWTPs). However, less knowledge is obtained regarding the transformation pathways between various chemical structures of ECs under different treatment processes. This study unveiled the transformation pathways of ECs with different structures in 15 WWTPs distributed across China by simplified network analysis (SNA) we proposed. After treatment, the molecular weight of the whole component of wastewater decreased and the hydrophilicity increased. There are significant differences in the structure of eliminated, consistent and formed pollutants. Amino acids, peptides, and analogues (AAPAs) were detected most frequently and most removable. Benzenoids were refractory. Triazoles were often produced. The high-frequency reactions in different WWTPs were similar, (de)methylation and dehydration occurred most frequently. Different biological treatment processes performed similarly, while some advanced treatment processes differed, such as a significant increase of -13.976 (2HO reaction) paired mass distances (PMDs) in the chlorine alone process. Further, the common structural transformation was uncovered. 4 anti-hypertensive drugs, including irbesartan, valsartan, olmesartan, and losartan, were identified, along with 22 transformation products (TPs) of them. OH2 and H2O PMDs occurred most frequently and in 80.81 % of the parent-transformation product pairs, the intensity of the product was higher than parent in effluents, whose risk should be considered in future assessment activity. Together our results provide a macrography perspective on the transformation processes of ECs in WWTPs. In the future, selectively adopting wastewater treatment technology according to structures is conductive for eliminating recalcitrant ECs in WWTPs.

Pharmaceutically active compounds (PhACs) in surface water: Occurrence, trends and risk assessment in the Tagus River Basin (Spain).

In this study, the presence of 23 pharmaceutically active compounds (PhACs) including antibiotics, analgesics, anti-inflammatories, psychiatric and cardiovascular drugs, antifungals and metabolites was investigated in surface waters. A total of 89 samples were collected during 3 years (2020, 2021 and 2022) from a European representative river basin (Tagus, Spain). To elucidate PhAC potential sources, sampling points located in areas with low, median and high anthropogenic influence were selected. The analytical method based on solid phase extraction (SPE) followed by UHPLC-MS/MS analysis was validated meeting SANTE/2020/12830 and SANTE/12682/2019 performance criteria. PhACs were quantified above limits of quantification (LOQs) in 96 % of water samples, being the antihypertensives valsartan (648 ng/L, 87 % quantification frequency) and irbesartan (390 ng/L, 75 %) and the antidepressant o-desmethylvenlafaxine (495 ng/L, 76 %) the predominant pollutants. The rest of the target PhACs showed median concentrations between 4 and 172 ng/L with quantification frequencies ranging from 35 to 75 %. ∑PhAC concentrations did not show temporal or seasonal trends. However, valsartan and naproxen presented lower levels in drier (spring and summer) compared to the wetter. Source identification revealed a clear anthropogenic origin since concentrations obtained in highly populated areas were statistically higher (p < 0.01) than those quantified in sparsely populated ones. This finding was also confirmed by calculating PhACs mass flow rates, which ranged between 1.4 and 235 kg/y. Finally, data generated were used to estimate the potential risk to the aquatic ecosystem for three trophic levels (phototrophic, invertebrate and vertebrate organisms). Risk quotient ratios (RQs) were calculated for all PhACs at the median (P50) and worst-case (max) scenarios. Up to 7 PhACs (acetaminophen, carbamazepine, gemfibrozil, ibuprofen, irbesartan, ketoprofen and venlafaxine) showed high risk for the highest trophic level (fish) in >45 % of investigated locations.

Screening and prioritization of organic chemicals in a large river basin by suspect and non-target analysis.

Many organic chemicals are present in aquatic environments, but how to screen and prioritize these chemicals has always been a difficult task. Here we investigated organic chemicals in the West River Basin by using a developed non-target identification workflow. A total of 957 chemicals were tentatively identified, with 96 assigned as high confidence levels by matching with reference standards, MassBank spectral library, and using CompTox Chemistry Dashboard database as the compound library for MetFrag. More pesticides and their transformation products (e.g., metolachlor ESA, acetochlor ESA, deethylatrazine, and hydroxyatrazine) were detected in the wet season due to the increasing usage. High detection of pharmaceutical and personal care products and their transformation products in the tributaries was linked to rural farming and human activities. Irbesartan that is used to treat high blood pressure was recognized in the river and positive correlations between some detected chemicals and irbesartan were observed, indicating a domestic wastewater source. Ecological risks of the identified chemicals were calculated by toxicological prioritization ranking schemes, and 24 chemicals showed high ToxPi scores in the river. The results from this study show the presence of a large number of emerging organic chemicals in our waterways, and demonstrated conceptual schemes for integrating risk assessment into a non-target screening workflow.

Investigation of Carcinogenic Impurities of N-Nitrosamines in Sartan Pharmaceutical Products Marketed in Brazil: Development and Validation of Method Based on High-Performance Liquid Chromatography-Tandem Mass Spectrometry.

N-nitrosamines (NA) impurities have unexpectedly been found in sartan products, angiotensin II receptor antagonists that are used to control hypertension, representing an urgent concern for industry, global regulators and for the patients. In this study, an HPLC-MS/MS method was developed and validated for the quantification of six NA (N-nitrosodimethylamine, N-Nitroso-N-methyl-4-aminobutyric acid, N-Nitrosodiethylamine, N-ethyl-N-nitroso-2-propanamine, N-nitroso-diisopropylamine and N-nitroso-di-n-butylamine) in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan products. The method was validated in terms of sensitivity, linearity, accuracy, precision, robustness and stability. The limits of quantification were 100, 31.25, 250, 33, 312.5 and 125 µg kg-1 in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan samples, respectively, which met the sensitivity requirements for the limits set by Food and Drug Administration of the United States. The standard curves showed good linearity. The recoveries ranged from 93.06 to 102.23% in losartan matrix, 83 to 85.9% in valsartan, 96.1 to 101.2% in olmesartan, 89.2 to 97.5% in irbesartan, 93.4 to 132.0% in candesartan and 62.3 to 106.2% in telmisartan matrix. The other parameters met the validation criteria, the good sensitivity and precision, high accuracy and simple and fast analysis provides a reliable method for quality control of NA in sartan pharmaceutical products. The developed method was successfully applied for the determination of N-nitrosamines in 71 sartan products marketed in Brazil.

Sartan blood pressure regulators in classical and biofilm wastewater treatment - Concentrations and metabolism.

Sartans are a group of pharmaceuticals widely used to regulate blood pressure. Their concentration levels were monitored in 80 wastewater treatment plants (WWTP) in the Baltic Sea Region, reached from limit of detection up to 6 µg/L. The concentrations were significantly different in different countries, but consistent within the respective country. The degradation of sartans (losartan, valsartan, irbesartan) in moving bed biofilm reactors (MBBRs) that utilize biofilms grown on mobile carriers to treat wastewater was investigated for the first time, and compared with the degradation in a conventional activated sludge (CAS) treatment plant. The results showed the formation of six microbial transformation products (TPs) of losartan, four of valsartan, and four of irbesartan in biological wastewater treatment. Four of these metabolites have not been described in the literature before. Chemical structures were suggested and selected TPs were verified and quantified depending on availability of true standards. Valsartan acid was a common TP of losartan, valsartan, and irbesartan. Losartan and irbesartan also shared one TP: losartan/irbesartan TP335. Based on the mass balance analysis, losartan carboxylic acid is the main TP of losartan, and valsartan acid is the main TP of valsartan during the biotransformation process. For irbesartan, TP447 is likely to be the main TP, as its peak areas were two orders of magnitude higher than those of all the other detected TPs of this compound. The effects of adapting biofilms to different biological oxygen demand (BOD) loading on the degradation of sartans as well as the formation of their TPs were investigated. Compared to feeding a poor substrate (pure effluent wastewater from a CAS), feeding with richer substrate (1/3 raw and 2/3 effluent wastewater) promoted the metabolism of most compounds (co-metabolization). However, the addition of raw wastewater inhibited some metabolic pathways of other compounds, such as from losartan/irbesartan to TP335 (competitive inhibition). The formation of irbesartan TP447 did not change with or without raw wastewater. Finally, the sartans and their TPs were investigated in a full-scale CAS wastewater treatment plant (WWTP). The removal of losartan, valsartan, and irbesartan ranged from 3.0 % to 72% and some of the transformation products (TPs) from human metabolism were also removed in the WWTP. However, some of the sartan TPs, i.e., valsartan acid, losartan carboxylic acid, irbesartan TP443 and losartan TP453, were formed in the WWTP. Relative high amounts of especially losartan carboxylic acid, which was detected with concentrations up to 2.27 µg/L were found in the effluent.

Residues of Cardiovascular and Lipid-Lowering Drugs Pose a Risk to the Aquatic Ecosystem despite a High Wastewater Treatment Ratio in the Megacity Shanghai, China.

The residues of pharmaceuticals in surface waters of megacities and ecotoxicological implications are of particular concern. In this study, we combined field investigations and model simulations to explore the contamination of cardiovascular and lipid-lowering drugs, one group of the most prescribed medications globally, in surface waters of a typical megacity, Shanghai, with a high wastewater treatment ratio (≈96%). Among 26 target substances, 19 drugs were detected with aqueous concentrations ranging from 0.2 (ketanserin) to 715 ng/L (telmisartan). Of them, angiotensin II receptor antagonists, telmisartan and irbesartan, were dominant besides ß-blockers. Spatial distribution analysis demonstrated their much higher levels in tributaries compared to the mainstream. The results of model simulations and field investigation revealed relatively low concentrations of cardiovascular and lipid-lowering drugs in surface waters of Shanghai compared to other cities in highly developed countries, which is associated with low per capita usage in China. Ecotoxicological studies in zebrafish embryos further revealed developmental effects, including altered hatching success and heart rate, by irbesartan, telmisartan, lidocaine, and their mixtures at ng/L concentrations, which are typical levels in surface waters. Overall, the present results suggest that the high wastewater treatment ratio was not sufficient to protect fish species in the aquatic ecosystem of Shanghai. Exposure to cardiovascular and lipid-lowering drugs and associated risks will further increase in the future due to healthcare improvements and population aging.

Simultaneous quantification of candesartan and irbesartan in rabbit eye tissues by liquid chromatography-tandem mass spectrometry.

Diabetic retinopathy is a major cause of vision loss in adults. Novel eye-drop formulations of candesartan and irbesartan are being developed for its cure or treatment. To support a preclinical trial in rabbits, it was critical to develop and validate a new LC-MS/MS method for simultaneous quantification of candesartan and irbesartan in rabbit eye tissues (cornea, aqueous humor, vitreous body and retina/choroid). Eye tissue samples were first homogenized in H2 O-diluted rabbit plasma. The candesartan and irbesartan in the supernatants together with their respective internal standards (candesartan-d4 and irbesartan-d4 ) were extracted by solid-phase extraction. The extracted samples were injected onto a C18 column for gradient separation. The MS detection was in the positive electrospray ionization mode using the multiple reaction monitoring transitions of m/z 441 → 263, 445 → 267, 429 → 207, and 433 → 211 for candesartan, candesartan-d4 , irbesartan and irbesartan-d4 , respectively. For the validated concentration ranges (2-2000 and 5-5000 ng/g for candesartan and irbesartan, respectively), the within-run and between-run accuracies (% bias) were within the range of -8.0-10.0. The percentage CV ranged from 0.6 to 7.3. There was no significant matrix interference nor matrix effect from different eye tissues and different rabbits. The validated method was successfully used in the Good Laboratory Practice (GLP) study of rabbits.

HPLC method transfer study for simultaneous determination of seven angiotensin II receptor blockers.

In this study, a sensitive high-performance liquid chromatography method was developed and validated for the simultaneous determination of seven angiotensin II receptor blockers, namely, hydrochlorothiazide, chlorthalidone, eprosartan mesylate, valsartan, losartan potassium, irbesartan, and candesartan cilexetil. Different chromatographic parameters were tested and fully optimized. Best chromatographic separation was accomplished on a reversed-phase octadecylsilyl column (250 × 4.6 mm id; 5 µm) under gradient elution using methanol/sodium phosphate monobasic buffer (0.01 M, pH 6.5) as mobile phase. The detection of target analytes was obtained at 254 nm. The pH of the buffer has been selected according to Marvin® sketch software. The proposed method was validated according to ICH guidelines and showed good precision (relative standard deviation < 1), good linearity (square of correlation coefficient ≥ 0.999), and high accuracy (between 98 and 102%) with detection limit and quantitation limit (40 and 160 ng/mL, respectively) for all the detected analytes.

Selective and validated kinetic spectrophotometric method for the determination of irbesartan in pure and pharmaceutical formulations.

A novel-coupling reagent is used for the simple and sensitive kinetic spectrophotometric determination of irbesartan (IRB) in pure or pharmaceutical formulations. The method utilizes an oxidative coupling reaction based on oxidation of 3-methyl-2-benzothiazolinone hydrazone hydrochloride monohydrate (MBTH) with Ce(IV) in 2% sulfuric acid medium, followed by coupling the produced electrophilic intermediate (diazonium salt of the reagent) with IRB to give greenish-blue colored product (1:1, stoichiometry) having maximum absorption at 629nm and the colored species is stable for more than 1h. The initial rate and fixed time (at 35min) methods are adopted for determination of IRB concentration. The linearity is in the ranges of 5.0-40.0µg/mL and 2.0-45.0µg/mL and the limit of detection is 0.46 and 0.40µg/mL for initial rate and fixed time methods, respectively. Molar absorptivity for the method was found to be 1.50×104L/molcm. The validated kinetic methods can be successfully applied to the analysis of IRB in bulk and tablet dosage form and in the routine quality control analysis. The percentage recoveries were above 100% for both methods. The excipients did not interfere in the analysis.