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Antiviral drugs in aquatic environment and wastewater treatment plants: A review on occurrence, fate, removal and ecotoxicity
Journal Pre-proof Antiviral drugs in aquatic environment and wastewater treatment plants: A review on occurrence, fate, removal and ecotoxicity
Christina Nannou, Anna Ofrydopoulou, Eleni Evgenidou, David Heath, Ester Heath, Dimitra Lambropoulou PII:
S0048-9697(19)34313-X
DOI:
https://doi.org/10.1016/j.scitotenv.2019.134322
Reference:
STOTEN 134322
To appear in:
Science of the Total Environment
Received date:
13 July 2019
Revised date:
4 September 2019
Accepted date:
5 September 2019
Please cite this article as: C. Nannou, A. Ofrydopoulou, E. Evgenidou, et al., Antiviral drugs in aquatic environment and wastewater treatment plants: A review on occurrence, fate, removal and ecotoxicity, Science of the Total Environment (2018), https://doi.org/ 10.1016/j.scitotenv.2019.134322
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© 2018 Published by Elsevier.
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Antiviral drugs in aquatic environment and wastewater treatment plants: A review on occurrence, fate, removal and ecotoxicity
Christina Nannou a, Anna Ofrydopoulou a, Eleni Evgenidoua, David Heathb, Ester
Department of Chemistry, Aristotle University of Thessaloniki. GR 54124,
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a
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Heath b,c, Dimitra Lambropoulou a*
Department of Environmental Sciences, Jožef Stefan Institute, Jamova cesta 39,
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b
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Thessaloniki, Greece
1000 Ljubljana, Slovenia Jožef Stefan International Postgraduate School, Jamova cesta 39, 1000 Ljubljana,
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c
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Slovenia
*Corresponding author: Tel: +30 2310 997687, Fax: +30 2310 997799 E-mail: [email protected] (D. Lambropoulou)
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ABSTRACT The environmental release of antiviral drugs is of considerable concern due to potential ecosystem alterations and the development of antiviral resistance. As a result, interest on their occurrence and fate in natural and engineered systems has grown substantially in recent years. The main scope of this review is to fill the void of information on the knowledge on the worldwide occurrence of antiviral drugs in
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wastewaters and natural waters and correlate their levels with their environmental
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fate. According to the conducted literature survey, few monitoring data exists for
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several European countries, such as Germany, France, and the UK. Lesser data are available for Asia, where approximately 80% of the studies focus on Japan. Several
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articles study the occurrence of mostly antiretroantivirals in sub-Saharan African
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countries, while there is a lack of data for other developing regions of the world, including the rest of Africa, South America, and the biggest part of Asia. An
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importantly smaller number of studies exists for North America, while no studies
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exist for Oceania. The against innfluenza drug oseltamivir along with its active
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carboxy metabolite is found to be the most studied antiviral drug. The distribution of antiviral drugs across all geographic regions varies from low ng L -1 to high μg L-1 levels, in some cases, even in surface waters. This overarching review reveals that monitoring of antiviral drugs is necessary, and some of those compounds may require toxicological attention, in the light of either spatial and temporal high concentration or potential antiviral resistance. Based on the information provided herein, the need for a better understanding of the water quality hazards posed by antiviral drugs existence in wastewater outputs and freshwater ecosystems is demosntrated. Finally, the future challenges concerning the occurrence, fate, and potential ecotoxicological risk to organisms posed by antiviral drug residues are discussed. 2
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Keywords: Antiviral drugs, Aquatic environment, Ecotoxicity, Fate, Occurrence, Removal, Wastewaters
Abbreviations:
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3TC, lamivudine; 8,14-DiOH-EFV, 8,14-dihydroxy-efavirenz; 12-OH-NVP, 12-
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hydroxy-nevirapine; ABC, abacavir; ACV, acyclovir; ADV, adefovir; AMT,
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amantadine; ARVs, antiretrovirals; ATV, atazanavir; AZT, zidovudine; AZTG, zidovudine glucuronide; CAGR, compound annual growth rate; CAS, conventional
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active sludge; CBX-ABC, carboxy-abacavir; CBX-ACV, carboxy-acyclovir; CBX-
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AZT, carboxy-zidovudine; CBX-3TC, carboxy-lamivudine; CBX-FTC, carboxy– emtricitabine; D4T, stavudine; DDC, zalcitabine; DDD; defined daily dose; DDI, DES-ABC,
descyclopropyl-abacavir;
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didanosine;
DLV,
delavirdine;
DOR,
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doravirine; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ETR, etravirine;
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EVG, elvitegravir; FCV, famciclovir; FDC, fix-dose combination; FDA, Food and Drug Administration; FTC, emtricitabine; GCV, ganciclovir; HAART, highly active antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; HCMV, human cytomegalovirus; HIV, human immunodeficiency virus; HPV, human papillomavirus, HSV, herpes simplex virus; HRT; hydraulic retention time; IDV, indinavir; LAN, laninamivir; LANO, laninamivir octanoate; LOD, limit of detection; LOQ, limit of quantification LPV, lopinavir; MVC, maraviroc; n.a., not available; n.d., not detected; n.q., not quantified; NFV, nelfinavir; NNRTI, non-nucleoside reverse-transcriptase inhibitors; NVP, nevirapine; OS, oseltamivir; OS-Et, oseltamivir ethylester; OC, oseltamivir carboxylate; PLC, pleconaril; PCV, 3
Journal Pre-proof penciclovir; PRV, peramivir; RAL, raltegravir; RBV, ribavirin; RPV, rilpivirine; RIM,
rimantadine; RSV,
respiratory
syncytial; RTV,
ritonavir;
RTVM,
desthiazolylmethyloxycarbonyl; SQV, saquinavir; SRT, solid retention time; T20, enfuvirtide; T-705, favipiravir; TDF, tenofovir; VACV, valacyclovir; VZV, varicella zoster virus; ZAN; zanamivir,
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1. Introduction
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Among the plethora of contaminants of anthropogenic origin reaching the
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environment, pharmaceuticals, cosmeceuticals, biomedical, personal care products (PCPs), endocrine-disrupting chemicals (EDCs), and flame-retardants are of utmost
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importance (Bilal et al., 2019). Various classes of pharamceuticals constitute an
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emerging class raising concerns about long-term consequences on human health (López-Pacheco et al., 2019), since widespread contamination from them has been
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observed in the water cycle, concluding finally in drinking water, due to their
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hydrophilic character and low removal in wastewater treatment plants at
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concentrations from few ng L-1 to several mg L-1 (Kosma et al., 2019). Continuous discharge into aquatic systems make the residues of those compounds ubiquitous in the environment.
Antiviral drugs comprise a class of medication used to treat viral infections including influenza, herpes, hepatitis, and HIV (He, 2013). The worrisome rate of deaths due to viral infections has motivated the development of more and more antiviral drugs, after the approval and release of the first antiviral idoxuridine in the market, in 1963 (De Clercq, 2007; De Clercq and Li, 2016). These newly-developed antiviral drugs positively influence human health and prosperity, since the deadly outcomes and suffering of many infectious diseases are lessened, as well as life 4
Journal Pre-proof expectancy is increased and hospital stays are shortened (Flanagan et al., 2011). The development of new antiviral drugs is an integral part of the global pharmaceutical industry, and many facets of healthcare since the treatment of non-communicable diseases requires breakthroughs to be effective and confront resistant strains (Barr et al., 2016). Some antivirals are (highly) bioactive, they may negatively affect non-target organisms and persist in aquatic environments (Jain et al., 2013). In case that both the
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antiviral drug and the virus to be treated co-occur in the same water body, resistance strains are developed. This accelerates the establishment of antiviral resistance and it
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limits the clinical utility of the antivirals in human and animals (Laughlin et al., 2015;
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Olsen et al., 2006; Singer et al., 2014). Antivirals can also be toxic, and according to
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(Q)SAR, modeling and toxicity data rank eighth among the most hazardous
(Sanderson et al., 2004).
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therapeutic classes towards aquatic organisms such as algae, daphnia and fish
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The consequences of adverse effects of antiviral drugs in the environment are
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worrisome given the limited accessibility of specific populations to vaccines, increasing infectious diseases that demand large amounts of antiviral drugs on a longterm basis (Laughlin et al., 2015). Also, influenza pandemics or outbursts often result in seasonal variations and peak emissions of antiviral drugs residues (Singer et al., 2007) that merit investigation. A typical example of a sharp increase in the antiviral drugs load is the pandemic outbreaks of influenza in 2009, mainly in the UK (Singer et al., 2014, 2013). Other unpredictable sources, such as the direct disposal of nonexpired drugs due to changes in treatment regimens because of decreased medical efficiency (Pomerantz, 2004) is noteworthy.
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Journal Pre-proof Evidence regarding the environmental occurrence and behavior of antiviral drugs is scarce and covers limited geographical regions (Fig.1). Despite their alarming high consumption rates, various antiviral drugs have been detected but not often systematically monitored in the aquatic environment (Abafe et al., 2018; Aminot et al., 2015; Azuma et al., 2019, 2017a, 2014; Funke et al., 2016; Mosekiemang et al., 2019; Prasse et al., 2010). The majority of studies concern WWTPs and surface waters, while there are fewer number of articles looking at groundwaters (Boulard et
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al., 2018; Fisher et al., 2016; K’oreje et al., 2016; Rimayi et al., 2018; Swanepoel et al., 2015), and drinking water (Boulard et al., 2018; Dévier et al., 2013; Funke et al.,
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2016; Furlong et al., 2017; Giebułtowicz et al., 2018; Swanepoel et al., 2015; Wood et
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al., 2015). Overall, antiviral drugs in wastewaters, surface waters, groundwaters, and
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drinking water have not been documented to the same extent as for other pharmaceuticals. Also, many existing articles on the environmental occurrence of
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antiviral drugs were either published after influenza pandemics or are concerned
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mainly with antiretrovirals (ARVs) used in the fight against HIV.
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Although, the number of studies focused on environmental relevance of antiviral drugs have been steadily increasing in recent years, the literature on antiviral drugs has not been reviewed in detail. In particular, only a handful of reviews deal with their analysis, occurrence and adverse effects on the environment and almost all of them have exclusively focused on specific antiviral groups. For example, the analytical methodologies and presence of antiviral drugs in the environment were last reviewed in 2013 (Jain et al., 2013). However, almost all information in this review are available only for anti-influenza drugs and data for other groups are missing. There is also one review on the fate and ecotoxicological effects of antiretrovirals against HIV (Ncube et al., 2018), but survey data for the rest of antivirals was not
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Journal Pre-proof included. Therefore, there is a need to compile the existing information and summarize up-to date progress in evaluation of antiviral drugs as environmental contaminants. To fill this gap, the current analytical approaches for the determination of antiviral drugs in the environment have been very recently reviewed by the authors (Nannou et al., 2019) with great emphasis on sample preparation and detection systems. In continuation of our recent review reporting on the analytical aspects of
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antiviral drugs determination in aqueous environmental matrices (Nannou et al., 2019), this review aims to discuss several aspects that were inadequately addressed
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until recently, by providing a comprehensive overview on the occurrence and removal
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of antiviral drugs in aquatic environment and wastewater treatment systems
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worldwide. Our specific objectives were to: (a) present an extensive up-to-date pattern on sales data worldwide, (b) investigate their occurrence in natural waters (surface
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waters, groundwaters, drinking water) and wastewaters (c) address their behavior and
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removal in WWTPs and (d) identify challenges and perspectives of studying antiviral
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residues in the environment. To the best of our knowledge, this review is the first to gather all available data on antiviral drug environmental occurrence, removals rate and fate in WWTPs.
2. Types and usage of antiviral drugs Antiviral therapy aims to mitigate infectivity and symptoms, as well as to minimize the illness duration, by arresting the replication cycle of the virus in different stages of the viral life cycle (Bagga and Bouchard, 2014). A large part of antiviral infections are self-limited illnesses and can be resolved without treatment by immunocompetent individuals (Jin et al., 2018; Razonable, 2011). However, a 7
Journal Pre-proof relatively limited number of infections can be treated by the available antiviral therapies, since the resistance to antiviral drugs may restrict their clinical utility. The currently approved antiviral drugs are divided in 13 functional groups: (i) 5substituted 2’-deoxyuridine analogues; (ii) nucleoside analogues; (iii) (nonnucleoside) pyrophosphate analogues; (iv) nucleoside reverse transcriptase (RT) inhibitors (NRTIs); (v) nonnucleoside reverse transcriptase inhibitors (NNRTIs); (vi) protease inhibitors (PIs); (vii) integrase inhibitors; (viii) entry inhibitors; (ix) acyclic guanosine
(HCV)
NS5A
and
NS5B
inhibitors;
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analogues; (x) acyclic nucleoside phosphonate (ANP) analogues; (xi) hepatitis C virus (xii)
influenza
virus;
and
(xiii)
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immunostimulators, interferons, oligonucleotides, and antimitotic inhibitors. Ninety
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antiviral drugs are licensed today (De Clercq and Li, 2016). The inhibitory spectrum
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of the released antivirals concerns nine out of the 200 discovered human infectious diseases; namely, human immunodeficiency virus (HIV), hepatitis B virus (HBV),
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hepatitis C virus (HCV), human cytomegalovirus (HCMV), herpes simplex virus
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(HSV), human papillomavirus (HPV), respiratory syncytial virus (RSV), varicella-
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zoster virus (VZV), and influenza virus (De Clercq and Li, 2016; Razonable, 2011). Among them, the four main groups include HIV, herpes, hepatitis, and influenza viruses (Razonable, 2011).
According to global pharmaceutical sales data, antivirals are among the top 10 therapeutic classes (Mikulic, 2018). The global antiviral market was accounted for $42.65 billion in 2016 and is expected to reach $63.11 billion by 2022 growing at a CAGR of 5.8% (European Centre for Disease Prevention and Control, 2018). The average consumption of antivirals for systemic use in the 25 member countries of the Eurοpean Union is 1.97 DDD (defined daily dose)/ per 1,000 inhabitants per day, where antivirals to treat HIV infections predominate, and theay are followed by
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Journal Pre-proof substances to treat influenza (European Centre for Disease Prevention and Control, 2018). Recent data (2018) on the consumption of antiviral drugs in Europe are depicted in Fig. 2. More than half of all of the produced antiviral agents are used against HIV, which is commonly referred as ‘highly active antiretroviral therapy’ (HAART). The pharmaceutical industry has developed more than 35 antiretroviral treatments for HIV, with an estimated cost of 26.7 billion US dollars (International Federation of
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Pharmaceutical Maufacturers and Associations, 2017). Until recently, zidovudine, tenofovir, lamivudine and abacavir were the ARVs (Abafe et al., 2018). From 2015
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on, less expensive and more effective regimens have been established, by introducing
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combination therapy of two or more drugs (tenofovir, emtricitabine, lamivudine, and
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efavirenz) (Meintjes et al., 2017). This cocktail medication is appropriate for adolescents, adults and pregnant women. If psychiatric comorbidity occurs, efavirenz
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is replaced by nevirapine (Gaida et al., 2017).
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In Europe, HIV combinational therapy accounts for 54% of the total antiviral
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drugs (European Centre for Disease Prevention and Control, 2018). In Africa, three million people are under HAART (Unaids, 2016), and ARVs constitute the “lion’s share” of pharmaceuticals prescribed in sub-Saharan countries. Given that the estimated daily dosage per capita for ARVs is approximately 991 mg/day, over 1085 tons of ARVs are ingested per year in this ontinent. This number is approximately 326 tons lower if the <30% average excretion via urine to sewage is taken into account. Antiviral drugs to treat influenza are an equally important group, being the key component of an influenza pandemic preparedness plan. According to WHO data, every year 250,000 to 500,000 people die, and more than 3 million are severely infected (WHO, 2018). Notably, only 8% of the antiviral drugs (mainly oseltamivir,
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Journal Pre-proof zanamivir, amantadine, laninamivir, peramivir, rimantadine, umifenovir) are used to treat influenza. In Europe, the average consumption oseltamivir carboxylate (OC) that is the active metabolite of the most prescribed drug against influenza (Tamiflu®) (Hurt, 2019; Singer et al., 2014), zanamivir (ZAN) and rimantadine (RIM) is estimated 0.03 DDD/1000 inhabs/day (European Centre for Disease Prevention and Control, 2018). In the light influenza outbreaks during the 21st century, efforts have been made to simulate pandemic events in lab-scale experiments, in particular for
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oseltamivir carboxylate.
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3. Analytical approaches for the determination of antiviral drugs in
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aqueous environmental matrices
Analytical approaches to determine antiviral drugs in the environment are
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demanding, not only due to the complexity of the matrix but also due to the ultra-trace
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occurrence. Even more, when antiviral drugs co-exist with other trace contaminants method development and validation are more laborious tasks. More detailed
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information can be found in a recent review of the authors, which summarizes a critical number of good works on the analytical strategies employed (Nannou et al., 2019).
The majority of published methods are based on solid phase extraction (SPE) for the isolation and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) for the determination of analytes. In particular, offline SPE is most common (Abafe et al., 2018; Azuma et al., 2019, 2017b, 2017a; Giebułtowicz et al., 2018; Martínez-Piernas et al., 2018), while the on-line mode is also used but to a lesser extent (Khan et al., 2012; Kovalova et al., 2012; Singer et al., 2014, 2013). As for the majority of pharmaceuticals, Oasis HLB cartridges are the ‘golden’ sorbent, 10
Journal Pre-proof due to its versatility and efficiency for a wide spectrum of compounds with differing in physicohemical properties (Abafe et al., 2018; Azuma et al., 2019). Mixed-mode sorbents such as MCX were also used successfully (Aminot et al., 2016, 2015; Leknes et al., 2012; Takanami et al., 2012). Other cartridge types that have been employed as SPE sorbents were Bond Elut SCX (Azuma et al., 2019, 2017a, 2015a, 2014, 2013), Isolute ENV+ (Prasse et al., 2011, 2010), Strata SDB-L, (Mosekiemang et al., 2019), Cleanert PEP, (Schoeman et al., 2015), Bond Elut Plexa (Rimayi et al., 2018), Sep-
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Pak plus NH2 (Ghosh et al., 2010a), or combinations of more than two commercially available sorbents. Namely, Strata WCX, ZT, WAX and Isolute ENV+ (Ibáñez et al.,
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2017), HLB, Strata X-CW, Strata X-AW and Isolute ENV+ (Margot et al., 2013),
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HLB and Bond Elut SCX (Azuma et al., 2017a, 2016), and medium sized SPE disks
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for a large volume (800 mL) extraction (Ferrando-Climent et al., 2016). A more straightforward solution is the direct injection to the LC-MS systems
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(Burns et al., 2018; Fisher et al., 2016; Funke et al., 2016; Furlong et al., 2017;
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Mosekiemang et al., 2019; Seitz and Winzenbacher, 2017), although the absence of
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sample preconcentration may pose limitations at ultra-trace level analysis. In this case, a guard column should also be used to prevent damaging the analytical column. Alternative extraction methods, such as molecularly imprinted polymer (MIP) SPE (Mtolo et al., 2019; Terzopoulou et al., 2016) and extraction on an in-house sorptive disposable PDMS loop sampler (Wooding et al., 2017) have been successfully applied. These lab-made sorbents are promising but of limited application, since they are highly selective, and as mentioned before, antiviral drugs are mostly studied as part of multiresidue studies. Freeze-drying has also been used as a preconcentration step for aqueous sample preparation (Boulard et al., 2018).
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Journal Pre-proof Liquid chromatography coupled to (tandem) mass spectrometry is the ‘key’ analytical instrumentation (Martínez-Piernas et al., 2018; Mosekiemang et al., 2019; Rimayi et al., 2018). High-resolution mass spectrometers, such as Orbitrap and Q-ToF that allow both suspect and non-target analysis, are yet to be fully exploited for environmental analysis of antivirals. Non-target identification of antivirals is reported twice (Ferrando-Climent et al., 2016; Ibáñez et al., 2017). Boulard et al. (2018) were the first to use hydrophilic interaction liquid chromatography (HILIC). GC–MS
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remains less popular; a two-dimensional gas chromatography with time of flight mass spectrometry (GC×GC-TOFMS) was also employed (Furlong et al., 2017; Wooding
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retrospective analysis is impossible.
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et al., 2017). The main limitation posed when non-HRMS is employed is that the
4. Fate of antiviral drugs in aquatic environment and WWTPs Fate of antiviral drugs in WWTPs
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4.1
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Wastewater treatment plants (WWTPs) are the first receiver of pharmaceutical
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and consequently antiviral drugs residues, where they are partially or completely eliminated, through various treatment processes, such as adsorption on activated carbon, oxidation, chlorination, ozonation and reverse osmosis, they can be released to the aquatic bodies as parent compounds, or (a)biotic transformation products (TPs) (metabolites, conjugates, and degradation products) (Evgenidou et al., 2015). Hence, WWTPs may determine the route and fate of pharmaceuticals after being ingested by humans. The employed technologies in WWTPs target primarily at the elimination of compounds of carbon (proteins, carbohydrates, lipids), and to a smaller extent, biogenic pollutants and emerging contaminants such as antiviral drugs, as proved by the concentrations of those substances in treated wastewater. Also, antiviral drugs are 12
Journal Pre-proof only recently recognized as contaminants, and WWTPs are not designed to remove them efficiently. Discharge of pharmaceuticals into the environment and therefore, contamination of water bodies is derived from WWTP effluents. Municipal or hospital WWTPs operate with primary, secondary, and less frequently tertiary treatment. Primary treatment includes physical processes of screening, comminution, grit removal, and sedimentation and aims to reduce the suspended solids. As expected, it is not sufficient to remove antivirals. Especially
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hydrophobic antivirals that exhibit log Dow (distribution ratio) >3 tend to be sorbed onto the sludge, and they are partially released once the primary treatment is
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completed (Ternes et al., 2004). Secondary treatment usually involves a biological
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process. The conventional practice is to employ an activated sludge (CAS) system
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(Grandclement et al., 2017), while ozonation and membrane bioreactors (MBR) are less commonly applied (Vergeynst et al., 2015a). Also, when biological nutrient
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removal is applied, the removal efficiencies can be higher than for conventional CAS
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process (Grandclement et al., 2017). Tertiary treatment increases the operation cost
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and is practiced when the intended receiving water is prone to the effects of pollution. Tertiary treatments include coagulation, filtration, activated carbon adsorption of organics, reverse osmosis and additional disinfection (e.g., chlorination, ozonation, and UV).
The applied treatment is a multi-factorial process that has a substantial impact on the removal efficiency. The treatment process is susceptible both to environmental (temperature, pH, redox conditions) and operation conditions such as the type of treatment, biodegradation kinetics, hydraulic retention time (HRT), sludge retention time (SRT), the oxygen source, and the concentration of pollutant in the influent (Dolar et al., 2012; Evgenidou et al., 2015; Verlicchi et al., 2012). It is probable that
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Journal Pre-proof removal efficiency varies between different WWTPs, and even within the same WWTPs. There is also a lack of knowledge of the efficiency of WWTPs to cope with excessive loads of antiviral drugs, which means that antiviral drugs enter the aquatic environment. Physicochemical characteristics of the compounds to be treated (volatility, water solubility, absorption capacity on activating sludge and degradation half-life for (a)biotic processes are also crucial (Evgenidou et al., 2015; Gulkowska et al., 2007;
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Luo et al., 2014). The polarity of compounds plays a primary role in determining removal efficiency since polar compounds (logKow<3) are rarely adsorbed to the
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sludge and are poorly removed during the primary treatment. A large part of antivirals
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is polar and stable in water. Several antivirals exhibit low adsorption coefficients and
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are more likely to occur in the aqueous phase and easily end up in water bodies. The dissociation of contaminants during treatment in the aqueous phase is enhanced when
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their pKa is below the pH of the wastewater. Other constituents present in the
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wastewaters may react with the parent antivirals to form more persistent molecules
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that can threaten the aquatic environment (Pinon and Vialette, 2018). Despite the advances in water treatment technologies, effluents remain an important source of antiviral drugs load, given the occasionally low or negative removal efficiencies (Funke et al., 2016; Prasse et al., 2010). It is evident from the available data (Table 1) that it is difficult to conclude the removal rates of antiviral drugs. For instance, WWTPs operational conditions may differ significantly, while especially in the developing countries they may still operate in an early stage, without applying advanced treatment (Ncube et al., 2018). Also, there are significant differences in the concentrations between the inputs of many WWTPs, therefore, the removal rates are not easily comparable (Cramer et al., 2018).
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4.2.
Fate of antiviral drugs in the aquatic environment Once consumed and ingested by humans, antiviral drugs may be either
partially metabolized and excreted in urine and feces as active metabolites (Jain et al., 2013). A figure summarizing the fate of antiviral drugs in aquatic environment is given to depict the transmission of drugs to aquatic environment (Fig. 3). Typically, antivirals are excreted to a great extent in the bioactive form of the parent dose. Their
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human metabolism plays an important role to the antiviral drugs load that enter the environment. The major biotransformation pathways include glucuronidation,
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sulfoxidation, dimethylamine N-demethylation, and sulfate conjugation. Finally, these
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compounds reach the urban or hospital wastewater treatment plants (WWTPs) before
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ending up into the aquatic environment. Other potential sources may include illegal or improper disposal into water bodies or leachate from landfills (Nannou et al., 2015).
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The latter is the main reason for enantiomeric profiling since no metabolism takes
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less important source.
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place (Petrie et al., 2015). Antiviral drugs administered to animals are considered a
Once they enter into the environment, antiviral drugs are exposed to different processes. Although only a few articles are focusing on the fate of antiviral drugs in the environment, there is sufficient evidence that many of them may undergo photolysis, hydrolysis, sorption and biodegradation (Ncube et al., 2018). Most antiviral drugs are stable to photodegradation (Azuma et al., 2017a). Namely, oseltamivir carboxylate (Azuma et al., 2017a; Goncalves et al., 2011), emtricitabine, zanamivir, favipiravir, laninamivir, laninamivir octanoate, peramivir, amantadine, indinavir and stavudine are persistent to photodegradation (Dunge et al., 2004; Russo et al., 2018). In particular, abacavir is not photodegraded in either solid
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Journal Pre-proof or solution form (Rao et al., 2011). Alternatively, the acyclovir is susceptible to photolysis in both freshwater and seawater (Russo et al., 2017; Zhou et al., 2015), as is zidovudine which photodegrades rapidly (>80%) (Dunge et al., 2004; Russo et al., 2018; Zhou et al., 2015). Regarding sorption mechanisms of antiviral drugs onto complex matrices such as soils and activated/deactivated sludges are not simply defined and are largely unknown. Up to now, only few data were published investigating their sorption onto
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sediments, sludge and soils. For example, the sorption of the antiviral drugs in river sediments was recently studied by Azuma et al. (Azuma et al., 2017a). Findings of the
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latter study reveal that of all targeted anti-influenza drugs (oseltamivir, oseltamivir
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carboxylate, zanamivir, favipiravir, laninamivir, laninamivir octanoate, peramivir,
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amantadine) exhibited low sorption tendency indicating that removal via sorption to sewage sludge is possibly negligible.
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Similarly to sorption, biotransformation of antiviral drugs is still unclear since
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only limited attention has been paid towards their biodegradability in natural
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environments (Saccà et al., 2009); (Azuma et al., 2017a). An interesting study in this area has been recently reported by Azuma et al, in which a clear difference in biodegradability among the targeted anti-influenza drugs was observed. For instance, laninamivir octanoate and oseltamivir were effectively biodegraded while oseltamivir carboxylate, zanamivir, favipiravir, peramivir and amantadine were highly resistant to biotransformation. In summary, we currently lack sufficient knowledge of the types, rates, and extent of transformations expected for antiviral drugs in natural systems and therefore further research is needed in this field in order to understand better the reactivity, fate, transport and persistence of these compounds in the environment.
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5. Occurrence of antiviral drugs in WWTPs The occurrence of antiviral drugs in WWTPs depends on various factors, such as the country, different medical needs, standard of living that largely affects the operation of advanced WWTPs, and sampling season, since pandemic outbursts of influenza are a major reason for the prescription of antiviral drugs. The inhibitory
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spectrum of antiviral drugs studied in the environment includes mostly the
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antiretrovirals (against HIV) and the antivirals to treat influenza, followed by
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antiherpetics and to a far lesser extent by antivirals against cytomegalovirus and hepatitis C. The investigated antivirals in WWTPs are discussed per family of drugs,
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which is defined according to the inhibitory spectrum of the drug.
5.1 Antiretrovirals
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Abacavir (ABC) is a powerful nucleoside analogue reverse transcriptase
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inhibitor (NRTI) used to treat HIV. After oral administration, it is rapidly and
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extensively metabolized (83% bioavailability). Data on its occurrence is available only for German (Boulard et al., 2018; Funke et al., 2016; Prasse et al., 2010) and South African WWTPs (Abafe et al., 2018). Prasse et al. (2010) studied abacavir in two WWTP by applying either 24-h composite or grab samples (Prasse et al., 2010). In this study, the removal efficiencies indicated almost complete removal (>99%) in both cases, while the maximum reported concentration was 225 ng L-1 (Prasse et al., 2010). Two more studies in Germany included its main metabolites apart from the parent compund (Boulard et al., 2018; Funke et al., 2016). Funke et al. detected abacavir descyclopropylate (ABC-DES) apart from the parent compound as well as the main metabolite abacavir carboxylate (ABC-CBX). Abacavir was eliminated 17
Journal Pre-proof (removal >99%), probably due to is metabolization to glucuronide-adducts and further metabolization (15%) to ABC-CBX and ABC-DES, which exhibited negative removal rates (Funke et al., 2016). Biodegradation of abacavir is via the oxidation of the hydroxyl moiety to the corresponding carboxylic acid. Autoclaved control experiments show that abacavir is stable under abiotic conditions. Hence all the transformations are attributable to biological reactions. A high degradation rate of ABC was observed (Kbiol =55.8±1.8 L d-1 g SS, t1/2= 0.44 ± 0.003 h). The elevated
oo
f
polarity of carboxy-TPs indicates that powdered activated carbon (PAC) filtration alone is not capable of removing polar compounds. Another European study was
pr
performed by Aminot et al., who detected abacavir in effluents at a maximum
e-
concentration of 33 ng L-1 during two samplings (Aminot et al., 2015). Abafe et al.
Pr
carried out a study in South Africa, which is interesting because it raises the issue of the efficacy of DEWATS (decentralized wastewater treatment system) - a type of
al
facility that is proliferating in peri-urban areas of cities of the future in Africa, in
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comparison with a traditional WWTP. Abacavir was detected neither in influents nor
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in effluents in DEWATS, while in the influents of other WWTPs levels in the thousands of ng L-1. However, high removal rates were observed, since ABC was not detected in effluents. The effluent samples in conventional WWTPs were collected before the step of chlorination to allow the comparison with samples from DEWATS, where no disinfection with chlorination takes place. It is reported that this process leads to the formation of disinfection TPs that are still undescribed (Wood et al., 2016). The most recent study by Boulard et al. detected the parent compound below the limit of quantification in the effluents, while ABC-CBX was detected at a mean concentration of 86 ng L-1 in effluents. (Boulard et al., 2018).
18
Journal Pre-proof Atazanavir (ATV) is a protease inhibitor prescribed for infected adults and children three months of age and older, and is always used in combination with other HIV medicines. It is present in the effluents of WWTPs and Abafe et al. suggest that the hydraulic residence time that is usually only a few hours for wastewaters in the activated sludge system accounts for the accumulation of atazanavir in the effluent of DEWATS and other WWTPs (Abafe et al., 2018). However, the degradation kinetics and breakdown products of ATV should be explored to understand its fate and
oo
f
removal in WWTPs (Abafe et al., 2018). Ferrando-Climent et al. (2016) and Ibanez et al. (2017) also detected ATV during non-target screenings of WWTPs in Norway and
pr
Athens, respectively.
e-
Darunavir is the most recent protease inhibitor used as a component of
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HAART in combination with the pharmacokinetic booster ritonavir (Belkhir et al., 2016). It is 94% excreted via urine, but there is not enough data available to interpret
al
its presence in WWTPs. In two conventional WWTPs in South Africa, it was detected
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at concentrations up to 920 ng L-1 and 350 ng L-1 in the influents and effluents
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respectively, exhibiting negative removal rates. On the contrary, in a DEWAT plant, a very high concentration in the influent (43000 ng L-1) was substsntially decreased in the effluent, exhibiting removal close to 60%, a much better rate than in the conventional WWTPs (Abafe et al., 2018). Efavirenz (EFV) is another NNRT and a constituent of a cocktail prescribed to HIV patients that can be replaced by NVP, in case of unavailability or medical contradiction (Mbuagbaw et al., 2016). This drug is excreted altered or metabolized into several hydroxylated metabolites that can be further glucuronidated before excretion. Faecal excretion rates of EFV range from 16 to 61% and as a result, elevated concentrations are expected in WWTPs. Abafe et al. observed that EFV
19
Journal Pre-proof persisted in the effluents from all the three studied, and accumulates more in conventional WWTPs. According to the authors, this was attributed to the hydraulic residence time for wastewater in the activated sludge system, which does not exceed a few hours (Abafe et al., 2018). Efavirenz was investigated in three more studies in South Africa (K’oreje et al., 2016; Schoeman et al., 2017, 2015). Schoeman et al., 2017 monitored EFV during all the stages of the treatment (anoxic, aerobic, pre- and post-chlorination) over four weeks. Efavirenz concentrations entering the WWTP
oo
f
ranged from 5500 to almost 14 000 ng L -1. The removal of efavirenz by the WWTP ranged between 27 and 71%. Most of the compound was removed the anoxic zone,
pr
while smaller amounts were removed in the aerators. Slight increases in efavirenz
e-
concentrations were found after chlorination of the final effluent. The log Kow value
Pr
for efavirenz indicates the potential to bind to the sludge in the PST. Solids were found to contain efavirenz at concentrations between 17 and 43 mg/kg in dried
al
primary settling tank sludge. The authors propose that adsorption to solids is the
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WWTP.
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primary removal mechanism for efavirenz from wastewater as it passes through the
The concentration levels of EFV indicate that it is a recalcitrant antiviral drug. The anoxic zone in a WWTP is considered a secondary treatment process and is designed to remove nitrogen. During this process, it is more likely that efavirenz is bound to the pulverized material produced during primary treatment. This material remains in the wastewater flow and is later removed in the primary settling tank (Schoeman et al., 2017). Efavirenz and its known metabolite 8,14- dihydroxy-efavirenz was monitored in another study in South Africa, found at low concentrations, but the removal rate was from 33 to 100%, depending on the region (Mosekiemang et al., 2019). Lower
20
Journal Pre-proof concentrations of EFV were reported in Kenya (K’oreje et al., 2012, 2016). In this study, 8,14-dihydroxy-efavirenz was detected at roughly similar concentrations as the parent drug. Generally, concentrations of compounds were higher in raw compared to treated wastewater, in domestic compared to industrial wastewater and dry compared to wet seasons (Mosekiemang et al., 2019). Emtricitabine (FTC) is metabolized to a small extent in the human body (1030%) (Funke et al., 2016). For emtricitabine, the oxidation of thioether moieties to
oo
f
sulfoxides has been observed (Funke et al., 2016). Funke et al. detected FTC in influents of municipal WWTPs at concentrations up to 980 ng L -1. The removal
pr
efficiency of 74% meant that the concentrations in the effluents were much lower.
e-
Biodegradation of emtricitabine broadly follows the same transformation reactions via
Pr
hydroxyl moiety oxidation to the corresponding carboxylic acid. Interestingly, emtricitabine carboxylate (FTC-CBX) and emtricitabine S-oxide (FTC-S-oxide)
al
exhibited negative removal rates. Similar or higher (74%, 100%) removal rates for the
rn
parent compound were also observed by Mosekiemnag et al. Boulard et al. who
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studied FTC, FTC-CBX and FTC-S-oxide in wastewaters effluents found them at moderate to low mean concentrations (<380 ng L -1) (Boulard et al., 2018). Indinavir is a protease inhibitor that is almost always used in combination with at least two other anti-HIV drugs. It is considered as a ‘heavy’ antiretroviral, not recommended for initial therapy because of pill burden and the risk of nephrolithiasis (Tsibris and Hirsch, 2015). Less than 20% of indinavir is excreted unchanged in the urine (Cvetkovic and Goa, 2003). It was monitored both in conventional WWTPs and DEWATS. Slightly lower concentrations were observed in both influents and effluents in DEWATS. However, the removal rates for the two types of treatment
21
Journal Pre-proof plants were comparable (Abafe et al., 2018). In France, indinavir was detected in very low concentrations in effluents (Aminot et al., 2015). Maraviroc is always used in combination with other HIV medicines. To the best of our knowledge, it has been studied only in South Africa, where it was detected in moderate concentrations in the effluents. The high removal efficiency was observed, resulting in its elimination from effluents. Lamivudine (3TC) is a first-line antiretroviral regimen. It has high water
oo
f
solubility (70,000 mg/L), and polarity (log Kow= −2.62). Like emtricitabine, the oxidation of thioether moieties to sulfoxides was observed for lamivudine (Funke et
pr
al., 2016). The drug was detected up to 60680 ng L -1 in influents Kenya, exhibiting
e-
low removals (24-59%). Another study in Kenya revealed a concentration range
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between LOQ–5430 ng L-1. This data is consistent with the consumption figures since the drugs constitute the first line daily dose antiretroviral regimen for people living
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with HIV and under antiretroviral therapy. The same authors conducted another study
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with antiretrovirals, including lamivudine in Finland and reported maximum
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concentrations of 55 ng L-1 in influents and 22 ng L-1 in effluents (Ngumba et al., 2016b). Prasse et al. detected 3TC in German wastewaters at a concentration up to 720 ng L-1, but they calculated an almost complete removal. Similar removal efficiencies were reported by Funke et al. (2016), Abafe et al. (2018) Vergeynst et al. (2015) and Mosekiemang et al. (2019); the latter observed that tertiary stage treatment efficiency was higher in biologically compared to MBR treated waste with subsequent UV-irradiation in the WWTPs studied. Boulard et al. reported a detection frequency of 50% in WWTPs in moderate concentrations. The carboxy metabolite of lamivudine mostly exhibited negative removal rates. It was found at concentrations from 25 ng L 1
in the influents up to 220 ng L-1 in the effluents in Germany (Funke et al., 2016).
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Journal Pre-proof Abafe et al. found residues of lopinavir in the effluents from the WWTPs. Its presence was also reported (Wood et al., 2015) although only data for the effluent were available, making it difficult to make conclusions about the overall behavior of these drugs in WWTPs The nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) is used in combination with other agents in the therapy of HIV, and it is either excreted unchanged (2.7%) or metabolized into several hydroxylated metabolites, which may
oo
f
be further glucuronidated before excretion. The most widely known hydroxylated metabolite is 12-hydroxy-nevirapine (12-OH-NVP). This antiretroviral drug is the
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most investigated drug in many countries (Aminot et al., 2015; K’oreje et al., 2012,
e-
2016; Ngumba et al., 2016b; Prasse et al., 2010), but mainly in South Africa (Abafe et
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al., 2018; Mosekiemang et al., 2019; Ngumba et al., 2016a; Schoeman et al., 2017, 2015). The reported poor removal of nevirapine in WWTPs activated sludge may
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occur due to its photostability and poor biodegradability (Prasse et al., 2010)
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In South Africa, Mosekiemang et al. (2019) reported similar (low)
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concentrations for both the parent drug and 12-OH-NVP, while they implied the possible occurrence of additional metabolites in these analyzed samples. The authors measured similar concentrations in raw and treated wastewater, concluding to removal efficiency close to zero, no matter the existence of a tertiary stage treatment, either biological or with a membrane with subsequent UV-irradiation. The authors also report higher concentrations in the dry season compared to the wet. In the same country, (Abafe et al., 2018) reported that NVP was accumulated in the effluents of all three studied WWTPs. That accumulation in the effluents was attributed to the reduced degradation of nevirapine at an acidic pH used in wastewater treatment. However, the authors discuss the limitation posed by the absence of 24-h composite
23
Journal Pre-proof samples, which make interpreting the results easier. Interestingly, the effluent concentrations from DEWATS and conventional WWTPs were similar. Although a more localized nature characterizes the DEWATS, it removes the compound to the same extent as WWTPs. Schoeman et al. found the mean concentrations of nevirapine in wastewater influent and effluents to be as high as 2100 and 350 ng L -1, respectively (Schoeman et al., 2015) and concludes that chlorination does not affect the removal of NVP. In a more recent study, the same authors found that the concentrations of NVP
oo
f
increase through the various stages of purification in the WWTP (between 92 and 473 ng L-1 in the effluents). This phenomenon is probably the result of the deconjugation
pr
of the hydroxylated metabolites of nevirapine, its recalcitrance and the lack of binding
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of the nevirapine to the primary settling tank (PST) sludge.
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In different WWTPs in Kenya, the levels of NVP in influents and effluents were very similar with those reported by Abafe et al., proving their claims about the
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fate of NVP in WWTPs (K’oreje et al., 2012; Ngumba et al., 2016a; Vergeynst et al.,
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2015a). Prasse et al. reported much lower concentrations, and negative removal rates
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were considered unreasonable, although they did mention that the confidence interval underestimates the real statistical uncertainties of the nevirapine concentrations (Prasse et al., 2010).
Raltegravir is a newly approved by U.S. FDA (2007) integrase inhibitor. It was ubiquitous in DEWATS and WWTPs in South Africa, while it was better removed in conventional WWTPs (80%) (Abafe et al., 2018). Ritonavir is an apolar compound with logKow>4. It is metabolized into several non-glucuronide
derivatives,
of
which
the
primary
metabolite
is
desthiazolylmethyloxycarbonyl ritonavir. It was detected in 54% of the effluent samples analyzed, with a removal rate of 78% in a pilot-scale membrane bioreactor
24
Journal Pre-proof (MBR) installed and operated for one year at a Swiss hospital (Kovalova et al., 2012). Margot et al. measured ritonavir concentration up to 110 ng L -1 in effluents. The removal efficiency when applying conventional WWTP treatment was less than 25%, while ozonation and powdered activated carbon on ultrafiltration (UF) membrane surfaces (PAC-UF) removal efficiency increases by 8% and 56% respectively (Margot et al., 2013). These were the only two studies conducted in Switzerland for antiviral drugs. The highest concentrations for ritonavir were measured in South
oo
f
Africa; Ritonavir was detected in all the studied plants at μg L-1 levels (maximum mean concentration 3200 ng L-1 in the influents), while the removal rate was <50% in
pr
all cases (Abafe et al., 2018).
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The protease inhibitor saquinavir shows high activity against HIV. Scarce data
Pr
are available about its presence in WWTPs. In France, it was found at a maximum concentration of 0.2 ng L-1 (Aminot et al., 2015), while in South Africa it was
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2018).
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detected only in one out of three studied WWTPs, only in the influents (Abafe et al.,
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Stavudine was present in WWTP influents but not detected in WWTP effluents (Prasse et al., 2010). Stavudine is highly removed thanks to activated sludge (>78%) and biological treatment (>89%) (Prasse et al., 2010; Wood et al., 2015). The NRTI zidovudine (ZDV) is predominantly metabolized to its glucuronideadduct (zidovudine-glucuronide-ZDVG) where it is found in human urine along with the parent compound. Mosekiemang et al. studied both the parent compound and the glucuronide in WWTPs in South Africa, but neither of the two was detected. A separate study revealed elevated concentrations in the influents, reaching the μg L-1 scale in all the three studied WWTPs. Removal was 99% both in the conventional WWTPs and DEWATS, which used mostly anaerobic digestion technology in its
25
Journal Pre-proof treatment processes (Abafe et al., 2018). Zidovudine was also detected at several to hundreds of ng L−1 in German wastewaters. The elevated concentration was attributed to the cleavage of glucuronide conjugates, which are excreted by humans (70%), as reported by Prasse et al. (2010). K’oreje et al. in a Kenyan study concluded that ZDV is not only one of the most frequently detected compounds among the studied analytes, but also found at the highest concentrations (μg L-1 scale). However, the removal efficiency was 99% (K’oreje et al., 2016). According to Funke et al., who
oo
f
conducted autoclaved experiments in order to confirm its abiotic stability, the transformation of zidovudine is due to biological reactions. In addition, the
pr
comparison between the rate constants indicated an elimination efficiency of <50%.
e-
This is also partially explained by the formation of unknown TPs as already revealed
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by lab-scale experiments. The unclosed mass balance of ZDV in both lab-scale and full-scale experiments imply the formation of other unknown TPs. Zidovudine widely
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followed the same transformation reactions via hydroxyl moiety oxidation to the
rn
corresponding carboxylic acid (Funke et al., 2016). According to the only study on
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antiviral drugs in Finland published by Ngumba et al. in Finland, ZDV had the highest measured concentration among other pharmaceuticals in both influent and effluent, although they were much lower than what has been reported in other countries. Although the rate of HIV in Finland is low, the presence of ZDV and two more antiretrovirals, namely nevirapine (NVP) and lamivudine (3TC) would suggest that a combination is a first-line antiretroviral regimen that most patients take daily (Ngumba et al., 2016b, 2016a).
5.2 Antivirals against influenza
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Journal Pre-proof Amantadine (AMT) is a M2 ion channel inhibitor with multiple applications, since apart from against influenza, it is also used against hepatitis C as well as it serves as neurological medication in Parkinson’s disease and multiple sclerosis (Suzuki et al., 2003). The compound is excreted almost unchanged in urine (90%). Ghosh et al. explored the presence of AMT in three sewage treatment plants (WWTPs) during the 2008–2009 and 2009–2010 influenza seasons in Japan and the drug was ubiquitous in both sampling seasons (Ghosh et al., 2010b). In raw influents,
oo
f
the levels of AMT were from 184 to 538 ng L -1. During primary treatment, no substantial removal was observed (7–17%). The removal efficiency of amantadine
pr
during primary sedimentation is a result of adsorption to solid particles, which is
e-
related to its logKow (2.44). During secondary biological nutrient treatment (anoxic–
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oxic–anoxic–oxic and anaerobic– anoxic–oxic, the concentration of AMT decreased by 30-40%. Extended-aeration removed only 20% of AMT during secondary
al
treatment. According to the results obtained from all the three WWTPs, the authors
rn
concluded that anoxic–oxic–anoxic–oxic and anaerobic– anoxic–oxic (AOAO)
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process with pure oxygen have shorter sludge retention times and shorter hydraulic retention times compared to the same process using ambient air. The use of pure oxygen is important in enhancing bacterial biomass activity. Also, ozonation removed substantial amounts of AMT (93%) from the secondary effluent. Therefore, AMT can reach almost unchanged through primary and biological secondary treatments, and only tertiary treatment can remove it effectively. This capability proves the powerfulness of ozonation after secondary treatment during an influenza pandemic to restrict the release of antiviral drugs into the environment. Notably, AMT levels differed between the 2008–2009 and 2009–2010 sampling campaigns, but the overall removal efficiencies were in similar. Although AMT has been licensed in Japan since
27
Journal Pre-proof 1998 to treat influenza A, after the introduction of neuraminidase inhibitors, there has been a decrease in its annual consumption. Also, many strains of influenza virus have become resistant; this fact made the US Centers for Disease Control and Prevention to recommend its use only for susceptible virus strains and those resistant to other antiinfluenza drugs (FDA, 2018). Amantadine was studied by Vergeynst et al. in Belgium, where it was detected in all wastewater samples (50 ng L-1 to 1 μg L-1), and a negative removal rate was
oo
f
observed (Vergeynst et al., 2015a), possibly due to its desorption of suspended solids in the influent (logKow=2.44), since its deconjugation is less likely (<3.6% human
pr
excretion as acetyl-amantadine) (Vergeynst et al., 2015a).
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The recently licensed laninamivir octanoate (LANO) is a prodrug
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administered by inhalation, being inactive when taken. It is its pharmacologically active metabolite, laninamivir (LAN) that has the therapeutic effects. Its excretion rate
al
does not exceed 13%. In a recent investigation in Japan, it was detected in the
rn
effluents, at a concentration range from 18 to 21 ng L -1, in parallel with the increase of
al., 2015a).
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influenza incidents, while it was not detected by the end of the outbreak (Azuma et
Oseltamivir phosphate (OS), marketed as Tamiflu ®, is a prodrug of oseltamivir carboxylate (OC). Those substances are suggested by WHO as antiinfluenza inhibitors used for the treatment and prophylaxis of both A and B strains of influenza (Ghosh et al., 2010a). Oseltamivir is converted into its active metabolite (OC) in the human body; it is discharged as a mixture of about 15% OS and about 80% OC, giving an OS/OC ratio of about 0.2 (Azuma et al., 2013). Both compounds are the most studied antiviral drugs (Azuma et al., 2017a, 2014; Burns et al., 2018; Peng et al., 2014; Vergeynst et al., 2015b). The reason is not only because of the
28
Journal Pre-proof frequent outbursts of influenza but also because of the recent increase in OS resistance of the influenza A virus (H1N1). The latter raised concerns about the universal use of Tamiflu ® in pandemics and the potential associated ecotoxicological risks. As shown in Table 1, OS and OC occurred frequently in both influents and effluents in Japan (Azuma et al., 2015a, 2014, 2013; Ghosh et al., 2010a; Takanami et al., 2012) that is the top in per capita consumption of OS (Söderström et al., 2009). Quantifiable concentrations are also reported in Germany (Prasse et al., 2010), China
oo
f
(Peng et al., 2014), the United Kingdom (Singer et al., 2014, 2013), Norway (Leknes et al., 2012), Belgium (Vergeynst et al., 2015a), and in effluents in Sweden (Khan et
pr
al., 2012).
e-
Oseltamivir can be degraded via sorption, biodegradation, and photolysis
Pr
according to both bench-scale and realistic approaches in sewage treatment plants (Peng et al., 2014; Wallensten et al., 2007). The structure (amine and carboxylate
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groups) and physicochemical properties of OS (logP =1.1, water solubility=588
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mg/mL at 25° C) indicate a low potential for the compound to be sorbed in suspended
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solids during treatment (Singer et al., 2007). Therefore, the concentration in the effluent is expected to be low in the solid phase and higher in the liquid phase. In most cases, the concentration of the parent compound was below or close to the limits of quantification. However, in Japan and the UK, elevated concentrations were observed during or after pandemics (Azuma et al., 2014, 2013; Singer et al., 2014, 2013). This is mainly attributed to the fast metabolism of oseltamivir in the human body yielding 70-80% oseltamivir carboxylate. Prasse et al. (2010) calculated the ratio of the parent compound/metabolite as 0.3 in wastewater. In treated wastewater, the ratio was higher but varied for different WWTPs effluents, and hence, no specific claims could be made based on the available data.
29
Journal Pre-proof The removals of OC were moderate to low and showed discrepancies. Ghosh et al. recorded OC in WWTPs influents of between 140–460 ng L-1 (Ghosh et al., 2010b). Primary treatment only removed 2.1–8.5% of OC, conventional WWTPs (primary plus biological secondary treatment) removed <50%, while additional of tertiary treatment by ozonation removed >90%. Ozonation is considered in several studies as an excellent treatment practice for the removal of both OS and OC since there is an evident decrease in their concentrations in ozonation plants (Azuma et al.,
oo
f
2013, 2012; Ghosh et al., 2010a). The length of incubation time also affects the removal of OC. For example, in the presence of activated sludge inoculum, a 40-day
pr
batch incubation resulted in 76% removal of OC in DEWATS. However, this is not
e-
true for WWTPs, where the HRT is in the activated sludge system has been estimated
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approximately 24 h (Abafe et al., 2018; Slater et al., 2010). Peramivir was introduced clinically in 2010, during the influenza prevalence
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season The drug is administered intravenously and exhibits a high excretion rate
rn
(91%) (Azuma et al., 2015a). It has been detected in effluents in Japan, at a
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concentration range from 53 to 64 ng L -1 (Azuma et al., 2015a). Interestingly, according to Azuma et al., peramivir was not detected at the end of October 2013, while its levels then began to increase in December by several ng L-1 synchronously with the increase in the number of influenza patients, peaking at the end of January and in early February 2014. After the end of the outbreak, the drug was no longer detectable. Its maximum concentration in the effluent from WWTPs that used the CAS process followed by chlorination for disinfection 64 ng L -1. At the beginning of the ozone treatment using a batch ozonation reactor, the concentration decreased (4 ng L-1), and after a further 20 min, they were below the detection levels (Azuma et al., 2015a).
30
Journal Pre-proof Another M2 ion channel inhibitor used against influenza is rimantadine (RIM). This antiviral drug is less reported in WWTPs. K’oreje et al. (2016) included RIM in their study in three different WWTPs in Kenya, and it was only detected in the WWTP influents but was below the LOQ (K’oreje et al., 2016). Another study included samples from influents and effluents from two WWTPs in Belgium; a CAS and parallel membrane bioreactor/conventional active sludge plant. Rimantadine was not detected in the CAS, but it was above the LOD in the influents, CAS effluents and
oo
f
total effluents (i.e., after CAS and membrane bioreactor). In the membrane bioreactor effluent, levels of AMT were 2 ng L-1.
pr
Zanamivir (ZAN), also known as Relenza, is used widely to treat and prevent
e-
influenza, both in adults and pediatric patients (over five years old) (Shelton et al.,
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2011). Little is known regarding the fate and occurrence, although Its removal by ozonation after chlorination in WWTPs has been reported (Giri et al., 2010). Its
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occurrence in environmental samples was unknown until recently, probably due to
rn
analytical limitations posed by its highly polar nature (Takanami et al., 2012).
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However, it is extensively studied in Japan, where it is the second most prescribed drug against influenza (Azuma et al., 2015a, 2014, 2013; Takanami et al., 2012). The data on its occurrence in WWTPs (Table 1), as well as the concentrations found in the receiving bodies of the corresponding WWTPs, reveal declining concentrations thanks to wastewater treatment. According to Azuma et al. (2013), the median concentration of ZAN was 4.7 ng L -1 in non-ozonation plants, while in ozonation plants, the drug was not detected. Higher concentrations reported in 2015 (109-110 ng L-1 in effluents) are attributed to the decline in the preventive use of Tamiflu since the beginning of the flu outbreak and a preference towards prescribing zanamivir since H1N1 resistance to Tamiflu was reported (Takanami et al., 2012). In
31
Journal Pre-proof another study, ZAN was not detected during the sampling campaign that took place in October 2013, but began to be detected from December onwards, reaching a peak in early February 2014, coinciding with the influenza outburst. In May, the compound was no longer detectable (Azuma et al., 2015a).
5.3 Antiherpetics Acyclovir is widely used for antiherpetic medication, and it is excreted mainly
oo
f
as the unchanged parent compound, while acyclovir carboxylate (ACV-CBX) is its main metabolite occurs after the oxidation of the primary hydroxyl group in ACV and
pr
is shown to be recalcitrant (Sinha et al., 2007). Data on their environmental
e-
monitoring is largely available comparing to other antivirals. This may be attributed
Pr
to the fact that acyclovir is an antiviral drug covering a broad spectrum of viral infections; namely, cold sores around the mouth -caused by herpes simplex, shingles-
al
caused by herpes zoster), and chickenpox, as well as to treat outbreaks of genital
rn
herpes. For individuals with frequent outbreaks, it may reduce the number of future
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episodes (Cunningham et al., 2012). Also, the vast majority of published articles regarding WWTPs located in Germany (Boulard et al., 2018; Funke et al., 2016; Prasse et al., 2011, 2010; Seitz and Winzenbacher, 2017), while only three studies investigate the occurrence of ACV (but not ACV-CBX) in Japan (Azuma et al., 2019), China (Peng et al., 2014), and in the USA (Bear et al., 2017). Acyclovir was readily removed (>80%) both in urban WWTPs in Germany (Seitz and
Winzenbacher, 2017), probably due to the almost
complete
biotransformation of the drug during the activated sludge process. In the same study, the highest median observed concentration for ACV-CBX was 4800 ng L-1 in raw wastewater, and 5800 ng L-1 in the effluents (Seitz and Winzenbacher, 2017). Prasse
32
Journal Pre-proof et al. detected acyclovir at concentrations up to 1800 ng L -1 in influents and observed that it was nearly eliminated in effluents, after analyzing 24-h samples (Prasse et al., 2010). In general, it is reported that the removal of acyclovir in conventional WWTPs is high (>95%). However, it is not known if it is partially transformed or mineralized (Prasse et al., 2011). Acyclovir is rapidly dissipated in the activated sludge system (t1/2=5.3 h, and has a first-order rate constant about the amount of suspended solids (SS), 4.9 s-1) (Prasse et al., 2011). High concentrations of ACV and ACV-CBX were
oo
f
also reported by (Funke et al., 2016). However, while 91% of ACV was removed the metabolite removal rate was negative. The concentrations of ACV-CBX should not be
pr
neglected since it is reported that it exhibits increased toxicity towards Daphnia
e-
magna (Schlüter-Vorberg et al., 2015). In China, acyclovir was ubiquitously detected
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with levels of 238 ± 56 (177–406) and 154 ± 24 (114–205) ng L−1 in the influent and final effluent samples, respectively. Aerobic biodegradation appeared to be the main
al
elimination process for acyclovir in the wastewater (Peng et al., 2014). In wastewater,
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acyclovir is found in the aqueous with more than 99% of the acyclovir present in the
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filtrates of the wastewater samples (Peng et al., 2014). The concentration of ACV decreases slightly in the anaerobic and anoxic effluents. In the secondary effluent, after clarification, the concentration was even lower, chlorination had no significant effect on the levels of acyclovir. However, variations in the transformation rate of acyclovir may occur, because of different treatment techniques, different HRT/SRT, and microbial consortia in the WWTPs (Peng et al., 2014). Sampling may also contribute to introducing bias in the estimation of the HRT when it is not possible to adopt composite samplings. Thus the influent and effluents collected during the same period are not the same wastewater package. In addition, the transformation of the parent compound to ACV-CBX to is also possible. This carboxy- TP is found to be
33
Journal Pre-proof highly recalcitrant to further microbial degradation, resulting its occurrence in surface waters, groundwater even in finished drinking water (Prasse and Ternes, 2016). Under typical treatment conditions (pH 7–8 and ozone content of dissolved organic carbon of 0.4), rapid ozonation of acyclovir and carboxy-acyclovir has been reported (Prasse et al., 2011). Finally, in a study on the occurrence of several pharmaceuticals in a scale unit process open-water treatment wetland, revealed modest removal (70%) of acyclovir by photolysis and biotransformation in the open-water cells when the
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hydraulic residence time for cell 2 was increased to four days (Bear et al., 2017). Famciclovir (FCV) is a guanine analogue used to treat herpes virus infections.
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It is most commonly used to treat herpes zoster (shingles), and it is a prodrug of
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penciclovir (PCV) with higher oral bioavailability. Azuma et al. studied both drugs
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and detected FCV only in a hospital effluent, indicating the importance to established advanced treatment in hospital WWTPs (Azuma et al., 2019). Results from the 24 h
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composite samples collected from another WWTP show that penciclovir is almost
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completely removed (>94%). Similar removal rates (>87%) were calculated for other
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WWTPs, although only grab samples were taken (Prasse et al., 2010). Valacyclovir has been detected at mean concentrations of 11 and 8 ng L -1 in influents in Japan, exhibiting excellent removal rate, since it was no longer detected in the effluents (Azuma et al., 2019).
5.4 Antivirals against Cytomegalovirus Ganciclovir is a thymidine kinase inhibitor and is one of the most frequently administered nucleoside agents used for the treatment of viral infections of the respiratory tract, apart from herpes virus. It is indicated for the treatment of lifethreatening or vision-threatening CMV infections in immunosuppressed patients
34
Journal Pre-proof (Razonable, 2011). It is poorly metabolized in the human body, and regarding its biodegradation, it is transformed via hydroxyl moiety oxidation to the corresponding carboxylic acid (Funke et al., 2016). Its occurrence in WWTPs is far less documented. In China, ganciclovir was below the quantification limits in both the influent and effluents (Peng et al., 2014). Funke et al., who studied its fate and occurrence in Germany, observed relatively low concentrations in WWTPs with a removal rate of
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>99% (Funke et al., 2016).
5.5 Antivirals against hepatitis C
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Ribavirin is a nucleoside agent that is used to treat encephalitis B and
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hepatitis. Since 2015 ribavirin is typically used as an adjunct therapy to various first-
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line and second-line combination therapies recommended for each genotype. It has been studied in WWTPs in Germany (Prasse et al., 2010) and China (Peng et al.,
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2014), but in non-quantifiable levels. However, it is reported that this drug is one of
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the most frequently administered are nucleoside agents in China.
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Figure 4 (a) and (b) is a Box-Whisker plot summarizing the quantifiable concentrations of antivirals in influents and effluents, respectively. In total, 28 parent compounds and 12 metabolites were investigated in WWTPs. As shown in Fig. 4, 34 and 32 out of the 40 investigated antivirals have been quantified in influents and effluents respectively. The maximum observed concentrations were for darunavir. ritonavir and efavirenz in the influents, while the minimum ones were for the metabolites 12-OHnevirapine and 8,14-dihydroxy efavirenz, and the parent compound rimantadine. For the effluents, important discrepancies exist, since removal is a multi-factorial process, hence it is difficult to claim that ere is a specific pattern. Hoever, efavirenz, darunavir
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Journal Pre-proof and emtricitabine were found at relatively high concnetrations. In addition, according to our survey, antiviral drugs in hospital wastewaters are higher than in urban ones.The concentration levels of antiviral drugs in influents and effluents of WWTPs ranged from the low ng L-1 to μg L-1, and their removal ranged from 100% to negative rates. The recorded occasions of negative removal rates imply not only insufficient removal but also the release of the parent compound from conjugates or glucuronides during the treatment process. Spatial discrepancies both in the occurrence and
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removal rates are observed, due to the different therapeutical needs as well as the different treatment systems in the corresponding regions.
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Regarding the spatial distribution of available data for antiviral drugs, it seems
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that Japan is not only the leading country in terms of antiviral drug consumption and
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especially that of anti-influenza drugs, but also that a lot of investigation has been conducted for this therapeutic family. The high levels found in African wastewaters
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are partially attributed to factors such as the large percentage of population infected
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from HIV, as well as the lack of advanced wastewater treatment methods.
6. Occurrence in surface waters Determining the presence and concentrations of antiviral drugs in surface waters is important for risk assessment of these compounds in aquatic ecosystems especially in systems receiving wastewater effluents. In total, 25 antiviral drugs (parent compounds) and six metabolites have been found in surface waters (river, lake and dam) from eleven countries belonging to Asia, Europe and Africa, during different sampling seasons. Most of the available literature focuses on pandemic events or countries with high antiviral drug consumption, such as Japan, South Africa and Kenya, according to selected data. The occurrence data, including the average, 36
Journal Pre-proof maximum and minimum quantified concentration (ng L -1), depending on availability, are presented in Table 2.
6.1 Antiretrovirals Abacavir has been detected at very low concentrations in surface waters around Hessian Ried, in Germany, at a maximum concentration of 1.4 ng L -1 (Prasse et al., 2010). In two other studies in the same country, abacavir was either below the
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quantification limit in various sampling stations (Funke et al., 2016) or at an average concentration <5 ng L-1, in the River Rhine (Boulard et al., 2018). Aminot et al.
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detected abacavir in France, both in the river and estuarine waters and reported
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maximum mean concentrations from two sampling campaigns at 2.6 and 2.3 ng L -1,
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respectively (Aminot et al., 2016, 2015). In South Africa, abacavir was not quantified in surface waters (Wood et al., 2015). Boulard et al. also included abacavir
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carboxylate that is estimated to be formed in proportions of 15% (Funke et al., 2016)
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in their study of the river Rhine, which was detected at a mean concentration below 5
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ng L-1. Its poor removal during bank and sand filtration is attributed to its high biological stability and it comprise a source of contamination for groundwater and drinking water originating from these sources. This widely studied antiviral is claimed to be substantially removed during wastewater treatment (Prasse et al., 2010), a fact that explains the low concentrations in surface waters are predicted. Darunavir was investigated in Poland, and it was detected in river waters at a concentration of 72.7 ng L-1 (Giebułtowicz and Nałecz-Jawecki, 2016). For this drug, it is reported that concentrations increase downstream inside WWTPs, before the effluent mixes with with water; after mixing, the concentration can be decreased
37
Journal Pre-proof (Giebułtowicz et al., 2018). This implies a sufficient persistence for the drug to bypass the treatment process and occur in surface water. Dididanosine that can be excreted as largely unchanged parent compound was investigated by Wood et al. at many sampling points in South Africa but was quantified only in dam water (54 ng L-1) (Wood et al., 2015). In the same study, another more widely used antiretroviral, efavirenz, was also detected but not quantified. On the contrary, Rimayi et al. and Wooding et al. report maximum
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detected concentrations of efavirenz of 303 and 148 ng L -1 in dam water, respectively, and 354 ng L-1 in the river (Rimayi et al., 2018; Wooding et al., 2017). Slightly higher
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results were found in Kisumu, Kenya (560 ng L-1) (K’oreje et al., 2016).
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The poorly metabolized in the human body emtricitabine was detected in
1
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uMngeni and Juskei Rivers in South Africa, with average concentrations of 8-13 ng L(Rimayi et al., 2018). Boulard et al. investigated its occurrence along with its
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metabolites emtricitabine carboxylate and emtricitabine S-oxide in the River Rhine
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(Germany) and reported maximum concentrations of 45, 110 and 200 ng L-1, proving
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the fast metabolization of the parent drug (Boulard et al., 2018). Emtricitabine carboxylate was also included in a study of Funke et al. who when analyzing various surface waters in Germany reports concentrations of 25 to 280 ng L-1 (Funke et al., 2016).
Lamivudine, which has a low metabolism rate in the human body, is one of the most investigated antiviral drugs in the environment along with oseltamivir and nevirapine, according to our literature survey. It has been detected in Japan (Azuma et al., 2016), France (Aminot et al., 2015), Kenya (K’oreje et al., 2012, 2016), Germany (Boulard et al., 2018; Prasse et al., 2010), South Africa (Wood et al., 2015), and Finland (Ngumba et al., 2016b). However, it is difficult to conclude about its
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Journal Pre-proof behaviour, given the discrepancies in its concentration. In France, Germany and Japan it has been detected at the very low ng L -1 scale, but in Kenya, was detected in mg L -1 levels (0. 67 mg L-1 in Kisumu) (K’oreje et al., 2016). Such levels in river water is a result of inefficient wastewater treatment. Its carboxy- metabolite has been detected in rivers and streams in Germany, at concentrations varying from 16-230 ng L-1 (Funke et al., 2016). Lopinavir was detected in South Africa at an average concentration of 239 ng
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L-1 (Wood et al., 2015), but no other studies included it. Limited to the one study is also the investigation of nelfinavir, which was not detected in France (Aminot et al.,
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2015).
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Nevirapine, which is also used to prevent mother to child spread during birth,
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is among the most studied antiretrovirals, and its concentrations varies depending on the country. It is observed that nevirapine exhibits a desorptive preference as the raw
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effluent enters into water bodies, so it is diluted by environmental water (Bagnis et al.,
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2018). In Germany and France, it is detected in low levels (Aminot et al., 2016;
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Prasse et al., 2010). In three different studies in South Africa, no pattern was observed. Rimayi et al. reported 68 ng L-1 in the estuaries of the uMnegeni River during winter and is similar average concentrations during all seasons in dam water in the Hartbeespoort catchment and Juskei River (Rimayi et al., 2018). Much higher concentrations were found by Wooding et al., and Wood et al., reaching in the second case 1480 ng L-1 (Wood et al., 2015; Wooding et al., 2017). Interestingly, in Kenya, concentrations were in the thousands of ng L -1 level in the Nairobi River Basin as well as in Kisumu (K’oreje et al., 2016; Ngumba et al., 2016a). Nevirapine was not detected in Lake Päijänne, Finland, in one of the few studies of lake waters (Ngumba et al., 2016b). It is a low water soluble (0.1 mg mL -1) and higly lipophilic drug (log
39
Journal Pre-proof p=3.89), exhibiting weak basic character and ionization (pKa=2.8). Despite its relevant environmental occurrence, the environmental fate and behavior of nevirapine has not been studied extensively in the literature, hence insufficient data are available to explain if its occurrence is consitstent with the known phsyichemical properties Ritonavir was not quantified in South Africa (Wood et al., 2015), while in French rivers and estuarine waters it occurred at maximum concentration of 12 and 0.5 ng L-1, respectively (Aminot et al., 2016, 2015). Between 5 and 40% of ritonavir
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has been found to adsorb on suspended solids in a river system (Aminot et al., 2015). Ritonavir is hydrophobic, and in hot seasonal conditions, it has been found to partition
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onto solid particulate matter, explaining its low levels in aquatic bodies. Its half-life
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under biochemical conditions in the surface water is <5 days (Aminot et al., 2015).
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Saquinavir did not occur in French estuarine waters, investigated by Aminot et al. (2015), which is attributed to the fact that saquinavir and its metabolites are
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eliminated from the body primarily through the biliary system and feces (more than
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(Patrick, 2002).
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95% of the drug), with minimal urinary excretion (less than 3% of administered drug)
The metabolic fate of stavudine has not been elucidated in humans. Hence it is difficult to comment on its occurrence, which can be explained only on a treatment basis. Besides, it was detected at a maximum concentration of 440 and 778 ng L -1 in Kenya and South Africa, respectively (K’oreje et al., 2012; Wood et al., 2015). The expectation that tenofovir could potentially reach surface water is high, given its extensive and rapid excretion as unchanged compound in the urine (Al-Rajab et al., 2010). Indeed, Wood et al. note concentrations up to 243 ng L-1 in South Africa. Tenofovir is also persistent in soils with no evidence of transformation products or microbial based degradation (Al-Rajab et al., 2010).
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Journal Pre-proof Zalcitabine, whose metabolic fate has not been thoroughly evaluated in humans, undergoes minimal hepatic metabolism to dideoxyuridine, and less than 10% of an administered dose is excreted in feces. Its average concentration in South African surface waters was 36 ng L-1 (Wood et al., 2015). Zidovudine (AZT) exhibits high bioavailability (50–75%) and limited removal in biological treatment (Kumar et al., 2015). Extremely high concentrations (high μg L-1) have been observed in Kenya both by Ngumba et al. (2016a) and K’Oreje et al.
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(2016), and in South Africa (973 ng L-1) (Wood et al., 2015), while lower concentrations have been reported in Germany (Funke et al., 2016; Prasse et al.,
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6.2 Antivirals against influenza
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2010). Its environmental fate and behavior has not been discussed in detail yet.
Amantadine was detected at a mean concentration of 14 ng L -1 in Japan
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(Azuma et al., 2013) and more recently from 5-61 ng L-1 (Azuma et al., 2017a),
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exhibiting non-synchronization discrepancy with the number of influenza patients. In
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China, in the Yangtze River Delta, the highest median concentration was 351 ng L-1, with a maximum value of 10.29 μg L-1(Peng et al., 2018). No ecotoxicological data is available; thus, more research is necessary for a better understanding of the risks posed by this compound in the environment. Oseltamivir and oseltamivir carboxylate concentrations varied significantly in surface waters, not only depending on the region but also the sampling period, since a lot of them took place after influenza pandemics or outbursts, as indicated in Table 2. As discussed before, the prodrug is readily absorbed and has high oral bioavailability (Achenbach and Bowen, 2013), and after extensive metabolization in the liver is excreted as oseltamivir carboxylate (Ghosh et al., 2010a), explaining the higher
41
Journal Pre-proof concentrations reported for this metabolite. Proposed calculations based on hydrologic modeling suggest that OC may remain in the environment for up to 18 days at levels of <300 to 32,000 ng L-1 during a pandemic (Achenbach and Bowen, 2013). Indicatively, concentrations were ≤864.8 ng L -1 in Japan, where several studies were conducted (Azuma et al., 2013; Ghosh et al., 2010a; Takanami et al., 2012, 2011). In the River Thames and River Wye (UK) the maximum concentrations were 193 and 6 ng L-1 in a study exploring the intra- and interpandemic variations of
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the metabolite (Singer et al., 2014). In Ebro river in Spain, Gonçalves et al. found concentrations of 50-100 ng L-1 (Goncalves et al., 2011), while in Germany and
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Sweden, concentrations did not exceed 2.4 ng L -1 (Khan et al., 2012; Prasse et al.,
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2010). In Europe, oseltamivir was not detected at levels above 15 ng L -1 (Burns et al.,
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2018; Prasse et al., 2010). In Japan, the maximum concentration was 58 ng L -1, in Yodo River (Söderström et al., 2009). Specifically, in rivers, small amounts of
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sediment may favor the degradation of OS, since microbial degradation is promoted.
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Yet, it needs several weeks to be completed (Bartels and von Tümpling, 2008). The
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low sorption affinity of OC for sediments explains its poor degradation. In addition, OC is not susceptible to direct photolysis and has a half-life in the ufiltered river water of 427 h (Bartels and von Tümpling, 2008). As a result, OC is expected to persist in water so that during influenza pandemics, a vast reduction of OC in WWTPs is necessary. It is reported that OC is unlikely to endanger aquatic organisms or to have a significant impact on the growth of aquatic flora and fauna through effects on neuraminidase in surface waters (Ghosh et al., 2010b). However, limited data means that an assessment of the long-term effects of this drug in the aquatic environment is not possible. The reported half-life of oseltamivir ranges from 15 to 150 days during photodegradation in surface water under natural solar irradiation,
42
Journal Pre-proof whereas under simulated solar irradiation, the half-lives of oseltamivir carboxylate were 48 h in pure water and 12 h in surface water (Goncalves et al., 2011). Zanamivir is among the most prescribed antiviral drug globally, and the second widespread antiviral in Japan, where it occurs in various concentrations up to 89 ng L-1 in rivers (Azuma et al., 2017a). This concentration was reported in winter, in parallel with an increase of the influenza patients, while in the other sampling
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seasons, the drug was not detected (Azuma et al., 2017a).
6.3 Antiherpetics
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Acyclovir has been frequently quantified in surface waters (Azuma et al.,
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2019; Boulard et al., 2018; Peng et al., 2014; Prasse et al., 2010). The highest
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concentration has been reported by Prasse et al. (2010) in the Hessian Ried region in Germany, while the same study revealed its lower concentration in the tributaries of
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River Ruhr (20 ng L-1). Equally high concentrations (114 ng L -1) mentioned by Peng
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et al. (2014) in Pearl River Delta, China. In a recent investigation of Boulard et al.
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(2018), acyclovir was found to be 70 ng L -1 in the River Rhine, in Koblenz region (Germany) (Boulard et al., 2018). An average concentration of 10 ng L -1 was reported by Azuma et al. (2019) in Yodo River, Japan (Azuma et al., 2019). In a study by K’oreje et al. in Kenyan waters, acyclovir did not contribute at all to the load of antiviral drugs in the aquatic bodies (K’oreje et al., 2012). Recently, acyclovir was detected but not quantified in the Nau and Danube Rivers in Germany by Seitz et al. (2017) (Seitz and Winzenbacher, 2017). The same research group also studied the main biotransformation product and active metabolite of acyclovir, carboxy-acyclovir, and report average concentrations of 100 and 70 ng L -1, respectively. The same metabolite was detected (58-750 ng L-1) in various German rivers and streams by
43
Journal Pre-proof Funke et al. (2016). Valacyclovir, a prodrug of acyclovir, is indicated for the prophylaxis of CMV infection and disease following solid organ transplantation. Azuma et al. (2019) reported a mean valacyclovir concentration of 1 ng L -1 in the Yodo River, Japan (Azuma et al., 2019). Penciclovir is the active metabolite of the oral product famciclovir, which is eliminated principally by the kidneys as penciclovir and other metabolites. It is mainly used to treat infections from herpes simplex virus, and as indicated in Table 2,
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it has been detected at low concentrations (Azuma et al., 2019; Prasse et al., 2010),
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6.4 Antiviral against cytomegalovirus
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with a maximum of 11 ng L-1 in Japan (Yodo River) (Azuma et al., 2015a).
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The poorly metabolized in humans was detected in high concentrations in landfill leachates close to Pearl River (China) (418–1131 ng L-1, with a mean
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concentration of 794 ng L-1). However, it was not detected in neither the river delta
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nor in well water near the municipal landfills (Peng et al., 2014).
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Finally, the occurrence of antiviral drugs is higly depended on geographic, seasonal, and social data. Typical examples are the spatial distribution of influenza pandemics, the different therapeutic needs, the standard of living in developing countries that suffer from viral illnesses (e.g. HIV). According to the results, it can be concluded that Japan is a pioneer in the study of the antiviral drug occurrence in the environment and it also prescribes more than 80% of the globally available Tamiflu® to treat common seasonal influenza (Sugaya et al., 2007). The most frequently detected antivirals were oseltamivir carboxylate and lamivudine. It is evident that among surface waters, rivers are usually acceptors of antiviral drugs. In addition, it derives from the findings that several
44
Journal Pre-proof African water bodies suffer from proper drinking water scarcity, or non-organized sanitary systems for bath end excretion, while the absence of rainfalls that hinders dilution in surface waters poses an extra factor that deteriorates the water quality. It is difficult to observe a specific pattern in the occurrence of antiviral drugs in surface waters since significant discrepancies are observed even within the same country. This is highly related to the sampling season, the existence or not of a pandemic event or an outburst, the environmental conditions and the prescription
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potential in each country. The latter affects the antiviral drug load entering the
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7. Occurrence in groundwaters
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influents, which is accordingly treated before being discharged in surface waters.
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Groundwaters can be receivers of the contaminated surface water through natural and artificial exchanges (Charuaud et al., 2019). Antiviral drugs exhibit
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relatively high biological stability; hence they may show insufficient removal during
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bank filtration and sand filtration, and thus be present in groundwater, especially close
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to municipal wastewaters (Dévier et al., 2013). Data about the occurrence of antiviral drugs in groundwaters are limited compared to those in WWTPs and surface waters. However, they should not be underestimated since they indicate the extent of the emerging concern as well as the potential of such compounds to contaminate the drinking water, especially in regions with obsolete or where drinking water systems have not been upgraded. The fact that antiviral drugs are not studied to a great extent implies a bias on the estimations. The occurrence of antiviral drugs in groundwaters worldwide is summarized in Table 3. Detailed information for the behavior of each antiviral drug has already been given, and hence, the most imprortant results deriving from Table 3 are discussed herein. 45
Journal Pre-proof Among antiretrovirals, abacavir, its active metabolite abacavir carboxylate, as well as acyclovir were detected below the quantification limit Germany (Boulard et al., 2018). Abacavir was neither quantified in South Africa, in a study by Swanepoel et al. In the same study, didanosine and efavirenz were also below the quantification limit. However, efavirenz was detected in sampling campaigns conducted in South Africa, especially in Hartbeespoort Dam catchment and Gauteng Province, at a concentration range from 2 to 71 ng L -1 (Rimayi et al., 2018). Boulard et al.
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investigated the occurrence of emtricitabine, emtricitabine carboxylate and emtricitabine S-oxide in the groundwaters of Koblenz in Germany, and revealed
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maximum concentrations of 3.9, 370 and 23 ng L -1 (Boulard et al., 2018). Notably, the
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carboxy metabolite was detected in relatively high levels with an average
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concentration of 140 ng L-1. Lamivudine was found at a concentration of 25.2 ng L -1 during the only study concerning antivirals in groundwaters in the USA (Fisher et al.,
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2016). Nevirapine was detected at a wide concentrations range of 4.9-1600 ng L-1
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(Fisher et al., 2016; Rimayi et al., 2018; Swanepoel et al., 2015). The maximum
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concentration of 1600 ng L-1 was reached in Kisumu, Kenya (K’oreje et al., 2016). Stavudine was detected at a concentration of 0.9 ng L-1 by Swanepoel et al. (2015) in South Africa.
8. Occurrence in drinking water Since antiviral drugs may be present in groundwater, drinking water deriving from ground sources can be contaminated as well. Treatment methods for drinking waters are part of tertiary treatment which is practiced when the intended receiving water is very prone to the effects of pollution. These purification methods can be conventional or advanced. The conventional treatment is mostly applied in small and 46
Journal Pre-proof medium-sized facilities, and it can be achieved by chemical coagulation, filtration, sedimentation, and adsorption on activated carbon, being less sufficient to remove emerging contaminants such as antivirals. More advanced treatment techniques include membrane filtration (i.e. reverse osmosis, nano-filtration) and additional disinfection with chlorination, ozonation, UV, etc (Simazaki et al., 2015). The analysis of antiviral drugs in drinking water is rarely reported and concern samples from South Africa (Swanepoel et al., 2015; Wood et al., 2015), France
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(Dévier et al., 2013), Germany (Boulard et al., 2018; Funke et al., 2016), Poland (Giebułtowicz et al., 2018), Japan (Simazaki et al., 2015), and USA (one sample)
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(Furlong et al., 2017) In total, nineteen parent compounds and five metabolites of
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antiviral drugs were investigated, while quantification was feasible in very few
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samples (at the low ng L-1scale). Regular monitoring programs to test drinking water for pharmaceuticals are not yet implemented. The ultra-trace level (even sub-ng L-1)
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that antivirals are expected in drinking water, the analytical difficulties in quantifying
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them and the absence of defined regulatory limits are the main limitations and reasons
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for the availability of data (Dévier et al., 2013). In particular, finished drinking water in Germany contained traces of lamivudine, emtricitabine, emtricitabine carboxylate, emtricitabine S-oxide, abacavir, abacavir carboxylate and acyclovir (Boulard et al., 2018). A study by Funke et al. reported the carboxy- transformation products of acyclovir, emtricitabine and lamivudine were quantified at a maximum concentration of 41, 80 and 85 ng L -1, respectively in drinking water originated from groundwater and surface water subjected to different treatments, (ozonation, activated carbon filtration). Darunavir was recently detected in tap water in Poland, at a maximum concentration of 169 ng L-1 (Giebułtowicz et al., 2018). In another study of Wood et al. (Wood et al., 2015),
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Journal Pre-proof lopinavir, nevirapine, ritonavir, zalcitabine and zidovudine were found in tap water originating from the Hartbeespoort Dam, but only zalcitabine and zidovudine were quantified (8.4 and 72.7 ng L-1, respectively). In this the case, it should be taken into consideration that the method detection limits were relatively high (approximately 100 ng L-1 or higher), implying that the non- quantified concentrations may be not negligible. Swanepoel et al. with their report to the Water Research Commission underline the significance of the occurrence of antiviral drugs in South Africa’s tap
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water (Swanepoel et al., 2015). In this report, 31 municipal tap water samples had been analyzed to check for the presence of HIV antiretroviral drugs prescribed in
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Africa. Out of the eleven studied antiretrovirals, nevirapine was quantified in five
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samples (0.3 to 3.5 ng L-1) followed by didanosine (0.4-3 ng L-1), while lamivudine,
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tenofovir, efavirenz, lopinavir, and saquinavir were not quantifiable. In France, Devier et al. investigated the presence of antiviral drugs in mineral water stotred in
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PET and glass bottles (Dévier et al., 2013). Unsurprisingly, none of the nine target
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antiviral drugs was detected. The results are logical, given that the samples of natural where
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mineral water are collected from areas of low anthropogenic pressure,
submission to filtration and geo-epuratation during the relatively long transit time within the aquifers is also possible (Dévier et al., 2013). Lamivudine was detected in 25% of the source-treated water samples collected during joint research of the U.S. Environmental Protection Agency (USEPA) and the U.S. Geological Survey (USGS). In this case, the water was treated in a frequently renewed, deep bed depth, activated carbon treatment (Furlong et al., 2017). Oseltamivir occurred in the finished water of a drinking water treatment plant in Japan at a concentration of 38 ng L-1, exhibiting removal efficiency to be as high as 60-88% in the course of purification with ozonation and granular activated carbon filtration. On the contrary, in the absence of
48
Journal Pre-proof ozonation and granular activated carbon filtration, the removal efficiency was zero (Simazaki et al., 2015). According to the above-mentioned data, the removal efficiency of antivirals during drinking water treatment is satisfactory, since in most cases the occurring concentrations are below or close to the quantification limits. Most of the residual antivirals are removed to a great extent during advanced water treatment processes, while their persistence is more possible during the conventional ones. Also, carboxy-
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TPs are present in the drinking water at concentrations varying from the ultra-low ng L-1 scale to approximately one hundred ng L-1. This is an evidence for the stability of
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TPs in the environment and it further confirms the expected lowerremoval during
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filtration as a conventional purification method, while ozonation and/or addition of
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activated carbon for filtration enhances their removal (Funke et al., 2016). However, if a compound is detected in the finished water at a higher concentration than in the
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sources, there is probably a deviation between the actual and estimated HRT. This
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means that the same plug of water may not be captured well at several drinking water
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treatment plants. In addition, the cleavage of conjugated pharmaceuticals during water purification could increase the concentrations of original substances. Finally, antivirals may be unintentionally consumed through final drinking water, and the impact of such human ingestion even at race levels may exert changes to the homeostatic mechanisms in the human body (Simazaki et al., 2015).
9. Ecotoxicity of antiviral drugs for non-target organisms A study of Sanderson et. al (2004) using (Q)SAR modeling of almost 3000 different compounds proved that antivirals are potentially hazardous and toxic mainly towards biota, such as crustaceans, fish and algae (Sanderson et al., 2004). However, 49
Journal Pre-proof their potential ecotoxicity and subsequent antiviral resistance are yet underexplored. Moreover, the potential synergistic interactions between antivirals leading to unexpected adverse effects to humans and other organisms should be considered. These implications underline the need to comprehend the toxicity during the life cycle instead of investigating extensively the acute toxicity. Herein, indicative information on the antivirals with the most relevant environmental concentrations are provided. Several studies are devoted to the ecotoxicity of antiviral drugs against non-
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target organisms, but antiviral drugs to treat influenza are on the spotlight, especially during pandemic incidents. Oseltamivir and oseltamivir carboxylate have attracted
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most of researchers’ interest (Escher et al., 2010; Hutchinson et al., 2009; Singer et
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al., 2011; Straub, 2009), due to their widespread consumption and proved
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environmental occurrence. Mestankova et al. (2012), who studied both compounds, stated that the chronic non-observed concentrations (NOEC) for algae, daphnia and
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fish are high (>1 mg L-1) (Mestankova et al., 2012). This claim is also confirmed by
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an older study for (sub)chronic NOEC found to be higher than 1 mg L -1 as well
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(Hutchinson et al., 2009). Escher et al. (2010) studied the toxic action to non-target organisms posed by both the individual compounds and their mixture. For the parent compound, the The EC50 value in a 30-min bioluminescence inhibition test with V. fischeri was close to 10.5mM, corrsponding to apporximately an EC50 value of 4.3 g L-1. In the algal toxicity with D. subspicatus, the photosynthesis inhibition after 24 h gave an EC50 of 15.5mM, which corresponds to 6.4 g L-1. Although high, these EC50 values are in good accordance with the low hydrophobicity of the compound. The additional insight into the mode of mixture interactions revealed that in V. fischeri both compounds were toxicants with the mixture effects to be close to concentration addition, while in green algae only the prodrug oseltamivir was a baseline toxicant
50
Journal Pre-proof (Escher et al., 2010). Given the widespread consumption of Tamiflu, it is urgent to study the ecotoxicological risks posed by its pharmaceutically active ingredients both in activated sludge and the receiving waters. Rare ecotoxicological data was found in open literature for the widely used anti-influenza drug amantadine. A general claim is that its effects are negligible even during periods large-scale influenza pandemics, while only concentrations above 1 mg/L can exert acute and chronic toxic effects occur (Azuma et al., 2015b). However,
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the evolution of ecotoxicity for this in three different trophic levels, namely in phosphoreum, S. capricornutum and D. magna, showed that phosphoreum (15 min),
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S. capricornutum (72 h) and D. magna (48 h) were found to be inhibited by 12.6, 8.9
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and 56.0 % for 0.1 mM 1-amantadine. In the same study, rimantadine (0.1mM) was
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investigated and the inhibition was 15.4,8.9 and 46.0% for 0.1 mM rimantadine exposure for the three trophic levels, respectively.
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Regarding the ecotoxicity of antiretrovirals, data are sparsely available, but the
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findings are remarkable. According to available data for freshwaters, abacavir has an
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EC50 value of 57 mg L-1, being harmful to green algae. On the other hand, the value of this marker is higher (100 mg L-1) for diatoms and crustaceans (Minguez et al., 2016). However, since algae are the primary “producer” in an aquatic ecosystem, these results are rather inauspicious. In a reproduction test with D. Magna for abacavir (21 days), no mortality was observed, since the population growth rate of D. magna exposed to a concentration of 92.1 mg L −1 did not differ from the medium control (Schlüter-Vorberg et al., 2015). Efavirenz is hazardous in the environment, as it is persistent and toxic to aquatic life. According to Robson et al. (2017), the exposure (96 h) of fish (O. mossambicus) to efavirenz at a concentration of 20.6 ng L 1
provoked liver damage, as well as higher total fish deaths comparing to the control
51
Journal Pre-proof sample (Robson et al., 2017). Emtricitabine exhibited negligible ecotoxicity risk for three trophic levels (algae, daphnia, and fish), since the median measurements for the risk quotient (RQ) were 0, and the used PNEC was in the high μg L-1 scale (7927.3, 332.1, and 47662.1, for the previoysly mentioned organisms, respectively) (Ngumba et al., 2016a). No data are available for the parent compound of lamivudine, which is not biodegradable. Nevirapine had also potential ecotoxicological effects on algae, daphnia and fish with algae being the most affected (RQ=29.1) (Ngumba et al.,
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2016a). Zidovudine was found to be toxic for algae, with a median value of RQ at 50, while the maximum observed value was 271.5, as reported by (Ngumba et al., 2016a).
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Regarding antiherpetics, a recent study for the chronic ecotoxicity posed by
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the not readily biodegradable ganciclovir used algae and daphnids as test organisms,
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revealed no persistence or bioaccumulation. No inhibition was observed on the tested microorganisms, at the highest tested concentrations (1000 mg L -1). In the same study,
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a comparison between predicted environmental concentrations and predicted non-
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effect concentrations revealed no significant risk for wastewater treatment, surface
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waters, groundwater, or sediment, while the potential risks to aquatic predators or to human consumers of water and fish are exceedingly low (Straub, 2017). Like ganciclovir, valganciclovir exhibited no relevant risk to aquatic organisms and humans that consume water and fish exposed to its traces. The toxicity assessment of mixtures of parent compounds and their metabolites is a future challenge for a more systematic approach of risk assessment. In addition, when there is a lack of available data, QSAR predictions could be employed in order to cover the data gaps and simple mixture toxicity models can be applied. Apart from ecotoxicity, the potential development of viral resistance is a subsequent burning issue, since the chronic exposure to antivirals imply serious
52
Journal Pre-proof damages, with regard to human health, and despite the efforts to prevent this process, it oftens proves futile. Antiviral resistance in wildfowl is of primary concern, especially for the anti‐influenza drugs, since birds host influenza virus(es). The risk is even higher
during pandemic
events,
when the predicted environmental
concentrations of OS and OC may reach 80 μg L-1 (Ellis, 2010). It is of high importance to underline that the antiviral resistance differs, according to the biology of each virus, and should be considered in any analysis of resistance conferral. More
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research on antiviral resistance evolution should be motivated, embracing both the biological and environmnetal approaches, since the two aspects are complementary.
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Further discussion on antiviral resistance is out of the scope of this review, as well as
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the contribution of the biological, pharmacological and medical aspects would be
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requisite. Excellent reviews that compile crucial information from relevant research articles in an effort to shed light on the issue of antiviral drug resistance as an adaptive
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process are readily available (Duffy et al., 2008; Foll et al., 2014; Irwin et al., 2016;
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Lurain and Chou, 2010; Piret and Boivin, 2014; Thorlund et al., 2011).
10. Concluding remarks and future challenges The presence of antiviral drugs in the environment is an emerging issue that raises concerns not only for the environment but also for humans, since resistant virus strains could be developed. This review is an update of the available data and provides the most crucial information for the environmental occurrence of antiviral drugs in aqueous environmental matrices originating from different geographical regions. Nevertheless, the continuous discharge of drugs in the aquatic environment through wastewater outputs, along with the lack of systematic governmental programs to prevent their entry into aquatic environment implies this field is unlimited. 53
Journal Pre-proof The occurrence of antiviral drugs in the aquatic environment exhibits significant discrepancies, hindering the observation of a particular pattern. This is attributed to factors such as the different consumption and prescription rates and different treatment technologies, but also environmental and geographical conditions. Regarding the antiretroviral drugs, the therapeutical schemes are individual and specialized, in order to protect infected people from any mutations of the virus, which mean that variations are inevitable. The withdrawal of drugs due to the release of
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novel, advanced drugs to face any resistant strains of the virus and to improve the standard of living of the infected people is another source of disposal which should be
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regulated by the pharmaceutical industries. To the best of the authors' knowledge,
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there is very few data on the occurrence of antiviral drugs in industrial wastewaters.
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The removal of antiviral drugs from WWTPs should be enhanced. This can be achieved by optimizing existing WWTP technology, upgrading with new technologies
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and controlling contamination at the source.
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The spatial distribution of the published articles revealed that African water
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bodies and wastewaters are the most investigated, targeting the sub-class of antiretroviral drugs. This is an alert for greater awareness of the current situation of the antiretroviral drugs in the continent that most suffers from HIV. The poor sanitation systems and drinking water treatment in the area, as well as the low rates of precipitation which would otherwise dilute the antivirals when entering water bodies, urges comprehensive studies in the aquatic environment and the drinking water sources. Several articles studied the antiviral drugs in Europe and Asia, with a lot of investigations carried out in Germany/UK and China/Japan, respectively. Scarce data are available for Norway, Belgium and the USA. A large part of the published works
54
Journal Pre-proof have been published after pandemic incidents of influenza, to assess the environmental impact of the systematic oseltamivir administration. In the case of antiviral drugs against flu, there are occasional unpredictable events, such as pandemics, when the performance of WWTPs is limited. It would be precarious to claim that a trend characterizes the urban and hospital wastewaters, since their reported levels vary between developed and developing countries, where the treatment systems are of poor quality or efficiency, if not absent.
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Many steps should be taken, and investigation should be conducted purposefully to cover the gaps in the existing knowledge on the environmental fate,
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occurrence and risks posed by antiviral drug residues. In addition, to observe if
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antiviral drugs follow specific patterns, nationwide studies are necessary, in both high
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and low-income countries. More studies to comprehend the correlation between the parent antiviral drugs and their metabolites/transformation products and their
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environmental fate and occurrence would be of great help to estimate the fate of this
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emerging class of contaminants that barrens of proper attention. The evolution in the
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drug-use patterns led to the release into the market of new drugs. This implies the need to monitor more antiviral drugs and to assess the risks posed due to the development of new resistant virus strains. The extensive study of antiviral drugs occurrence in influents and effluents of wastewaters addresses the major questions whether the appropriate wastewater treatment is applied for sufficient removal. It is imperative to select the appropriate wastewater treatment according to the removal needs of each plant and to increase further the efficiency of the currently used treatments. Also, new treatment technologies practising bioplastic moving bed biofilm carriers and electrochemical degradation may help to increase removal rates.
55
Journal Pre-proof Wastewater analysis tends to be carried out only in the aqueous phase since particulate and solid phase are not routinely analyzed. However, the determination of the load of antiviral drugs in this phase could elucidate the obtained results, especially regarding influents concentration, since certain drugs have high affinity to particulate matter. In addition, the analysis of treated and untreated sludge, as well as biosolids, would be of vital importance to study the fate in WWTPs. The correlation between aqueous and solid matrices provide unique information about the fate of the drugs in
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WWTPs, which up to now are almost unmonitored. The monitoring studies should be broadened by analyzing also receiving seawater, biota, soils, sediments, as well as
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irrigated crops and animals that feed the populations, especially in developing
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countries, where surveys are needed to investigate the appropriateness of drinking
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water.
From an analytical point of view, it is necessary to take advantage of the most advances
in mass spectrometry and employ high-resolution mass
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recent
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spectrometers, such as Orbitrap and Q-TOF. Using these it is then possible to conduct
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dynamic suspect and non-target screenings and enlarge the number of compounds included in target analysis, given that among the published articles dealing only with antiviral drugs, only a few are included. The use of such sensitive instrumentation would also provide lower quantification limits that are needed to quantify trace level of antivirals in surface and drinking water. Moreover, retrospective analysis is also feasible when applying advanced MS technologies. The results highlight the importance of evaluating the ecotoxicity of TPs of antiviral drugs. The formation of carboxy-TPs via oxidation of the hydroxyl-moiety may result in the loss of antiviral activity, decreasing the phosphorylation in virally infected cells. Moreover, the toxicity of some carboxy metabolites comparing to the
56
Journal Pre-proof parent compounds in typical test organisms (i.e. Daphnia magna) indicates that transformation reactions can lead to more toxic compounds. Thus, it is necessary to incorporate ecotoxicity studies for a variety of antiviral drugs and test systems to obtain reliable results. Toxicological tests simulating environmental conditions and antiviral drugs consumption are necessary to test the behavior of various organisms belonging to different trophic levels, apart from the typical indicator species. This will be of great help to estimate the ecotoxicology effect to non-target organisms.
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Particular attention should be paid to the agonizing issue of the occurrence of drug mixtures, let alone with antibiotics, with which antiviral drugs are typically prescribed
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in parallel.
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Antiviral drugs are strictly prescribed medicine. Equally strict is the potential
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to deviate from the recommended and prescribed dosages, in order to avoid any undesirable development of resistant strains of the virus. This fact can facilitate the
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prediction of environmental concentrations as well as the prioritization of target
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antiviral drugs incorporated in monitoring studies. Therefore, the number of antivirals
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to be target screened can easily be enlarged. It is valuable to investigate the simultaneous occurrence of antiviral drugs with antibiotics, given that those classes of pharmaceuticals are frequently prescribed together, to deal with bacteria that threaten the strained immune system of the patients.
Acknowledgements This research has been funded by 2014 - 2020 Interreg IPA Cross Border Cooperation Programme CCI 2014 TC 16 I5CB 009, Research Project: Aqua-M II: Sustainable management of cross-border water resources, Project number (MIS): 5030774, which is gratefully acknowledged. 57
Journal Pre-proof Ms Α. Ofrydopoulou would like to thank the General Secretariat for Research and Technology (GSRT) and the Hellenic Foundation for Research and Innovation (H.F.R.I.) for providing her scholarship through the action '1 st Proclamation of Scholarships from ELIDEK for PhD Candidates' - Scholarship Code: 429.
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Barceló, D.D., Chromatography, L., Mass, T., Vanderford, B.J., Snyder, S. a, Choi, B.K., Hercules, D.M., Gusev, A.I., Brieudes, V., Lardy-Fontan, S., Lalere, B., Vaslin-Reimann, S., Budzinski, H., 2015b. Analysis of Pharmaceuticals in Water by Isotope Dilution Analysis of Pharmaceuticals in Water by Isotope Dilution Liquid Chromatography / Tandem Mass. Anal. Chem. 40, 7312–7320. https://doi.org/10.1016/S0021-9673(00)01052-9 Verlicchi, P., Al Aukidy, M., Zambello, E., 2012. Occurrence of pharmaceutical compounds in urban wastewater: Removal, mass load and environmental risk after a secondary treatment—A review. Sci. Total Environ. 429, 123–155. https://doi.org/10.1016/j.scitotenv.2012.04.028
78
Journal Pre-proof Wallensten, A., Fick, J., Lindberg, R.H., Tysklind, M., Haemig, P.D., Waldenström, J., Wallensten, A., Olsen, B., 2007. Antiviral oseltamivir is not removed or degraded in normal sewage water treatment: Implications for development of resistance by influenza A virus. PLoS One 2, e986. https://doi.org/10.1371/journal.pone.0000986 WHO, 2018. Influenza (Seasonal) [WWW Document]. URL https://www.who.int/news-room/fact-sheets/detail/influenza-(seasonal)
oo
f
Wood, T.P., Basson, A.E., Duvenage, C., Rohwer, E.R., 2016. The chlorination behaviour and environmental fate of the antiretroviral drug nevirapine in South
pr
African surface water. Water Res. 104, 349–360.
e-
https://doi.org/10.1016/J.WATRES.2016.08.038
Pr
Wood, T.P., Duvenage, C.S.J., Rohwer, E., 2015. The occurrence of anti-retroviral compounds used for HIV treatment in South African surface water. Environ.
al
Pollut. 199, 235–243. https://doi.org/10.1016/j.envpol.2015.01.030
rn
Wooding, M., Rohwer, E.R., Naudé, Y., 2017. Determination of endocrine disrupting
Jo u
chemicals and antiretroviral compounds in surface water: A disposable sorptive sampler with comprehensive gas chromatography – Time-of-flight mass spectrometry and large volume injection with ultra-high performance li. J. Chromatogr. A 1496, 122–132. https://doi.org/10.1016/j.chroma.2017.03.057 Zhou, C., Chen, J., Xie, Q., Wei, X., Zhang, Y., Fu, Z., 2015. Photolysis of three antiviral drugs acyclovir, zidovudine and lamivudine in surface freshwater and seawater. Chemosphere 138, 792–797. https://doi.org/10.1016/j.chemosphere.2015.08.033
79
oo
f
Journal Pre-proof
pr
Legends of figures
e-
Fig. 1 Location and number of studies reporting on the environmental occurrence of
Pr
antiviral drugs worldwide
Fig. 2 Systemic use different groups of antiviral drugs in Europe (a) in DDD per 1000
al
inhabitants per day, (b) as a percentage of the total use (European Centre for Disease Prevention and Control, 2018)
rn
Fig. 3 Transmission of antiviral drugs in the aquatic environment
Jo u
Fig. 4 Box and Whisker graph showing the concentrations (ng/L) of antiviral drugs in (a) influents (b) effluents
Fig. 1
80
Journal Pre-proof
0.00
1.00
2.00
3.00
pr
oo
f
Spain Malta Slovenia Lithuania Croatia Hungary Iceland Finland Bulgaria Norway Cyprus Germany Sweden Austria Belgium Netherlands Romania Latvia Luxembourg Italy Denmark Poland France Estonia Portugal
4.00
5.00
6.00
7.00
HIV/hepatitis B
Hepatitis B
Hepatitis C
Herpes
Influenza
Other antivirals
Pr
HIV/AIDS
e-
DDD/1000 inhabitants per day
(a)
Jo u
rn
al
Spain Malta Slovenia Lithuania Croatia Hungary Iceland Finland Bulgaria Norway Cyprus Germany Sweden Austria Belgium Netherlands Romania Latvia Luxembourg Italy Denmark Poland France Estonia Portugal
0%
HIV/AIDS
10%
20%
HIV/hepatitis B
30%
40%
Hepatitis B
50%
Hepatitis C
(b) Fig. 2 81
60%
Herpes
70%
80%
Influenza
90%
100%
Other antivirals
e-
pr
oo
f
Journal Pre-proof
Jo u
rn
al
Pr
Fig. 3
82
500.0
50.0
al
rn
Jo u
5000.0
ABC ABC-CBX ABC-DES ATV AZT D4T DAR EFV 8,14-DiOH-EFV FTC FTC-CBX FTC-S-oxide IDV MVC LPV NVP 12-OH-NVP RAL RTV SQV 3TC 3TC-CBX AMT OS OC RIM ZAN ACV CBX-ACV PCV GCV RBV
ng/L
(a)
50000.0
pr
e-
Pr
ABC ABC-CBX ABC-DES ATV AZT D4T DAR EFV 8,14-DiOH-EFV FTC FTC-CBX FTC-S-oxide IDV MVC LPV NVP 12-OH-NVP RAL RTV SQV 3TC 3TC-CBX AMT OS OC RIM ZAN ACV CBX-ACV FCV PCV VACV GCV RBV
0.5
f
oo
ng/L
Journal Pre-proof
50000.0
5000.0
500.0
50.0
5.0
5.0
0.5
(b)
Fig. 4
83
Journal Pre-proof
Table 1. Occurrence of antiviral drugs in WWTPs influents and effluents worldwide, listed by therapeutic class
n/a
33
>99% >99% n/a n/a n/a n/a n/a >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 <10 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
Germany Germany Germany 1 KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa France Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany
(Pras (Pras (Bou (Aba (Aba (Aba (Ami (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Bou (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun
n/a
Germany
(Fun
n/a n/a n/a n/a n/a n/a n/a n/a n/a
Germany Germany Germany Germany Germany Germany Germany Germany Germany
(Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun
f
31
Ref.
oo
n.d.
Region/Country
Pr
e-
pr
n.d.
Removal (%) Mean
20
170
al
n/a
n.d.
Max
rn
n.d.
81.7±5.3 225±40 n.d. n.d. 3500±210 14000±2300 n/a 110±26 74±7 110±16
Effluents Min
Jo u
Occurrence (ng L-1)* Influents Min Max Mean
84
Journal Pre-proof -1 *
5589 13450 7485 12090
4046 3872 3879 4040
15.4
9.15
40
Western Cape, South Africa
0.982
31
Western Cape, South Africa
8.04
33
Western Cape, South Africa
100
Western Cape, South Africa
51
n/a
Germany
41.7
76
Western Cape, South Africa
100
Western Cape, South Africa
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany
Ref. (Aba (Aba (Aba (Ferr 2016 (Ibáñ (Aba (Aba (Aba (Aba (Aba (Aba (K’or (K’or (K’or (K’or (Sch (Sch (Sch (Sch (Sch (Mo 2019 (Mo 2019 (Mo 2019 (Mos 2019 (Bou (Mo 2019 (Mo 2019 (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun
Germany
(Bou
n/a
Germany
(Fun
78±1 740±100 300±20
43000±930 920±27 69±2 34000±1900 24000±1400 34000±2400 780 460 1020 26.49
Pr al
1.42
rn
12.4 1.48 n/a
n/a 172 31.3
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
440±37 370±3 500±10 460±41 980±50 540±114 320±14 100±10 370±35 280±29 120±18
n/a
n/a
n/a 27±6
130
Jo u
n/a
Greece 1 KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa 1 KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa Dandora, Nairobi, Kenya Nyalenda, Kisumu, Kenya Kisat, Kisumu, Kenya Dandora, Nairobi, Kenya Gauteng, South Africa Eldoret, Gauteng, South Africa Kitale, Gauteng, South Africa Mumias, Gauteng, South Africa Kakamega, Gauteng, South Africa
n/a n/a n/a n/a 90 83 92 n/a n/a n/a n/a n/a n/a
pr
14000
n/a n/a n/a
e-
5500
Region/Country KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa
120
1000
330 220±15
85
Norway
f
64±6 1400±140 210±24
Removal (%) n/a n/a n/a n/a
oo
Occurrence (ng L )
-1 *
Occurrence (ng L )
25±7 38±6 250±14 100±5 81±25 34±8 24±1 80±13 40±7 100±10
160±15 270±13 150±26 480±59 300±90 140±26 76±19 75±9 83±6 100±6
Removal (%) n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
Region/Country Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany
Ref. (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun
n/a
n/a
380
n/a
Germany
(Bou
n/a
40±6
68±7
52±2
none
Germany
(Fun
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a >76 >93 51 59 24 n/a
Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa France Germany Germany Germany Dandora, Nairobi, Kenya Nyalenda, Kisumu, Kenya Kisat, Kisumu, Kenya Dandora, Nairobi, Kenya
(Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Aba (Aba (Aba (Ami (Bou (Pras (Pras (K’or (K’or (K’or (K’or (Mo 2019 (Mo 2019 (Ngu (Ngu (Ngu (Ami (Fun (Fun (Fun (Fun
n/a
n/a
n/a 210±13 720±130 30300 60680 31460 3.25
Pr
oo
e-
pr
40±6 51±3
al rn
f
n/a
n.d.
1.5 58
Jo u
e
Journal Pre-proof
21
20.9
100
Western Cape, South Africa
3.67
100
Western Cape, South Africa
3985
n/a n/a n/a n/a n/a n/a n/a n/a
Nairobi, Kenya Jyväskylä, Finland Jyväskylä, Finland France Germany Germany Germany Germany
37 55 270±52 200±10 280±30 330±49 370±44
5430
86
Journal Pre-proof -1 *
Occurrence (ng L )
220±28
34±4
180±40
25±6
75±12
72±17 51±8
140±23 81±11 51±10
130
83±140 320±63 82±90
n.d.
2100±150 670±23 2800±190 850 3300 2080 33.45 2100 189 53 121 254
n.d. 1900±68 540±34 1400±63 1030 2110 2030 350 473 92 242 225
3 4.8±2.9 21.8±2.3
3800±350 3800±360 1900±36 117.2
al
2500±370 1300±110 1200±210
rn
57±1
Jo u
Germany
(Fun
n/a
Germany
(Fun
n/a n/a
Germany
(Fun
Germany
(Fun
n/a n/a
Germany Germany
(Fun (Fun
n/a
Germany
(Fun
n/a
Germany
(Fun
none
Germany
(Fun
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 11 49 22 n/a n/a n/a n/a n/a n/a n/a none none
KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa South Africa KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa France KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa Dandora, Nairobi, Kenya Nyalenda, Kisumu, Kenya Kisat, Kisumu, Kenya Dandora, Nairobi, Kenya Gauteng, South Africa Eldoret, Gauteng, South Africa Kitale, Gauteng, South Africa Mumias, Gauteng, South Africa Kakamega, Gauteng, South Africa France Germany Germany
(Aba (Aba (Aba (Wo (Aba (Aba (Aba (Ami (Aba (Aba (Aba (K’or (K’or (K’or (K’or (Sch (Sch (Sch (Sch (Sch (Ami (Pras (Pras
oo
220±18
(Fun
pr
110±10
44±4
Germany
n/a
e-
84±6
Region/Country Germany Germany Germany Germany Germany Germany 1 KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa Lede, Belgium Lede, Belgium Germany Germany
f
Pr
ate
270±24 180±31 290±51 340±52 130±35 52±2 2200±190 840±60 1900±290 n.d. 507±80
Removal (%) n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a >89 n/a n/a n/a
7.7 7.2±2.3 32.1±0.5
87
Ref. (Fun (Fun (Fun (Fun (Fun (Fun (Aba (Aba (Aba (Ver (Ver (Fun (Fun
Journal Pre-proof -1 *
Occurrence (ng L )
none
Western Cape, South Africa
none
Western Cape, South Africa
n/a 25 n/a n/a n/a
Switzerland2 Switzerland KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa
Ref. (Mo 2019 (Mo 2019 (Ngu (Ngu (Ngu (Mo 2019 (Mo 2019 (Aba (Aba (Aba (Mo 2019 (Mo 2019 (Kov (Mar (Aba (Aba (Aba
n/a n/a >78 >89 n/a
Phoenix KwaZulu-Natal, South Africa France Germany Germany
(Aba (Ami (Pras (Pras
Guangzhou, China
(Pen
98.2±17.6 564±22 90 90 110
68 none 99 99 99
Germany Germany Dandora, Nairobi, Kenya Nyalenda, Kisumu, Kenya Kisat, Kisumu, Kenya
n.d.
n.d.
n/a
Western Cape, South Africa
n.d.
n.d.
n/a
Western Cape, South Africa
(Pras (Pras (K’or (K’or (K’or (Mo 2019 (Mo 2019
0.658
3
Western Cape, South Africa
100
Western Cape, South Africa
1357
n/a n/a n/a
Nairobi, Kenya Jyväskylä, Finland Jyväskylä, Finland
0.519
100
Western Cape, South Africa
100
Western Cape, South Africa
17000±2600 61±9.0 810±240
3500±1300
n/a n/a n/a
KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa
Pr
e-
110±14 3200±170 1600±130 1600±150
n.d. 11.6±5.3 22.8±5.6
46 62
0.2
Jo u
n.d.
al
rn
180±36
7680
n/a
513
38.6
88
f
1
oo
4860
pr
108
n.d.
Region/Country
0.681
13 19
n.d.
Removal (%)
Nairobi, Kenya
(Ngu
n/a n/a n/a
Jyväskylä, Finland Jyväskylä, Finland
(Ngu (Ngu
Guangzhou, China
(Pen
n/a n/a
France South Africa
(Ami (Wo
105.1
160.9
44±8 326±394 538 310 230 325 184 280
55±6 592±325 274 230 125 175 89 151
131.4
91.4 22.5 89.1 18
n.d.
33.7 6.5 74
173.2 180 258.4 21
2070
394±435
257
550
350±60 433±472 350±59
152.5 15.8±4.0 8.9±0.7
n.d. n.d. n.d.
59
none
Germany
(Fun
n/a
Western Cape, South Africa
(Mo 2019
-21 -109 41.7 20.4 39.6 39.4 41.4 39.4 n/a n/a n/a n/a none none n/a
Lede, Belgium Lede, Belgium Japan Japan Japan Japan Japan Japan Katsura, Japan Uji, Japan Yodo River System, Japan Japan Germany Germany
(Ver (Ver (Gho (Gho (Gho (Gho (Gho (Gho (Azu (Azu (Azu (Azu (Pras (Pras
Guangzhou, China
(Pen
n/a n/a n/a n/a n/a n/a n/a n/a
Katsura, Japan Uji, Japan Japan York, UK York, UK York, UK Umeå, Västerbotten, Sweden
(Azu (Azu (Azu (Bur (Bur (Bur (Kha
Benson, UK
(Sing
Oxford, UK
(Sing
Benson, UK Oxford, UK
(Sing (Sing
e-
n.d.
Ref. (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Aba (Aba (Aba
pr
n.d.
11.9±4.2
Pr
de
n/a
al
rn
91±12 76±3 110±21 87±12 150±27 85±15
Region/Country Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany 1 KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa
f
170±12 140±10 210±7 290±31 390±33
Removal (%) n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
oo
-1 *
Occurrence (ng L )
Jo u
ate
Journal Pre-proof
n.d. n.d. n.d. 48.29
n/a 208±40 358±60
89
50 -2
-1 *
55.9 2.1 243
293.3 74.6 18.2
208
568.8
9 n.d.
186.7
704.3
n.d.
336.8 n.d.
n.d. 53
n.d.
23.1
11.9
1300
0.65
30
2200
700
120
60
110
2200
930
12000 0
34000
7700 n/a
64
374.1 n.d. n.d. 171.7
n.d. n.d. n.d.
rn
al
n.d.
n.d. 27.9 110 12.7
Guangzhou, China
(Pen
n/a n/a n/a −30 to +47% n/a n/a n/a n/a −72 to +53% n/a n/a n/a n/a n/a n/a n/a n/a n/a
Katsura, Japan Uji, Japan Japan VEAS, Norway Yodo River System, Japan Lede, Belgium Lede, Belgium Osaka, Japan VEAS, Norway Japan Dandora, Nairobi, Kenya Nyalenda, Kisumu, Kenya Kisat, Kisumu, Kenya Lede, Belgium Lede, Belgium Osaka, Japan Katsura/Uji Japan Japan Yodo River System, Japan
(Azu (Azu (Azu (Lekn (Azu (Ver (Ver (Tak (Lekn (Azu (K’or (K’or (K’or (Ver (Ver (Tak (Azu (Azu (Azu
f
375 360 403 195 460 140
oo
n.d.
59.9 17.3±5.4 12.2±2.9 482.5 285 295 245 147 345 91
Region/Country Yodo River System, Japan Germany Germany Osaka, Japan Japan Japan Japan Japan Japan Japan Kyoto, Japan Kyoto, Japan Kyoto, Japan
pr
80.7
Removal (%) n/a 59 59 n/a 20.6 16.2 37.6 20.8 18.1 32.1 n/a n/a n/a n/a
e-
36.7
Pr
Occurrence (ng L ) 35.2 72.4 51.5 42.7±9.3 29.4±4.9
Jo u
ate
Journal Pre-proof
2.5
370
140
82
Langenau, Germany
100
40
95
Halzhausen, Germany
120
40
n/a
Asselfingen, Germany
230
90
92
Steinhäule, Germany
n/a
n/a
n/a
2330
n/a
n/a
n/a
n/a
250
110
n/a
90
Ulm, Germany
2
n/a
Langenau, Germany2
n/a
Germany
Ref. (Azu (Pras (Pras (Tak (Gho (Gho (Gho (Gho (Gho (Gho (Gho (Gho (Gho
(Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Bou
Journal Pre-proof
270±20 130±8 85±5 240±15 260±36 170±31
Guangzhou, China
(Pen
70 91 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
California Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany
(Bea (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Pras (Pras (Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Azu (Azu
e-
1900
0.76
5100
2050
140
1800
740
360
8500
2750
50
770
280
80
710
490
390
13000
5750
870
8000
5120
2700
44000
20000
n/a
n/a
n/a
6700
2810
n/a
n/a
n/a
n.d. 63
n.d. 16
n.d.
n.d.
n.d.
Ref. (Pras (Pras (Pras (Pras (K’or (Azu (Azu
f
205
Region/Country Germany Germany Germany Germany Nairobi, Kenya Japan 2 Japan
pr
114
120
Pr
e
202
al
302±58 3780±480 2850±130 2510±70 1070±140 4980±280 2180±110 1740±230 520±42 530±25 760±64 1830±390 690±140 600±82 490±3 1790±82 3420±210 2680±62 670±39 1790±200 2010±38 2290±130 520±100 430 247±75
19
rn
177
3691 113
27.3±1.6 53.3±3.5 140 148±11
Jo u
1530 9
1780±99 1780±50 1990 1800±300 n.d. 2505 60
Removal (%) 98 97 n/a n/a n/a n/a n/a n/a
oo
-1 *
Occurrence (ng L )
n/a n/a n/a n/a n/a n/a n/a n/a
91
Langenau, Germany Halzhausen, Germany Asselfingen, Germany Steinhäule, Germany Ulm, Germany2 2
Langenau, Germany Japan Japan2
Journal Pre-proof -1 *
Occurrence (ng L )
40 n.d. n.d. n.d.
120 29 21 22
n.d.
42.8±9.8 19.5±9.7 79 9 11 8
n.d.
13
n.d.
n.d.
n.d.
n.d.
Removal (%) >94 >87 n/a n/a n/a n/a
Region/Country Germany Germany Japan Japan2 Japan Japan2
Ref. (Pras (Pras (Azu (Azu (Azu (Azu
Guangzhou, China
(Pen
Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany
(Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun
n/a n/a
Germany Germany
(Pras (Pras
n/a
Guangzhou, China
(Pen
irus
e-
n.d.
Pr
f
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
oo
27±4
pr
38±5
al
n.d.
n/a
Abacavir
Occurrence (ng L-1)* Min. Max Mean
Jo u
Antiviral drugs Antiretroviral s
rn
iven in brackets; ffluents; n.d., not detected; n/a, not available Table 2. Occurrence of antiviral drugs in surface waters worldwide, listed by therapeutic class
1.4
2.6±1. 7 2.3
Region/Country
Reference
Hessian Ried, Germany
(Prasse et al., 2010)
Neckar, Germany Weschnitz, Germany Modau Germany Schwarzbach, Germany Rodau, Germany Main, Germany Nahe, Germany Lahn, Germany River Rhine, Germany
(Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016)
France
(Aminot et al., 2015)
France
(Aminot et al., 2016)
South Africa
(Wood et al., 2015)
River Rhine, Koblenz,
(Boulard et al., 2018)
92
Journal Pre-proof Antiviral drugs Abacavir carboxylate
Occurrence (ng L-1)* Min. Max Mean (5) (5)
Darunavir
Region/Country Germany River Rhine, Koblenz, Germany
72.7
Poland
Didanosine Efavirenz
n.d.
54.1
3
303
134
354
South Africa South Africa Hartbeespoort Dam catchment, South Africa Juskei River, South Africa uMngeni River, South Africa Kisumu, Kenya Mathare River, Nairobi, Kenya Rietvlei Nature Reserve, Gauteng Province, South Africa
138 n.d.
560
148
n.d.
<1
45
2.9
Emtricitabine carboxylate
n.d.
Lamivudine n.d. n.d.
(Rimayi et al., 2018) (Rimayi et al., 2018) (K’oreje et al., 2016) (K’oreje et al., 2012) (Wooding et al., 2017) (Wood et al., 2015) (Boulard et al., 2018) (Rimayi et al., 2018) (Rimayi et al., 2018)
110
Weschnitz, Germany Modau, Germany Schwarzbach, Germany Rodau, Germany Main, Germany Nahe, Germany Lahn, Germany Rhine River, Germany Rhine River, Germany
(Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Boulard et al., 2018)
200
Rhine River, Germany
(Boulard et al., 2018)
South Africa
(Wood et al., 2015)
Yodo River basin, Japan
(Azuma et al., 2015)
France
(Aminot et al., 2015)
Kisumu, Kenya
(K’oreje et al., 2016)
3150
(Rimayi et al., 2018)
49±5 70±1 280±20 73±2 44±1 25±2 30±3
rn Indinavir
10
(Giebułtowicz and Nałecz-Jawecki, 2016) (Wood et al., 2015) (Wood et al., 2015)
(Funke et al., 2016)
Jo u
Emtricitabine S-oxide
(Boulard et al., 2018)
Neckar, Germany
al
29±2
River Rhine, Koblenz, Germany uMngeni River, South Africa Juskei River, South Africa
Pr
8 13
n.d.
South Africa
e-
n.d.
pr
oo
f
33
Emtricitabine
Reference
20
<5
2.6 242
160
n.d.
n.d.
n.d.
n.d.
Mathare River, Nairobi, Kenya River Rhine, Koblenz, Germany France South Africa Ruhr River and tributaries, Germany Hessian Ried, Germany
93
(K’oreje et al., 2012) (Boulard et al., 2018) (Azuma et al., 2016) (Wood et al., 2015) (Prasse et al., 2010) (Prasse et al., 2010)
Journal Pre-proof
n.d.
12
Lake Päijänne, Finland
5428
Nairobi River Basin, Kenya
16
230
Germany
(Funke et al., 2016)
n.d.
n.d.
Japan
(Azuma et al., 2017)
n.d.
n.d.
Japan
(Azuma et al., 2017)
n.d. n.d.
305 n.d.
South Africa France
n.d.
n.d.
Lake Päijänne, Finland
4859
Nairobi River Basin, Kenya
(Wood et al., 2015) (Aminot et al., 2015) (Ngumba et al., 2016b) (Ngumba et al., 2016a)
n.d. n.d.
239
1.3±0. 6 5620
France
17
Hessian Ried, Germany
(Prasse et al., 2010)
12±5 0.5
France France
(Aminot et al., 2015) (Aminot et al., 2016)
South Africa
(Wood et al., 2015)
n.d.
Pearl River Delta, China Mathare River, Nairobi, Kenya South Africa Orange River System, South Africa Roodeplaat Dam System, South Africa South Africa Ruhr River and tributaries, Germany
(Peng et al., 2014)
e-
227
6
71
n.d.
57
68 360
rn
1480
Pr
0.5
al
0.2
3.8
Jo u
Ritonavir
n.d.
(Aminot et al., 2015) (K’oreje et al., 2016)
<148
n.d.
(Ngumba et al., 2016b) (Ngumba et al., 2016a)
Kisumu, Kenya Mathare River, Nairobi, Kenya Rietvlei Nature Reserve, Gauteng Province, South Africa Limpopo Province, South Africa France Hartbeespoort Dam catchment, South Africa Juskei River, South Africa uMngeni River, South Africa South Africa Ruhr River and tributaries, Germany
300 44.4
Reference
f
Nevirapine
Region/Country
oo
Lamivudine carboxylate Laninamivir Laninamivir octanoate Lopinavir Nelfinavir
Occurrence (ng L-1)* Min. Max Mean
pr
Antiviral drugs
Stavudine 440
(Wooding et al., 2017) (Wooding et al., 2017) (Aminot et al., 2016) (Rimayi et al., 2018) (Rimayi et al., 2018) (Rimayi et al., 2018) (Wood et al., 2015) (Prasse et al., 2010)
(K’oreje et al., 2012)
n.d.
778
0
189
n.d.
243
Zalcitabine
n.d.
71.3
Zidovudine
1.2
94
170
Hessian Ried, Germany
(Prasse et al., 2010)
7684
Nairobi River Basin, Kenya
(Ngumba et al., 2016a)
Tenofovir
431
(K’oreje et al., 2012)
36
94
(Wood et al., 2015) (Wood et al., 2015) (Wood et al., 2015) (Wood et al., 2015) (Prasse et al., 2010)
Journal Pre-proof Antiviral drugs
Occurrence (ng L-1)* Min. Max Mean n.d. 33±27 n.d. 17410 n.d. 30 18
Region/Country
Reference
France Kisumu, Kenya Pearl River Delta, China Rivers and streams, Germany Mathare River, Nairobi, Kenya
(Aminot et al., 2015) (K’oreje et al., 2012) (Peng et al., 2014) (Funke et al., 2016) (K’oreje et al., 2012)
973
319
South Africa
(Wood et al., 2015)
10290
351 (highest median)
Yangtze River Delta, China
(Peng et al., 2018)
5
61
Japan Yodo River, Japan Yodo River, Japan Yodo River basin, Japan Pearl River Delta, China
oo
Amantadine
f
Antiinfluenza drugs
14 10.7
Oseltamivir
pr
10-41 n.d.
n.d.
19
12
58
n.d.
8.8
0.3
17
15
e-
Kamo River, Japan
Katsura River, Japan Yodo River, Japan
Pr
2
al
n.d.
(Prasse et al., 2010)
Japan
Yodo River, Japan
(Azuma et al., 2017) (Takanami et al., 2011) (Azuma et al., 2017) (Takanami et al., 2012) (Azuma et al., 2013)
39125
Yodo River basin, Japan
(Azuma et al., 2015)
2.4
(Prasse et al., 2010)
21
Hessian Ried, Germany
(Prasse et al., 2010)
rn
Neya River, Osaka, Japan
Jo u
864.8 70
Japan
556.9
Osaka, Japan
Ruhr River and tributaries, Germany
n.d.
(Prasse et al., 2010)
Hessian Ried, Germany
20 Oseltamivir carboxylate
River Foss, UK Ruhr River and tributaries, Germany
(Azuma et al., 2017) (Azuma et al., 2013) (Azuma et al., 2013) (Azuma et al., 2015) (Peng et al., 2014) (Söderström et al., 2009) (Söderström et al., 2009) (Söderström et al., 2009) (Burns et al., 2018)
43.8
6.6
190.2
n.d.
193 6
66 1.29
Katsura and Kamo Rivers, Japan River Thames catchment, UK River Wye, UK Umeå surface water, Sweden
50
Ebro river, Spain
100
Ebro river, Spain
154.2
Neya River, Osaka, Japan
95
(Ghosh et al., 2010a) (Singer et al., 2014) (Singer et al., 2014) (Khan et al., 2012) (Gonc̀alves et al., 2011) (Gonc̀alves et al., 2011) (Takanami et al.,
Journal Pre-proof Antiviral drugs
Occurrence (ng L-1)* Min. Max Mean n.d.
Peramivir Zanamivir
n.d.
Region/Country
165.9
Osaka, Japan
10
Japan
58.8
Osaka, Japan
Reference
n.d.
Yodo River, Japan Yodo River, Japan Yodo River basin, Japan
Nau River, Germany
Danube River, Germany
10
Yodo River, Japan Pearl River Delta, China River Rhine, Koblenz, Germany River Ruhr and tributaries, Germany Hessian Ried, Germany rivers and streams in Germany
89 13-35
2011) (Takanami et al., 2012) (Azuma et al., 2017) (Takanami et al., 2012) (Azuma et al., 2013) (Azuma et al., 2017) (Azuma et al., 2015)
2.6
20
2.2
190
58
750
oo
70
6
pr
2
160
100
150
70
Nau River, Germany Danube River, Germany
rn
al
3 2 Yodo River, Japan 7 Hessian Ried, Germany 2-11 Yodo River basin, Japan Valacyclovir n.d. 5 1 Yodo River, Japan * Values of LOQ are given in brackets; n.d., not detected; n/a, not available
Jo u
Penciclovir
e-
Αcyclovir carboxylate
Pr
Acyclovir
f
Antiherpetics
96
(Seitz and Winzenbacher, 2017) (Seitz and Winzenbacher, 2017) (Azuma et al., 2019) (Peng et al., 2014) (Boulard et al., 2018) (Prasse et al., 2010) (Prasse et al., 2010) (Funke et al., 2016) (Seitz and Winzenbacher, 2017) (Seitz and Winzenbacher, 2017) (Azuma et al., 2019) (Prasse et al., 2010) (Azuma et al., 2015) (Azuma et al., 2019)
Journal Pre-proof Table 3. Occurrence of antiviral drugs in groundwaters worldwide, listed by therapeutic class Antiviral drug
Occurrence (ng L-1)* Freq. Min. Max. (%)
Mean
Region/Country
Ref.
North West and Gauteng Provinces, South Africa
Antiretrovirals
Efavirenz
2
5
20
30
Kisumu, Kenya
North West and Gauteng Provinces, South Africa
10
Kisumu, Kenya
(K’oreje et al.,
n/a
Emtricitabine Emtricitabine carboxylate Emtricitabine S-oxide Lamivudine
20 87 13 13
5
370
140
23 1,8
Lopinavir
Nevirapine
n/a
Zidovudine
Anti-influenza drugs Amantadine
n/a
n/a
25.2
USA
Kisumu, Kenya
27.73
USA
Tenofovir
Koblenz, Germany
1600
8
Stavudine
Koblenz, Germany
20
n/a
Saquinavir
Koblenz, Germany
North West and Gauteng Provinces, South Africa North West and Gauteng Provinces, South Africa North West and Gauteng Provinces, South Africa
Jo u
Nelfinavir
al
Koblenz, Germany
rn
n/a
Koblenz, Germany North West and Gauteng Provinces, South Africa Hartbeespoort Dam catchment, South Africa Gauteng Province, South Africa North West and Gauteng Provinces, South Africa
71
Koblenz, Germany
f
Didanosine
11
oo
7
(Swanepoel et al., 2015) (Boulard et al., 2018) (Boulard et al., 2018) (Swanepoel et al., 2015) (Rimayi et al., 2018) (Rimayi et al., 2018) (Swanepoel et al., 2015) (Boulard et al., 2018) (Boulard et al., 2018) (Boulard et al., 2018) (Boulard et al., 2018) (Fisher et al., 2016) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (K’oreje et al., 2016) (Fisher et al., 2016) (Rimayi et al., 2018) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (K’oreje et al., 2016) (Swanepoel et al., 2015)
pr
Abacavir carboxylate
e-
0
Pr
Abacavir
0.9
Hartbeespoort Dam catchment, South Africa North West and Gauteng Provinces, South Africa North West and Gauteng Provinces, South Africa North West and Gauteng Provinces, South Africa North West and Gauteng Provinces, South Africa
13 4.9 1.3 0.9 2.4
97
Journal Pre-proof
Rimantadine
n/a
2016) (K’oreje et al., 2016)
Kisumu, Kenya
Antiherpetics
(Boulard et al., 2018)
0
Table 4. Occurrence of antiviral drugs in drinking water worldwide (in alphabetical order) -1 *
Occurrence (ng L )
Acyclovir Acyclovir carboxylate Amantadine (LOQ2.2)
f
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a 41±7 9
169
rn
Jo u
3.3
n/a
n/a
n/a
n/a
n/a
n/a
n/a
80±2 n/a
Indinavir
n.d.
n/a
n/a
n.d. Lamivudine
n.d. n.d. n/a
n/a
n/a
oo
0.5
Emtricitabine S-oxide
Volvic water (PET bottles)/France municipal tap water/South Africa treated drinking water/Germany treated drinking water/Germany treated drinking water/Germany treated drinking water/Germany final drinking water/Japan
pr
Didanosine
Emtricitabine Emtricitabine carboxylate
Mean
n.d.
Darunavir
Efavirenz
Max.
e-
Abacavir carboxylate
Min.
Water type/Country of origin
Pr
Abacavir
Freq . (%)
al
Antiviral drug
<1
tap water/ Vistula River, Warsaw region, Poland municipal tap water/South Africa tap water/ Hartbeespoort Dam, South Africa municipal tap water/South Africa treated drinking water/Germany treated drinking water/Germany treated drinking water/Germany treated drinking water/Germany Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France treated drinking
98
Ref.
(Dévier et al., 2013) (Swanepoel et al., 2015) (Boulard et al., 2018) (Boulard et al., 2018) (Boulard et al., 2018)
(Funke et al., 2016) (Simazaki et al., 2015) (Giebułtowicz and Nałecz-Jawecki, 2016) (Swanepoel et al., 2015)
(Wood et al., 2015) (Swanepoel et al., 2015) (Boulard et al., 2018) (Boulard et al., 2018)
(Funke et al., 2016) (Boulard et al., 2018) (Dévier et al., 2013) (Dévier et al., 2013) (Dévier et al., 2013) (Dévier et al., 2013) (Boulard et al., 2018)
Journal Pre-proof Occurrence (ng L-1)*
Antiviral drug
25
4
Lamivudine carboxylate
Lopinavir
Nelfinavir
f
oo
n.d. n.d. n.d.
pr
Nevirapine
e-
n.d.
n.d.
Jo u
n.d.
Saquinavir
al
38
rn
Ritonavir
3.5
Pr
Oseltamivir LOQ 2
n.d. n.d.
n.d. n.d.
Tenofovir
Zalcitabine Zidovudine
0.9
8.4 n.d.
Water type/Country of origin water/Germany drinking water treatment plants/USA municipal tap water/South Africa treated drinking water/Germany tap water/ Hartbeespoort Dam, South Africa municipal tap water/South Africa municipal tap water/South Africa Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France tap water/ Hartbeespoort Dam, South Africa municipal tap water/South Africa treated drinking water/Japan Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France tap water/ Hartbeespoort Dam, South Africa Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France municipal tap water/South Africa Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France municipal tap water/South Africa municipal tap water/South Africa tap water/ Hartbeespoort Dam, South Africa Evian water (PET and glass bottles)/France
99
Ref.
(Furlong et al., 2017) (Swanepoel et al., 2015) (Funke et al., 2016)
(Wood et al., 2015) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (Dévier et al., 2013) (Dévier et al., 2013) (Dévier et al., 2013) (Dévier et al., 2013)
(Wood et al., 2015) (Swanepoel et al., 2015) (Simazaki et al., 2015) (Dévier et al., 2013) (Dévier et al., 2013)
(Wood et al., 2015) (Dévier et al., 2013) (Dévier et al., 2013) (Swanepoel et al., 2015) (Dévier et al., 2013) (Dévier et al., 2013) (Swanepoel et al., 2015) (Swanepoel et al., 2015)
(Wood et al., 2015) (Dévier et al., 2013)
Journal Pre-proof Occurrence (ng L-1)*
Antiviral drug n.d.
72.7
1.9
Water type/Country of origin Volvic water (PET bottles)/France tap water/ Hartbeespoort Dam, South Africa municipal tap water/South Africa
*
Values of LOQ are given in brackets; n.d., not detected; n/a, not available
Jo u
rn
al
Pr
e-
pr
oo
f
Graphical abstract
100
Ref. (Dévier et al., 2013)
(Wood et al., 2015) (Swanepoel et al., 2015)
Journal Pre-proof Highlights
Global review on the occurrence of antivirals in WWTPs, groundwater, surface and drinking water
The determination of antivirals should be incorporated to multi-class analytical methods
Occurrence of antiviral drugs in influents and effluents varies significantly worldwide
More surveys are required to assess the chemical status in groundwater and
oo
rn
al
Pr
e-
pr
Urgent need for risk assessment and toxicity studies against non-target organisms
Jo u
f
drinking water
101
Figure 1
Figure 2
Figure 3
Figure 4
Christina Nannou, Anna Ofrydopoulou, Eleni Evgenidou, David Heath, Ester Heath, Dimitra Lambropoulou PII:
S0048-9697(19)34313-X
DOI:
https://doi.org/10.1016/j.scitotenv.2019.134322
Reference:
STOTEN 134322
To appear in:
Science of the Total Environment
Received date:
13 July 2019
Revised date:
4 September 2019
Accepted date:
5 September 2019
Please cite this article as: C. Nannou, A. Ofrydopoulou, E. Evgenidou, et al., Antiviral drugs in aquatic environment and wastewater treatment plants: A review on occurrence, fate, removal and ecotoxicity, Science of the Total Environment (2018), https://doi.org/ 10.1016/j.scitotenv.2019.134322
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2018 Published by Elsevier.
Journal Pre-proof
Antiviral drugs in aquatic environment and wastewater treatment plants: A review on occurrence, fate, removal and ecotoxicity
Christina Nannou a, Anna Ofrydopoulou a, Eleni Evgenidoua, David Heathb, Ester
Department of Chemistry, Aristotle University of Thessaloniki. GR 54124,
oo
a
f
Heath b,c, Dimitra Lambropoulou a*
Department of Environmental Sciences, Jožef Stefan Institute, Jamova cesta 39,
e-
b
pr
Thessaloniki, Greece
1000 Ljubljana, Slovenia Jožef Stefan International Postgraduate School, Jamova cesta 39, 1000 Ljubljana,
Pr
c
Jo u
rn
al
Slovenia
*Corresponding author: Tel: +30 2310 997687, Fax: +30 2310 997799 E-mail: [email protected] (D. Lambropoulou)
1
Journal Pre-proof
ABSTRACT The environmental release of antiviral drugs is of considerable concern due to potential ecosystem alterations and the development of antiviral resistance. As a result, interest on their occurrence and fate in natural and engineered systems has grown substantially in recent years. The main scope of this review is to fill the void of information on the knowledge on the worldwide occurrence of antiviral drugs in
f
wastewaters and natural waters and correlate their levels with their environmental
oo
fate. According to the conducted literature survey, few monitoring data exists for
pr
several European countries, such as Germany, France, and the UK. Lesser data are available for Asia, where approximately 80% of the studies focus on Japan. Several
e-
articles study the occurrence of mostly antiretroantivirals in sub-Saharan African
Pr
countries, while there is a lack of data for other developing regions of the world, including the rest of Africa, South America, and the biggest part of Asia. An
al
importantly smaller number of studies exists for North America, while no studies
rn
exist for Oceania. The against innfluenza drug oseltamivir along with its active
Jo u
carboxy metabolite is found to be the most studied antiviral drug. The distribution of antiviral drugs across all geographic regions varies from low ng L -1 to high μg L-1 levels, in some cases, even in surface waters. This overarching review reveals that monitoring of antiviral drugs is necessary, and some of those compounds may require toxicological attention, in the light of either spatial and temporal high concentration or potential antiviral resistance. Based on the information provided herein, the need for a better understanding of the water quality hazards posed by antiviral drugs existence in wastewater outputs and freshwater ecosystems is demosntrated. Finally, the future challenges concerning the occurrence, fate, and potential ecotoxicological risk to organisms posed by antiviral drug residues are discussed. 2
Journal Pre-proof
Keywords: Antiviral drugs, Aquatic environment, Ecotoxicity, Fate, Occurrence, Removal, Wastewaters
Abbreviations:
f
3TC, lamivudine; 8,14-DiOH-EFV, 8,14-dihydroxy-efavirenz; 12-OH-NVP, 12-
oo
hydroxy-nevirapine; ABC, abacavir; ACV, acyclovir; ADV, adefovir; AMT,
pr
amantadine; ARVs, antiretrovirals; ATV, atazanavir; AZT, zidovudine; AZTG, zidovudine glucuronide; CAGR, compound annual growth rate; CAS, conventional
e-
active sludge; CBX-ABC, carboxy-abacavir; CBX-ACV, carboxy-acyclovir; CBX-
Pr
AZT, carboxy-zidovudine; CBX-3TC, carboxy-lamivudine; CBX-FTC, carboxy– emtricitabine; D4T, stavudine; DDC, zalcitabine; DDD; defined daily dose; DDI, DES-ABC,
descyclopropyl-abacavir;
al
didanosine;
DLV,
delavirdine;
DOR,
rn
doravirine; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ETR, etravirine;
Jo u
EVG, elvitegravir; FCV, famciclovir; FDC, fix-dose combination; FDA, Food and Drug Administration; FTC, emtricitabine; GCV, ganciclovir; HAART, highly active antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; HCMV, human cytomegalovirus; HIV, human immunodeficiency virus; HPV, human papillomavirus, HSV, herpes simplex virus; HRT; hydraulic retention time; IDV, indinavir; LAN, laninamivir; LANO, laninamivir octanoate; LOD, limit of detection; LOQ, limit of quantification LPV, lopinavir; MVC, maraviroc; n.a., not available; n.d., not detected; n.q., not quantified; NFV, nelfinavir; NNRTI, non-nucleoside reverse-transcriptase inhibitors; NVP, nevirapine; OS, oseltamivir; OS-Et, oseltamivir ethylester; OC, oseltamivir carboxylate; PLC, pleconaril; PCV, 3
Journal Pre-proof penciclovir; PRV, peramivir; RAL, raltegravir; RBV, ribavirin; RPV, rilpivirine; RIM,
rimantadine; RSV,
respiratory
syncytial; RTV,
ritonavir;
RTVM,
desthiazolylmethyloxycarbonyl; SQV, saquinavir; SRT, solid retention time; T20, enfuvirtide; T-705, favipiravir; TDF, tenofovir; VACV, valacyclovir; VZV, varicella zoster virus; ZAN; zanamivir,
f
1. Introduction
oo
Among the plethora of contaminants of anthropogenic origin reaching the
pr
environment, pharmaceuticals, cosmeceuticals, biomedical, personal care products (PCPs), endocrine-disrupting chemicals (EDCs), and flame-retardants are of utmost
e-
importance (Bilal et al., 2019). Various classes of pharamceuticals constitute an
Pr
emerging class raising concerns about long-term consequences on human health (López-Pacheco et al., 2019), since widespread contamination from them has been
al
observed in the water cycle, concluding finally in drinking water, due to their
rn
hydrophilic character and low removal in wastewater treatment plants at
Jo u
concentrations from few ng L-1 to several mg L-1 (Kosma et al., 2019). Continuous discharge into aquatic systems make the residues of those compounds ubiquitous in the environment.
Antiviral drugs comprise a class of medication used to treat viral infections including influenza, herpes, hepatitis, and HIV (He, 2013). The worrisome rate of deaths due to viral infections has motivated the development of more and more antiviral drugs, after the approval and release of the first antiviral idoxuridine in the market, in 1963 (De Clercq, 2007; De Clercq and Li, 2016). These newly-developed antiviral drugs positively influence human health and prosperity, since the deadly outcomes and suffering of many infectious diseases are lessened, as well as life 4
Journal Pre-proof expectancy is increased and hospital stays are shortened (Flanagan et al., 2011). The development of new antiviral drugs is an integral part of the global pharmaceutical industry, and many facets of healthcare since the treatment of non-communicable diseases requires breakthroughs to be effective and confront resistant strains (Barr et al., 2016). Some antivirals are (highly) bioactive, they may negatively affect non-target organisms and persist in aquatic environments (Jain et al., 2013). In case that both the
oo
f
antiviral drug and the virus to be treated co-occur in the same water body, resistance strains are developed. This accelerates the establishment of antiviral resistance and it
pr
limits the clinical utility of the antivirals in human and animals (Laughlin et al., 2015;
e-
Olsen et al., 2006; Singer et al., 2014). Antivirals can also be toxic, and according to
Pr
(Q)SAR, modeling and toxicity data rank eighth among the most hazardous
(Sanderson et al., 2004).
al
therapeutic classes towards aquatic organisms such as algae, daphnia and fish
rn
The consequences of adverse effects of antiviral drugs in the environment are
Jo u
worrisome given the limited accessibility of specific populations to vaccines, increasing infectious diseases that demand large amounts of antiviral drugs on a longterm basis (Laughlin et al., 2015). Also, influenza pandemics or outbursts often result in seasonal variations and peak emissions of antiviral drugs residues (Singer et al., 2007) that merit investigation. A typical example of a sharp increase in the antiviral drugs load is the pandemic outbreaks of influenza in 2009, mainly in the UK (Singer et al., 2014, 2013). Other unpredictable sources, such as the direct disposal of nonexpired drugs due to changes in treatment regimens because of decreased medical efficiency (Pomerantz, 2004) is noteworthy.
5
Journal Pre-proof Evidence regarding the environmental occurrence and behavior of antiviral drugs is scarce and covers limited geographical regions (Fig.1). Despite their alarming high consumption rates, various antiviral drugs have been detected but not often systematically monitored in the aquatic environment (Abafe et al., 2018; Aminot et al., 2015; Azuma et al., 2019, 2017a, 2014; Funke et al., 2016; Mosekiemang et al., 2019; Prasse et al., 2010). The majority of studies concern WWTPs and surface waters, while there are fewer number of articles looking at groundwaters (Boulard et
oo
f
al., 2018; Fisher et al., 2016; K’oreje et al., 2016; Rimayi et al., 2018; Swanepoel et al., 2015), and drinking water (Boulard et al., 2018; Dévier et al., 2013; Funke et al.,
pr
2016; Furlong et al., 2017; Giebułtowicz et al., 2018; Swanepoel et al., 2015; Wood et
e-
al., 2015). Overall, antiviral drugs in wastewaters, surface waters, groundwaters, and
Pr
drinking water have not been documented to the same extent as for other pharmaceuticals. Also, many existing articles on the environmental occurrence of
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antiviral drugs were either published after influenza pandemics or are concerned
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mainly with antiretrovirals (ARVs) used in the fight against HIV.
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Although, the number of studies focused on environmental relevance of antiviral drugs have been steadily increasing in recent years, the literature on antiviral drugs has not been reviewed in detail. In particular, only a handful of reviews deal with their analysis, occurrence and adverse effects on the environment and almost all of them have exclusively focused on specific antiviral groups. For example, the analytical methodologies and presence of antiviral drugs in the environment were last reviewed in 2013 (Jain et al., 2013). However, almost all information in this review are available only for anti-influenza drugs and data for other groups are missing. There is also one review on the fate and ecotoxicological effects of antiretrovirals against HIV (Ncube et al., 2018), but survey data for the rest of antivirals was not
6
Journal Pre-proof included. Therefore, there is a need to compile the existing information and summarize up-to date progress in evaluation of antiviral drugs as environmental contaminants. To fill this gap, the current analytical approaches for the determination of antiviral drugs in the environment have been very recently reviewed by the authors (Nannou et al., 2019) with great emphasis on sample preparation and detection systems. In continuation of our recent review reporting on the analytical aspects of
oo
f
antiviral drugs determination in aqueous environmental matrices (Nannou et al., 2019), this review aims to discuss several aspects that were inadequately addressed
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until recently, by providing a comprehensive overview on the occurrence and removal
e-
of antiviral drugs in aquatic environment and wastewater treatment systems
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worldwide. Our specific objectives were to: (a) present an extensive up-to-date pattern on sales data worldwide, (b) investigate their occurrence in natural waters (surface
al
waters, groundwaters, drinking water) and wastewaters (c) address their behavior and
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removal in WWTPs and (d) identify challenges and perspectives of studying antiviral
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residues in the environment. To the best of our knowledge, this review is the first to gather all available data on antiviral drug environmental occurrence, removals rate and fate in WWTPs.
2. Types and usage of antiviral drugs Antiviral therapy aims to mitigate infectivity and symptoms, as well as to minimize the illness duration, by arresting the replication cycle of the virus in different stages of the viral life cycle (Bagga and Bouchard, 2014). A large part of antiviral infections are self-limited illnesses and can be resolved without treatment by immunocompetent individuals (Jin et al., 2018; Razonable, 2011). However, a 7
Journal Pre-proof relatively limited number of infections can be treated by the available antiviral therapies, since the resistance to antiviral drugs may restrict their clinical utility. The currently approved antiviral drugs are divided in 13 functional groups: (i) 5substituted 2’-deoxyuridine analogues; (ii) nucleoside analogues; (iii) (nonnucleoside) pyrophosphate analogues; (iv) nucleoside reverse transcriptase (RT) inhibitors (NRTIs); (v) nonnucleoside reverse transcriptase inhibitors (NNRTIs); (vi) protease inhibitors (PIs); (vii) integrase inhibitors; (viii) entry inhibitors; (ix) acyclic guanosine
(HCV)
NS5A
and
NS5B
inhibitors;
oo
f
analogues; (x) acyclic nucleoside phosphonate (ANP) analogues; (xi) hepatitis C virus (xii)
influenza
virus;
and
(xiii)
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immunostimulators, interferons, oligonucleotides, and antimitotic inhibitors. Ninety
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antiviral drugs are licensed today (De Clercq and Li, 2016). The inhibitory spectrum
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of the released antivirals concerns nine out of the 200 discovered human infectious diseases; namely, human immunodeficiency virus (HIV), hepatitis B virus (HBV),
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hepatitis C virus (HCV), human cytomegalovirus (HCMV), herpes simplex virus
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(HSV), human papillomavirus (HPV), respiratory syncytial virus (RSV), varicella-
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zoster virus (VZV), and influenza virus (De Clercq and Li, 2016; Razonable, 2011). Among them, the four main groups include HIV, herpes, hepatitis, and influenza viruses (Razonable, 2011).
According to global pharmaceutical sales data, antivirals are among the top 10 therapeutic classes (Mikulic, 2018). The global antiviral market was accounted for $42.65 billion in 2016 and is expected to reach $63.11 billion by 2022 growing at a CAGR of 5.8% (European Centre for Disease Prevention and Control, 2018). The average consumption of antivirals for systemic use in the 25 member countries of the Eurοpean Union is 1.97 DDD (defined daily dose)/ per 1,000 inhabitants per day, where antivirals to treat HIV infections predominate, and theay are followed by
8
Journal Pre-proof substances to treat influenza (European Centre for Disease Prevention and Control, 2018). Recent data (2018) on the consumption of antiviral drugs in Europe are depicted in Fig. 2. More than half of all of the produced antiviral agents are used against HIV, which is commonly referred as ‘highly active antiretroviral therapy’ (HAART). The pharmaceutical industry has developed more than 35 antiretroviral treatments for HIV, with an estimated cost of 26.7 billion US dollars (International Federation of
oo
f
Pharmaceutical Maufacturers and Associations, 2017). Until recently, zidovudine, tenofovir, lamivudine and abacavir were the ARVs (Abafe et al., 2018). From 2015
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on, less expensive and more effective regimens have been established, by introducing
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combination therapy of two or more drugs (tenofovir, emtricitabine, lamivudine, and
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efavirenz) (Meintjes et al., 2017). This cocktail medication is appropriate for adolescents, adults and pregnant women. If psychiatric comorbidity occurs, efavirenz
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is replaced by nevirapine (Gaida et al., 2017).
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In Europe, HIV combinational therapy accounts for 54% of the total antiviral
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drugs (European Centre for Disease Prevention and Control, 2018). In Africa, three million people are under HAART (Unaids, 2016), and ARVs constitute the “lion’s share” of pharmaceuticals prescribed in sub-Saharan countries. Given that the estimated daily dosage per capita for ARVs is approximately 991 mg/day, over 1085 tons of ARVs are ingested per year in this ontinent. This number is approximately 326 tons lower if the <30% average excretion via urine to sewage is taken into account. Antiviral drugs to treat influenza are an equally important group, being the key component of an influenza pandemic preparedness plan. According to WHO data, every year 250,000 to 500,000 people die, and more than 3 million are severely infected (WHO, 2018). Notably, only 8% of the antiviral drugs (mainly oseltamivir,
9
Journal Pre-proof zanamivir, amantadine, laninamivir, peramivir, rimantadine, umifenovir) are used to treat influenza. In Europe, the average consumption oseltamivir carboxylate (OC) that is the active metabolite of the most prescribed drug against influenza (Tamiflu®) (Hurt, 2019; Singer et al., 2014), zanamivir (ZAN) and rimantadine (RIM) is estimated 0.03 DDD/1000 inhabs/day (European Centre for Disease Prevention and Control, 2018). In the light influenza outbreaks during the 21st century, efforts have been made to simulate pandemic events in lab-scale experiments, in particular for
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oseltamivir carboxylate.
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3. Analytical approaches for the determination of antiviral drugs in
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e-
aqueous environmental matrices
Analytical approaches to determine antiviral drugs in the environment are
al
demanding, not only due to the complexity of the matrix but also due to the ultra-trace
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occurrence. Even more, when antiviral drugs co-exist with other trace contaminants method development and validation are more laborious tasks. More detailed
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information can be found in a recent review of the authors, which summarizes a critical number of good works on the analytical strategies employed (Nannou et al., 2019).
The majority of published methods are based on solid phase extraction (SPE) for the isolation and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) for the determination of analytes. In particular, offline SPE is most common (Abafe et al., 2018; Azuma et al., 2019, 2017b, 2017a; Giebułtowicz et al., 2018; Martínez-Piernas et al., 2018), while the on-line mode is also used but to a lesser extent (Khan et al., 2012; Kovalova et al., 2012; Singer et al., 2014, 2013). As for the majority of pharmaceuticals, Oasis HLB cartridges are the ‘golden’ sorbent, 10
Journal Pre-proof due to its versatility and efficiency for a wide spectrum of compounds with differing in physicohemical properties (Abafe et al., 2018; Azuma et al., 2019). Mixed-mode sorbents such as MCX were also used successfully (Aminot et al., 2016, 2015; Leknes et al., 2012; Takanami et al., 2012). Other cartridge types that have been employed as SPE sorbents were Bond Elut SCX (Azuma et al., 2019, 2017a, 2015a, 2014, 2013), Isolute ENV+ (Prasse et al., 2011, 2010), Strata SDB-L, (Mosekiemang et al., 2019), Cleanert PEP, (Schoeman et al., 2015), Bond Elut Plexa (Rimayi et al., 2018), Sep-
oo
f
Pak plus NH2 (Ghosh et al., 2010a), or combinations of more than two commercially available sorbents. Namely, Strata WCX, ZT, WAX and Isolute ENV+ (Ibáñez et al.,
pr
2017), HLB, Strata X-CW, Strata X-AW and Isolute ENV+ (Margot et al., 2013),
e-
HLB and Bond Elut SCX (Azuma et al., 2017a, 2016), and medium sized SPE disks
Pr
for a large volume (800 mL) extraction (Ferrando-Climent et al., 2016). A more straightforward solution is the direct injection to the LC-MS systems
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(Burns et al., 2018; Fisher et al., 2016; Funke et al., 2016; Furlong et al., 2017;
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Mosekiemang et al., 2019; Seitz and Winzenbacher, 2017), although the absence of
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sample preconcentration may pose limitations at ultra-trace level analysis. In this case, a guard column should also be used to prevent damaging the analytical column. Alternative extraction methods, such as molecularly imprinted polymer (MIP) SPE (Mtolo et al., 2019; Terzopoulou et al., 2016) and extraction on an in-house sorptive disposable PDMS loop sampler (Wooding et al., 2017) have been successfully applied. These lab-made sorbents are promising but of limited application, since they are highly selective, and as mentioned before, antiviral drugs are mostly studied as part of multiresidue studies. Freeze-drying has also been used as a preconcentration step for aqueous sample preparation (Boulard et al., 2018).
11
Journal Pre-proof Liquid chromatography coupled to (tandem) mass spectrometry is the ‘key’ analytical instrumentation (Martínez-Piernas et al., 2018; Mosekiemang et al., 2019; Rimayi et al., 2018). High-resolution mass spectrometers, such as Orbitrap and Q-ToF that allow both suspect and non-target analysis, are yet to be fully exploited for environmental analysis of antivirals. Non-target identification of antivirals is reported twice (Ferrando-Climent et al., 2016; Ibáñez et al., 2017). Boulard et al. (2018) were the first to use hydrophilic interaction liquid chromatography (HILIC). GC–MS
oo
f
remains less popular; a two-dimensional gas chromatography with time of flight mass spectrometry (GC×GC-TOFMS) was also employed (Furlong et al., 2017; Wooding
e-
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retrospective analysis is impossible.
pr
et al., 2017). The main limitation posed when non-HRMS is employed is that the
4. Fate of antiviral drugs in aquatic environment and WWTPs Fate of antiviral drugs in WWTPs
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4.1
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Wastewater treatment plants (WWTPs) are the first receiver of pharmaceutical
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and consequently antiviral drugs residues, where they are partially or completely eliminated, through various treatment processes, such as adsorption on activated carbon, oxidation, chlorination, ozonation and reverse osmosis, they can be released to the aquatic bodies as parent compounds, or (a)biotic transformation products (TPs) (metabolites, conjugates, and degradation products) (Evgenidou et al., 2015). Hence, WWTPs may determine the route and fate of pharmaceuticals after being ingested by humans. The employed technologies in WWTPs target primarily at the elimination of compounds of carbon (proteins, carbohydrates, lipids), and to a smaller extent, biogenic pollutants and emerging contaminants such as antiviral drugs, as proved by the concentrations of those substances in treated wastewater. Also, antiviral drugs are 12
Journal Pre-proof only recently recognized as contaminants, and WWTPs are not designed to remove them efficiently. Discharge of pharmaceuticals into the environment and therefore, contamination of water bodies is derived from WWTP effluents. Municipal or hospital WWTPs operate with primary, secondary, and less frequently tertiary treatment. Primary treatment includes physical processes of screening, comminution, grit removal, and sedimentation and aims to reduce the suspended solids. As expected, it is not sufficient to remove antivirals. Especially
oo
f
hydrophobic antivirals that exhibit log Dow (distribution ratio) >3 tend to be sorbed onto the sludge, and they are partially released once the primary treatment is
pr
completed (Ternes et al., 2004). Secondary treatment usually involves a biological
e-
process. The conventional practice is to employ an activated sludge (CAS) system
Pr
(Grandclement et al., 2017), while ozonation and membrane bioreactors (MBR) are less commonly applied (Vergeynst et al., 2015a). Also, when biological nutrient
al
removal is applied, the removal efficiencies can be higher than for conventional CAS
rn
process (Grandclement et al., 2017). Tertiary treatment increases the operation cost
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and is practiced when the intended receiving water is prone to the effects of pollution. Tertiary treatments include coagulation, filtration, activated carbon adsorption of organics, reverse osmosis and additional disinfection (e.g., chlorination, ozonation, and UV).
The applied treatment is a multi-factorial process that has a substantial impact on the removal efficiency. The treatment process is susceptible both to environmental (temperature, pH, redox conditions) and operation conditions such as the type of treatment, biodegradation kinetics, hydraulic retention time (HRT), sludge retention time (SRT), the oxygen source, and the concentration of pollutant in the influent (Dolar et al., 2012; Evgenidou et al., 2015; Verlicchi et al., 2012). It is probable that
13
Journal Pre-proof removal efficiency varies between different WWTPs, and even within the same WWTPs. There is also a lack of knowledge of the efficiency of WWTPs to cope with excessive loads of antiviral drugs, which means that antiviral drugs enter the aquatic environment. Physicochemical characteristics of the compounds to be treated (volatility, water solubility, absorption capacity on activating sludge and degradation half-life for (a)biotic processes are also crucial (Evgenidou et al., 2015; Gulkowska et al., 2007;
oo
f
Luo et al., 2014). The polarity of compounds plays a primary role in determining removal efficiency since polar compounds (logKow<3) are rarely adsorbed to the
pr
sludge and are poorly removed during the primary treatment. A large part of antivirals
e-
is polar and stable in water. Several antivirals exhibit low adsorption coefficients and
Pr
are more likely to occur in the aqueous phase and easily end up in water bodies. The dissociation of contaminants during treatment in the aqueous phase is enhanced when
al
their pKa is below the pH of the wastewater. Other constituents present in the
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wastewaters may react with the parent antivirals to form more persistent molecules
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that can threaten the aquatic environment (Pinon and Vialette, 2018). Despite the advances in water treatment technologies, effluents remain an important source of antiviral drugs load, given the occasionally low or negative removal efficiencies (Funke et al., 2016; Prasse et al., 2010). It is evident from the available data (Table 1) that it is difficult to conclude the removal rates of antiviral drugs. For instance, WWTPs operational conditions may differ significantly, while especially in the developing countries they may still operate in an early stage, without applying advanced treatment (Ncube et al., 2018). Also, there are significant differences in the concentrations between the inputs of many WWTPs, therefore, the removal rates are not easily comparable (Cramer et al., 2018).
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4.2.
Fate of antiviral drugs in the aquatic environment Once consumed and ingested by humans, antiviral drugs may be either
partially metabolized and excreted in urine and feces as active metabolites (Jain et al., 2013). A figure summarizing the fate of antiviral drugs in aquatic environment is given to depict the transmission of drugs to aquatic environment (Fig. 3). Typically, antivirals are excreted to a great extent in the bioactive form of the parent dose. Their
oo
f
human metabolism plays an important role to the antiviral drugs load that enter the environment. The major biotransformation pathways include glucuronidation,
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sulfoxidation, dimethylamine N-demethylation, and sulfate conjugation. Finally, these
e-
compounds reach the urban or hospital wastewater treatment plants (WWTPs) before
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ending up into the aquatic environment. Other potential sources may include illegal or improper disposal into water bodies or leachate from landfills (Nannou et al., 2015).
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The latter is the main reason for enantiomeric profiling since no metabolism takes
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less important source.
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place (Petrie et al., 2015). Antiviral drugs administered to animals are considered a
Once they enter into the environment, antiviral drugs are exposed to different processes. Although only a few articles are focusing on the fate of antiviral drugs in the environment, there is sufficient evidence that many of them may undergo photolysis, hydrolysis, sorption and biodegradation (Ncube et al., 2018). Most antiviral drugs are stable to photodegradation (Azuma et al., 2017a). Namely, oseltamivir carboxylate (Azuma et al., 2017a; Goncalves et al., 2011), emtricitabine, zanamivir, favipiravir, laninamivir, laninamivir octanoate, peramivir, amantadine, indinavir and stavudine are persistent to photodegradation (Dunge et al., 2004; Russo et al., 2018). In particular, abacavir is not photodegraded in either solid
15
Journal Pre-proof or solution form (Rao et al., 2011). Alternatively, the acyclovir is susceptible to photolysis in both freshwater and seawater (Russo et al., 2017; Zhou et al., 2015), as is zidovudine which photodegrades rapidly (>80%) (Dunge et al., 2004; Russo et al., 2018; Zhou et al., 2015). Regarding sorption mechanisms of antiviral drugs onto complex matrices such as soils and activated/deactivated sludges are not simply defined and are largely unknown. Up to now, only few data were published investigating their sorption onto
oo
f
sediments, sludge and soils. For example, the sorption of the antiviral drugs in river sediments was recently studied by Azuma et al. (Azuma et al., 2017a). Findings of the
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latter study reveal that of all targeted anti-influenza drugs (oseltamivir, oseltamivir
e-
carboxylate, zanamivir, favipiravir, laninamivir, laninamivir octanoate, peramivir,
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amantadine) exhibited low sorption tendency indicating that removal via sorption to sewage sludge is possibly negligible.
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Similarly to sorption, biotransformation of antiviral drugs is still unclear since
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only limited attention has been paid towards their biodegradability in natural
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environments (Saccà et al., 2009); (Azuma et al., 2017a). An interesting study in this area has been recently reported by Azuma et al, in which a clear difference in biodegradability among the targeted anti-influenza drugs was observed. For instance, laninamivir octanoate and oseltamivir were effectively biodegraded while oseltamivir carboxylate, zanamivir, favipiravir, peramivir and amantadine were highly resistant to biotransformation. In summary, we currently lack sufficient knowledge of the types, rates, and extent of transformations expected for antiviral drugs in natural systems and therefore further research is needed in this field in order to understand better the reactivity, fate, transport and persistence of these compounds in the environment.
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Journal Pre-proof
5. Occurrence of antiviral drugs in WWTPs The occurrence of antiviral drugs in WWTPs depends on various factors, such as the country, different medical needs, standard of living that largely affects the operation of advanced WWTPs, and sampling season, since pandemic outbursts of influenza are a major reason for the prescription of antiviral drugs. The inhibitory
f
spectrum of antiviral drugs studied in the environment includes mostly the
oo
antiretrovirals (against HIV) and the antivirals to treat influenza, followed by
pr
antiherpetics and to a far lesser extent by antivirals against cytomegalovirus and hepatitis C. The investigated antivirals in WWTPs are discussed per family of drugs,
Pr
e-
which is defined according to the inhibitory spectrum of the drug.
5.1 Antiretrovirals
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Abacavir (ABC) is a powerful nucleoside analogue reverse transcriptase
rn
inhibitor (NRTI) used to treat HIV. After oral administration, it is rapidly and
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extensively metabolized (83% bioavailability). Data on its occurrence is available only for German (Boulard et al., 2018; Funke et al., 2016; Prasse et al., 2010) and South African WWTPs (Abafe et al., 2018). Prasse et al. (2010) studied abacavir in two WWTP by applying either 24-h composite or grab samples (Prasse et al., 2010). In this study, the removal efficiencies indicated almost complete removal (>99%) in both cases, while the maximum reported concentration was 225 ng L-1 (Prasse et al., 2010). Two more studies in Germany included its main metabolites apart from the parent compund (Boulard et al., 2018; Funke et al., 2016). Funke et al. detected abacavir descyclopropylate (ABC-DES) apart from the parent compound as well as the main metabolite abacavir carboxylate (ABC-CBX). Abacavir was eliminated 17
Journal Pre-proof (removal >99%), probably due to is metabolization to glucuronide-adducts and further metabolization (15%) to ABC-CBX and ABC-DES, which exhibited negative removal rates (Funke et al., 2016). Biodegradation of abacavir is via the oxidation of the hydroxyl moiety to the corresponding carboxylic acid. Autoclaved control experiments show that abacavir is stable under abiotic conditions. Hence all the transformations are attributable to biological reactions. A high degradation rate of ABC was observed (Kbiol =55.8±1.8 L d-1 g SS, t1/2= 0.44 ± 0.003 h). The elevated
oo
f
polarity of carboxy-TPs indicates that powdered activated carbon (PAC) filtration alone is not capable of removing polar compounds. Another European study was
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performed by Aminot et al., who detected abacavir in effluents at a maximum
e-
concentration of 33 ng L-1 during two samplings (Aminot et al., 2015). Abafe et al.
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carried out a study in South Africa, which is interesting because it raises the issue of the efficacy of DEWATS (decentralized wastewater treatment system) - a type of
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facility that is proliferating in peri-urban areas of cities of the future in Africa, in
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comparison with a traditional WWTP. Abacavir was detected neither in influents nor
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in effluents in DEWATS, while in the influents of other WWTPs levels in the thousands of ng L-1. However, high removal rates were observed, since ABC was not detected in effluents. The effluent samples in conventional WWTPs were collected before the step of chlorination to allow the comparison with samples from DEWATS, where no disinfection with chlorination takes place. It is reported that this process leads to the formation of disinfection TPs that are still undescribed (Wood et al., 2016). The most recent study by Boulard et al. detected the parent compound below the limit of quantification in the effluents, while ABC-CBX was detected at a mean concentration of 86 ng L-1 in effluents. (Boulard et al., 2018).
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Journal Pre-proof Atazanavir (ATV) is a protease inhibitor prescribed for infected adults and children three months of age and older, and is always used in combination with other HIV medicines. It is present in the effluents of WWTPs and Abafe et al. suggest that the hydraulic residence time that is usually only a few hours for wastewaters in the activated sludge system accounts for the accumulation of atazanavir in the effluent of DEWATS and other WWTPs (Abafe et al., 2018). However, the degradation kinetics and breakdown products of ATV should be explored to understand its fate and
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removal in WWTPs (Abafe et al., 2018). Ferrando-Climent et al. (2016) and Ibanez et al. (2017) also detected ATV during non-target screenings of WWTPs in Norway and
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Athens, respectively.
e-
Darunavir is the most recent protease inhibitor used as a component of
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HAART in combination with the pharmacokinetic booster ritonavir (Belkhir et al., 2016). It is 94% excreted via urine, but there is not enough data available to interpret
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its presence in WWTPs. In two conventional WWTPs in South Africa, it was detected
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at concentrations up to 920 ng L-1 and 350 ng L-1 in the influents and effluents
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respectively, exhibiting negative removal rates. On the contrary, in a DEWAT plant, a very high concentration in the influent (43000 ng L-1) was substsntially decreased in the effluent, exhibiting removal close to 60%, a much better rate than in the conventional WWTPs (Abafe et al., 2018). Efavirenz (EFV) is another NNRT and a constituent of a cocktail prescribed to HIV patients that can be replaced by NVP, in case of unavailability or medical contradiction (Mbuagbaw et al., 2016). This drug is excreted altered or metabolized into several hydroxylated metabolites that can be further glucuronidated before excretion. Faecal excretion rates of EFV range from 16 to 61% and as a result, elevated concentrations are expected in WWTPs. Abafe et al. observed that EFV
19
Journal Pre-proof persisted in the effluents from all the three studied, and accumulates more in conventional WWTPs. According to the authors, this was attributed to the hydraulic residence time for wastewater in the activated sludge system, which does not exceed a few hours (Abafe et al., 2018). Efavirenz was investigated in three more studies in South Africa (K’oreje et al., 2016; Schoeman et al., 2017, 2015). Schoeman et al., 2017 monitored EFV during all the stages of the treatment (anoxic, aerobic, pre- and post-chlorination) over four weeks. Efavirenz concentrations entering the WWTP
oo
f
ranged from 5500 to almost 14 000 ng L -1. The removal of efavirenz by the WWTP ranged between 27 and 71%. Most of the compound was removed the anoxic zone,
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while smaller amounts were removed in the aerators. Slight increases in efavirenz
e-
concentrations were found after chlorination of the final effluent. The log Kow value
Pr
for efavirenz indicates the potential to bind to the sludge in the PST. Solids were found to contain efavirenz at concentrations between 17 and 43 mg/kg in dried
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primary settling tank sludge. The authors propose that adsorption to solids is the
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WWTP.
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primary removal mechanism for efavirenz from wastewater as it passes through the
The concentration levels of EFV indicate that it is a recalcitrant antiviral drug. The anoxic zone in a WWTP is considered a secondary treatment process and is designed to remove nitrogen. During this process, it is more likely that efavirenz is bound to the pulverized material produced during primary treatment. This material remains in the wastewater flow and is later removed in the primary settling tank (Schoeman et al., 2017). Efavirenz and its known metabolite 8,14- dihydroxy-efavirenz was monitored in another study in South Africa, found at low concentrations, but the removal rate was from 33 to 100%, depending on the region (Mosekiemang et al., 2019). Lower
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Journal Pre-proof concentrations of EFV were reported in Kenya (K’oreje et al., 2012, 2016). In this study, 8,14-dihydroxy-efavirenz was detected at roughly similar concentrations as the parent drug. Generally, concentrations of compounds were higher in raw compared to treated wastewater, in domestic compared to industrial wastewater and dry compared to wet seasons (Mosekiemang et al., 2019). Emtricitabine (FTC) is metabolized to a small extent in the human body (1030%) (Funke et al., 2016). For emtricitabine, the oxidation of thioether moieties to
oo
f
sulfoxides has been observed (Funke et al., 2016). Funke et al. detected FTC in influents of municipal WWTPs at concentrations up to 980 ng L -1. The removal
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efficiency of 74% meant that the concentrations in the effluents were much lower.
e-
Biodegradation of emtricitabine broadly follows the same transformation reactions via
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hydroxyl moiety oxidation to the corresponding carboxylic acid. Interestingly, emtricitabine carboxylate (FTC-CBX) and emtricitabine S-oxide (FTC-S-oxide)
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exhibited negative removal rates. Similar or higher (74%, 100%) removal rates for the
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parent compound were also observed by Mosekiemnag et al. Boulard et al. who
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studied FTC, FTC-CBX and FTC-S-oxide in wastewaters effluents found them at moderate to low mean concentrations (<380 ng L -1) (Boulard et al., 2018). Indinavir is a protease inhibitor that is almost always used in combination with at least two other anti-HIV drugs. It is considered as a ‘heavy’ antiretroviral, not recommended for initial therapy because of pill burden and the risk of nephrolithiasis (Tsibris and Hirsch, 2015). Less than 20% of indinavir is excreted unchanged in the urine (Cvetkovic and Goa, 2003). It was monitored both in conventional WWTPs and DEWATS. Slightly lower concentrations were observed in both influents and effluents in DEWATS. However, the removal rates for the two types of treatment
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Journal Pre-proof plants were comparable (Abafe et al., 2018). In France, indinavir was detected in very low concentrations in effluents (Aminot et al., 2015). Maraviroc is always used in combination with other HIV medicines. To the best of our knowledge, it has been studied only in South Africa, where it was detected in moderate concentrations in the effluents. The high removal efficiency was observed, resulting in its elimination from effluents. Lamivudine (3TC) is a first-line antiretroviral regimen. It has high water
oo
f
solubility (70,000 mg/L), and polarity (log Kow= −2.62). Like emtricitabine, the oxidation of thioether moieties to sulfoxides was observed for lamivudine (Funke et
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al., 2016). The drug was detected up to 60680 ng L -1 in influents Kenya, exhibiting
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low removals (24-59%). Another study in Kenya revealed a concentration range
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between LOQ–5430 ng L-1. This data is consistent with the consumption figures since the drugs constitute the first line daily dose antiretroviral regimen for people living
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with HIV and under antiretroviral therapy. The same authors conducted another study
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with antiretrovirals, including lamivudine in Finland and reported maximum
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concentrations of 55 ng L-1 in influents and 22 ng L-1 in effluents (Ngumba et al., 2016b). Prasse et al. detected 3TC in German wastewaters at a concentration up to 720 ng L-1, but they calculated an almost complete removal. Similar removal efficiencies were reported by Funke et al. (2016), Abafe et al. (2018) Vergeynst et al. (2015) and Mosekiemang et al. (2019); the latter observed that tertiary stage treatment efficiency was higher in biologically compared to MBR treated waste with subsequent UV-irradiation in the WWTPs studied. Boulard et al. reported a detection frequency of 50% in WWTPs in moderate concentrations. The carboxy metabolite of lamivudine mostly exhibited negative removal rates. It was found at concentrations from 25 ng L 1
in the influents up to 220 ng L-1 in the effluents in Germany (Funke et al., 2016).
22
Journal Pre-proof Abafe et al. found residues of lopinavir in the effluents from the WWTPs. Its presence was also reported (Wood et al., 2015) although only data for the effluent were available, making it difficult to make conclusions about the overall behavior of these drugs in WWTPs The nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) is used in combination with other agents in the therapy of HIV, and it is either excreted unchanged (2.7%) or metabolized into several hydroxylated metabolites, which may
oo
f
be further glucuronidated before excretion. The most widely known hydroxylated metabolite is 12-hydroxy-nevirapine (12-OH-NVP). This antiretroviral drug is the
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most investigated drug in many countries (Aminot et al., 2015; K’oreje et al., 2012,
e-
2016; Ngumba et al., 2016b; Prasse et al., 2010), but mainly in South Africa (Abafe et
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al., 2018; Mosekiemang et al., 2019; Ngumba et al., 2016a; Schoeman et al., 2017, 2015). The reported poor removal of nevirapine in WWTPs activated sludge may
al
occur due to its photostability and poor biodegradability (Prasse et al., 2010)
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In South Africa, Mosekiemang et al. (2019) reported similar (low)
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concentrations for both the parent drug and 12-OH-NVP, while they implied the possible occurrence of additional metabolites in these analyzed samples. The authors measured similar concentrations in raw and treated wastewater, concluding to removal efficiency close to zero, no matter the existence of a tertiary stage treatment, either biological or with a membrane with subsequent UV-irradiation. The authors also report higher concentrations in the dry season compared to the wet. In the same country, (Abafe et al., 2018) reported that NVP was accumulated in the effluents of all three studied WWTPs. That accumulation in the effluents was attributed to the reduced degradation of nevirapine at an acidic pH used in wastewater treatment. However, the authors discuss the limitation posed by the absence of 24-h composite
23
Journal Pre-proof samples, which make interpreting the results easier. Interestingly, the effluent concentrations from DEWATS and conventional WWTPs were similar. Although a more localized nature characterizes the DEWATS, it removes the compound to the same extent as WWTPs. Schoeman et al. found the mean concentrations of nevirapine in wastewater influent and effluents to be as high as 2100 and 350 ng L -1, respectively (Schoeman et al., 2015) and concludes that chlorination does not affect the removal of NVP. In a more recent study, the same authors found that the concentrations of NVP
oo
f
increase through the various stages of purification in the WWTP (between 92 and 473 ng L-1 in the effluents). This phenomenon is probably the result of the deconjugation
pr
of the hydroxylated metabolites of nevirapine, its recalcitrance and the lack of binding
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of the nevirapine to the primary settling tank (PST) sludge.
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In different WWTPs in Kenya, the levels of NVP in influents and effluents were very similar with those reported by Abafe et al., proving their claims about the
al
fate of NVP in WWTPs (K’oreje et al., 2012; Ngumba et al., 2016a; Vergeynst et al.,
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2015a). Prasse et al. reported much lower concentrations, and negative removal rates
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were considered unreasonable, although they did mention that the confidence interval underestimates the real statistical uncertainties of the nevirapine concentrations (Prasse et al., 2010).
Raltegravir is a newly approved by U.S. FDA (2007) integrase inhibitor. It was ubiquitous in DEWATS and WWTPs in South Africa, while it was better removed in conventional WWTPs (80%) (Abafe et al., 2018). Ritonavir is an apolar compound with logKow>4. It is metabolized into several non-glucuronide
derivatives,
of
which
the
primary
metabolite
is
desthiazolylmethyloxycarbonyl ritonavir. It was detected in 54% of the effluent samples analyzed, with a removal rate of 78% in a pilot-scale membrane bioreactor
24
Journal Pre-proof (MBR) installed and operated for one year at a Swiss hospital (Kovalova et al., 2012). Margot et al. measured ritonavir concentration up to 110 ng L -1 in effluents. The removal efficiency when applying conventional WWTP treatment was less than 25%, while ozonation and powdered activated carbon on ultrafiltration (UF) membrane surfaces (PAC-UF) removal efficiency increases by 8% and 56% respectively (Margot et al., 2013). These were the only two studies conducted in Switzerland for antiviral drugs. The highest concentrations for ritonavir were measured in South
oo
f
Africa; Ritonavir was detected in all the studied plants at μg L-1 levels (maximum mean concentration 3200 ng L-1 in the influents), while the removal rate was <50% in
pr
all cases (Abafe et al., 2018).
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The protease inhibitor saquinavir shows high activity against HIV. Scarce data
Pr
are available about its presence in WWTPs. In France, it was found at a maximum concentration of 0.2 ng L-1 (Aminot et al., 2015), while in South Africa it was
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2018).
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detected only in one out of three studied WWTPs, only in the influents (Abafe et al.,
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Stavudine was present in WWTP influents but not detected in WWTP effluents (Prasse et al., 2010). Stavudine is highly removed thanks to activated sludge (>78%) and biological treatment (>89%) (Prasse et al., 2010; Wood et al., 2015). The NRTI zidovudine (ZDV) is predominantly metabolized to its glucuronideadduct (zidovudine-glucuronide-ZDVG) where it is found in human urine along with the parent compound. Mosekiemang et al. studied both the parent compound and the glucuronide in WWTPs in South Africa, but neither of the two was detected. A separate study revealed elevated concentrations in the influents, reaching the μg L-1 scale in all the three studied WWTPs. Removal was 99% both in the conventional WWTPs and DEWATS, which used mostly anaerobic digestion technology in its
25
Journal Pre-proof treatment processes (Abafe et al., 2018). Zidovudine was also detected at several to hundreds of ng L−1 in German wastewaters. The elevated concentration was attributed to the cleavage of glucuronide conjugates, which are excreted by humans (70%), as reported by Prasse et al. (2010). K’oreje et al. in a Kenyan study concluded that ZDV is not only one of the most frequently detected compounds among the studied analytes, but also found at the highest concentrations (μg L-1 scale). However, the removal efficiency was 99% (K’oreje et al., 2016). According to Funke et al., who
oo
f
conducted autoclaved experiments in order to confirm its abiotic stability, the transformation of zidovudine is due to biological reactions. In addition, the
pr
comparison between the rate constants indicated an elimination efficiency of <50%.
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This is also partially explained by the formation of unknown TPs as already revealed
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by lab-scale experiments. The unclosed mass balance of ZDV in both lab-scale and full-scale experiments imply the formation of other unknown TPs. Zidovudine widely
al
followed the same transformation reactions via hydroxyl moiety oxidation to the
rn
corresponding carboxylic acid (Funke et al., 2016). According to the only study on
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antiviral drugs in Finland published by Ngumba et al. in Finland, ZDV had the highest measured concentration among other pharmaceuticals in both influent and effluent, although they were much lower than what has been reported in other countries. Although the rate of HIV in Finland is low, the presence of ZDV and two more antiretrovirals, namely nevirapine (NVP) and lamivudine (3TC) would suggest that a combination is a first-line antiretroviral regimen that most patients take daily (Ngumba et al., 2016b, 2016a).
5.2 Antivirals against influenza
26
Journal Pre-proof Amantadine (AMT) is a M2 ion channel inhibitor with multiple applications, since apart from against influenza, it is also used against hepatitis C as well as it serves as neurological medication in Parkinson’s disease and multiple sclerosis (Suzuki et al., 2003). The compound is excreted almost unchanged in urine (90%). Ghosh et al. explored the presence of AMT in three sewage treatment plants (WWTPs) during the 2008–2009 and 2009–2010 influenza seasons in Japan and the drug was ubiquitous in both sampling seasons (Ghosh et al., 2010b). In raw influents,
oo
f
the levels of AMT were from 184 to 538 ng L -1. During primary treatment, no substantial removal was observed (7–17%). The removal efficiency of amantadine
pr
during primary sedimentation is a result of adsorption to solid particles, which is
e-
related to its logKow (2.44). During secondary biological nutrient treatment (anoxic–
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oxic–anoxic–oxic and anaerobic– anoxic–oxic, the concentration of AMT decreased by 30-40%. Extended-aeration removed only 20% of AMT during secondary
al
treatment. According to the results obtained from all the three WWTPs, the authors
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concluded that anoxic–oxic–anoxic–oxic and anaerobic– anoxic–oxic (AOAO)
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process with pure oxygen have shorter sludge retention times and shorter hydraulic retention times compared to the same process using ambient air. The use of pure oxygen is important in enhancing bacterial biomass activity. Also, ozonation removed substantial amounts of AMT (93%) from the secondary effluent. Therefore, AMT can reach almost unchanged through primary and biological secondary treatments, and only tertiary treatment can remove it effectively. This capability proves the powerfulness of ozonation after secondary treatment during an influenza pandemic to restrict the release of antiviral drugs into the environment. Notably, AMT levels differed between the 2008–2009 and 2009–2010 sampling campaigns, but the overall removal efficiencies were in similar. Although AMT has been licensed in Japan since
27
Journal Pre-proof 1998 to treat influenza A, after the introduction of neuraminidase inhibitors, there has been a decrease in its annual consumption. Also, many strains of influenza virus have become resistant; this fact made the US Centers for Disease Control and Prevention to recommend its use only for susceptible virus strains and those resistant to other antiinfluenza drugs (FDA, 2018). Amantadine was studied by Vergeynst et al. in Belgium, where it was detected in all wastewater samples (50 ng L-1 to 1 μg L-1), and a negative removal rate was
oo
f
observed (Vergeynst et al., 2015a), possibly due to its desorption of suspended solids in the influent (logKow=2.44), since its deconjugation is less likely (<3.6% human
pr
excretion as acetyl-amantadine) (Vergeynst et al., 2015a).
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The recently licensed laninamivir octanoate (LANO) is a prodrug
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administered by inhalation, being inactive when taken. It is its pharmacologically active metabolite, laninamivir (LAN) that has the therapeutic effects. Its excretion rate
al
does not exceed 13%. In a recent investigation in Japan, it was detected in the
rn
effluents, at a concentration range from 18 to 21 ng L -1, in parallel with the increase of
al., 2015a).
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influenza incidents, while it was not detected by the end of the outbreak (Azuma et
Oseltamivir phosphate (OS), marketed as Tamiflu ®, is a prodrug of oseltamivir carboxylate (OC). Those substances are suggested by WHO as antiinfluenza inhibitors used for the treatment and prophylaxis of both A and B strains of influenza (Ghosh et al., 2010a). Oseltamivir is converted into its active metabolite (OC) in the human body; it is discharged as a mixture of about 15% OS and about 80% OC, giving an OS/OC ratio of about 0.2 (Azuma et al., 2013). Both compounds are the most studied antiviral drugs (Azuma et al., 2017a, 2014; Burns et al., 2018; Peng et al., 2014; Vergeynst et al., 2015b). The reason is not only because of the
28
Journal Pre-proof frequent outbursts of influenza but also because of the recent increase in OS resistance of the influenza A virus (H1N1). The latter raised concerns about the universal use of Tamiflu ® in pandemics and the potential associated ecotoxicological risks. As shown in Table 1, OS and OC occurred frequently in both influents and effluents in Japan (Azuma et al., 2015a, 2014, 2013; Ghosh et al., 2010a; Takanami et al., 2012) that is the top in per capita consumption of OS (Söderström et al., 2009). Quantifiable concentrations are also reported in Germany (Prasse et al., 2010), China
oo
f
(Peng et al., 2014), the United Kingdom (Singer et al., 2014, 2013), Norway (Leknes et al., 2012), Belgium (Vergeynst et al., 2015a), and in effluents in Sweden (Khan et
pr
al., 2012).
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Oseltamivir can be degraded via sorption, biodegradation, and photolysis
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according to both bench-scale and realistic approaches in sewage treatment plants (Peng et al., 2014; Wallensten et al., 2007). The structure (amine and carboxylate
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groups) and physicochemical properties of OS (logP =1.1, water solubility=588
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mg/mL at 25° C) indicate a low potential for the compound to be sorbed in suspended
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solids during treatment (Singer et al., 2007). Therefore, the concentration in the effluent is expected to be low in the solid phase and higher in the liquid phase. In most cases, the concentration of the parent compound was below or close to the limits of quantification. However, in Japan and the UK, elevated concentrations were observed during or after pandemics (Azuma et al., 2014, 2013; Singer et al., 2014, 2013). This is mainly attributed to the fast metabolism of oseltamivir in the human body yielding 70-80% oseltamivir carboxylate. Prasse et al. (2010) calculated the ratio of the parent compound/metabolite as 0.3 in wastewater. In treated wastewater, the ratio was higher but varied for different WWTPs effluents, and hence, no specific claims could be made based on the available data.
29
Journal Pre-proof The removals of OC were moderate to low and showed discrepancies. Ghosh et al. recorded OC in WWTPs influents of between 140–460 ng L-1 (Ghosh et al., 2010b). Primary treatment only removed 2.1–8.5% of OC, conventional WWTPs (primary plus biological secondary treatment) removed <50%, while additional of tertiary treatment by ozonation removed >90%. Ozonation is considered in several studies as an excellent treatment practice for the removal of both OS and OC since there is an evident decrease in their concentrations in ozonation plants (Azuma et al.,
oo
f
2013, 2012; Ghosh et al., 2010a). The length of incubation time also affects the removal of OC. For example, in the presence of activated sludge inoculum, a 40-day
pr
batch incubation resulted in 76% removal of OC in DEWATS. However, this is not
e-
true for WWTPs, where the HRT is in the activated sludge system has been estimated
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approximately 24 h (Abafe et al., 2018; Slater et al., 2010). Peramivir was introduced clinically in 2010, during the influenza prevalence
al
season The drug is administered intravenously and exhibits a high excretion rate
rn
(91%) (Azuma et al., 2015a). It has been detected in effluents in Japan, at a
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concentration range from 53 to 64 ng L -1 (Azuma et al., 2015a). Interestingly, according to Azuma et al., peramivir was not detected at the end of October 2013, while its levels then began to increase in December by several ng L-1 synchronously with the increase in the number of influenza patients, peaking at the end of January and in early February 2014. After the end of the outbreak, the drug was no longer detectable. Its maximum concentration in the effluent from WWTPs that used the CAS process followed by chlorination for disinfection 64 ng L -1. At the beginning of the ozone treatment using a batch ozonation reactor, the concentration decreased (4 ng L-1), and after a further 20 min, they were below the detection levels (Azuma et al., 2015a).
30
Journal Pre-proof Another M2 ion channel inhibitor used against influenza is rimantadine (RIM). This antiviral drug is less reported in WWTPs. K’oreje et al. (2016) included RIM in their study in three different WWTPs in Kenya, and it was only detected in the WWTP influents but was below the LOQ (K’oreje et al., 2016). Another study included samples from influents and effluents from two WWTPs in Belgium; a CAS and parallel membrane bioreactor/conventional active sludge plant. Rimantadine was not detected in the CAS, but it was above the LOD in the influents, CAS effluents and
oo
f
total effluents (i.e., after CAS and membrane bioreactor). In the membrane bioreactor effluent, levels of AMT were 2 ng L-1.
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Zanamivir (ZAN), also known as Relenza, is used widely to treat and prevent
e-
influenza, both in adults and pediatric patients (over five years old) (Shelton et al.,
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2011). Little is known regarding the fate and occurrence, although Its removal by ozonation after chlorination in WWTPs has been reported (Giri et al., 2010). Its
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occurrence in environmental samples was unknown until recently, probably due to
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analytical limitations posed by its highly polar nature (Takanami et al., 2012).
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However, it is extensively studied in Japan, where it is the second most prescribed drug against influenza (Azuma et al., 2015a, 2014, 2013; Takanami et al., 2012). The data on its occurrence in WWTPs (Table 1), as well as the concentrations found in the receiving bodies of the corresponding WWTPs, reveal declining concentrations thanks to wastewater treatment. According to Azuma et al. (2013), the median concentration of ZAN was 4.7 ng L -1 in non-ozonation plants, while in ozonation plants, the drug was not detected. Higher concentrations reported in 2015 (109-110 ng L-1 in effluents) are attributed to the decline in the preventive use of Tamiflu since the beginning of the flu outbreak and a preference towards prescribing zanamivir since H1N1 resistance to Tamiflu was reported (Takanami et al., 2012). In
31
Journal Pre-proof another study, ZAN was not detected during the sampling campaign that took place in October 2013, but began to be detected from December onwards, reaching a peak in early February 2014, coinciding with the influenza outburst. In May, the compound was no longer detectable (Azuma et al., 2015a).
5.3 Antiherpetics Acyclovir is widely used for antiherpetic medication, and it is excreted mainly
oo
f
as the unchanged parent compound, while acyclovir carboxylate (ACV-CBX) is its main metabolite occurs after the oxidation of the primary hydroxyl group in ACV and
pr
is shown to be recalcitrant (Sinha et al., 2007). Data on their environmental
e-
monitoring is largely available comparing to other antivirals. This may be attributed
Pr
to the fact that acyclovir is an antiviral drug covering a broad spectrum of viral infections; namely, cold sores around the mouth -caused by herpes simplex, shingles-
al
caused by herpes zoster), and chickenpox, as well as to treat outbreaks of genital
rn
herpes. For individuals with frequent outbreaks, it may reduce the number of future
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episodes (Cunningham et al., 2012). Also, the vast majority of published articles regarding WWTPs located in Germany (Boulard et al., 2018; Funke et al., 2016; Prasse et al., 2011, 2010; Seitz and Winzenbacher, 2017), while only three studies investigate the occurrence of ACV (but not ACV-CBX) in Japan (Azuma et al., 2019), China (Peng et al., 2014), and in the USA (Bear et al., 2017). Acyclovir was readily removed (>80%) both in urban WWTPs in Germany (Seitz and
Winzenbacher, 2017), probably due to the almost
complete
biotransformation of the drug during the activated sludge process. In the same study, the highest median observed concentration for ACV-CBX was 4800 ng L-1 in raw wastewater, and 5800 ng L-1 in the effluents (Seitz and Winzenbacher, 2017). Prasse
32
Journal Pre-proof et al. detected acyclovir at concentrations up to 1800 ng L -1 in influents and observed that it was nearly eliminated in effluents, after analyzing 24-h samples (Prasse et al., 2010). In general, it is reported that the removal of acyclovir in conventional WWTPs is high (>95%). However, it is not known if it is partially transformed or mineralized (Prasse et al., 2011). Acyclovir is rapidly dissipated in the activated sludge system (t1/2=5.3 h, and has a first-order rate constant about the amount of suspended solids (SS), 4.9 s-1) (Prasse et al., 2011). High concentrations of ACV and ACV-CBX were
oo
f
also reported by (Funke et al., 2016). However, while 91% of ACV was removed the metabolite removal rate was negative. The concentrations of ACV-CBX should not be
pr
neglected since it is reported that it exhibits increased toxicity towards Daphnia
e-
magna (Schlüter-Vorberg et al., 2015). In China, acyclovir was ubiquitously detected
Pr
with levels of 238 ± 56 (177–406) and 154 ± 24 (114–205) ng L−1 in the influent and final effluent samples, respectively. Aerobic biodegradation appeared to be the main
al
elimination process for acyclovir in the wastewater (Peng et al., 2014). In wastewater,
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acyclovir is found in the aqueous with more than 99% of the acyclovir present in the
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filtrates of the wastewater samples (Peng et al., 2014). The concentration of ACV decreases slightly in the anaerobic and anoxic effluents. In the secondary effluent, after clarification, the concentration was even lower, chlorination had no significant effect on the levels of acyclovir. However, variations in the transformation rate of acyclovir may occur, because of different treatment techniques, different HRT/SRT, and microbial consortia in the WWTPs (Peng et al., 2014). Sampling may also contribute to introducing bias in the estimation of the HRT when it is not possible to adopt composite samplings. Thus the influent and effluents collected during the same period are not the same wastewater package. In addition, the transformation of the parent compound to ACV-CBX to is also possible. This carboxy- TP is found to be
33
Journal Pre-proof highly recalcitrant to further microbial degradation, resulting its occurrence in surface waters, groundwater even in finished drinking water (Prasse and Ternes, 2016). Under typical treatment conditions (pH 7–8 and ozone content of dissolved organic carbon of 0.4), rapid ozonation of acyclovir and carboxy-acyclovir has been reported (Prasse et al., 2011). Finally, in a study on the occurrence of several pharmaceuticals in a scale unit process open-water treatment wetland, revealed modest removal (70%) of acyclovir by photolysis and biotransformation in the open-water cells when the
oo
f
hydraulic residence time for cell 2 was increased to four days (Bear et al., 2017). Famciclovir (FCV) is a guanine analogue used to treat herpes virus infections.
pr
It is most commonly used to treat herpes zoster (shingles), and it is a prodrug of
e-
penciclovir (PCV) with higher oral bioavailability. Azuma et al. studied both drugs
Pr
and detected FCV only in a hospital effluent, indicating the importance to established advanced treatment in hospital WWTPs (Azuma et al., 2019). Results from the 24 h
al
composite samples collected from another WWTP show that penciclovir is almost
rn
completely removed (>94%). Similar removal rates (>87%) were calculated for other
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WWTPs, although only grab samples were taken (Prasse et al., 2010). Valacyclovir has been detected at mean concentrations of 11 and 8 ng L -1 in influents in Japan, exhibiting excellent removal rate, since it was no longer detected in the effluents (Azuma et al., 2019).
5.4 Antivirals against Cytomegalovirus Ganciclovir is a thymidine kinase inhibitor and is one of the most frequently administered nucleoside agents used for the treatment of viral infections of the respiratory tract, apart from herpes virus. It is indicated for the treatment of lifethreatening or vision-threatening CMV infections in immunosuppressed patients
34
Journal Pre-proof (Razonable, 2011). It is poorly metabolized in the human body, and regarding its biodegradation, it is transformed via hydroxyl moiety oxidation to the corresponding carboxylic acid (Funke et al., 2016). Its occurrence in WWTPs is far less documented. In China, ganciclovir was below the quantification limits in both the influent and effluents (Peng et al., 2014). Funke et al., who studied its fate and occurrence in Germany, observed relatively low concentrations in WWTPs with a removal rate of
oo
f
>99% (Funke et al., 2016).
5.5 Antivirals against hepatitis C
pr
Ribavirin is a nucleoside agent that is used to treat encephalitis B and
e-
hepatitis. Since 2015 ribavirin is typically used as an adjunct therapy to various first-
Pr
line and second-line combination therapies recommended for each genotype. It has been studied in WWTPs in Germany (Prasse et al., 2010) and China (Peng et al.,
al
2014), but in non-quantifiable levels. However, it is reported that this drug is one of
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the most frequently administered are nucleoside agents in China.
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Figure 4 (a) and (b) is a Box-Whisker plot summarizing the quantifiable concentrations of antivirals in influents and effluents, respectively. In total, 28 parent compounds and 12 metabolites were investigated in WWTPs. As shown in Fig. 4, 34 and 32 out of the 40 investigated antivirals have been quantified in influents and effluents respectively. The maximum observed concentrations were for darunavir. ritonavir and efavirenz in the influents, while the minimum ones were for the metabolites 12-OHnevirapine and 8,14-dihydroxy efavirenz, and the parent compound rimantadine. For the effluents, important discrepancies exist, since removal is a multi-factorial process, hence it is difficult to claim that ere is a specific pattern. Hoever, efavirenz, darunavir
35
Journal Pre-proof and emtricitabine were found at relatively high concnetrations. In addition, according to our survey, antiviral drugs in hospital wastewaters are higher than in urban ones.The concentration levels of antiviral drugs in influents and effluents of WWTPs ranged from the low ng L-1 to μg L-1, and their removal ranged from 100% to negative rates. The recorded occasions of negative removal rates imply not only insufficient removal but also the release of the parent compound from conjugates or glucuronides during the treatment process. Spatial discrepancies both in the occurrence and
oo
f
removal rates are observed, due to the different therapeutical needs as well as the different treatment systems in the corresponding regions.
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Regarding the spatial distribution of available data for antiviral drugs, it seems
e-
that Japan is not only the leading country in terms of antiviral drug consumption and
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especially that of anti-influenza drugs, but also that a lot of investigation has been conducted for this therapeutic family. The high levels found in African wastewaters
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are partially attributed to factors such as the large percentage of population infected
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from HIV, as well as the lack of advanced wastewater treatment methods.
6. Occurrence in surface waters Determining the presence and concentrations of antiviral drugs in surface waters is important for risk assessment of these compounds in aquatic ecosystems especially in systems receiving wastewater effluents. In total, 25 antiviral drugs (parent compounds) and six metabolites have been found in surface waters (river, lake and dam) from eleven countries belonging to Asia, Europe and Africa, during different sampling seasons. Most of the available literature focuses on pandemic events or countries with high antiviral drug consumption, such as Japan, South Africa and Kenya, according to selected data. The occurrence data, including the average, 36
Journal Pre-proof maximum and minimum quantified concentration (ng L -1), depending on availability, are presented in Table 2.
6.1 Antiretrovirals Abacavir has been detected at very low concentrations in surface waters around Hessian Ried, in Germany, at a maximum concentration of 1.4 ng L -1 (Prasse et al., 2010). In two other studies in the same country, abacavir was either below the
oo
f
quantification limit in various sampling stations (Funke et al., 2016) or at an average concentration <5 ng L-1, in the River Rhine (Boulard et al., 2018). Aminot et al.
pr
detected abacavir in France, both in the river and estuarine waters and reported
e-
maximum mean concentrations from two sampling campaigns at 2.6 and 2.3 ng L -1,
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respectively (Aminot et al., 2016, 2015). In South Africa, abacavir was not quantified in surface waters (Wood et al., 2015). Boulard et al. also included abacavir
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carboxylate that is estimated to be formed in proportions of 15% (Funke et al., 2016)
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in their study of the river Rhine, which was detected at a mean concentration below 5
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ng L-1. Its poor removal during bank and sand filtration is attributed to its high biological stability and it comprise a source of contamination for groundwater and drinking water originating from these sources. This widely studied antiviral is claimed to be substantially removed during wastewater treatment (Prasse et al., 2010), a fact that explains the low concentrations in surface waters are predicted. Darunavir was investigated in Poland, and it was detected in river waters at a concentration of 72.7 ng L-1 (Giebułtowicz and Nałecz-Jawecki, 2016). For this drug, it is reported that concentrations increase downstream inside WWTPs, before the effluent mixes with with water; after mixing, the concentration can be decreased
37
Journal Pre-proof (Giebułtowicz et al., 2018). This implies a sufficient persistence for the drug to bypass the treatment process and occur in surface water. Dididanosine that can be excreted as largely unchanged parent compound was investigated by Wood et al. at many sampling points in South Africa but was quantified only in dam water (54 ng L-1) (Wood et al., 2015). In the same study, another more widely used antiretroviral, efavirenz, was also detected but not quantified. On the contrary, Rimayi et al. and Wooding et al. report maximum
oo
f
detected concentrations of efavirenz of 303 and 148 ng L -1 in dam water, respectively, and 354 ng L-1 in the river (Rimayi et al., 2018; Wooding et al., 2017). Slightly higher
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results were found in Kisumu, Kenya (560 ng L-1) (K’oreje et al., 2016).
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The poorly metabolized in the human body emtricitabine was detected in
1
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uMngeni and Juskei Rivers in South Africa, with average concentrations of 8-13 ng L(Rimayi et al., 2018). Boulard et al. investigated its occurrence along with its
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metabolites emtricitabine carboxylate and emtricitabine S-oxide in the River Rhine
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(Germany) and reported maximum concentrations of 45, 110 and 200 ng L-1, proving
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the fast metabolization of the parent drug (Boulard et al., 2018). Emtricitabine carboxylate was also included in a study of Funke et al. who when analyzing various surface waters in Germany reports concentrations of 25 to 280 ng L-1 (Funke et al., 2016).
Lamivudine, which has a low metabolism rate in the human body, is one of the most investigated antiviral drugs in the environment along with oseltamivir and nevirapine, according to our literature survey. It has been detected in Japan (Azuma et al., 2016), France (Aminot et al., 2015), Kenya (K’oreje et al., 2012, 2016), Germany (Boulard et al., 2018; Prasse et al., 2010), South Africa (Wood et al., 2015), and Finland (Ngumba et al., 2016b). However, it is difficult to conclude about its
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Journal Pre-proof behaviour, given the discrepancies in its concentration. In France, Germany and Japan it has been detected at the very low ng L -1 scale, but in Kenya, was detected in mg L -1 levels (0. 67 mg L-1 in Kisumu) (K’oreje et al., 2016). Such levels in river water is a result of inefficient wastewater treatment. Its carboxy- metabolite has been detected in rivers and streams in Germany, at concentrations varying from 16-230 ng L-1 (Funke et al., 2016). Lopinavir was detected in South Africa at an average concentration of 239 ng
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f
L-1 (Wood et al., 2015), but no other studies included it. Limited to the one study is also the investigation of nelfinavir, which was not detected in France (Aminot et al.,
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2015).
e-
Nevirapine, which is also used to prevent mother to child spread during birth,
Pr
is among the most studied antiretrovirals, and its concentrations varies depending on the country. It is observed that nevirapine exhibits a desorptive preference as the raw
al
effluent enters into water bodies, so it is diluted by environmental water (Bagnis et al.,
rn
2018). In Germany and France, it is detected in low levels (Aminot et al., 2016;
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Prasse et al., 2010). In three different studies in South Africa, no pattern was observed. Rimayi et al. reported 68 ng L-1 in the estuaries of the uMnegeni River during winter and is similar average concentrations during all seasons in dam water in the Hartbeespoort catchment and Juskei River (Rimayi et al., 2018). Much higher concentrations were found by Wooding et al., and Wood et al., reaching in the second case 1480 ng L-1 (Wood et al., 2015; Wooding et al., 2017). Interestingly, in Kenya, concentrations were in the thousands of ng L -1 level in the Nairobi River Basin as well as in Kisumu (K’oreje et al., 2016; Ngumba et al., 2016a). Nevirapine was not detected in Lake Päijänne, Finland, in one of the few studies of lake waters (Ngumba et al., 2016b). It is a low water soluble (0.1 mg mL -1) and higly lipophilic drug (log
39
Journal Pre-proof p=3.89), exhibiting weak basic character and ionization (pKa=2.8). Despite its relevant environmental occurrence, the environmental fate and behavior of nevirapine has not been studied extensively in the literature, hence insufficient data are available to explain if its occurrence is consitstent with the known phsyichemical properties Ritonavir was not quantified in South Africa (Wood et al., 2015), while in French rivers and estuarine waters it occurred at maximum concentration of 12 and 0.5 ng L-1, respectively (Aminot et al., 2016, 2015). Between 5 and 40% of ritonavir
oo
f
has been found to adsorb on suspended solids in a river system (Aminot et al., 2015). Ritonavir is hydrophobic, and in hot seasonal conditions, it has been found to partition
pr
onto solid particulate matter, explaining its low levels in aquatic bodies. Its half-life
e-
under biochemical conditions in the surface water is <5 days (Aminot et al., 2015).
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Saquinavir did not occur in French estuarine waters, investigated by Aminot et al. (2015), which is attributed to the fact that saquinavir and its metabolites are
al
eliminated from the body primarily through the biliary system and feces (more than
Jo u
(Patrick, 2002).
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95% of the drug), with minimal urinary excretion (less than 3% of administered drug)
The metabolic fate of stavudine has not been elucidated in humans. Hence it is difficult to comment on its occurrence, which can be explained only on a treatment basis. Besides, it was detected at a maximum concentration of 440 and 778 ng L -1 in Kenya and South Africa, respectively (K’oreje et al., 2012; Wood et al., 2015). The expectation that tenofovir could potentially reach surface water is high, given its extensive and rapid excretion as unchanged compound in the urine (Al-Rajab et al., 2010). Indeed, Wood et al. note concentrations up to 243 ng L-1 in South Africa. Tenofovir is also persistent in soils with no evidence of transformation products or microbial based degradation (Al-Rajab et al., 2010).
40
Journal Pre-proof Zalcitabine, whose metabolic fate has not been thoroughly evaluated in humans, undergoes minimal hepatic metabolism to dideoxyuridine, and less than 10% of an administered dose is excreted in feces. Its average concentration in South African surface waters was 36 ng L-1 (Wood et al., 2015). Zidovudine (AZT) exhibits high bioavailability (50–75%) and limited removal in biological treatment (Kumar et al., 2015). Extremely high concentrations (high μg L-1) have been observed in Kenya both by Ngumba et al. (2016a) and K’Oreje et al.
oo
f
(2016), and in South Africa (973 ng L-1) (Wood et al., 2015), while lower concentrations have been reported in Germany (Funke et al., 2016; Prasse et al.,
Pr
6.2 Antivirals against influenza
e-
pr
2010). Its environmental fate and behavior has not been discussed in detail yet.
Amantadine was detected at a mean concentration of 14 ng L -1 in Japan
al
(Azuma et al., 2013) and more recently from 5-61 ng L-1 (Azuma et al., 2017a),
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exhibiting non-synchronization discrepancy with the number of influenza patients. In
Jo u
China, in the Yangtze River Delta, the highest median concentration was 351 ng L-1, with a maximum value of 10.29 μg L-1(Peng et al., 2018). No ecotoxicological data is available; thus, more research is necessary for a better understanding of the risks posed by this compound in the environment. Oseltamivir and oseltamivir carboxylate concentrations varied significantly in surface waters, not only depending on the region but also the sampling period, since a lot of them took place after influenza pandemics or outbursts, as indicated in Table 2. As discussed before, the prodrug is readily absorbed and has high oral bioavailability (Achenbach and Bowen, 2013), and after extensive metabolization in the liver is excreted as oseltamivir carboxylate (Ghosh et al., 2010a), explaining the higher
41
Journal Pre-proof concentrations reported for this metabolite. Proposed calculations based on hydrologic modeling suggest that OC may remain in the environment for up to 18 days at levels of <300 to 32,000 ng L-1 during a pandemic (Achenbach and Bowen, 2013). Indicatively, concentrations were ≤864.8 ng L -1 in Japan, where several studies were conducted (Azuma et al., 2013; Ghosh et al., 2010a; Takanami et al., 2012, 2011). In the River Thames and River Wye (UK) the maximum concentrations were 193 and 6 ng L-1 in a study exploring the intra- and interpandemic variations of
oo
f
the metabolite (Singer et al., 2014). In Ebro river in Spain, Gonçalves et al. found concentrations of 50-100 ng L-1 (Goncalves et al., 2011), while in Germany and
pr
Sweden, concentrations did not exceed 2.4 ng L -1 (Khan et al., 2012; Prasse et al.,
e-
2010). In Europe, oseltamivir was not detected at levels above 15 ng L -1 (Burns et al.,
Pr
2018; Prasse et al., 2010). In Japan, the maximum concentration was 58 ng L -1, in Yodo River (Söderström et al., 2009). Specifically, in rivers, small amounts of
al
sediment may favor the degradation of OS, since microbial degradation is promoted.
rn
Yet, it needs several weeks to be completed (Bartels and von Tümpling, 2008). The
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low sorption affinity of OC for sediments explains its poor degradation. In addition, OC is not susceptible to direct photolysis and has a half-life in the ufiltered river water of 427 h (Bartels and von Tümpling, 2008). As a result, OC is expected to persist in water so that during influenza pandemics, a vast reduction of OC in WWTPs is necessary. It is reported that OC is unlikely to endanger aquatic organisms or to have a significant impact on the growth of aquatic flora and fauna through effects on neuraminidase in surface waters (Ghosh et al., 2010b). However, limited data means that an assessment of the long-term effects of this drug in the aquatic environment is not possible. The reported half-life of oseltamivir ranges from 15 to 150 days during photodegradation in surface water under natural solar irradiation,
42
Journal Pre-proof whereas under simulated solar irradiation, the half-lives of oseltamivir carboxylate were 48 h in pure water and 12 h in surface water (Goncalves et al., 2011). Zanamivir is among the most prescribed antiviral drug globally, and the second widespread antiviral in Japan, where it occurs in various concentrations up to 89 ng L-1 in rivers (Azuma et al., 2017a). This concentration was reported in winter, in parallel with an increase of the influenza patients, while in the other sampling
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seasons, the drug was not detected (Azuma et al., 2017a).
6.3 Antiherpetics
pr
Acyclovir has been frequently quantified in surface waters (Azuma et al.,
e-
2019; Boulard et al., 2018; Peng et al., 2014; Prasse et al., 2010). The highest
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concentration has been reported by Prasse et al. (2010) in the Hessian Ried region in Germany, while the same study revealed its lower concentration in the tributaries of
al
River Ruhr (20 ng L-1). Equally high concentrations (114 ng L -1) mentioned by Peng
rn
et al. (2014) in Pearl River Delta, China. In a recent investigation of Boulard et al.
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(2018), acyclovir was found to be 70 ng L -1 in the River Rhine, in Koblenz region (Germany) (Boulard et al., 2018). An average concentration of 10 ng L -1 was reported by Azuma et al. (2019) in Yodo River, Japan (Azuma et al., 2019). In a study by K’oreje et al. in Kenyan waters, acyclovir did not contribute at all to the load of antiviral drugs in the aquatic bodies (K’oreje et al., 2012). Recently, acyclovir was detected but not quantified in the Nau and Danube Rivers in Germany by Seitz et al. (2017) (Seitz and Winzenbacher, 2017). The same research group also studied the main biotransformation product and active metabolite of acyclovir, carboxy-acyclovir, and report average concentrations of 100 and 70 ng L -1, respectively. The same metabolite was detected (58-750 ng L-1) in various German rivers and streams by
43
Journal Pre-proof Funke et al. (2016). Valacyclovir, a prodrug of acyclovir, is indicated for the prophylaxis of CMV infection and disease following solid organ transplantation. Azuma et al. (2019) reported a mean valacyclovir concentration of 1 ng L -1 in the Yodo River, Japan (Azuma et al., 2019). Penciclovir is the active metabolite of the oral product famciclovir, which is eliminated principally by the kidneys as penciclovir and other metabolites. It is mainly used to treat infections from herpes simplex virus, and as indicated in Table 2,
oo
f
it has been detected at low concentrations (Azuma et al., 2019; Prasse et al., 2010),
e-
6.4 Antiviral against cytomegalovirus
pr
with a maximum of 11 ng L-1 in Japan (Yodo River) (Azuma et al., 2015a).
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The poorly metabolized in humans was detected in high concentrations in landfill leachates close to Pearl River (China) (418–1131 ng L-1, with a mean
al
concentration of 794 ng L-1). However, it was not detected in neither the river delta
rn
nor in well water near the municipal landfills (Peng et al., 2014).
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Finally, the occurrence of antiviral drugs is higly depended on geographic, seasonal, and social data. Typical examples are the spatial distribution of influenza pandemics, the different therapeutic needs, the standard of living in developing countries that suffer from viral illnesses (e.g. HIV). According to the results, it can be concluded that Japan is a pioneer in the study of the antiviral drug occurrence in the environment and it also prescribes more than 80% of the globally available Tamiflu® to treat common seasonal influenza (Sugaya et al., 2007). The most frequently detected antivirals were oseltamivir carboxylate and lamivudine. It is evident that among surface waters, rivers are usually acceptors of antiviral drugs. In addition, it derives from the findings that several
44
Journal Pre-proof African water bodies suffer from proper drinking water scarcity, or non-organized sanitary systems for bath end excretion, while the absence of rainfalls that hinders dilution in surface waters poses an extra factor that deteriorates the water quality. It is difficult to observe a specific pattern in the occurrence of antiviral drugs in surface waters since significant discrepancies are observed even within the same country. This is highly related to the sampling season, the existence or not of a pandemic event or an outburst, the environmental conditions and the prescription
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potential in each country. The latter affects the antiviral drug load entering the
e-
7. Occurrence in groundwaters
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influents, which is accordingly treated before being discharged in surface waters.
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Groundwaters can be receivers of the contaminated surface water through natural and artificial exchanges (Charuaud et al., 2019). Antiviral drugs exhibit
al
relatively high biological stability; hence they may show insufficient removal during
rn
bank filtration and sand filtration, and thus be present in groundwater, especially close
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to municipal wastewaters (Dévier et al., 2013). Data about the occurrence of antiviral drugs in groundwaters are limited compared to those in WWTPs and surface waters. However, they should not be underestimated since they indicate the extent of the emerging concern as well as the potential of such compounds to contaminate the drinking water, especially in regions with obsolete or where drinking water systems have not been upgraded. The fact that antiviral drugs are not studied to a great extent implies a bias on the estimations. The occurrence of antiviral drugs in groundwaters worldwide is summarized in Table 3. Detailed information for the behavior of each antiviral drug has already been given, and hence, the most imprortant results deriving from Table 3 are discussed herein. 45
Journal Pre-proof Among antiretrovirals, abacavir, its active metabolite abacavir carboxylate, as well as acyclovir were detected below the quantification limit Germany (Boulard et al., 2018). Abacavir was neither quantified in South Africa, in a study by Swanepoel et al. In the same study, didanosine and efavirenz were also below the quantification limit. However, efavirenz was detected in sampling campaigns conducted in South Africa, especially in Hartbeespoort Dam catchment and Gauteng Province, at a concentration range from 2 to 71 ng L -1 (Rimayi et al., 2018). Boulard et al.
oo
f
investigated the occurrence of emtricitabine, emtricitabine carboxylate and emtricitabine S-oxide in the groundwaters of Koblenz in Germany, and revealed
pr
maximum concentrations of 3.9, 370 and 23 ng L -1 (Boulard et al., 2018). Notably, the
e-
carboxy metabolite was detected in relatively high levels with an average
Pr
concentration of 140 ng L-1. Lamivudine was found at a concentration of 25.2 ng L -1 during the only study concerning antivirals in groundwaters in the USA (Fisher et al.,
al
2016). Nevirapine was detected at a wide concentrations range of 4.9-1600 ng L-1
rn
(Fisher et al., 2016; Rimayi et al., 2018; Swanepoel et al., 2015). The maximum
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concentration of 1600 ng L-1 was reached in Kisumu, Kenya (K’oreje et al., 2016). Stavudine was detected at a concentration of 0.9 ng L-1 by Swanepoel et al. (2015) in South Africa.
8. Occurrence in drinking water Since antiviral drugs may be present in groundwater, drinking water deriving from ground sources can be contaminated as well. Treatment methods for drinking waters are part of tertiary treatment which is practiced when the intended receiving water is very prone to the effects of pollution. These purification methods can be conventional or advanced. The conventional treatment is mostly applied in small and 46
Journal Pre-proof medium-sized facilities, and it can be achieved by chemical coagulation, filtration, sedimentation, and adsorption on activated carbon, being less sufficient to remove emerging contaminants such as antivirals. More advanced treatment techniques include membrane filtration (i.e. reverse osmosis, nano-filtration) and additional disinfection with chlorination, ozonation, UV, etc (Simazaki et al., 2015). The analysis of antiviral drugs in drinking water is rarely reported and concern samples from South Africa (Swanepoel et al., 2015; Wood et al., 2015), France
oo
f
(Dévier et al., 2013), Germany (Boulard et al., 2018; Funke et al., 2016), Poland (Giebułtowicz et al., 2018), Japan (Simazaki et al., 2015), and USA (one sample)
pr
(Furlong et al., 2017) In total, nineteen parent compounds and five metabolites of
e-
antiviral drugs were investigated, while quantification was feasible in very few
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samples (at the low ng L-1scale). Regular monitoring programs to test drinking water for pharmaceuticals are not yet implemented. The ultra-trace level (even sub-ng L-1)
al
that antivirals are expected in drinking water, the analytical difficulties in quantifying
rn
them and the absence of defined regulatory limits are the main limitations and reasons
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for the availability of data (Dévier et al., 2013). In particular, finished drinking water in Germany contained traces of lamivudine, emtricitabine, emtricitabine carboxylate, emtricitabine S-oxide, abacavir, abacavir carboxylate and acyclovir (Boulard et al., 2018). A study by Funke et al. reported the carboxy- transformation products of acyclovir, emtricitabine and lamivudine were quantified at a maximum concentration of 41, 80 and 85 ng L -1, respectively in drinking water originated from groundwater and surface water subjected to different treatments, (ozonation, activated carbon filtration). Darunavir was recently detected in tap water in Poland, at a maximum concentration of 169 ng L-1 (Giebułtowicz et al., 2018). In another study of Wood et al. (Wood et al., 2015),
47
Journal Pre-proof lopinavir, nevirapine, ritonavir, zalcitabine and zidovudine were found in tap water originating from the Hartbeespoort Dam, but only zalcitabine and zidovudine were quantified (8.4 and 72.7 ng L-1, respectively). In this the case, it should be taken into consideration that the method detection limits were relatively high (approximately 100 ng L-1 or higher), implying that the non- quantified concentrations may be not negligible. Swanepoel et al. with their report to the Water Research Commission underline the significance of the occurrence of antiviral drugs in South Africa’s tap
oo
f
water (Swanepoel et al., 2015). In this report, 31 municipal tap water samples had been analyzed to check for the presence of HIV antiretroviral drugs prescribed in
pr
Africa. Out of the eleven studied antiretrovirals, nevirapine was quantified in five
e-
samples (0.3 to 3.5 ng L-1) followed by didanosine (0.4-3 ng L-1), while lamivudine,
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tenofovir, efavirenz, lopinavir, and saquinavir were not quantifiable. In France, Devier et al. investigated the presence of antiviral drugs in mineral water stotred in
al
PET and glass bottles (Dévier et al., 2013). Unsurprisingly, none of the nine target
rn
antiviral drugs was detected. The results are logical, given that the samples of natural where
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mineral water are collected from areas of low anthropogenic pressure,
submission to filtration and geo-epuratation during the relatively long transit time within the aquifers is also possible (Dévier et al., 2013). Lamivudine was detected in 25% of the source-treated water samples collected during joint research of the U.S. Environmental Protection Agency (USEPA) and the U.S. Geological Survey (USGS). In this case, the water was treated in a frequently renewed, deep bed depth, activated carbon treatment (Furlong et al., 2017). Oseltamivir occurred in the finished water of a drinking water treatment plant in Japan at a concentration of 38 ng L-1, exhibiting removal efficiency to be as high as 60-88% in the course of purification with ozonation and granular activated carbon filtration. On the contrary, in the absence of
48
Journal Pre-proof ozonation and granular activated carbon filtration, the removal efficiency was zero (Simazaki et al., 2015). According to the above-mentioned data, the removal efficiency of antivirals during drinking water treatment is satisfactory, since in most cases the occurring concentrations are below or close to the quantification limits. Most of the residual antivirals are removed to a great extent during advanced water treatment processes, while their persistence is more possible during the conventional ones. Also, carboxy-
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TPs are present in the drinking water at concentrations varying from the ultra-low ng L-1 scale to approximately one hundred ng L-1. This is an evidence for the stability of
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TPs in the environment and it further confirms the expected lowerremoval during
e-
filtration as a conventional purification method, while ozonation and/or addition of
Pr
activated carbon for filtration enhances their removal (Funke et al., 2016). However, if a compound is detected in the finished water at a higher concentration than in the
al
sources, there is probably a deviation between the actual and estimated HRT. This
rn
means that the same plug of water may not be captured well at several drinking water
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treatment plants. In addition, the cleavage of conjugated pharmaceuticals during water purification could increase the concentrations of original substances. Finally, antivirals may be unintentionally consumed through final drinking water, and the impact of such human ingestion even at race levels may exert changes to the homeostatic mechanisms in the human body (Simazaki et al., 2015).
9. Ecotoxicity of antiviral drugs for non-target organisms A study of Sanderson et. al (2004) using (Q)SAR modeling of almost 3000 different compounds proved that antivirals are potentially hazardous and toxic mainly towards biota, such as crustaceans, fish and algae (Sanderson et al., 2004). However, 49
Journal Pre-proof their potential ecotoxicity and subsequent antiviral resistance are yet underexplored. Moreover, the potential synergistic interactions between antivirals leading to unexpected adverse effects to humans and other organisms should be considered. These implications underline the need to comprehend the toxicity during the life cycle instead of investigating extensively the acute toxicity. Herein, indicative information on the antivirals with the most relevant environmental concentrations are provided. Several studies are devoted to the ecotoxicity of antiviral drugs against non-
oo
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target organisms, but antiviral drugs to treat influenza are on the spotlight, especially during pandemic incidents. Oseltamivir and oseltamivir carboxylate have attracted
pr
most of researchers’ interest (Escher et al., 2010; Hutchinson et al., 2009; Singer et
e-
al., 2011; Straub, 2009), due to their widespread consumption and proved
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environmental occurrence. Mestankova et al. (2012), who studied both compounds, stated that the chronic non-observed concentrations (NOEC) for algae, daphnia and
al
fish are high (>1 mg L-1) (Mestankova et al., 2012). This claim is also confirmed by
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an older study for (sub)chronic NOEC found to be higher than 1 mg L -1 as well
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(Hutchinson et al., 2009). Escher et al. (2010) studied the toxic action to non-target organisms posed by both the individual compounds and their mixture. For the parent compound, the The EC50 value in a 30-min bioluminescence inhibition test with V. fischeri was close to 10.5mM, corrsponding to apporximately an EC50 value of 4.3 g L-1. In the algal toxicity with D. subspicatus, the photosynthesis inhibition after 24 h gave an EC50 of 15.5mM, which corresponds to 6.4 g L-1. Although high, these EC50 values are in good accordance with the low hydrophobicity of the compound. The additional insight into the mode of mixture interactions revealed that in V. fischeri both compounds were toxicants with the mixture effects to be close to concentration addition, while in green algae only the prodrug oseltamivir was a baseline toxicant
50
Journal Pre-proof (Escher et al., 2010). Given the widespread consumption of Tamiflu, it is urgent to study the ecotoxicological risks posed by its pharmaceutically active ingredients both in activated sludge and the receiving waters. Rare ecotoxicological data was found in open literature for the widely used anti-influenza drug amantadine. A general claim is that its effects are negligible even during periods large-scale influenza pandemics, while only concentrations above 1 mg/L can exert acute and chronic toxic effects occur (Azuma et al., 2015b). However,
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the evolution of ecotoxicity for this in three different trophic levels, namely in phosphoreum, S. capricornutum and D. magna, showed that phosphoreum (15 min),
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S. capricornutum (72 h) and D. magna (48 h) were found to be inhibited by 12.6, 8.9
e-
and 56.0 % for 0.1 mM 1-amantadine. In the same study, rimantadine (0.1mM) was
Pr
investigated and the inhibition was 15.4,8.9 and 46.0% for 0.1 mM rimantadine exposure for the three trophic levels, respectively.
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Regarding the ecotoxicity of antiretrovirals, data are sparsely available, but the
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findings are remarkable. According to available data for freshwaters, abacavir has an
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EC50 value of 57 mg L-1, being harmful to green algae. On the other hand, the value of this marker is higher (100 mg L-1) for diatoms and crustaceans (Minguez et al., 2016). However, since algae are the primary “producer” in an aquatic ecosystem, these results are rather inauspicious. In a reproduction test with D. Magna for abacavir (21 days), no mortality was observed, since the population growth rate of D. magna exposed to a concentration of 92.1 mg L −1 did not differ from the medium control (Schlüter-Vorberg et al., 2015). Efavirenz is hazardous in the environment, as it is persistent and toxic to aquatic life. According to Robson et al. (2017), the exposure (96 h) of fish (O. mossambicus) to efavirenz at a concentration of 20.6 ng L 1
provoked liver damage, as well as higher total fish deaths comparing to the control
51
Journal Pre-proof sample (Robson et al., 2017). Emtricitabine exhibited negligible ecotoxicity risk for three trophic levels (algae, daphnia, and fish), since the median measurements for the risk quotient (RQ) were 0, and the used PNEC was in the high μg L-1 scale (7927.3, 332.1, and 47662.1, for the previoysly mentioned organisms, respectively) (Ngumba et al., 2016a). No data are available for the parent compound of lamivudine, which is not biodegradable. Nevirapine had also potential ecotoxicological effects on algae, daphnia and fish with algae being the most affected (RQ=29.1) (Ngumba et al.,
oo
f
2016a). Zidovudine was found to be toxic for algae, with a median value of RQ at 50, while the maximum observed value was 271.5, as reported by (Ngumba et al., 2016a).
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Regarding antiherpetics, a recent study for the chronic ecotoxicity posed by
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the not readily biodegradable ganciclovir used algae and daphnids as test organisms,
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revealed no persistence or bioaccumulation. No inhibition was observed on the tested microorganisms, at the highest tested concentrations (1000 mg L -1). In the same study,
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a comparison between predicted environmental concentrations and predicted non-
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effect concentrations revealed no significant risk for wastewater treatment, surface
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waters, groundwater, or sediment, while the potential risks to aquatic predators or to human consumers of water and fish are exceedingly low (Straub, 2017). Like ganciclovir, valganciclovir exhibited no relevant risk to aquatic organisms and humans that consume water and fish exposed to its traces. The toxicity assessment of mixtures of parent compounds and their metabolites is a future challenge for a more systematic approach of risk assessment. In addition, when there is a lack of available data, QSAR predictions could be employed in order to cover the data gaps and simple mixture toxicity models can be applied. Apart from ecotoxicity, the potential development of viral resistance is a subsequent burning issue, since the chronic exposure to antivirals imply serious
52
Journal Pre-proof damages, with regard to human health, and despite the efforts to prevent this process, it oftens proves futile. Antiviral resistance in wildfowl is of primary concern, especially for the anti‐influenza drugs, since birds host influenza virus(es). The risk is even higher
during pandemic
events,
when the predicted environmental
concentrations of OS and OC may reach 80 μg L-1 (Ellis, 2010). It is of high importance to underline that the antiviral resistance differs, according to the biology of each virus, and should be considered in any analysis of resistance conferral. More
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research on antiviral resistance evolution should be motivated, embracing both the biological and environmnetal approaches, since the two aspects are complementary.
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Further discussion on antiviral resistance is out of the scope of this review, as well as
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the contribution of the biological, pharmacological and medical aspects would be
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requisite. Excellent reviews that compile crucial information from relevant research articles in an effort to shed light on the issue of antiviral drug resistance as an adaptive
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process are readily available (Duffy et al., 2008; Foll et al., 2014; Irwin et al., 2016;
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Lurain and Chou, 2010; Piret and Boivin, 2014; Thorlund et al., 2011).
10. Concluding remarks and future challenges The presence of antiviral drugs in the environment is an emerging issue that raises concerns not only for the environment but also for humans, since resistant virus strains could be developed. This review is an update of the available data and provides the most crucial information for the environmental occurrence of antiviral drugs in aqueous environmental matrices originating from different geographical regions. Nevertheless, the continuous discharge of drugs in the aquatic environment through wastewater outputs, along with the lack of systematic governmental programs to prevent their entry into aquatic environment implies this field is unlimited. 53
Journal Pre-proof The occurrence of antiviral drugs in the aquatic environment exhibits significant discrepancies, hindering the observation of a particular pattern. This is attributed to factors such as the different consumption and prescription rates and different treatment technologies, but also environmental and geographical conditions. Regarding the antiretroviral drugs, the therapeutical schemes are individual and specialized, in order to protect infected people from any mutations of the virus, which mean that variations are inevitable. The withdrawal of drugs due to the release of
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novel, advanced drugs to face any resistant strains of the virus and to improve the standard of living of the infected people is another source of disposal which should be
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regulated by the pharmaceutical industries. To the best of the authors' knowledge,
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there is very few data on the occurrence of antiviral drugs in industrial wastewaters.
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The removal of antiviral drugs from WWTPs should be enhanced. This can be achieved by optimizing existing WWTP technology, upgrading with new technologies
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and controlling contamination at the source.
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The spatial distribution of the published articles revealed that African water
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bodies and wastewaters are the most investigated, targeting the sub-class of antiretroviral drugs. This is an alert for greater awareness of the current situation of the antiretroviral drugs in the continent that most suffers from HIV. The poor sanitation systems and drinking water treatment in the area, as well as the low rates of precipitation which would otherwise dilute the antivirals when entering water bodies, urges comprehensive studies in the aquatic environment and the drinking water sources. Several articles studied the antiviral drugs in Europe and Asia, with a lot of investigations carried out in Germany/UK and China/Japan, respectively. Scarce data are available for Norway, Belgium and the USA. A large part of the published works
54
Journal Pre-proof have been published after pandemic incidents of influenza, to assess the environmental impact of the systematic oseltamivir administration. In the case of antiviral drugs against flu, there are occasional unpredictable events, such as pandemics, when the performance of WWTPs is limited. It would be precarious to claim that a trend characterizes the urban and hospital wastewaters, since their reported levels vary between developed and developing countries, where the treatment systems are of poor quality or efficiency, if not absent.
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Many steps should be taken, and investigation should be conducted purposefully to cover the gaps in the existing knowledge on the environmental fate,
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occurrence and risks posed by antiviral drug residues. In addition, to observe if
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antiviral drugs follow specific patterns, nationwide studies are necessary, in both high
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and low-income countries. More studies to comprehend the correlation between the parent antiviral drugs and their metabolites/transformation products and their
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environmental fate and occurrence would be of great help to estimate the fate of this
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emerging class of contaminants that barrens of proper attention. The evolution in the
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drug-use patterns led to the release into the market of new drugs. This implies the need to monitor more antiviral drugs and to assess the risks posed due to the development of new resistant virus strains. The extensive study of antiviral drugs occurrence in influents and effluents of wastewaters addresses the major questions whether the appropriate wastewater treatment is applied for sufficient removal. It is imperative to select the appropriate wastewater treatment according to the removal needs of each plant and to increase further the efficiency of the currently used treatments. Also, new treatment technologies practising bioplastic moving bed biofilm carriers and electrochemical degradation may help to increase removal rates.
55
Journal Pre-proof Wastewater analysis tends to be carried out only in the aqueous phase since particulate and solid phase are not routinely analyzed. However, the determination of the load of antiviral drugs in this phase could elucidate the obtained results, especially regarding influents concentration, since certain drugs have high affinity to particulate matter. In addition, the analysis of treated and untreated sludge, as well as biosolids, would be of vital importance to study the fate in WWTPs. The correlation between aqueous and solid matrices provide unique information about the fate of the drugs in
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WWTPs, which up to now are almost unmonitored. The monitoring studies should be broadened by analyzing also receiving seawater, biota, soils, sediments, as well as
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irrigated crops and animals that feed the populations, especially in developing
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countries, where surveys are needed to investigate the appropriateness of drinking
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water.
From an analytical point of view, it is necessary to take advantage of the most advances
in mass spectrometry and employ high-resolution mass
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recent
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spectrometers, such as Orbitrap and Q-TOF. Using these it is then possible to conduct
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dynamic suspect and non-target screenings and enlarge the number of compounds included in target analysis, given that among the published articles dealing only with antiviral drugs, only a few are included. The use of such sensitive instrumentation would also provide lower quantification limits that are needed to quantify trace level of antivirals in surface and drinking water. Moreover, retrospective analysis is also feasible when applying advanced MS technologies. The results highlight the importance of evaluating the ecotoxicity of TPs of antiviral drugs. The formation of carboxy-TPs via oxidation of the hydroxyl-moiety may result in the loss of antiviral activity, decreasing the phosphorylation in virally infected cells. Moreover, the toxicity of some carboxy metabolites comparing to the
56
Journal Pre-proof parent compounds in typical test organisms (i.e. Daphnia magna) indicates that transformation reactions can lead to more toxic compounds. Thus, it is necessary to incorporate ecotoxicity studies for a variety of antiviral drugs and test systems to obtain reliable results. Toxicological tests simulating environmental conditions and antiviral drugs consumption are necessary to test the behavior of various organisms belonging to different trophic levels, apart from the typical indicator species. This will be of great help to estimate the ecotoxicology effect to non-target organisms.
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Particular attention should be paid to the agonizing issue of the occurrence of drug mixtures, let alone with antibiotics, with which antiviral drugs are typically prescribed
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in parallel.
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Antiviral drugs are strictly prescribed medicine. Equally strict is the potential
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to deviate from the recommended and prescribed dosages, in order to avoid any undesirable development of resistant strains of the virus. This fact can facilitate the
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prediction of environmental concentrations as well as the prioritization of target
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antiviral drugs incorporated in monitoring studies. Therefore, the number of antivirals
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to be target screened can easily be enlarged. It is valuable to investigate the simultaneous occurrence of antiviral drugs with antibiotics, given that those classes of pharmaceuticals are frequently prescribed together, to deal with bacteria that threaten the strained immune system of the patients.
Acknowledgements This research has been funded by 2014 - 2020 Interreg IPA Cross Border Cooperation Programme CCI 2014 TC 16 I5CB 009, Research Project: Aqua-M II: Sustainable management of cross-border water resources, Project number (MIS): 5030774, which is gratefully acknowledged. 57
Journal Pre-proof Ms Α. Ofrydopoulou would like to thank the General Secretariat for Research and Technology (GSRT) and the Hellenic Foundation for Research and Innovation (H.F.R.I.) for providing her scholarship through the action '1 st Proclamation of Scholarships from ELIDEK for PhD Candidates' - Scholarship Code: 429.
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Legends of figures
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Fig. 1 Location and number of studies reporting on the environmental occurrence of
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antiviral drugs worldwide
Fig. 2 Systemic use different groups of antiviral drugs in Europe (a) in DDD per 1000
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inhabitants per day, (b) as a percentage of the total use (European Centre for Disease Prevention and Control, 2018)
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Fig. 3 Transmission of antiviral drugs in the aquatic environment
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Fig. 4 Box and Whisker graph showing the concentrations (ng/L) of antiviral drugs in (a) influents (b) effluents
Fig. 1
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0.00
1.00
2.00
3.00
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Spain Malta Slovenia Lithuania Croatia Hungary Iceland Finland Bulgaria Norway Cyprus Germany Sweden Austria Belgium Netherlands Romania Latvia Luxembourg Italy Denmark Poland France Estonia Portugal
4.00
5.00
6.00
7.00
HIV/hepatitis B
Hepatitis B
Hepatitis C
Herpes
Influenza
Other antivirals
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HIV/AIDS
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DDD/1000 inhabitants per day
(a)
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rn
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Spain Malta Slovenia Lithuania Croatia Hungary Iceland Finland Bulgaria Norway Cyprus Germany Sweden Austria Belgium Netherlands Romania Latvia Luxembourg Italy Denmark Poland France Estonia Portugal
0%
HIV/AIDS
10%
20%
HIV/hepatitis B
30%
40%
Hepatitis B
50%
Hepatitis C
(b) Fig. 2 81
60%
Herpes
70%
80%
Influenza
90%
100%
Other antivirals
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pr
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al
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Fig. 3
82
500.0
50.0
al
rn
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5000.0
ABC ABC-CBX ABC-DES ATV AZT D4T DAR EFV 8,14-DiOH-EFV FTC FTC-CBX FTC-S-oxide IDV MVC LPV NVP 12-OH-NVP RAL RTV SQV 3TC 3TC-CBX AMT OS OC RIM ZAN ACV CBX-ACV PCV GCV RBV
ng/L
(a)
50000.0
pr
e-
Pr
ABC ABC-CBX ABC-DES ATV AZT D4T DAR EFV 8,14-DiOH-EFV FTC FTC-CBX FTC-S-oxide IDV MVC LPV NVP 12-OH-NVP RAL RTV SQV 3TC 3TC-CBX AMT OS OC RIM ZAN ACV CBX-ACV FCV PCV VACV GCV RBV
0.5
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ng/L
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50000.0
5000.0
500.0
50.0
5.0
5.0
0.5
(b)
Fig. 4
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Table 1. Occurrence of antiviral drugs in WWTPs influents and effluents worldwide, listed by therapeutic class
n/a
33
>99% >99% n/a n/a n/a n/a n/a >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 <10 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
Germany Germany Germany 1 KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa France Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany
(Pras (Pras (Bou (Aba (Aba (Aba (Ami (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Bou (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun
n/a
Germany
(Fun
n/a n/a n/a n/a n/a n/a n/a n/a n/a
Germany Germany Germany Germany Germany Germany Germany Germany Germany
(Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun
f
31
Ref.
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n.d.
Region/Country
Pr
e-
pr
n.d.
Removal (%) Mean
20
170
al
n/a
n.d.
Max
rn
n.d.
81.7±5.3 225±40 n.d. n.d. 3500±210 14000±2300 n/a 110±26 74±7 110±16
Effluents Min
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Occurrence (ng L-1)* Influents Min Max Mean
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5589 13450 7485 12090
4046 3872 3879 4040
15.4
9.15
40
Western Cape, South Africa
0.982
31
Western Cape, South Africa
8.04
33
Western Cape, South Africa
100
Western Cape, South Africa
51
n/a
Germany
41.7
76
Western Cape, South Africa
100
Western Cape, South Africa
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany
Ref. (Aba (Aba (Aba (Ferr 2016 (Ibáñ (Aba (Aba (Aba (Aba (Aba (Aba (K’or (K’or (K’or (K’or (Sch (Sch (Sch (Sch (Sch (Mo 2019 (Mo 2019 (Mo 2019 (Mos 2019 (Bou (Mo 2019 (Mo 2019 (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun
Germany
(Bou
n/a
Germany
(Fun
78±1 740±100 300±20
43000±930 920±27 69±2 34000±1900 24000±1400 34000±2400 780 460 1020 26.49
Pr al
1.42
rn
12.4 1.48 n/a
n/a 172 31.3
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
440±37 370±3 500±10 460±41 980±50 540±114 320±14 100±10 370±35 280±29 120±18
n/a
n/a
n/a 27±6
130
Jo u
n/a
Greece 1 KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa 1 KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa Dandora, Nairobi, Kenya Nyalenda, Kisumu, Kenya Kisat, Kisumu, Kenya Dandora, Nairobi, Kenya Gauteng, South Africa Eldoret, Gauteng, South Africa Kitale, Gauteng, South Africa Mumias, Gauteng, South Africa Kakamega, Gauteng, South Africa
n/a n/a n/a n/a 90 83 92 n/a n/a n/a n/a n/a n/a
pr
14000
n/a n/a n/a
e-
5500
Region/Country KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa
120
1000
330 220±15
85
Norway
f
64±6 1400±140 210±24
Removal (%) n/a n/a n/a n/a
oo
Occurrence (ng L )
-1 *
Occurrence (ng L )
25±7 38±6 250±14 100±5 81±25 34±8 24±1 80±13 40±7 100±10
160±15 270±13 150±26 480±59 300±90 140±26 76±19 75±9 83±6 100±6
Removal (%) n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
Region/Country Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany
Ref. (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun
n/a
n/a
380
n/a
Germany
(Bou
n/a
40±6
68±7
52±2
none
Germany
(Fun
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a >76 >93 51 59 24 n/a
Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa France Germany Germany Germany Dandora, Nairobi, Kenya Nyalenda, Kisumu, Kenya Kisat, Kisumu, Kenya Dandora, Nairobi, Kenya
(Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Aba (Aba (Aba (Ami (Bou (Pras (Pras (K’or (K’or (K’or (K’or (Mo 2019 (Mo 2019 (Ngu (Ngu (Ngu (Ami (Fun (Fun (Fun (Fun
n/a
n/a
n/a 210±13 720±130 30300 60680 31460 3.25
Pr
oo
e-
pr
40±6 51±3
al rn
f
n/a
n.d.
1.5 58
Jo u
e
Journal Pre-proof
21
20.9
100
Western Cape, South Africa
3.67
100
Western Cape, South Africa
3985
n/a n/a n/a n/a n/a n/a n/a n/a
Nairobi, Kenya Jyväskylä, Finland Jyväskylä, Finland France Germany Germany Germany Germany
37 55 270±52 200±10 280±30 330±49 370±44
5430
86
Journal Pre-proof -1 *
Occurrence (ng L )
220±28
34±4
180±40
25±6
75±12
72±17 51±8
140±23 81±11 51±10
130
83±140 320±63 82±90
n.d.
2100±150 670±23 2800±190 850 3300 2080 33.45 2100 189 53 121 254
n.d. 1900±68 540±34 1400±63 1030 2110 2030 350 473 92 242 225
3 4.8±2.9 21.8±2.3
3800±350 3800±360 1900±36 117.2
al
2500±370 1300±110 1200±210
rn
57±1
Jo u
Germany
(Fun
n/a
Germany
(Fun
n/a n/a
Germany
(Fun
Germany
(Fun
n/a n/a
Germany Germany
(Fun (Fun
n/a
Germany
(Fun
n/a
Germany
(Fun
none
Germany
(Fun
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 11 49 22 n/a n/a n/a n/a n/a n/a n/a none none
KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa South Africa KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa France KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa Dandora, Nairobi, Kenya Nyalenda, Kisumu, Kenya Kisat, Kisumu, Kenya Dandora, Nairobi, Kenya Gauteng, South Africa Eldoret, Gauteng, South Africa Kitale, Gauteng, South Africa Mumias, Gauteng, South Africa Kakamega, Gauteng, South Africa France Germany Germany
(Aba (Aba (Aba (Wo (Aba (Aba (Aba (Ami (Aba (Aba (Aba (K’or (K’or (K’or (K’or (Sch (Sch (Sch (Sch (Sch (Ami (Pras (Pras
oo
220±18
(Fun
pr
110±10
44±4
Germany
n/a
e-
84±6
Region/Country Germany Germany Germany Germany Germany Germany 1 KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa Lede, Belgium Lede, Belgium Germany Germany
f
Pr
ate
270±24 180±31 290±51 340±52 130±35 52±2 2200±190 840±60 1900±290 n.d. 507±80
Removal (%) n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a >89 n/a n/a n/a
7.7 7.2±2.3 32.1±0.5
87
Ref. (Fun (Fun (Fun (Fun (Fun (Fun (Aba (Aba (Aba (Ver (Ver (Fun (Fun
Journal Pre-proof -1 *
Occurrence (ng L )
none
Western Cape, South Africa
none
Western Cape, South Africa
n/a 25 n/a n/a n/a
Switzerland2 Switzerland KwaZulu-Natal, South Africa1 Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa
Ref. (Mo 2019 (Mo 2019 (Ngu (Ngu (Ngu (Mo 2019 (Mo 2019 (Aba (Aba (Aba (Mo 2019 (Mo 2019 (Kov (Mar (Aba (Aba (Aba
n/a n/a >78 >89 n/a
Phoenix KwaZulu-Natal, South Africa France Germany Germany
(Aba (Ami (Pras (Pras
Guangzhou, China
(Pen
98.2±17.6 564±22 90 90 110
68 none 99 99 99
Germany Germany Dandora, Nairobi, Kenya Nyalenda, Kisumu, Kenya Kisat, Kisumu, Kenya
n.d.
n.d.
n/a
Western Cape, South Africa
n.d.
n.d.
n/a
Western Cape, South Africa
(Pras (Pras (K’or (K’or (K’or (Mo 2019 (Mo 2019
0.658
3
Western Cape, South Africa
100
Western Cape, South Africa
1357
n/a n/a n/a
Nairobi, Kenya Jyväskylä, Finland Jyväskylä, Finland
0.519
100
Western Cape, South Africa
100
Western Cape, South Africa
17000±2600 61±9.0 810±240
3500±1300
n/a n/a n/a
KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa
Pr
e-
110±14 3200±170 1600±130 1600±150
n.d. 11.6±5.3 22.8±5.6
46 62
0.2
Jo u
n.d.
al
rn
180±36
7680
n/a
513
38.6
88
f
1
oo
4860
pr
108
n.d.
Region/Country
0.681
13 19
n.d.
Removal (%)
Nairobi, Kenya
(Ngu
n/a n/a n/a
Jyväskylä, Finland Jyväskylä, Finland
(Ngu (Ngu
Guangzhou, China
(Pen
n/a n/a
France South Africa
(Ami (Wo
105.1
160.9
44±8 326±394 538 310 230 325 184 280
55±6 592±325 274 230 125 175 89 151
131.4
91.4 22.5 89.1 18
n.d.
33.7 6.5 74
173.2 180 258.4 21
2070
394±435
257
550
350±60 433±472 350±59
152.5 15.8±4.0 8.9±0.7
n.d. n.d. n.d.
59
none
Germany
(Fun
n/a
Western Cape, South Africa
(Mo 2019
-21 -109 41.7 20.4 39.6 39.4 41.4 39.4 n/a n/a n/a n/a none none n/a
Lede, Belgium Lede, Belgium Japan Japan Japan Japan Japan Japan Katsura, Japan Uji, Japan Yodo River System, Japan Japan Germany Germany
(Ver (Ver (Gho (Gho (Gho (Gho (Gho (Gho (Azu (Azu (Azu (Azu (Pras (Pras
Guangzhou, China
(Pen
n/a n/a n/a n/a n/a n/a n/a n/a
Katsura, Japan Uji, Japan Japan York, UK York, UK York, UK Umeå, Västerbotten, Sweden
(Azu (Azu (Azu (Bur (Bur (Bur (Kha
Benson, UK
(Sing
Oxford, UK
(Sing
Benson, UK Oxford, UK
(Sing (Sing
e-
n.d.
Ref. (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Aba (Aba (Aba
pr
n.d.
11.9±4.2
Pr
de
n/a
al
rn
91±12 76±3 110±21 87±12 150±27 85±15
Region/Country Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany 1 KwaZulu-Natal, South Africa Northern KwaZulu-Natal, South Africa Phoenix KwaZulu-Natal, South Africa
f
170±12 140±10 210±7 290±31 390±33
Removal (%) n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
oo
-1 *
Occurrence (ng L )
Jo u
ate
Journal Pre-proof
n.d. n.d. n.d. 48.29
n/a 208±40 358±60
89
50 -2
-1 *
55.9 2.1 243
293.3 74.6 18.2
208
568.8
9 n.d.
186.7
704.3
n.d.
336.8 n.d.
n.d. 53
n.d.
23.1
11.9
1300
0.65
30
2200
700
120
60
110
2200
930
12000 0
34000
7700 n/a
64
374.1 n.d. n.d. 171.7
n.d. n.d. n.d.
rn
al
n.d.
n.d. 27.9 110 12.7
Guangzhou, China
(Pen
n/a n/a n/a −30 to +47% n/a n/a n/a n/a −72 to +53% n/a n/a n/a n/a n/a n/a n/a n/a n/a
Katsura, Japan Uji, Japan Japan VEAS, Norway Yodo River System, Japan Lede, Belgium Lede, Belgium Osaka, Japan VEAS, Norway Japan Dandora, Nairobi, Kenya Nyalenda, Kisumu, Kenya Kisat, Kisumu, Kenya Lede, Belgium Lede, Belgium Osaka, Japan Katsura/Uji Japan Japan Yodo River System, Japan
(Azu (Azu (Azu (Lekn (Azu (Ver (Ver (Tak (Lekn (Azu (K’or (K’or (K’or (Ver (Ver (Tak (Azu (Azu (Azu
f
375 360 403 195 460 140
oo
n.d.
59.9 17.3±5.4 12.2±2.9 482.5 285 295 245 147 345 91
Region/Country Yodo River System, Japan Germany Germany Osaka, Japan Japan Japan Japan Japan Japan Japan Kyoto, Japan Kyoto, Japan Kyoto, Japan
pr
80.7
Removal (%) n/a 59 59 n/a 20.6 16.2 37.6 20.8 18.1 32.1 n/a n/a n/a n/a
e-
36.7
Pr
Occurrence (ng L ) 35.2 72.4 51.5 42.7±9.3 29.4±4.9
Jo u
ate
Journal Pre-proof
2.5
370
140
82
Langenau, Germany
100
40
95
Halzhausen, Germany
120
40
n/a
Asselfingen, Germany
230
90
92
Steinhäule, Germany
n/a
n/a
n/a
2330
n/a
n/a
n/a
n/a
250
110
n/a
90
Ulm, Germany
2
n/a
Langenau, Germany2
n/a
Germany
Ref. (Azu (Pras (Pras (Tak (Gho (Gho (Gho (Gho (Gho (Gho (Gho (Gho (Gho
(Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Bou
Journal Pre-proof
270±20 130±8 85±5 240±15 260±36 170±31
Guangzhou, China
(Pen
70 91 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
California Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany
(Bea (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Pras (Pras (Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Seit 2017 (Azu (Azu
e-
1900
0.76
5100
2050
140
1800
740
360
8500
2750
50
770
280
80
710
490
390
13000
5750
870
8000
5120
2700
44000
20000
n/a
n/a
n/a
6700
2810
n/a
n/a
n/a
n.d. 63
n.d. 16
n.d.
n.d.
n.d.
Ref. (Pras (Pras (Pras (Pras (K’or (Azu (Azu
f
205
Region/Country Germany Germany Germany Germany Nairobi, Kenya Japan 2 Japan
pr
114
120
Pr
e
202
al
302±58 3780±480 2850±130 2510±70 1070±140 4980±280 2180±110 1740±230 520±42 530±25 760±64 1830±390 690±140 600±82 490±3 1790±82 3420±210 2680±62 670±39 1790±200 2010±38 2290±130 520±100 430 247±75
19
rn
177
3691 113
27.3±1.6 53.3±3.5 140 148±11
Jo u
1530 9
1780±99 1780±50 1990 1800±300 n.d. 2505 60
Removal (%) 98 97 n/a n/a n/a n/a n/a n/a
oo
-1 *
Occurrence (ng L )
n/a n/a n/a n/a n/a n/a n/a n/a
91
Langenau, Germany Halzhausen, Germany Asselfingen, Germany Steinhäule, Germany Ulm, Germany2 2
Langenau, Germany Japan Japan2
Journal Pre-proof -1 *
Occurrence (ng L )
40 n.d. n.d. n.d.
120 29 21 22
n.d.
42.8±9.8 19.5±9.7 79 9 11 8
n.d.
13
n.d.
n.d.
n.d.
n.d.
Removal (%) >94 >87 n/a n/a n/a n/a
Region/Country Germany Germany Japan Japan2 Japan Japan2
Ref. (Pras (Pras (Azu (Azu (Azu (Azu
Guangzhou, China
(Pen
Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany Germany
(Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun (Fun
n/a n/a
Germany Germany
(Pras (Pras
n/a
Guangzhou, China
(Pen
irus
e-
n.d.
Pr
f
n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
oo
27±4
pr
38±5
al
n.d.
n/a
Abacavir
Occurrence (ng L-1)* Min. Max Mean
Jo u
Antiviral drugs Antiretroviral s
rn
iven in brackets; ffluents; n.d., not detected; n/a, not available Table 2. Occurrence of antiviral drugs in surface waters worldwide, listed by therapeutic class
1.4
2.6±1. 7 2.3
Region/Country
Reference
Hessian Ried, Germany
(Prasse et al., 2010)
Neckar, Germany Weschnitz, Germany Modau Germany Schwarzbach, Germany Rodau, Germany Main, Germany Nahe, Germany Lahn, Germany River Rhine, Germany
(Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016)
France
(Aminot et al., 2015)
France
(Aminot et al., 2016)
South Africa
(Wood et al., 2015)
River Rhine, Koblenz,
(Boulard et al., 2018)
92
Journal Pre-proof Antiviral drugs Abacavir carboxylate
Occurrence (ng L-1)* Min. Max Mean (5) (5)
Darunavir
Region/Country Germany River Rhine, Koblenz, Germany
72.7
Poland
Didanosine Efavirenz
n.d.
54.1
3
303
134
354
South Africa South Africa Hartbeespoort Dam catchment, South Africa Juskei River, South Africa uMngeni River, South Africa Kisumu, Kenya Mathare River, Nairobi, Kenya Rietvlei Nature Reserve, Gauteng Province, South Africa
138 n.d.
560
148
n.d.
<1
45
2.9
Emtricitabine carboxylate
n.d.
Lamivudine n.d. n.d.
(Rimayi et al., 2018) (Rimayi et al., 2018) (K’oreje et al., 2016) (K’oreje et al., 2012) (Wooding et al., 2017) (Wood et al., 2015) (Boulard et al., 2018) (Rimayi et al., 2018) (Rimayi et al., 2018)
110
Weschnitz, Germany Modau, Germany Schwarzbach, Germany Rodau, Germany Main, Germany Nahe, Germany Lahn, Germany Rhine River, Germany Rhine River, Germany
(Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Funke et al., 2016) (Boulard et al., 2018)
200
Rhine River, Germany
(Boulard et al., 2018)
South Africa
(Wood et al., 2015)
Yodo River basin, Japan
(Azuma et al., 2015)
France
(Aminot et al., 2015)
Kisumu, Kenya
(K’oreje et al., 2016)
3150
(Rimayi et al., 2018)
49±5 70±1 280±20 73±2 44±1 25±2 30±3
rn Indinavir
10
(Giebułtowicz and Nałecz-Jawecki, 2016) (Wood et al., 2015) (Wood et al., 2015)
(Funke et al., 2016)
Jo u
Emtricitabine S-oxide
(Boulard et al., 2018)
Neckar, Germany
al
29±2
River Rhine, Koblenz, Germany uMngeni River, South Africa Juskei River, South Africa
Pr
8 13
n.d.
South Africa
e-
n.d.
pr
oo
f
33
Emtricitabine
Reference
20
<5
2.6 242
160
n.d.
n.d.
n.d.
n.d.
Mathare River, Nairobi, Kenya River Rhine, Koblenz, Germany France South Africa Ruhr River and tributaries, Germany Hessian Ried, Germany
93
(K’oreje et al., 2012) (Boulard et al., 2018) (Azuma et al., 2016) (Wood et al., 2015) (Prasse et al., 2010) (Prasse et al., 2010)
Journal Pre-proof
n.d.
12
Lake Päijänne, Finland
5428
Nairobi River Basin, Kenya
16
230
Germany
(Funke et al., 2016)
n.d.
n.d.
Japan
(Azuma et al., 2017)
n.d.
n.d.
Japan
(Azuma et al., 2017)
n.d. n.d.
305 n.d.
South Africa France
n.d.
n.d.
Lake Päijänne, Finland
4859
Nairobi River Basin, Kenya
(Wood et al., 2015) (Aminot et al., 2015) (Ngumba et al., 2016b) (Ngumba et al., 2016a)
n.d. n.d.
239
1.3±0. 6 5620
France
17
Hessian Ried, Germany
(Prasse et al., 2010)
12±5 0.5
France France
(Aminot et al., 2015) (Aminot et al., 2016)
South Africa
(Wood et al., 2015)
n.d.
Pearl River Delta, China Mathare River, Nairobi, Kenya South Africa Orange River System, South Africa Roodeplaat Dam System, South Africa South Africa Ruhr River and tributaries, Germany
(Peng et al., 2014)
e-
227
6
71
n.d.
57
68 360
rn
1480
Pr
0.5
al
0.2
3.8
Jo u
Ritonavir
n.d.
(Aminot et al., 2015) (K’oreje et al., 2016)
<148
n.d.
(Ngumba et al., 2016b) (Ngumba et al., 2016a)
Kisumu, Kenya Mathare River, Nairobi, Kenya Rietvlei Nature Reserve, Gauteng Province, South Africa Limpopo Province, South Africa France Hartbeespoort Dam catchment, South Africa Juskei River, South Africa uMngeni River, South Africa South Africa Ruhr River and tributaries, Germany
300 44.4
Reference
f
Nevirapine
Region/Country
oo
Lamivudine carboxylate Laninamivir Laninamivir octanoate Lopinavir Nelfinavir
Occurrence (ng L-1)* Min. Max Mean
pr
Antiviral drugs
Stavudine 440
(Wooding et al., 2017) (Wooding et al., 2017) (Aminot et al., 2016) (Rimayi et al., 2018) (Rimayi et al., 2018) (Rimayi et al., 2018) (Wood et al., 2015) (Prasse et al., 2010)
(K’oreje et al., 2012)
n.d.
778
0
189
n.d.
243
Zalcitabine
n.d.
71.3
Zidovudine
1.2
94
170
Hessian Ried, Germany
(Prasse et al., 2010)
7684
Nairobi River Basin, Kenya
(Ngumba et al., 2016a)
Tenofovir
431
(K’oreje et al., 2012)
36
94
(Wood et al., 2015) (Wood et al., 2015) (Wood et al., 2015) (Wood et al., 2015) (Prasse et al., 2010)
Journal Pre-proof Antiviral drugs
Occurrence (ng L-1)* Min. Max Mean n.d. 33±27 n.d. 17410 n.d. 30 18
Region/Country
Reference
France Kisumu, Kenya Pearl River Delta, China Rivers and streams, Germany Mathare River, Nairobi, Kenya
(Aminot et al., 2015) (K’oreje et al., 2012) (Peng et al., 2014) (Funke et al., 2016) (K’oreje et al., 2012)
973
319
South Africa
(Wood et al., 2015)
10290
351 (highest median)
Yangtze River Delta, China
(Peng et al., 2018)
5
61
Japan Yodo River, Japan Yodo River, Japan Yodo River basin, Japan Pearl River Delta, China
oo
Amantadine
f
Antiinfluenza drugs
14 10.7
Oseltamivir
pr
10-41 n.d.
n.d.
19
12
58
n.d.
8.8
0.3
17
15
e-
Kamo River, Japan
Katsura River, Japan Yodo River, Japan
Pr
2
al
n.d.
(Prasse et al., 2010)
Japan
Yodo River, Japan
(Azuma et al., 2017) (Takanami et al., 2011) (Azuma et al., 2017) (Takanami et al., 2012) (Azuma et al., 2013)
39125
Yodo River basin, Japan
(Azuma et al., 2015)
2.4
(Prasse et al., 2010)
21
Hessian Ried, Germany
(Prasse et al., 2010)
rn
Neya River, Osaka, Japan
Jo u
864.8 70
Japan
556.9
Osaka, Japan
Ruhr River and tributaries, Germany
n.d.
(Prasse et al., 2010)
Hessian Ried, Germany
20 Oseltamivir carboxylate
River Foss, UK Ruhr River and tributaries, Germany
(Azuma et al., 2017) (Azuma et al., 2013) (Azuma et al., 2013) (Azuma et al., 2015) (Peng et al., 2014) (Söderström et al., 2009) (Söderström et al., 2009) (Söderström et al., 2009) (Burns et al., 2018)
43.8
6.6
190.2
n.d.
193 6
66 1.29
Katsura and Kamo Rivers, Japan River Thames catchment, UK River Wye, UK Umeå surface water, Sweden
50
Ebro river, Spain
100
Ebro river, Spain
154.2
Neya River, Osaka, Japan
95
(Ghosh et al., 2010a) (Singer et al., 2014) (Singer et al., 2014) (Khan et al., 2012) (Gonc̀alves et al., 2011) (Gonc̀alves et al., 2011) (Takanami et al.,
Journal Pre-proof Antiviral drugs
Occurrence (ng L-1)* Min. Max Mean n.d.
Peramivir Zanamivir
n.d.
Region/Country
165.9
Osaka, Japan
10
Japan
58.8
Osaka, Japan
Reference
n.d.
Yodo River, Japan Yodo River, Japan Yodo River basin, Japan
Nau River, Germany
Danube River, Germany
10
Yodo River, Japan Pearl River Delta, China River Rhine, Koblenz, Germany River Ruhr and tributaries, Germany Hessian Ried, Germany rivers and streams in Germany
89 13-35
2011) (Takanami et al., 2012) (Azuma et al., 2017) (Takanami et al., 2012) (Azuma et al., 2013) (Azuma et al., 2017) (Azuma et al., 2015)
2.6
20
2.2
190
58
750
oo
70
6
pr
2
160
100
150
70
Nau River, Germany Danube River, Germany
rn
al
3 2 Yodo River, Japan 7 Hessian Ried, Germany 2-11 Yodo River basin, Japan Valacyclovir n.d. 5 1 Yodo River, Japan * Values of LOQ are given in brackets; n.d., not detected; n/a, not available
Jo u
Penciclovir
e-
Αcyclovir carboxylate
Pr
Acyclovir
f
Antiherpetics
96
(Seitz and Winzenbacher, 2017) (Seitz and Winzenbacher, 2017) (Azuma et al., 2019) (Peng et al., 2014) (Boulard et al., 2018) (Prasse et al., 2010) (Prasse et al., 2010) (Funke et al., 2016) (Seitz and Winzenbacher, 2017) (Seitz and Winzenbacher, 2017) (Azuma et al., 2019) (Prasse et al., 2010) (Azuma et al., 2015) (Azuma et al., 2019)
Journal Pre-proof Table 3. Occurrence of antiviral drugs in groundwaters worldwide, listed by therapeutic class Antiviral drug
Occurrence (ng L-1)* Freq. Min. Max. (%)
Mean
Region/Country
Ref.
North West and Gauteng Provinces, South Africa
Antiretrovirals
Efavirenz
2
5
20
30
Kisumu, Kenya
North West and Gauteng Provinces, South Africa
10
Kisumu, Kenya
(K’oreje et al.,
n/a
Emtricitabine Emtricitabine carboxylate Emtricitabine S-oxide Lamivudine
20 87 13 13
5
370
140
23 1,8
Lopinavir
Nevirapine
n/a
Zidovudine
Anti-influenza drugs Amantadine
n/a
n/a
25.2
USA
Kisumu, Kenya
27.73
USA
Tenofovir
Koblenz, Germany
1600
8
Stavudine
Koblenz, Germany
20
n/a
Saquinavir
Koblenz, Germany
North West and Gauteng Provinces, South Africa North West and Gauteng Provinces, South Africa North West and Gauteng Provinces, South Africa
Jo u
Nelfinavir
al
Koblenz, Germany
rn
n/a
Koblenz, Germany North West and Gauteng Provinces, South Africa Hartbeespoort Dam catchment, South Africa Gauteng Province, South Africa North West and Gauteng Provinces, South Africa
71
Koblenz, Germany
f
Didanosine
11
oo
7
(Swanepoel et al., 2015) (Boulard et al., 2018) (Boulard et al., 2018) (Swanepoel et al., 2015) (Rimayi et al., 2018) (Rimayi et al., 2018) (Swanepoel et al., 2015) (Boulard et al., 2018) (Boulard et al., 2018) (Boulard et al., 2018) (Boulard et al., 2018) (Fisher et al., 2016) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (K’oreje et al., 2016) (Fisher et al., 2016) (Rimayi et al., 2018) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (K’oreje et al., 2016) (Swanepoel et al., 2015)
pr
Abacavir carboxylate
e-
0
Pr
Abacavir
0.9
Hartbeespoort Dam catchment, South Africa North West and Gauteng Provinces, South Africa North West and Gauteng Provinces, South Africa North West and Gauteng Provinces, South Africa North West and Gauteng Provinces, South Africa
13 4.9 1.3 0.9 2.4
97
Journal Pre-proof
Rimantadine
n/a
2016) (K’oreje et al., 2016)
Kisumu, Kenya
Antiherpetics
(Boulard et al., 2018)
0
Table 4. Occurrence of antiviral drugs in drinking water worldwide (in alphabetical order) -1 *
Occurrence (ng L )
Acyclovir Acyclovir carboxylate Amantadine (LOQ2.2)
f
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a 41±7 9
169
rn
Jo u
3.3
n/a
n/a
n/a
n/a
n/a
n/a
n/a
80±2 n/a
Indinavir
n.d.
n/a
n/a
n.d. Lamivudine
n.d. n.d. n/a
n/a
n/a
oo
0.5
Emtricitabine S-oxide
Volvic water (PET bottles)/France municipal tap water/South Africa treated drinking water/Germany treated drinking water/Germany treated drinking water/Germany treated drinking water/Germany final drinking water/Japan
pr
Didanosine
Emtricitabine Emtricitabine carboxylate
Mean
n.d.
Darunavir
Efavirenz
Max.
e-
Abacavir carboxylate
Min.
Water type/Country of origin
Pr
Abacavir
Freq . (%)
al
Antiviral drug
<1
tap water/ Vistula River, Warsaw region, Poland municipal tap water/South Africa tap water/ Hartbeespoort Dam, South Africa municipal tap water/South Africa treated drinking water/Germany treated drinking water/Germany treated drinking water/Germany treated drinking water/Germany Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France treated drinking
98
Ref.
(Dévier et al., 2013) (Swanepoel et al., 2015) (Boulard et al., 2018) (Boulard et al., 2018) (Boulard et al., 2018)
(Funke et al., 2016) (Simazaki et al., 2015) (Giebułtowicz and Nałecz-Jawecki, 2016) (Swanepoel et al., 2015)
(Wood et al., 2015) (Swanepoel et al., 2015) (Boulard et al., 2018) (Boulard et al., 2018)
(Funke et al., 2016) (Boulard et al., 2018) (Dévier et al., 2013) (Dévier et al., 2013) (Dévier et al., 2013) (Dévier et al., 2013) (Boulard et al., 2018)
Journal Pre-proof Occurrence (ng L-1)*
Antiviral drug
25
4
Lamivudine carboxylate
Lopinavir
Nelfinavir
f
oo
n.d. n.d. n.d.
pr
Nevirapine
e-
n.d.
n.d.
Jo u
n.d.
Saquinavir
al
38
rn
Ritonavir
3.5
Pr
Oseltamivir LOQ 2
n.d. n.d.
n.d. n.d.
Tenofovir
Zalcitabine Zidovudine
0.9
8.4 n.d.
Water type/Country of origin water/Germany drinking water treatment plants/USA municipal tap water/South Africa treated drinking water/Germany tap water/ Hartbeespoort Dam, South Africa municipal tap water/South Africa municipal tap water/South Africa Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France tap water/ Hartbeespoort Dam, South Africa municipal tap water/South Africa treated drinking water/Japan Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France tap water/ Hartbeespoort Dam, South Africa Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France municipal tap water/South Africa Evian water (PET and glass bottles)/France Volvic water (PET bottles)/France municipal tap water/South Africa municipal tap water/South Africa tap water/ Hartbeespoort Dam, South Africa Evian water (PET and glass bottles)/France
99
Ref.
(Furlong et al., 2017) (Swanepoel et al., 2015) (Funke et al., 2016)
(Wood et al., 2015) (Swanepoel et al., 2015) (Swanepoel et al., 2015) (Dévier et al., 2013) (Dévier et al., 2013) (Dévier et al., 2013) (Dévier et al., 2013)
(Wood et al., 2015) (Swanepoel et al., 2015) (Simazaki et al., 2015) (Dévier et al., 2013) (Dévier et al., 2013)
(Wood et al., 2015) (Dévier et al., 2013) (Dévier et al., 2013) (Swanepoel et al., 2015) (Dévier et al., 2013) (Dévier et al., 2013) (Swanepoel et al., 2015) (Swanepoel et al., 2015)
(Wood et al., 2015) (Dévier et al., 2013)
Journal Pre-proof Occurrence (ng L-1)*
Antiviral drug n.d.
72.7
1.9
Water type/Country of origin Volvic water (PET bottles)/France tap water/ Hartbeespoort Dam, South Africa municipal tap water/South Africa
*
Values of LOQ are given in brackets; n.d., not detected; n/a, not available
Jo u
rn
al
Pr
e-
pr
oo
f
Graphical abstract
100
Ref. (Dévier et al., 2013)
(Wood et al., 2015) (Swanepoel et al., 2015)
Journal Pre-proof Highlights
Global review on the occurrence of antivirals in WWTPs, groundwater, surface and drinking water
The determination of antivirals should be incorporated to multi-class analytical methods
Occurrence of antiviral drugs in influents and effluents varies significantly worldwide
More surveys are required to assess the chemical status in groundwater and
oo
rn
al
Pr
e-
pr
Urgent need for risk assessment and toxicity studies against non-target organisms
Jo u
f
drinking water
101
Figure 1
Figure 2
Figure 3
Figure 4