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Antibiotic transformation products (TPs) generated during water treatment can be considered as an environmental concern, since they can retain part of the bioactivity of the parent compound. Effect-directed analysis (EDA) was applied for the identification of bioactive intermediates of azithromycin (AZI) and ciprofloxacin (CFC) after water chlorination. Fractionation of samples allowed the identification of bioactive intermediates by measuring the antibiotic activity and acute toxicity, combined with an automated suspect screening approach for chemical analysis. While the removal of AZI was in line with the decrease of bioactivity in chlorinated samples, an increase of bioactivity after complete removal of CFC was observed (at >0.5 mgCl2/L). Principal component analysis (PCA) revealed that some of the CFC intermediates could contribute to the overall toxicity of the chlorinated samples. Fractionation of bioactive samples identified that the chlorinated TP296 (generated from the destruction of the CFC piperazine ring) maintained 41%, 44%, and 30% of the antibiotic activity of the parent compound in chlorinated samples at 2.0, 3.0, and 4.0 mgCl2/L, respectively. These results indicate the spectrum of antibacterial activity can be altered by controlling the chemical substituents and configuration of the CFC structure with chlorine. On the other hand, the potential presence of volatile DBPs and fractionation losses do not allow for tentative confirmation of the main intermediates contributing to the acute toxic effects measured in chlorinated samples. Our results encourage further development of new and advanced methodologies to study the bioactivity of isolated unknown TPs to understand their hazardous effects in treated effluents., This work was funded by the Spanish State Research Agency of the Spanish Ministry of Science, Innovation and Universities AEI-MICIU and the Fondo Europeo de Desarrollo Regional under the National Program for Research Aimed at the Challenges of Society (CTM2017-85335-R). Authors acknowledge the support from the Economy and Knowledge Department of the Catalan Government through the Consolidated Research Group (ICRA-ENV 2017 SGR 1124 and 2017-SGR-1404). ICRA researchers thank funding from CERCA program. M.J.F and S.R.M. acknowledge the Ramon y Cajal research fellowships RyC-2015-17108 and RYC-2014-16707 from the Spanish Ministry of Economy and Competitiveness. A.J.G. and A.S.C acknowledges the predoctoral grants 2019FI_B2_00202 and 2018FI_B2_00170 from AGAUR and co-financed by the European Social Fund. The authors would like to Wageningen Food Safety Research for their help with the antibiotic inhibition tests.

OBJECTIVES: The aim of this study was to review epidemiologic evidence, provide summary risk estimates of the association between exposure to chlorination disinfection by-products (DBPs) and congenital anomalies, and provide recommendations for future studies. DATA SOURCES AND EXTRACTION: We included all published epidemiologic studies that evaluated a relationship between an index of DBP exposure (treatment, water source, DBP measurements, and both DBP measurements and personal characteristics) and risk of congenital anomalies. When three or more studies examined the same exposure index and congenital anomaly, we conducted a meta-analysis to obtain a summary risk estimate comparing the highest exposure group with the lowest exposure group. When five or more studies examined total trihalomethane (TTHM) exposure and a specific congenital anomaly, we conducted a meta-analysis to obtain exposure-response risk estimates per 10 microg/L TTHM. DATA SYNTHESIS: For all congenital anomalies combined, the meta-analysis gave a statistically significant excess risk for high versus low exposure to water chlorination or TTHM [17%; 95% confidence interval (CI), 3-34] based on a small number of studies. The meta-analysis also suggested a statistically significant excess risk for ventricular septal defects (58%; 95% CI, 21-107), but this was based on only three studies, and there was little evidence of an exposure-response relationship. We observed no statistically significant relationships in the other meta-analyses. We found little evidence for publication bias, except for urinary tract defects and cleft lip and palate. CONCLUSION: Although some individual studies have suggested an association between chlorination disinfection by-products and congenital anomalies, meta-analyses of all currently available studies demonstrate little evidence of such an association. This work was conducted without specific allocated funding, but contributions were made by researchers working on the Integrated Assessment of Health Risks of Environmental Stressors in Europe (INTARESE) project, cofunded by the European Commission under the Sixth Framework Programme (2002–2006), and the Health Impacts of Long-term Exposure to Disinfection By-products in Drinking Water in Europe (HIWATE) project, which is a 3.5-year Specific Targeted Research Project funded under the European Union Sixth Framework Programme for Research and Technological Development by the Research Directorate–Biotechnology, Agriculture and Food Research Unit (contract Food-CT-2006-036224)

Aquesta tesi presenta resultats referits a noves metodologies aplicades cap a la obtenció de productes alfa-funcionalitzats i beta-borilats, que no tenen precedents en la bibliografia, a partir de cetones alfa,beta-insaturatdes. Les funcionalitzacions estudiades han sigut utilitzant fluor, per obtenir alfa-fluoro beta-boryl cetones; halogens, per obtenir alfa-halo beta-boryl cetones (sent els halogens clor i brom); i finalment difuncionalitzar cetones alfa,beta-insaturades per obtenir alfa-aryl beta-boryl cetones, que tal i com es reporta a la tesi, han sigut els intermedis cap a la sintesi de 2-aryl-1,3-diones, que són productes de sintesis molt valorats en la industria per les seves propietats com a pesticides. En tots tres casos, s'ha aconseguit la obtenció dels productes difuncionalitzats, dels quals cap havia sigut previament presentat a la bibligrafia existent, concluent per tant que aquest ha sigut un treball pioner cap a la sintesi i obtenció d'aquests compostos difuncionalitzats., Esta tesis presenta los resultados pertenecientes a nuevas metodologias aplicadas hacia la obtención de productos alfa-funcionalizados y beta-borilados que no tienen precedente en la bibliografia, a partir de cetonas alfa,beta-insaturadas. Las funcionalizaciones estudiadas han sido utilizando fluor, para obtener alfa-fluoro beta-boryl cetonas; halogenos, para obtener alfa-halo beta-boril cetonas (siendo los halogenos cloro y bromo); y finalmente la difuncionalización de cetonas alfa,beta-insaturadas para obtener alfa-aryl beta-boryl cetonas, que tal y como se presenta en la tesis, han sido los productos intermedios hacia la sintesi de 2-aryl-1,3-dionas, que són productos de sintesis muy valorados en la indústria por sus propiedades como pesticidas. En todos los tres casos, se consiguió la obtención de los productos difuncionalizados, de los cuales ninguno habia sido previamente presentado en la bibliografia existente, concluyendo que éste ha sido un trabajo pionero hacia la sintesi y obtención de estos compuestos difuncionalizados., This thesis presents the results concerning new methodologies towards the obtantion of alpha-functionalized beta-borylated compounds from alpha,beta-unsaturated carbonyl compounds, with no precedent in the litherature. The functionalizations studied focused on fluorine, to obtain alpha-fluoro beta-boryl ketones; halogens, to obtain alpha-halo beta-boryl ketones (being the halogens chlorine and bromine); and finally, the difunctionalization of alpha,beta-unsaturated ketones to obtain the corresponding alpha-aryl beta-boryl ketones, which as presented in this thesis, they have been the intermadiates towards the synthesis of 2-aryl-1,3-diones. 2-aryl-1,3-diones are highly valued products in industry for their properties as pesticides. In the three cases studied, we obtained the desired difunctionalized products, which any of them has been previously presented in the existing literature, concluding that this has been a pioneering work towards the synthesis and obtantion of such difunctionalized compounds.