International audience | Methotrexate is an antineoplastic folate analog of high environmental concern, due to its low biodegradability and toxicological properties. This study focused on its photodegradation under two irradiation conditions, aiming to be representative of environment (300-450 nm) and drinking water treatment (254 nm). The photodegradation experiments were conducted at two pH, to vary the methotrexate ionization state and to produce a large variety of transformation products (TPs). The degradation kinetics determined through LC-UV monitoring were contrasted according to pH and irradiation wavelength. However, the quantum yields were independent of ionization state at 254 nm and the changes in kinetics at higher wavelengths were attributed to a change in the degradation mechanism. The TPs formed during the reactions were identified by UHPLC-MS/MS, using both the positive and negative modes. Among the eleven proposed structures, five were described as methotrexate TPs for the first time. The TPs result from N-demethylation, glutamic acid oxidation, and C-N cleavage, all of them leading to further degraded photoproducts presenting modified or lost glutamic acid part. This was made possible thanks to the negative mode, which allowed the exploration of the glutamic acid moiety modifications. Cytotoxicity assessment on A549 cancer cells demonstrated that all photoproducts formed at pH 7 were less toxic than the parent compound.

The presence of 10 anticancer drugs was studied along the entire urban water cycle -from hospital effluents through urban wastewater treatment plant till surface waters- and their potential environmental risk was assessed. Azathioprine, etoposide, docetaxel, paclitaxel, methotrexate, cyclophosphamide, tamoxifen and ciprofloxacin were detected in hospital effluent and in the urban influent of the sewage treatment plant although most of them were totally eliminated after WWTP. Only cyclophosphamide, tamoxifen and ciprofloxacin were found in both WWTP effluent and in the receiving river at a concentration range between nd-20 ng L−1, 25–38 ng L−1 and 7–103 ng L−1 respectively. Tamoxifen and ciprofloxacin, commonly used for veterinary practices, were also detected in the river upstream the sewage discharge. In addition, they both were considered to pose a potential risk to the environment based on the levels found in the WWTP effluent together with their ecotoxicological impact in selected organisms.

Anticancer drugs are continuously released into hospital and urban wastewaters, where they, most commonly, undergo conventional treatment in wastewater treatment plants (WWTPs). Wastewaters contain complex mixtures of substances including parent compounds, their metabolites and transformation products (TPs). In this study, samples of hospital effluents and WWTP influents and effluents from Slovenia and Spain were analyzed for twenty-two selected anticancer drugs, their metabolites and transformation products. Acute and chronic toxicity tests were performed on the crustacean Ceriodaphnia dubia, genotoxicity was determined with Tradescantia and Allium cepa micronucleus (MN) assays and in vitro comet assay in zebrafish (Danio rerio) liver cell line (ZFL cells). Sixty of the two hundred-twenty determinations revealed detectable levels of anticancer drug residues. Among the targeted compounds, platinum based were most frequently detected (90%). Furthermore, erlotinib was detected in 80%, cyclophosphamide and tamoxifen in 70% and methotrexate in 60% of the samples. Seven of ten samples were toxic to C. dubia after acute exposure, whereas after chronic exposure all samples reduced reproduction of C. dubia at high sample dilutions. Allium cepa proved insensitive to the potential genotoxicity of the tested samples, while in Tradescantia increased MN frequencies were induced by a hospital effluent and WWTP influents. In ZFL comet assay all but one sample induced a significant increase of DNA strand breaks. Correlations of chemotherapeutics or their TPs were detected for all bioassays except for Allium cepa genotoxicity test, however for each test the highest correlations were found for different substances indicating differential sensitivities of the test organisms.

The consumption of hazardous antineoplastic drugs (ADs) used in anticancer chemotherapies is steadily increasing representing thus risks to both human health and the environment. Hospitals may serve as a contamination source, and pharmacists preparing the antineoplastic drugs (ADs) as well as nurses administering chemotherapy and caring for oncology patients are among the healthcare professionals being highly exposed. Here, we present the results of systematic monitoring (2018–2020) of surface contamination by 13 ADs in the pharmacies and hospitals in the Czech Republic (CZ; large-scale monitoring, 20 workplaces) and Slovak Republic (SK; pilot study at 4 workplaces). The study evaluated contamination by three commonly monitored ADs, i.e., 5-fluorouracil (FU), cyclophosphamide (CP), and platinum (total Pt representing cis-, carbo-, and oxaliplatin) together with ten less explored ADs, i.e., gemcitabine (GEM), ifosfamide (IF), paclitaxel (PX), irinotecan (IRI), docetaxel (DOC), methotrexate (MET), etoposide (ETOP), capecitabine (CAP), imatinib (IMAT), and doxorubicin (DOX). Floors and desktop surfaces in hospitals (chemotherapy application rooms, nurse working areas) were found to be more contaminated, namely with CP and Pt, in both countries when compared to pharmacies. Comparison between the countries showed that hospital surfaces in SK are generally more contaminated (e.g., CP median was 20 times higher in SK), while some pharmacy areas in the CZ were more contamined in comparison with SK. The newly studied ADs were detected at lower concentrations in comparison to FU, CP, and Pt, but some markers (GEM, IF, PX, and IRI) were frequently observed, and adding these compounds to routine monitoring is recommended.

Benzotriazole (BT) and 5-methyl-1H-benzotriazole (5-MeBT) are broadly used in industrial applications, such as anti-icing fluids and dishwashing detergent, and act as the primary building blocks for UV absorbers and photostabilizers. This study examined the occurrence of these two compounds in the environment and their unique photochemical behavior affecting photosensitizers and other micro-organic pollutants in aqueous environments. BT and 5-MeBT were detected in all river water samples from the major rivers in Taipei City in the concentration ranges of 147 to 1560 ng/L and 22 to 235 ng/L, respectively, and both compounds persisted through a conventional wastewater treatment plant. The direct photolysis half-lives of BT and 5-MeBT were 56.9 and 14.0 h, respectively. The half-life of photolysis in river water for BT was 44.2 h, whereas the half-life of 5-MeBT was 24.7 h. The long half-lives in real-water matrices resulted in their prevalence in water bodies, and these compounds were also found to minimize the photosensitizing ability of nitrate and dissolved organic matter (DOM) and increase the persistence of other micro-organic pollutant. With BT present, the production of ·OH in nitrate photolysis was reduced, the degradation of DOM under sunlight was hindered, and the photodegradation of pharmaceutical residues in surface water, such as methotrexate, was completely impeded. This study suggests that in cases in which BT and 5-MeBT are highly concentrated, the effectiveness of natural attenuation process, i.e., photodegradation, in the aqueous environment is diminished, which increases the persistence of the pollutants as well as the risk of exposure.

Cytostatic drugs are pharmaceutically active compounds used in chemotherapy to prevent or disrupt cell division. Only a few environmental studies have been focused on cytostatic drugs, in spite of their toxicity, their increasing consumption, and their discharge into municipal sewage. This fact can be mainly due to the lack of methods for their simultaneous analysis. This research describes the occurrence of 14 cytostatic drugs in influent and effluent wastewater from four wastewater treatment plants located in Seville (Spain) during 1-year period. A preliminary environmental risk assessment was also carried out. Five cytostatic drugs (cytarabine, etoposide, gemcitabine, iphosphamide, and methotrexate) were detected in influent wastewater at concentration levels up to 464 ng L⁻¹(cytarabine). Six of them (cytarabine, doxorubicin, gemcitabine, iphosphamide, paclitaxel, and vinorelbine) were detected in effluent wastewater at concentration levels up to 190 ng L⁻¹(cytarabine). Most of the detected cytostatic drugs are not significantly removed during wastewater treatment. Nevertheless, neither ecotoxicological nor genotoxical risks are expected to occur at the measured concentrations on the aquatic environment.

Emerging pollutants are a group of substances involved in environmental contamination resulting mostly from incomplete drug metabolism, associated with inadequate disposal and ineffective effluent treatment techniques. Methotrexate (MTX), for instance, is excreted at high concentrations in unchanged form through the urine. Although the MTX is still effective in cancer and autoimmune disease treatment, this drug shows the ability of bioaccumulation and toxicity to the organism. Thus, the present work aimed to evaluate the adsorption of the MTX drug onto magnetic nanocomposites containing different amounts of incorporated magnetite (1:1, 1:5, and 1:10 wt%), combining the theoretical–experimental study as well as the in vitro cytotoxicity. Moreover, equilibrium studies (Langmuir, Freundlich, Temkin, Dubinin-Radushkevich, Hill, Redlich-Peterson, and Sips), kinetic (PFO, PSO, and IPD), and thermodynamic (ΔG°, ΔH°, and ΔS°) were used to describe the experimental data, and ab initio simulations were employed in the theoretical study. Magnetic nanocomposites were synthesized by the co-precipitation method using only FeCl₂ as the iron precursor. Adsorbents were characterized by FTIR, XRD, Raman, SEM–EDS, BET, and VSM analysis. Meanwhile, cytotoxic effects on L929 and A375 cell lines were evaluated through MTT, NR, and LDH assays. The adsorption of the MTX was carried out in a typical batch system, exploring the different experimental conditions. The theoretical study suggests the occurrence of chemisorption between CS·Fe₃O₄-MTX. The maximum adsorption capacity of MTX was 285.92 mg g⁻¹, using 0.125 g L⁻¹ of CS·Fe₃O₄ 1:1, with an initial concentration of the MTX (50 mg L⁻¹), pH 4.0 at 293 ± 1.00 K. The best adjustment of equilibrium and kinetic data were the Sips (low values for statistical errors) and PSO (qₑ = 96.73 mg g⁻¹) models, respectively. Thermodynamic study shows that the adsorption occurred spontaneously (ΔG° < 0), with exothermic (ΔH° = − 4698.89 kJ mol⁻¹) and random at the solid-solution interface (ΔS° = 1,476,022.00 kJ mol⁻¹ k⁻¹) behavior. Finally, the in vitro study shows that magnetic nanomaterials exhibit higher cytotoxicity in melanoma cells. Therefore, the magnetic nanocomposite reveals to be not only an excellent tool for water remediation studies but also a promising platform for drug delivery.

Methotrexate (MTX) and azathioprine (AZA) are chemotherapeutic, antimetabolic, and immunosuppressive agents with substantial risks such as oxidative lesions to the liver. This study examined the effect of grape seed extract (GSE; gervital) in attenuating hepatotoxicity caused by MTX or AZA treatment. Rats were divided into six groups (six rats per group): Group I, normal control group; Group II, GSE (150 mg/kg/day); Group III, MTX (8 mg/kg/week); Group IV, AZA (15 mg/kg/day); Group V, GSE (150 mg/kg/day) + MTX (8 mg/kg/week); and Group VI, GSE (150 mg/kg/day) + AZA (15 mg/kg/day). After 35-day experimental period, all rats were sacrificed and blood was collected for biochemical study and hemoglobin (Hb) assessment. The liver was weighed and triaged for histological, ultrastructural, and biochemical studies. MTX and AZA treatment decreased Hb levels, increased relative liver weight, increased the activity of glutamate pyruvate transaminase (ALT) and glutamate oxaloacetate transaminase (AST) aminotransferase (ALT) and aspartate aminotransferase (AST) values, and displayed histopathological and ultrastructural alterations. These changes included the disorganization of hepatocytes, pyknosis, karyolysis of some nuclei, and mononuclear leukocytic infiltration. The liver with significant oxidative stress (OS) showed decreased reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) and increased malondialdehyde (MDA) levels. In contrast, GSE administration ameliorated ALT, AST, and all histopathological and ultrastructural changes. GSE treatment also reduced MDA levels but increased the antioxidant parameters. In conclusion, it was concluded that GSE supplementation could be considered as a promising antioxidant in reducing OS, histopathological and ultrastructural alterations induced by MTX and AZA.

Due to the genotoxic, carcinogenic and teratogenic mechanism of action, anticancer drugs are highly hazardous compounds. Their occurrence, fate, and effects in the environment have not been systematically studied as compared to other medicaments. Therefore, reliable data, including their stability and persistency, is required in order to assess it. Taking into account, that hydrolysis is one of the most important factors regarding stability of chemicals in water, the aim of our study was to investigate the hydrolytic stability of five commonly used anticancer drugs (ifosfamide, cyclophosphamide, 5-fluorouracil, imatinib, and methotrexate) and one metabolite (7-hydroxymethotrexate), as the systematized and coherent data available is limited. The hydrolysis studies have been prepared according to the OECD 111 procedure to obtain standardized and comparable results. The preliminary tests at pH 4, 7, and 9 and 50 °C show that only cyclophosphamide and ifosfamide are unstable, whereas the estimated t₁/₂ at 25 °C is >1 year for other investigated compounds. Moreover, much more detailed experiments were performed and indicate that at environmentally relevant temperatures, cyclophosphamide, and ifosfamide would be quite persistent in the terms of hydrolytic stability. Moreover, the preliminary investigation on the hydrolysis products was performed.

The purpose of this investigation was to analyze the performance of magnetite graphene oxide modified with β-cyclodextrin (GO@Fe₃O₄@β-CD) for adsorption of methotrexate (MTX) and doxorubicin (DOX) from aqueous solutions. Characterization of GO@Fe₃O₄@β-CD was carried out using some methods. The perfect conditions for the adsorption of MTX and DOX were 7.0, 45 min, 20 mg, and 25 °C for solution pH, contact time, adsorbent dose, and temperature, respectively, with removal efficiency values of 97.8% and 98.5% for MTX and DOX, respectively. The adsorption kinetic of MTX and DOX via GO@Fe₃O₄@β-CD followed pseudo second-order (PSO) model, while the adsorption isotherm obeyed Langmuir model by monolayer adsorption with maximum adsorption capacities of 198.5 and 204.5 mg g⁻¹ for MTX and DOX, respectively. Therefore, it could be argued that HCl and 0.1 mol L⁻¹ NaOH would reflect adequate elution properties for GO@Fe₃O₄@β-CD recovery.