Occurrence of pharmaceutical residues in drinking water: a systematic review

Occurrence of pharmaceutical residues in drinking water: a systematic review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Occurrence of pharmaceutical residues in drinking water: a systematic review Stefano Zanni, Vincenzo Cammalleri, Ludovica D'Agostino, Carmela Protano, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3799343/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Aug, 2024 Read the published version in Environmental Science and Pollution Research → Version 1 posted 3 You are reading this latest preprint version Abstract In the last decades, the use of drugs, both in clinical practice and in intensive livestock farms, has increased exponentially. Following urinary and/or faecal excretion, these compounds are only partially retained in the depuration facilities, reaching fresh or marine surface waters even distant from the source of entrance. The main consequence of this phenomenon is the presence, increasingly frequently found, of traces of drugs and their metabolites in the aquatic environment including drinking water. The aim of this review is to evaluate the contamination of drinking water by pharmaceutical residues all over the world. For this purpose, a systematic review was carried out for identifying all available research reporting original data resulting by sampling campaign and analysis of “real” drinking water samples to detect pharmaceutical residues. The investigated databases were PUBMED, SCOPUS and WEB OF SCIENCE. A total of 124 studies were included in the review and 33 of them found target analytes below the limit of detection, while the remaining 91 studies reported positivity for one or more compounds, in concentrations ranging from a few to a few tens of nanograms. This finding confirms the concern about drinking water contamination on a global scale and requires close attention from health authorities, pharmaceutical industries, and scientific community. Preventive interventions for drinking water contamination should be also targeted on technological improvement of wastewater purification plants and drinking water treatment plants to raise pharmaceutical residues removal. Pharmaceutical Residues Drinking Water Environmental Monitoring Emerging Contaminants Systematic Review. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Pharmaceuticals are powerful allies in the struggle against diseases contributing, over the years, to enhance human health and extend life expectancy. Survival has improved thanks to medical advances, between 1990 and 2015, life expectancy increased by 3.3 years. 44% of improved life expectancy was attributable to public health, 13% was attributable to other medical care, 7% was attributable to unknown factors, but a great contribution, estimated to be around 35%, was attributable to pharmaceutical innovations (Buxbaum et al. 2020 ). In 2021, overall pharmaceutical expenses in the US grew 7.7%, for a total of $ 576.9 billion. Non-federal hospitals accounted for $ 39.6 billion in prescription expenditures in 2020, an increase of 8.4% in 2021 after a historic decrease in 2020, whereas in clinics spending grew 7.7% to $ 105.0 billion. (Tichy et al. 2021). Besides, the process of developing, testing, and commercialising new drugs is constantly increasing, to meet the global health demand that grows in step with the increase in lifespan and the access of new populations to the pharmaceutical global market (OECD 2018 ). Categories of medications for which different kinds of pharmacologically active molecules are prescribed, listed in descending order of the number of different molecules prescribed, are: drugs for the cardiovascular system, nervous system, endocrine system, musculoskeletal system, respiratory system, immunological drugs, and gastrointestinal tract (Fuentes et al. 2018 ). From a purely economic point of view, total pharmaceutical revenues worldwide exceeded 1 trillion dollars in 2014 and the market has been growing at an annual rate of 5.8% since 2017 (González Peña et al. 2021 ). This constant growth in availability and the related increase in the use of drugs has determined, over the years, an increasingly significant environmental impact, resulting from the urinary and/or faecal excretion of the active ingredients as such or their various metabolites. As a result, human drugs and their metabolites have become "almost" ubiquitous pollutants, found in matrices such as fresh surface waters (Fekadu et al. 2019) and marine waters (MacKeown et al. 2022 ), sediments and soils (Białk-Bielińska et al. 2016 ), foods of animal and vegetable origin (Baron et al. 2014 ), wildlife (Herrero-Villar et al. 2021 ). In particular, urban and hospital wastewaters are the main contributors to this occurrence; indeed, Wastewater Treatment Plants (WWTPs) are able to remove only in part those compounds from sewage (Gu et al. 2018 ), releasing the unretained portion of drugs and their metabolites into surface waters, coastal marine waters and soil and, thus, leading to “ubiquitous” pollution through phenomena of diffusion, accumulation in sediments and soils and biomagnification in plants and animals according to the specific chemical-physical characteristics of drugs and metabolites. Other possible sources of contamination are represented by improper storage or "accidents" occurring during the phases of storage, transport, and disposal of expired pharmaceutical products, or by wastewater and/or solid wastes from pharmaceutical industries. In addition, a further source of release of drugs and their metabolites into the environment is represented by the increasingly widespread use of veterinary drugs in production of food animals to prevent and treat disease, and to promote growth. In this case, drugs and their metabolites enter the environment directly via urinary and/or faecal excretion, not passing through efficient WWTPs. Humans are exposed to pharmaceuticals and their metabolites, as environmental contaminants, primarily through ingestion of food of vegetal (Fu et al. 2019 ; Keerthanan et al. 2020) and animal origin, mainly fishery products (Dinh et al. 2020 ; Griboff et al. 2020 ; Lv et al. 2019 ; Rojo et al. 2019 ). The occurrence of pharmaceutical residues in the drinking water cycle represents a further exposure factor; in the last years, indeed, progress in instrumental analytical chemistry has enabled the detection of many different compounds at lower concentrations, contributing to the awareness of this environmental problem. Many studies have reported the presence of pharmaceuticals in raw water used for drinking water production (Castiglioni et al. 2018; Chen et al. 2020 ; Daneshvar et al. 2012 ; Kümmerer et al. 2016 ; Petrie et al. 2016 ), and have investigated the fate of these molecules up to the domestic tap water, detecting residues and metabolites at trace levels (ng/L). From the environmental health point of view, many studies have demonstrated the effects of drugs and their metabolites on aquatic animal and plant species (Almeida et al. 2020 ; Nippes et al. 2021 ) while human health effects have been estimated based on environmental data (Courtier et al. 2019 ; Izadi et al. 2020 ; Jureczko et al. 2020; Khan et al. 2020 ). The aim of this review is to evaluate the contamination of drinking water by pharmaceutical residues all over the world. For this purpose, a systematic review was carried out for identifying all available research reporting original data resulting by sampling campaign and analysis of "real" drinking water samples to detect pharmaceutical residues. Methods This review follows a protocol published in PROSPERO (Registration number: CRD42022314276, available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022314276 ). The protocol was developed according to the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols (PRISMA 2020) (Page et al. 2021 ). The protocol was designed to include available research about the contamination by pharmaceuticals for human and veterinary use or their metabolites in drinking water samples all over the world. Potentially eligible studies were identified using electronic databases: PubMed, Scopus and Web of Science. Databases were investigated using the following search strings: for PubMed, (drug* OR pharmaceutic* OR medicin* OR "pharmaceutical preparations" [mesh] OR "veterinary drugs" [mesh]) AND ("tap water" OR "finished water" OR "drinking water" OR "potable water" OR "drinking water" [mesh] OR "water supply" [mesh]) AND (residue* OR metabolite* OR "drug residues"[mesh]); for Scopus, TITLE-ABS-KEY ((drug* OR pharmaceutic* OR medicin* OR "pharmaceutical preparations" OR "veterinary drugs") AND ("tap water" OR "finished water" OR "drinking water" OR "potable water" OR "drinking water" OR "water supply") AND (residue* OR metabolite* OR "drug residues")); for Web of Science, TS= ((drug* OR pharmaceutic* OR medicin* OR pharmaceutical preparations OR veterinary drugs) AND (tap water OR finished water OR drinking water OR potable water OR drinking water OR water supply) AND (residue* OR metabolite* OR drug residues)). No time limit on publication date was set and databases were searched from launch date to 4th April 2022. No time limit on publication date was set and databases were searched from launch date to 4th April 2022. The research was limited to papers written in English language. References of included studies were manually screened for further eligible studies in addition to the search in electronic databases. Studies reporting data for spiked, waste, surface and mineral water samples or reporting drugs of abuse detection only or other molecules such as contrast agents, pesticides, disinfectants were excluded. Besides, reviews, systematic reviews, letters to the editor, conference abstracts, books, PhD theses, and book chapters were excluded. This review is focused on drinking water contamination by pharmaceuticals or their metabolites, for human and veterinary use, lawfully prescribed: studies reporting were excluded. Data were extracted by two independent authors with any disagreements being resolved by consensus or consulting a third reviewer. Data regarding country, categories of pharmaceuticals searched for, analytical approach, sampling period and molecules identified were extracted and recorded in a database. To determine which medications should be given priority for preventing environmental risk, we investigated which types of pharmaceutical and their active components were most frequently found in drinking water. We provide a summary table of the sample's geographic origin, sampling period, pharmaceutical categories examined, active compounds or their metabolites detected, and analytical techniques used to detect pharmaceuticals in drinking water. The quality of the studies and overall certainty of evidence were assessed using the “RoB assessment tool” scale (Danopoulos et al. 2020), specifically adapted to the design of this review, that evaluates four domains: study design, sampling, analysis, and reporting, leading to an overall assessment. RoB results was rated as high, low, or unclear. Results and discussion A total of 6196 records was recovered and, after duplicate removal, 4413 records were screened. 4242 citations were eliminated in the first-level screening based on their title and abstract. 171 reports were sought for retrieval, 13 reports were not found, thus 158 reports were assessed for eligibility by full text during the second-level screening. 119 studies matching with inclusion criteria were included, 5 studies were included by citation searching, resulting in 124 studies finally included in this systematic review. The screening process is presented in the flow chart showed in Fig. 1 . The results of this review are presented in tables 1, 2, 3, and 4 according to their geographical area. We identified a total of 124 studies searching for pharmaceutical residues in drinking water, 91 reporting positivity for one or more compounds, in concentrations range from a few to a few tens of nanograms. In the remaining 33 studies, target analytes were below the limit of detection. We tried to understand how widespread the phenomenon of contamination by medicines for human and veterinary use is, so we reported in which countries pharmaceutical residues have been traced or not in drinking water, and how many studies have been carried out in each country to understand the extent of research on the issue (Fig. 2 ). Of the 124 studies included, 64 publications were from Europe (44 reported positivity for pharmaceutical residues), 33 from Asia (25 with positivity for pharmaceutical residues), 22 from Americas (19 with positivity for pharmaceutical residues), finally 3 from Africa and 2 from Oceania (2 and 1 reports that detected pharmaceutical residues, respectively). Spain was the country with more papers (20), China was the second country with 15 papers followed by Germany and Brazil with 12 and 8 papers, respectively. The most detected pharmaceutical categories overall and in Europe, Asia, and rest of the world are shown in Fig. 3 . We also reported the most detected pharmaceutical molecules all over the world, Europe, Asia, and rest of the world in Fig. 4 . The most represented category considering all included papers was NSAIDs and analgesics, detected in 39 studies, followed by anticonvulsants and antibiotics (respectively detected in 34 and 33 studies). These categories are also the most detected dividing the results by geographical area, but in Asia the most detected pharmaceuticals are antibiotics, detected in 15 works from Asian studies of 33 total studies positive for antibiotics, in contrast with Europe where the first two detected categories are anticonvulsants and NSAIDs or analgesics, with 20 and 19 detections respectively, followed by antibiotics with 11 detections. Beta blockers were detected in 17 studies, all from Asia and Europe, no beta-blockers were detected in selected studies from Americas, Africa, and Oceania. The most represented active principle considering total studies was Carbamazepine, detected in 24 studies. The other relevant active principles were Diclofenac (15 studies), Ibuprofen, Paracetamol and Sulfamethoxazole (13 studies). The most used sample preparation technique to concentrate the sample and remove unwanted interferences is solid phase extraction (SPE). The most common analytical techniques used to find pharmaceutical residues in drinking water in the selected studies are liquid chromatography, high-performance liquid chromatography, ultra-high-performance liquid chromatography, tandem mass spectrometry (LC-MS/MS, HPLC-MS/MS, UHPLC-MS/MS), and gas chromatography mass spectrometry (GC-MS). When determining trace amounts of such pollutants, it is crucial to use an analytical method that may provide both selectivity and sensitivity. The results of this review show agreement between different geographic areas and principal pharmaceuticals detected in drinking water. The possibility to detect a pharmaceutical molecule in drinking water depends not only on the amount of its clinical use and sold, but its presence in water is determined also by specific chemical properties that determine environmental persistence and from the efficacy of the removal from wastewater avoiding contamination of environmental waters, source for production of drinking water. Active ingredients and their metabolites are frequently found in wastewater and environmental waters (Baron et al. 2014 ; Białk-Bielińska, 2016; Fekadu et al. 2019; Herrero-Villar et al. 2021 ; MacKeown et al. 2022 ). Studies have been conducted to determine the effective concentration of drugs in wastewater, both before and after the treatment carried out by STPs and in surface waters. NSAIDs, due to their widespread use, represent one of the most investigated categories of drugs. Several studies on acetylsalicylic acid and paracetamol have demonstrated the effectiveness of purification systems (Ternes 2001 ). Another drug belonging to the class of NSAIDs which persists in water even after purification is ibuprofen, traces of which have been found in water purification plants in Austria, Brazil, Germany, and Switzerland (Buser et al. 1999 ; Heberer 2002 ; Ternes 1998 ; Ternes et al. 2002 ), and it was calculated that more than 60 kg of diclofenac was discharged into the Baltic Sea in 2018, while in the first half of 2021 it was equal to 20 Kg from the two WWTPs tested. The presence of 4OH-diclofenac in effluents often in higher concentration compared to diclofenac mean that this still biologically active compound needs to be considered in future risk assessment (Kołecka et al. 2022 ). Traces of naproxen have been found in STP effluents in Canada (Metcalfe et al. 2003 ) and Spain (Quintana et al. 2005 ). Among the neuroactive drugs, carbamazepine is the most studied active principle as it is removed only in very small part (less than 10%) from the STP (Ternes 2001 ; Heberer 2002 ); the result is frequently detection of positive samples for this active principle. Another class of drugs that has been particularly studied is lipid-lowering drugs; in particular, clofibric acid has historical importance as the first pharmacologically active molecule to be found in water samples from municipal water purification plants. The effects of long-term exposure to pharmaceutical residues through drinking water are difficult to assess. No long-term toxicity studies on humans are currently available, relating to doses much lower than therapeutic ones; however, the alterations observed in wildlife suggest potential effects on human health (Shore et al. 2014 ). Many of these molecules can act as endocrine disruptors: their structure could mimic that of other substances involved in the fine balance of the neuroendocrine system, hormones can act at very low doses and alter the normal physiology of the organism (Chen et al. 2019 ). Furthermore, since the effects that active ingredients and metabolites in water can have on the environment and what danger they can represent for human health, greater use of drugs that is currently implemented in the veterinary field, both for curative and productive purposes especially in intensive farming, should not be underestimated. This sector is undoubtedly responsible for a large amount of environmental and water contamination that is difficult to control, and it can aggravate this situation. Wastewater from intensive farms, generally undergoes less effective purification treatments than civil plants. To these residues must be added those of all the drugs widely used, illegally, on farm animals for auxinic, masking purposes, etc. The possibility that pharmaceutical residues can cause direct damage to the environment and indirect damage to humans led US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products - EMEA), to include environmental risk assessment as an essential requirement in each dossier presented to put new drugs on the market, as provided in the guidelines issued by both agencies, FDA and EMEA, in 1997 and 2001 respectively, updated in 1998 and 2006 (FDA 1998; EMEA 2006b). Both documents initially require a careful assessment of the predicted environmental distribution of the active ingredient and its main metabolites. In practice, through mathematical formulas that consider the quantity of product sold, the maximum therapeutic dose foreseen per patient/day and daily produced wastewater per inhabitant, it is possible to estimate predicted concentrations. For veterinary medicinal products also, the EMEA has issued a series of guidelines (EMEA, 2000; 2005; 2006a) which make it necessary to evaluate contamination and environmental persistence for the purposes of any marketing authorisation of veterinary medicines. Conclusions Detection of pharmaceutical residues, according to analysis of real drinking water samples in 91 studies from all over the world included in this review, confirms the concern about drinking water contamination on a global scale and requires close attention from health authorities, scientific community, and pharmaceutical industries. Preventive interventions for drinking water contamination should be also targeted on technological improvement of wastewater purification plants and drinking water treatment plants to raise pharmaceutical residues removal. Declarations Author Contributions Stefano Zanni: Conceptualization, Methodology, Software, Validation, Investigation, Data curation, Writing - Original Draft, Visualization. Vincenzo Cammalleri: Conceptualization, Methodology, Software, Validation, Investigation, Data curation, Writing - Original Draft, Visualization. Ludovica D’Agostino: Software, Validation, Data curation, Writing - Original Draft, Visualization. Carmela Protano: Conceptualization, Methodology, Writing - Review & Editing, Supervision, Project administration. Matteo Vitali: Conceptualization, Methodology, Writing - Review & Editing, Supervision, Project administration. 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Asian J Chem 31:1294–1300. 10.14233/ajchem.2019.21899 Ustun-Odabasi S, Maryam B, Ozdemir N, Buyukgungor H (2020) Occurrence and seasonal variations of pharmaceuticals and personal care products in drinking water and wastewater treatment plants in Samsun, Turkey. Environ Earth Sci 79:311. 10.1007/s12665-020-09047-7 Valcárcel Y, González Alonso S, Rodríguez-Gil JL, Gil A, Catalá M (2011) Detection of pharmaceutically active compounds in the rivers and tap water of the Madrid Region (Spain) and potential ecotoxicological risk. Chemosphere 84:1336–1348. 10.1016/j.chemosphere.2011.05.014 Valcárcel Y, Martínez F, González-Alonso S, Segura Y, Catalá M, Molina R, Montero-Rubio JC, Mastroianni N, López de Alda M, Postigo C, Barceló D (2012) Drugs of abuse in surface and tap waters of the Tagus River basin: heterogeneous photo-Fenton process is effective in their degradation. Environ Int 41:35–43. 10.1016/j.envint.2011.12.006 van der Aa M, Bijlsma L, Emke E, Dijkman E, van Nuijs ALN, van de Ven B, Hernández F, Versteegh A, de Voogt P (2013) Risk assessment for drugs of abuse in the Dutch watercycle. Water Res 47:1848–1857. 10.1016/j.watres.2013.01.013 Vanderford BJ, Snyder SA (2006) Analysis of pharmaceuticals in water by isotope dilution liquid chromatography/tandem mass spectrometry. Environ Sci Technol 2006 40:7312–7320. 10.1021/es0613198 Vilca FZ, Galarza NC, Tejedo JR, Cuba WAZ, Quiroz CNC, Tornisielo VL (2021) Occurrence of residues of veterinary antibiotics in water, sediment and trout tissue (Oncorhynchus mykiss) in the southern area of Lake Titicaca, Peru. J Great Lakes Res 47:1219. 10.1016/j.jglr.2021.04.012 Wahlberg C, Bjorlenius B, Paxeus N (2011) Fluxes of 13 selected pharmaceuticals in the water cycle of Stockholm, Sweden. Water Sci Technol 63:1772–1780. 10.2166/wst.2011.124 Wang Z, Gao S, Dai Q, Zhao M, Yang F (2020) Occurrence and risk assessment of psychoactive substances in tap water from China. Environ Pollut 2020 261:114163. 10.1016/j.envpol.2020.114163 Watkinson AJ, Murby EJ, Kolpin DW, Costanzo SD (2009) The occurrence of antibiotics in an urban watershed: From wastewater to drinking water. Sci Total Environ 407:2711–2723. 10.1016/j.scitotenv.2008.11.059 Wee SY, Ismail NAH, Haron DEM, Yusoff FM, Praveena SM, Aris AZ (2022) Pharmaceuticals, hormones, plasticizers, and pesticides in drinking water. J Hazard Mater 424:127327 Wu M, Xiang J, Que C, Chen F, Xu G (2015) Occurrence and fate of psychiatric pharmaceuticals in the urban water system of Shanghai, China. Chemosphere 138:486–493. 10.1016/j.chemosphere.2015.07.002 Yang GCC, Liou SH, Wang CL (2014) The influences of storage and further purification on residual concentrations of pharmaceuticals and phthalate esters in drinking water. Water Air Soil Pollut 225:1698. 10.1007/s11270-014-1968-z Chen Y, Cui K, Huang Q, Guo Z, Huang Y, Yu K, He Y (2020) Comprehensive insights into the occurrence, distribution, risk assessment and indicator screening of antibiotics in a large drinking reservoir system. Sci Total Environ 716:137060. 10.1016/j.scitotenv.2020.137060 Zgola-Grzeskowiak A (2010) Application of DLLME to Isolation and Concentration of Non-Steroidal Anti-Inflammatory Drugs in Environmental Water Samples. Chromatographia 72:671–678. 10.1365/s10337-010-1702-y0009-5893/10/10 Zhang J, Lee HK (2009) Application of dynarnic liquid-phase microextraction and injection port derivatization combined with gas chromatography-mass spectrometry to the determination of acidic pharmaceutically active compounds in water samples. J Chrom A 1216:7527–7532. 10.1016/j.chroma.2009.03.051 Zhang X, Shi J, Huang X, Shao B (2022) Formation and occurrence of disinfection byproducts of benzodiazepine drug estazolam in drinking water of Beijing. Sci Total Environ 804:150028. 10.1016/j.scitotenv.2021.150028 Zhang X, Yang Y, Zhang J, Yang Y, Shen F, Shen J, Shen J, Shao B (2019) Determination of emerging chlorinated byproducts of diazepam in drinking water. Chemosphere 218:223–231. 10.1016/j.chemosphere.2018.11.076 Zhou JL, Maskaoui K, Lufadeju A (2012) Optimization of antibiotic analysis in water by solid-phase extraction and high performance liquid chromatography-mass spectrometry/mass spectrometry. Anal Chim Acta 731:32–39. 10.1016/j.aca.2012.04.021 Zühlke S, Dünnbier U, Heberer T (2004) Detection and identification of phenazone-type drugs and their microbial metabolites in ground and drinking water applying solid-phase extraction and gas chromatography with mass spectrometric detection. J Chromatogr A 1050:201–209. 10.1016/j.chroma.2004.08.051 Tables Table 1 to 4 are available in the Supplementary Files section. Supplementary Files Table1.docx Table 1 Results of selected studies for Asian region. Table2.docx Table 2 Results of selected studies for Mediterranean Europe region Table3.docx Table 3 Results of selected studies for other European countries Table4.docx Table 4 Results of selected studies for other continents RoBfinal.xlsx Cite Share Download PDF Status: Published Journal Publication published 06 Aug, 2024 Read the published version in Environmental Science and Pollution Research → Version 1 posted Reviewers agreed at journal 30 Jan, 2024 Editor assigned by journal 12 Jan, 2024 First submitted to journal 04 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3799343","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":270252616,"identity":"7e49920d-307e-49a0-8697-9d0e687274c3","order_by":0,"name":"Stefano Zanni","email":"","orcid":"","institution":"Sapienza University of Rome: Universita degli Studi di Roma La Sapienza","correspondingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Zanni","suffix":""},{"id":270252617,"identity":"57b9ce6e-9ed8-4e03-907b-b713f4e9177c","order_by":1,"name":"Vincenzo Cammalleri","email":"","orcid":"","institution":"Sapienza University of Rome: Universita degli Studi di Roma La Sapienza","correspondingAuthor":false,"prefix":"","firstName":"Vincenzo","middleName":"","lastName":"Cammalleri","suffix":""},{"id":270252618,"identity":"a31eae8d-a186-42c0-b4bc-a2b10b9777db","order_by":2,"name":"Ludovica D'Agostino","email":"","orcid":"","institution":"Sapienza University of Rome: Universita degli Studi di Roma La Sapienza","correspondingAuthor":false,"prefix":"","firstName":"Ludovica","middleName":"","lastName":"D'Agostino","suffix":""},{"id":270252619,"identity":"7de30d81-bc27-44ed-bdd0-0dd759390cc6","order_by":3,"name":"Carmela Protano","email":"","orcid":"","institution":"Sapienza University of Rome: Universita degli Studi di Roma La Sapienza","correspondingAuthor":false,"prefix":"","firstName":"Carmela","middleName":"","lastName":"Protano","suffix":""},{"id":270252620,"identity":"a94d7f1d-a9b5-4a23-9a35-20f68d53b438","order_by":4,"name":"Matteo Vitali","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIiWNgGAWjYDADNgYGxgMJFWAGEBgw8OBWy8zYANYCVHog4QxMSwEDD249UC0gpQcY22CiHxhwWqPbfv74gw8VDIl98s0PDjycdziPT/rw0Q0/DBhk7HFoMTuTzNg44wxDYhsbm8GBxG2Hi9n40tJu9hjgdpjZgWTGZt42BmOgX8BaEtt4eMxu8ODTcv4xY/NfsBb2DwcS50C03PyDT8sNoC1AX8uxsfEAbWmAaLmN15Ybjw1n9pyRAGrJKTiQcCwdqIUt7baMgQQPzwFcDkt88OFHhQ2PfPPxjQ9/1Fgnzu9hPnbzzR8be/YGHNZAgAQRIqNgFIyCUTAKiAcA2f5VZ9n//c8AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-1001-6343","institution":"Sapienza University of Rome: Universita degli Studi di Roma La Sapienza","correspondingAuthor":true,"prefix":"","firstName":"Matteo","middleName":"","lastName":"Vitali","suffix":""}],"badges":[],"createdAt":"2023-12-24 07:26:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3799343/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3799343/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11356-024-34544-8","type":"published","date":"2024-08-06T15:57:33+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50548206,"identity":"251f3361-bf4f-4554-b363-4fdc3a44abf5","added_by":"auto","created_at":"2024-02-02 10:00:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26033,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers, and other sources.\u003c/p\u003e","description":"","filename":"Onlinefig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-3799343/v1/44de2e0d3f9eead67b5ea7cb.png"},{"id":50547597,"identity":"27352f53-a231-46b1-a00f-e9c8772e3ea9","added_by":"auto","created_at":"2024-02-02 09:44:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":567555,"visible":true,"origin":"","legend":"\u003cp\u003eCountry of origin of the selected studies.\u003c/p\u003e","description":"","filename":"Onlinefig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-3799343/v1/a884c7bfc6f9e1670fc524c9.png"},{"id":50547982,"identity":"349fb4f5-dec8-43d9-b825-a05b23b0b8c9","added_by":"auto","created_at":"2024-02-02 09:52:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":25406,"visible":true,"origin":"","legend":"\u003cp\u003eFrequency of the most detected pharmaceutical categories in included studies.\u003c/p\u003e","description":"","filename":"Onlinefig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-3799343/v1/4fd5467714158d3eeb63ebff.png"},{"id":50547983,"identity":"016d230b-5194-4316-8a89-1ce2a6f2e816","added_by":"auto","created_at":"2024-02-02 09:52:17","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":19286,"visible":true,"origin":"","legend":"\u003cp\u003eFrequency of the most detected pharmaceuticals in included studies.\u003c/p\u003e","description":"","filename":"Onlinefig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-3799343/v1/71b8e60f5e421dfb0287a580.png"},{"id":62298998,"identity":"d540cecb-3516-42be-ba84-6547f6e2a478","added_by":"auto","created_at":"2024-08-12 16:18:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1474312,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3799343/v1/fc845793-af0a-4178-aef5-c8c78354162a.pdf"},{"id":50547596,"identity":"402d539d-4e91-4268-aa10-5b8066f766b8","added_by":"auto","created_at":"2024-02-02 09:44:17","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21974,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1 Results of selected studies for Asian region.\u003c/p\u003e","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3799343/v1/347e1db9085a19c7c015fb35.docx"},{"id":50547602,"identity":"6db0d50c-1c70-4373-a77c-ab5b5eeb57b3","added_by":"auto","created_at":"2024-02-02 09:44:17","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":22032,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2 Results of selected studies for Mediterranean Europe region\u003c/p\u003e","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-3799343/v1/08dd201a71a367d6c3396ba0.docx"},{"id":50547599,"identity":"93a5e5fd-0f49-4024-bf33-add5c9f58559","added_by":"auto","created_at":"2024-02-02 09:44:17","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":21137,"visible":true,"origin":"","legend":"\u003cp\u003eTable 3 Results of selected studies for other European countries\u003c/p\u003e","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-3799343/v1/f0dee2d8a435b6c5e092e21b.docx"},{"id":50547603,"identity":"74aa8598-a451-45a7-ae35-e45a921c50c9","added_by":"auto","created_at":"2024-02-02 09:44:17","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":19405,"visible":true,"origin":"","legend":"\u003cp\u003eTable 4 Results of selected studies for other continents\u003c/p\u003e","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-3799343/v1/07562e7db8aae451d0de4d20.docx"},{"id":50547985,"identity":"4d3d170f-70e0-45b9-a785-c52477a88a6e","added_by":"auto","created_at":"2024-02-02 09:52:17","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":28307,"visible":true,"origin":"","legend":"","description":"","filename":"RoBfinal.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3799343/v1/8d404769a138b3e1ecb94d46.xlsx"}],"financialInterests":"","formattedTitle":"Occurrence of pharmaceutical residues in drinking water: a systematic review","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePharmaceuticals are powerful allies in the struggle against diseases contributing, over the years, to enhance human health and extend life expectancy. Survival has improved thanks to medical advances, between 1990 and 2015, life expectancy increased by 3.3 years. 44% of improved life expectancy was attributable to public health, 13% was attributable to other medical care, 7% was attributable to unknown factors, but a great contribution, estimated to be around 35%, was attributable to pharmaceutical innovations (Buxbaum et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). In 2021, overall pharmaceutical expenses in the US grew 7.7%, for a total of \u003cspan\u003e$\u003c/span\u003e576.9\u0026nbsp;billion. Non-federal hospitals accounted for \u003cspan\u003e$\u003c/span\u003e39.6\u0026nbsp;billion in prescription expenditures in 2020, an increase of 8.4% in 2021 after a historic decrease in 2020, whereas in clinics spending grew 7.7% to \u003cspan\u003e$\u003c/span\u003e105.0\u0026nbsp;billion. (Tichy et al. 2021). Besides, the process of developing, testing, and commercialising new drugs is constantly increasing, to meet the global health demand that grows in step with the increase in lifespan and the access of new populations to the pharmaceutical global market (OECD \u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Categories of medications for which different kinds of pharmacologically active molecules are prescribed, listed in descending order of the number of different molecules prescribed, are: drugs for the cardiovascular system, nervous system, endocrine system, musculoskeletal system, respiratory system, immunological drugs, and gastrointestinal tract (Fuentes et al. \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). From a purely economic point of view, total pharmaceutical revenues worldwide exceeded 1 trillion dollars in 2014 and the market has been growing at an annual rate of 5.8% since 2017 (Gonz\u0026aacute;lez Pe\u0026ntilde;a et al. \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis constant growth in availability and the related increase in the use of drugs has determined, over the years, an increasingly significant environmental impact, resulting from the urinary and/or faecal excretion of the active ingredients as such or their various metabolites. As a result, human drugs and their metabolites have become \"almost\" ubiquitous pollutants, found in matrices such as fresh surface waters (Fekadu et al. 2019) and marine waters (MacKeown et al. \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), sediments and soils (Białk-Bielińska et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), foods of animal and vegetable origin (Baron et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2014\u003c/span\u003e), wildlife (Herrero-Villar et al. \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In particular, urban and hospital wastewaters are the main contributors to this occurrence; indeed, Wastewater Treatment Plants (WWTPs) are able to remove only in part those compounds from sewage (Gu et al. \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), releasing the unretained portion of drugs and their metabolites into surface waters, coastal marine waters and soil and, thus, leading to \u0026ldquo;ubiquitous\u0026rdquo; pollution through phenomena of diffusion, accumulation in sediments and soils and biomagnification in plants and animals according to the specific chemical-physical characteristics of drugs and metabolites. Other possible sources of contamination are represented by improper storage or \"accidents\" occurring during the phases of storage, transport, and disposal of expired pharmaceutical products, or by wastewater and/or solid wastes from pharmaceutical industries. In addition, a further source of release of drugs and their metabolites into the environment is represented by the increasingly widespread use of veterinary drugs in production of food animals to prevent and treat disease, and to promote growth. In this case, drugs and their metabolites enter the environment directly via urinary and/or faecal excretion, not passing through efficient WWTPs.\u003c/p\u003e \u003cp\u003eHumans are exposed to pharmaceuticals and their metabolites, as environmental contaminants, primarily through ingestion of food of vegetal (Fu et al. \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Keerthanan et al. 2020) and animal origin, mainly fishery products (Dinh et al. \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Griboff et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Lv et al. \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Rojo et al. \u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). The occurrence of pharmaceutical residues in the drinking water cycle represents a further exposure factor; in the last years, indeed, progress in instrumental analytical chemistry has enabled the detection of many different compounds at lower concentrations, contributing to the awareness of this environmental problem. Many studies have reported the presence of pharmaceuticals in raw water used for drinking water production (Castiglioni et al. 2018; Chen et al. \u003cspan citationid=\"CR160\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Daneshvar et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; K\u0026uuml;mmerer et al. \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Petrie et al. \u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), and have investigated the fate of these molecules up to the domestic tap water, detecting residues and metabolites at trace levels (ng/L).\u003c/p\u003e \u003cp\u003eFrom the environmental health point of view, many studies have demonstrated the effects of drugs and their metabolites on aquatic animal and plant species (Almeida et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Nippes et al. \u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) while human health effects have been estimated based on environmental data (Courtier et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Izadi et al. \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Jureczko et al. 2020; Khan et al. \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe aim of this review is to evaluate the contamination of drinking water by pharmaceutical residues all over the world. For this purpose, a systematic review was carried out for identifying all available research reporting original data resulting by sampling campaign and analysis of \"real\" drinking water samples to detect pharmaceutical residues.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis review follows a protocol published in PROSPERO (Registration number: CRD42022314276, available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022314276\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022314276\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The protocol was developed according to the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols (PRISMA 2020) (Page et al. \u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). The protocol was designed to include available research about the contamination by pharmaceuticals for human and veterinary use or their metabolites in drinking water samples all over the world. Potentially eligible studies were identified using electronic databases: PubMed, Scopus and Web of Science.\u003c/p\u003e \u003cp\u003eDatabases were investigated using the following search strings: for PubMed, (drug* OR pharmaceutic* OR medicin* OR \"pharmaceutical preparations\" [mesh] OR \"veterinary drugs\" [mesh]) AND (\"tap water\" OR \"finished water\" OR \"drinking water\" OR \"potable water\" OR \"drinking water\" [mesh] OR \"water supply\" [mesh]) AND (residue* OR metabolite* OR \"drug residues\"[mesh]);\u003c/p\u003e \u003cp\u003efor Scopus, TITLE-ABS-KEY ((drug* OR pharmaceutic* OR medicin* OR \"pharmaceutical preparations\" OR \"veterinary drugs\") AND (\"tap water\" OR \"finished water\" OR \"drinking water\" OR \"potable water\" OR \"drinking water\" OR \"water supply\") AND (residue* OR metabolite* OR \"drug residues\"));\u003c/p\u003e \u003cp\u003efor Web of Science, TS= ((drug* OR pharmaceutic* OR medicin* OR pharmaceutical preparations OR veterinary drugs) AND (tap water OR finished water OR drinking water OR potable water OR drinking water OR water supply) AND (residue* OR metabolite* OR drug residues)).\u003c/p\u003e \u003cp\u003eNo time limit on publication date was set and databases were searched from launch date to 4th April 2022. No time limit on publication date was set and databases were searched from launch date to 4th April 2022. The research was limited to papers written in English language. References of included studies were manually screened for further eligible studies in addition to the search in electronic databases.\u003c/p\u003e \u003cp\u003eStudies reporting data for spiked, waste, surface and mineral water samples or reporting drugs of abuse detection only or other molecules such as contrast agents, pesticides, disinfectants were excluded. Besides, reviews, systematic reviews, letters to the editor, conference abstracts, books, PhD theses, and book chapters were excluded. This review is focused on drinking water contamination by pharmaceuticals or their metabolites, for human and veterinary use, lawfully prescribed: studies reporting were excluded.\u003c/p\u003e \u003cp\u003eData were extracted by two independent authors with any disagreements being resolved by consensus or consulting a third reviewer. Data regarding country, categories of pharmaceuticals searched for, analytical approach, sampling period and molecules identified were extracted and recorded in a database.\u003c/p\u003e \u003cp\u003eTo determine which medications should be given priority for preventing environmental risk, we investigated which types of pharmaceutical and their active components were most frequently found in drinking water. We provide a summary table of the sample's geographic origin, sampling period, pharmaceutical categories examined, active compounds or their metabolites detected, and analytical techniques used to detect pharmaceuticals in drinking water.\u003c/p\u003e \u003cp\u003eThe quality of the studies and overall certainty of evidence were assessed using the \u0026ldquo;RoB assessment tool\u0026rdquo; scale (Danopoulos et al. 2020), specifically adapted to the design of this review, that evaluates four domains: study design, sampling, analysis, and reporting, leading to an overall assessment. RoB results was rated as high, low, or unclear.\u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cp\u003eA total of 6196 records was recovered and, after duplicate removal, 4413 records were screened. 4242 citations were eliminated in the first-level screening based on their title and abstract. 171 reports were sought for retrieval, 13 reports were not found, thus 158 reports were assessed for eligibility by full text during the second-level screening. 119 studies matching with inclusion criteria were included, 5 studies were included by citation searching, resulting in 124 studies finally included in this systematic review. The screening process is presented in the flow chart showed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe results of this review are presented in tables 1, 2, 3, and 4 according to their geographical area.\u003c/p\u003e \u003cp\u003eWe identified a total of 124 studies searching for pharmaceutical residues in drinking water, 91 reporting positivity for one or more compounds, in concentrations range from a few to a few tens of nanograms. In the remaining 33 studies, target analytes were below the limit of detection. We tried to understand how widespread the phenomenon of contamination by medicines for human and veterinary use is, so we reported in which countries pharmaceutical residues have been traced or not in drinking water, and how many studies have been carried out in each country to understand the extent of research on the issue (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOf the 124 studies included, 64 publications were from Europe (44 reported positivity for pharmaceutical residues), 33 from Asia (25 with positivity for pharmaceutical residues), 22 from Americas (19 with positivity for pharmaceutical residues), finally 3 from Africa and 2 from Oceania (2 and 1 reports that detected pharmaceutical residues, respectively). Spain was the country with more papers (20), China was the second country with 15 papers followed by Germany and Brazil with 12 and 8 papers, respectively. The most detected pharmaceutical categories overall and in Europe, Asia, and rest of the world are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. We also reported the most detected pharmaceutical molecules all over the world, Europe, Asia, and rest of the world in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe most represented category considering all included papers was NSAIDs and analgesics, detected in 39 studies, followed by anticonvulsants and antibiotics (respectively detected in 34 and 33 studies). These categories are also the most detected dividing the results by geographical area, but in Asia the most detected pharmaceuticals are antibiotics, detected in 15 works from Asian studies of 33 total studies positive for antibiotics, in contrast with Europe where the first two detected categories are anticonvulsants and NSAIDs or analgesics, with 20 and 19 detections respectively, followed by antibiotics with 11 detections. Beta blockers were detected in 17 studies, all from Asia and Europe, no beta-blockers were detected in selected studies from Americas, Africa, and Oceania.\u003c/p\u003e \u003cp\u003eThe most represented active principle considering total studies was Carbamazepine, detected in 24 studies. The other relevant active principles were Diclofenac (15 studies), Ibuprofen, Paracetamol and Sulfamethoxazole (13 studies).\u003c/p\u003e \u003cp\u003eThe most used sample preparation technique to concentrate the sample and remove unwanted interferences is solid phase extraction (SPE). The most common analytical techniques used to find pharmaceutical residues in drinking water in the selected studies are liquid chromatography, high-performance liquid chromatography, ultra-high-performance liquid chromatography, tandem mass spectrometry (LC-MS/MS, HPLC-MS/MS, UHPLC-MS/MS), and gas chromatography mass spectrometry (GC-MS). When determining trace amounts of such pollutants, it is crucial to use an analytical method that may provide both selectivity and sensitivity.\u003c/p\u003e \u003cp\u003eThe results of this review show agreement between different geographic areas and principal pharmaceuticals detected in drinking water. The possibility to detect a pharmaceutical molecule in drinking water depends not only on the amount of its clinical use and sold, but its presence in water is determined also by specific chemical properties that determine environmental persistence and from the efficacy of the removal from wastewater avoiding contamination of environmental waters, source for production of drinking water.\u003c/p\u003e \u003cp\u003eActive ingredients and their metabolites are frequently found in wastewater and environmental waters (Baron et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Białk-Bielińska, 2016; Fekadu et al. 2019; Herrero-Villar et al. \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; MacKeown et al. \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Studies have been conducted to determine the effective concentration of drugs in wastewater, both before and after the treatment carried out by STPs and in surface waters. NSAIDs, due to their widespread use, represent one of the most investigated categories of drugs. Several studies on acetylsalicylic acid and paracetamol have demonstrated the effectiveness of purification systems (Ternes \u003cspan citationid=\"CR139\" class=\"CitationRef\"\u003e2001\u003c/span\u003e). Another drug belonging to the class of NSAIDs which persists in water even after purification is ibuprofen, traces of which have been found in water purification plants in Austria, Brazil, Germany, and Switzerland (Buser et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Heberer \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Ternes \u003cspan citationid=\"CR140\" class=\"CitationRef\"\u003e1998\u003c/span\u003e; Ternes et al. \u003cspan citationid=\"CR141\" class=\"CitationRef\"\u003e2002\u003c/span\u003e), and it was calculated that more than 60 kg of diclofenac was discharged into the Baltic Sea in 2018, while in the first half of 2021 it was equal to 20 Kg from the two WWTPs tested. The presence of 4OH-diclofenac in effluents often in higher concentration compared to diclofenac mean that this still biologically active compound needs to be considered in future risk assessment (Kołecka et al. \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Traces of naproxen have been found in STP effluents in Canada (Metcalfe et al. \u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e2003\u003c/span\u003e) and Spain (Quintana et al. \u003cspan citationid=\"CR117\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). Among the neuroactive drugs, carbamazepine is the most studied active principle as it is removed only in very small part (less than 10%) from the STP (Ternes \u003cspan citationid=\"CR139\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Heberer \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2002\u003c/span\u003e); the result is frequently detection of positive samples for this active principle. Another class of drugs that has been particularly studied is lipid-lowering drugs; in particular, clofibric acid has historical importance as the first pharmacologically active molecule to be found in water samples from municipal water purification plants.\u003c/p\u003e \u003cp\u003eThe effects of long-term exposure to pharmaceutical residues through drinking water are difficult to assess. No long-term toxicity studies on humans are currently available, relating to doses much lower than therapeutic ones; however, the alterations observed in wildlife suggest potential effects on human health (Shore et al. \u003cspan citationid=\"CR129\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Many of these molecules can act as endocrine disruptors: their structure could mimic that of other substances involved in the fine balance of the neuroendocrine system, hormones can act at very low doses and alter the normal physiology of the organism (Chen et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFurthermore, since the effects that active ingredients and metabolites in water can have on the environment and what danger they can represent for human health, greater use of drugs that is currently implemented in the veterinary field, both for curative and productive purposes especially in intensive farming, should not be underestimated. This sector is undoubtedly responsible for a large amount of environmental and water contamination that is difficult to control, and it can aggravate this situation.\u003c/p\u003e \u003cp\u003eWastewater from intensive farms, generally undergoes less effective purification treatments than civil plants. To these residues must be added those of all the drugs widely used, illegally, on farm animals for auxinic, masking purposes, etc.\u003c/p\u003e \u003cp\u003eThe possibility that pharmaceutical residues can cause direct damage to the environment and indirect damage to humans led US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products - EMEA), to include environmental risk assessment as an essential requirement in each dossier presented to put new drugs on the market, as provided in the guidelines issued by both agencies, FDA and EMEA, in 1997 and 2001 respectively, updated in 1998 and 2006 (FDA 1998; EMEA 2006b). Both documents initially require a careful assessment of the predicted environmental distribution of the active ingredient and its main metabolites. In practice, through mathematical formulas that consider the quantity of product sold, the maximum therapeutic dose foreseen per patient/day and daily produced wastewater per inhabitant, it is possible to estimate predicted concentrations.\u003c/p\u003e \u003cp\u003eFor veterinary medicinal products also, the EMEA has issued a series of guidelines (EMEA, 2000; 2005; 2006a) which make it necessary to evaluate contamination and environmental persistence for the purposes of any marketing authorisation of veterinary medicines.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eDetection of pharmaceutical residues, according to analysis of real drinking water samples in 91 studies from all over the world included in this review, confirms the concern about drinking water contamination on a global scale and requires close attention from health authorities, scientific community, and pharmaceutical industries.\u003c/p\u003e \u003cp\u003ePreventive interventions for drinking water contamination should be also targeted on technological improvement of wastewater purification plants and drinking water treatment plants to raise pharmaceutical residues removal.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStefano Zanni: Conceptualization, Methodology, Software, Validation, Investigation, Data curation, Writing - Original Draft, Visualization.\u003c/p\u003e\n\u003cp\u003eVincenzo Cammalleri: Conceptualization, Methodology, Software, Validation, Investigation, Data curation, Writing - Original Draft, Visualization.\u003c/p\u003e\n\u003cp\u003eLudovica D\u0026rsquo;Agostino: Software, Validation, Data curation, Writing - Original Draft, Visualization.\u003c/p\u003e\n\u003cp\u003eCarmela Protano: Conceptualization, Methodology, Writing - Review \u0026amp; Editing, Supervision, Project administration.\u003c/p\u003e\n\u003cp\u003eMatteo Vitali: Conceptualization, Methodology, Writing - Review \u0026amp; Editing, Supervision, Project administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they consent to participate in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they consent to the publication of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAfifi R, Elnwishy N, Hannora A, Hedstr\u0026ouml;m M, Mattiasson B, Omran H, Alharbi OML, Ali I (2016) SPE and HPLC monitoring of 17-β-estradiol in Egyptian aquatic ecosysetms. 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J Chromatogr A 1050:201\u0026ndash;209. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.chroma.2004.08.051\u003c/span\u003e\u003cspan address=\"10.1016/j.chroma.2004.08.051\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"environmental-science-and-pollution-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"espr","sideBox":"Learn more about [Environmental Science and Pollution Research](https://www.springer.com/journal/11356)","snPcode":"11356","submissionUrl":"https://submission.nature.com/new-submission/11356/3","title":"Environmental Science and Pollution Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Pharmaceutical Residues, Drinking Water, Environmental Monitoring, Emerging Contaminants, Systematic Review.","lastPublishedDoi":"10.21203/rs.3.rs-3799343/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3799343/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn the last decades, the use of drugs, both in clinical practice and in intensive livestock farms, has increased exponentially. Following urinary and/or faecal excretion, these compounds are only partially retained in the depuration facilities, reaching fresh or marine surface waters even distant from the source of entrance. The main consequence of this phenomenon is the presence, increasingly frequently found, of traces of drugs and their metabolites in the aquatic environment including drinking water. The aim of this review is to evaluate the contamination of drinking water by pharmaceutical residues all over the world. For this purpose, a systematic review was carried out for identifying all available research reporting original data resulting by sampling campaign and analysis of \u0026ldquo;real\u0026rdquo; drinking water samples to detect pharmaceutical residues. The investigated databases were PUBMED, SCOPUS and WEB OF SCIENCE. A total of 124 studies were included in the review and 33 of them found target analytes below the limit of detection, while the remaining 91 studies reported positivity for one or more compounds, in concentrations ranging from a few to a few tens of nanograms. This finding confirms the concern about drinking water contamination on a global scale and requires close attention from health authorities, pharmaceutical industries, and scientific community. Preventive interventions for drinking water contamination should be also targeted on technological improvement of wastewater purification plants and drinking water treatment plants to raise pharmaceutical residues removal.\u003c/p\u003e","manuscriptTitle":"Occurrence of pharmaceutical residues in drinking water: a systematic review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-02 09:44:12","doi":"10.21203/rs.3.rs-3799343/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-01-30T09:53:09+00:00","index":0,"fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-12T05:01:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"Environmental Science and Pollution Research","date":"2024-01-04T13:34:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"environmental-science-and-pollution-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"espr","sideBox":"Learn more about [Environmental Science and Pollution Research](https://www.springer.com/journal/11356)","snPcode":"11356","submissionUrl":"https://submission.nature.com/new-submission/11356/3","title":"Environmental Science and Pollution Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"216c5307-0b15-45f6-bf07-278c94a9e664","owner":[],"postedDate":"February 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-12T16:12:41+00:00","versionOfRecord":{"articleIdentity":"rs-3799343","link":"https://doi.org/10.1007/s11356-024-34544-8","journal":{"identity":"environmental-science-and-pollution-research","isVorOnly":false,"title":"Environmental Science and Pollution Research"},"publishedOn":"2024-08-06 15:57:33","publishedOnDateReadable":"August 6th, 2024"},"versionCreatedAt":"2024-02-02 09:44:12","video":"","vorDoi":"10.1007/s11356-024-34544-8","vorDoiUrl":"https://doi.org/10.1007/s11356-024-34544-8","workflowStages":[]},"version":"v1","identity":"rs-3799343","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3799343","identity":"rs-3799343","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}