key: cord-0855475-zh94v4iz authors: Kumar, Manish; Mazumder, Payal; Mohapatra, Sanjeeb; Thakur, Alok Kumar; Dhangar, Kiran; Taki, Kaling; Mukherjee, Santanu; Kumar Patel, Arbind; Bhattacharya, Prosun; Mohapatra, Pranab; Rinklebe, Jörg; Kitajima, Masaaki; Hai, Faisal I; Khursheed, Anwar; Furumai, Hiroaki; Sonne, Christian; Kuroda, Keisuke title: A Chronicle of SARS-CoV-2: Seasonality, Environmental Fate, Transport, Inactivation, and Antiviral Drug Resistance date: 2020-10-06 journal: J Hazard Mater DOI: 10.1016/j.jhazmat.2020.124043 sha: 4fe3c1f83f87f86486f578042c662cb7dae86427 doc_id: 855475 cord_uid: zh94v4iz In this review, we present the environmental perspectives of the viruses and antiviral drugs related to SARS-CoV-2. The present review paper discusses occurrence, fate, transport, susceptibility, and inactivation mechanisms of viruses in the environment as well as environmental occurrence and fate of antiviral drugs, and prospects (prevalence and occurrence) of antiviral drug resistance (both antiviral drug resistant viruses and antiviral resistance in the human). During winter, the number of viral disease cases and environmental occurrence of antiviral drug surge due to various biotic and abiotic factors such as transmission pathways, human behaviour, susceptibility, and immunity as well as cold climatic conditions. Adsorption and persistence critically determine the fate and transport of viruses in the environment. Inactivation and disinfection of virus include UV, alcohol, chemical-base methods but the susceptibility of virus against these methods varies. Wastewater treatment plants (WWTPs) are major sources of antiviral drugs and their metabolites and transformation products. Ecotoxicity of antiviral drug residues against aquatic organisms have been reported, however more threatening is the development of antiviral resistance, both in humans and in wild animal reservoirs. In particular, emergence of antiviral drug-resistant viruses via exposure of wild animals to high loads of antiviral residues during the current pandemic needs further evaluation. With dreadful global lockdown and search for effective medicine against the novel coronavirus (SARS-CoV-2), efforts to understand the perspectives of coronavirus disease 2019 (COVID-19) and its causative virus is ongoing. In this effort, our team has recently published a review on epidemiology, prognosis, diagnosis, transmission and treatment of COVID-19 [1] . Further, transport and infectivity of SARS-CoV-2 in wastewater/environmental waters are highly dependent on the physical and environmental susceptibility of SARS-CoV-2 as well as inactivation. As per the inactivation mechanism, environmental stressors become critical for the disruptions of proteins and lipids of viral envelope leading to their seasonal variations [6] . Along with host immunity, climatic factors would also influence human respiratory air passage defence. Since such information is barely available related to SARS-CoV-2, there is a dire need to understand similarities and dissimilarities of respiratory coronavirus (positivestranded RNA viruses with nucleocapsid) with various viruses including enteric viruses [7] . Such information will be of immense help to understand structural, and environmental susceptibility and inactivation mechanisms for SARS-CoV-2. J o u r n a l P r e -p r o o f 5 With surge in COVID -19 patients (>20 million people) as of the second week of August, 2020, large number of antiviral drugs (remdesivir, ivermectine chloroquine and hydroxychloroquine) have been clinically tested. However, there is no data available on the quantum of antiviral drugs being used to treat such extraordinary number of COVID-19 patients. So far, a large number of antiviral drugs have been discovered till date (Figure 1 ), but the quest of finding viral cure seems to be never ending due to insufficient effectiveness of such treatments and high viral mutation rates which lead to emergence of resistant strains [8] [9] [10] [11] . Furthermore, studies reported that the administered drugs are not fully metabolised in the human body, thus generating residues and metabolites. The drug residue and metabolite are discharged into the environment through sewage leading to spikes of antiviral drugs in wastewater and ambient waters [9, 12, 13] . In addition, studies confirmed incomplete removal of antiviral drugs in wastewater treatment plants (WWTPs) [14] [15] [16] . The unprecedented use of antiviral drug during pandemic events, has led to the development of antiviral-drug resistant viruses within wild animal reservoir and may compromise the treatment of COVID-19 patients [17, 18] . Therefore, the occurrence and fate of antiviral drugs in the environment during this unprecedented pandemic need a special attention. [19] Under the light of above discussions, we hereby present a comprehensive review on physical and environmental susceptibility, seasonal variations, inactivation mechanism, discovery and transport of antiviral drugs, transport and fate of viruses in the J o u r n a l P r e -p r o o f 6 Anthroposphere. The review also discusses the role of vital factors like carrier prevalence, treatment efficacy of wastewater burden (virus source), transport among environmental compartments of viruses and their inactivation mechanisms, and the current unprecedented use of antiviral drugs. Special emphasis is given on understanding the transport of both viruses and antiviral drugs, alongside treatments and governing mechanisms of SARS-CoV-2 inactivation. We then finally present the current global status of antiviral drug resistance, and future scenarios of antiviral drug resistance both in pandemic viruses and infected humans. Overall, we intended to prepare an insightful ready reference that can not only help the readers identifying critical variables governing COVID-19, but also raise awareness of some likely aftermaths of the current pandemic. Transmission of viruses and the manifestation of infection depend on transmission pathways, human behaviour, susceptibility and immunity. Environmental factors, such as climatic conditions and behaviour of virus hosts and vectors, also play a formidable role that translates into several distinct seasonal trends of viral infections. Wuhib et al, (1994) investigated the seasonal pervasiveness of Microsporidiosis and Cryptosporidium parvum in immuno-compromised HIV positive (+ve) patients, and reported a profuse infection in the rainy seasons [20] . However, the reported course of seasonal prevalence of these parasites was not statistically significant. Their prevalence depends on the HIV infection and hence, is mainly related to the fecal-oral route, zoonotic emanation, sexual transmission, and renaissance of passive condition observed for HIV. and observed that the key factors determining the prevalence of the virus were change in temperature and humidity [21] . The reported incidences of influenza and other respiratory epidemics are significantly higher in winter season than summer and spring seasons [22, 23] . In addition, in line with the various epidemiological research, the majority of the respiratory virus outbreaks in temperate zones exhibit seasonal fluctuations. In particular, human coronavirus (types: HKU1, 229E, OC43, and NL63), influenza virus and respiratory syncytial virus culminate in the winter season and are commonly known as winter viruses [24] [25] [26] [27] [28] . Incongruence in the replication of these viruses leads to a non-overlapping prevalence with respect to each other. It has been found that respiratory viruses such as respiratory syncytial and influenza viruses, even being pervasive in winter, do not occur simultaneously [29] . Antithetically, human bocavirus, rhinovirus, adenovirus, and human metapneumovirus are identified all along the year and are called as all-year viruses [30] . However, reported that rhinovirus infection surfaced during fall and spring, but the disease ferocity was highest in winter [31] . On the other hand, the rate of recurrence of several enteroviruses escalates during summer implying the significance of seasonality of viral infections [32, 33] . Further, the transmission efficiency of viral infections via all possible pathways depends on outdoor and indoor climatic factors. Kudo et al. (2019) illustrated that lower humidity could induce a decrease of Mx1 congenic mice weight, increase in mortality rate, pulmonary viral load, and infection with influenza virus [34] . pandemic emerged in winter before their subsequent worldwide spread [35] [36] [37] , these respiratory viruses (coronaviruses: SARS-CoV, MERS-CoV, and SARS-CoV-2) aggrandizes in the winter season. Seasonality also governs the host propensity by moderating human pulmonary or nasopharyngeal innate defense mechanisms, and thus, regulates respiratory virus effectiveness/viability and dissemination [38] . Therefore, the key determining characteristics of respiratory viral outbreak is pathogenicity which is severely affected by seasonality i.e. sunlight, temperature (winter), absolute humidity (dry season), host susceptibility due to cold weather, and seasonal changes in immunity [39] [40] [41] [42] [43] [44] . Adsorption and persistence are the two major elements that affect the fate and transport of viruses in the environment. Survival of viruses is typically evaluated by reduction time: T 90 , T 99 , or T 99.99 , which are the time required for viruses to reduce by 90%, 99%, or 99.99%, respectively, under certain environment. The reduction of various viruses in environmental waters are summarized in Table 1 . In general, viruses with high persistence have a high capability of causing infection within the environment. Although literature around transport of SARS-CoV-2 in the surface and subsurface medium is not available, several factors, including soil-specific, virus-specific, and environmental factors might influence the 9 Table 1 . Survival of viruses in water, wastewater and groundwater [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] Supplementary Table 1 : Governing factors responsible for fate of viruses in the environment. Being amphoteric in nature, coronaviruses are expected to be attracted and trapped by both positively and negatively charged soil colloids and humus species. Major adsorption is expected to occur in soil having a high concentration of clay. Bacteriophages that are considered to be surrogates for enteric viruses and also used as a process control in the detection of SARS-CoV-2 have shown greater adsorption potential to polyelectrolytes [60, 61] and minerals [62] . However, soil is a mixture of minerals, organic compounts, and living microrganisms thereby constituting a tridimensional structure with many particularities affecting retention potential where diffusive and convective fluxes are crucial. Thus, it would be difficult to predict the adsorption of SARS-CoV-2 to soil without field data. According to the Derjaguin-Landau-Verwey-Overbeek (DVLO) theory, at higher pH, viruses are weakly adsorbed to soil particles due to an increase in electrostatic repulsion [63] . Experiments conducted for adsorption study of human enteroviruses and bacteriophages onto different soils illustrated that decrese in pH increased the adsorption of the most viruses [64, 65] . The presence of envelope (lipoprotenacious membrane) and spike proteins, makes SARS-CoV-2 surface property significantly different from non-enveloped viruses [66] . Presence of various functional groups along with characteristics spike proteins are expected to govern the adsorption, fate and transport of the novel virus in the environment. Pseudomonas phase (ϕ6) have shown high adsorption potential onto wastewater solid fractions. Such a difference in adsorptive behaviour of enveloped viruses was possibly due to the dominance of both hydrophobic effects and electrostatic force amidst sorbent surface and capsid protein [57, 67] . Similar force of attraction would play a vital role in the transport of amphoteric SARS-CoV-2 in the aqueous medium. Howbeit, saturated soils filled with water during monsoon season and subsequently increased flow rate reported to increase the virus transport due to less interaction time with soil particles [68] [69] [70] [71] [72] . Similarly, smaller-sized viruses migrate at a faster rate due to lesser entrapment in the soil pore. Virus transport in fine-grained soil is expected to be slower due to its higher probability in virus retention than in coarse-grained soil. A typical diameter of a SARS-CoV-2 virion is 100 nm [73] , which is larger than many of non-enveloped viruses ( Table 2) . Therefore, lesser mobility in soil is expected for SARS-CoV-2 owing to its size than that of enveloped viruses which is yet to be demonstrated. While there is a debate about whether virus inactivation follows first-order or timedependent processes, several factors including temperature, conductivity, and water quality parameters are reported to inactivate the virus by disrupting the protein coat and nucleic acid. Again, the extent of inactivation of enveloped viruses is found to be high compared to the non-enveloped viruses in surface water, groundwater, and wastewater ( Table 1) . With J o u r n a l P r e -p r o o f 11 an increase in temperature, the rate of enveloped virus inactivation reported to increase compared to non-enveloped viruses. Surrogate coronaviruses are known to retain their infectivity in water from days to several weeks depending upon the surrounding temperature. At low temperature viruses are expected to survive for longer duration and subsequently migrate to a greater distance [55] . However, an association of viruses with the colloidal and particulate materials can protect the virus from inactivation and such phenomena were observed for poliovirus Type 1 and bacteriophages [99, 100] . Similarly, clay minerals are reported to protect adsorbed bacteriophages from UV radiation [101] . Several authors also highlighted the importance of nutrients such as phosphorus and metals towards the inactivation of viruses [102] . Organometallic complexes are reported to alleviate the toxicity of heavy metals towards virus inactivation. In many cases, septic tank effluents, leachate from sludge disposal sites, and direct land application of wastewater effluents considerably contribute to the groundwater contamination. However, the transportation of viruses in subsurface systems is a function of their retention time, nature, and geology of aquifer. Both efficacy and transport of virus are controlled by soil water content, temperature, sorption and desorption, pH, salt content, type of virus, and hydraulic stresses [103] . As discussed, both adsorption and inactivation collectively govern viruses transport during soil passage. While advection and dispersion control the virus spread, attenuation of virus concentrations. Irreversible reaction assumes no detachment of virus, and reversible reactions involve equilibrium and kinetics of adsorption. Thus in a subsurface system, adsorption and desorption are rapid in reference to flow velocity, favouring faster equilibrium. There might be another scenario where 12 adsorption is kinetically limited in reference to the flow velocity, with a fixed adsorption and desorption rate coefficients. Hence the corresponding kinetic equations of solute transport must take into account dispersion, advection, and inactivation while modeling virus transport in a three-dimensional saturated flow condition [104] . Various models were proposed to study the transport phenomena of viruses in environmental matrices. Some of them were VIRAL, working on the principle of irreversible sorption phenomena [105] , VIRULO based on Monte Carlo simulation to predict attenuation of virus in the unsaturated zone [106] (Park et al. 2011 ) and HYDRUS-2D working based on virus kinetics of deposition, surface chemistry of the sorption sites [107] . While enveloped viruses like SARS-CoV-2 may have notable mobility in the environment, further studies are needed to appraise its persistence and transport. Those above-developed models for nonenveloped viruses may be used to have a conservative estimation of enveloped virus transport. However, additional research is required to model SARS-CoV-2 transport in the soil, which can be used to model the transport of other enveloped viruses. Viruses that are small and elliptical in shape are considered to be highly infectious. Even a small amount of viral load is enough to cause gastroenteritis. Compared to non-enveloped norovirus, a significant number of enveloped viruses were found in vomit and excreta of infected persons. Infections by most of the viruses are transmitted through contact, fecaloral route, droplets, or aerosols [108] . Viral particles are also transmitted via contaminated surfaces, clothes, food, water, and fomites [109] . It is reported that SARS-CoV can survive on J o u r n a l P r e -p r o o f 13 the surface for several days and could retain its infectivity up to 9 days [88] . Similarly, Otter et al. (2016) revealed that other enveloped viruses, such as MERS and SARS viruses, could survive up to several months [110] . Various factors that govern the survival of viruses are i) type of strain ii) load of titer iii) type of surface and v) environmental condition [110] . Disinfection plays an important role in controlling microbial infection in medical settings, such as, health care facilities, and nursing homes [76] . Also, in controlling microbial safety in water treatment plants and WWTPs, and agricultural fields using treated wastewater [111] . Disinfection is one of the most fundamental ways of disrupting virus spread by reducing or inactivating their infectious nature [112] . In this section, different modes of virus inactivation such as, UV, alcohol, heat treatment, and other conventional and advanced methods, are discussed. Possible inactivation mechanism for SARS-CoV-2 has also been presented by referring to the available literature on other envelope viruses and nonenveloped viruses, as shown in Table 2 and Figure 2 . UV-based disinfection technique is profoundly used in the medical sectors to sterilize medical equipment, and PPEs [77] . UV(C) rays were proven to be more efficient than the UV(A) and UV(B) in inactivating viruses, as they possess high energy and are most absorbed by the DNA and RNA [113] . Darnell et al. (2004) compared the efficiencies of UV(A) and UV(C) to inactivate the viruses within a limited period [87] . UV(C) could increase the rate of virus inactivation to 400 times within 6 minutes, while UV(A) showed no effects when the J o u r n a l P r e -p r o o f 14 experiment was extended up to 15 minutes. The UV-based disinfection involves the absorption of UV rays by DNA/RNA bases followed by fusion with pyrimidines into covalently linked dimmers, which later becomes non-pairing bases [114] . DNA can absorb UV-C in the range of 245-285 in the most propitious way and thus proves to be suitable to disinfect microbes [115] Disinfection by means of alcohol is considered an important measure for the inactivation of viruses. Acohol-based sanitizers (a mixture of polyquaternium and organic acid) are used to inactivate non-enveloped viruses such as human rotavirus, poliovirus type 1, human norovirus, and murine norovirus that are inactivated by a factor of 10 3 times within 30 seconds [111] . Ethanol and propanol were also found to inactivate feline calicivirus Chemical-based inactivation is also an important tool for disinfecting viruses. Jelsma et al. (2019) studied the effect of sodium chloride (NaCl) and phosphate-based (P-salt) salts on enveloped swine fever viruses present in the porcine intestines [79] . The reduction values were determined at four different temperatures, namely, 4, 12, 20, and 25 o C. Compared to sodium-based salt, phosphate-based (P-salt) salts were found to be more effective across all the studied temperatures. Virus titers showed a reduction of 99% from its initial concentration. One of the enveloped viruses, HSV (Herpes Simplex Virus) was inactivated using zinc gluconate and zinc lactate salts in vitro. The former salt showed inactivation for 80% of the virus particles with more than 98% reduction, while the later inactivated 90% of the samples with more than 97% reduction. The reduction was found to be proportional to the concentration of salt used [118] . Kampf et al. (2020) studied the effect of several biocidal agents on the inactivation of SARS-CoV-2. Ethanol (62-71%), sodium hypochlorite (0.1-0.5%), glutardialdehyde (2%) were found to reduce the titers by 2 to 4 log 10 while on contrary, benzalkonium chloride (0.04%) and ortho-phtalaldehyde (0.55%) were less effective in inactivating SARS-CoV-2 [96] . Inactivation of many viruses in the drinking water treatment plants is usually done by [17, [121] [122] [123] [124] Thus, it becomes ever important to disinfect the viruses before they contaminate surface water bodies and enter into urban water cycle. Chlorination is one of the promising disinfectant for a sewage treatment process, a 2.8 log-unit inactivation was noticed for poliorvirus [94] . Reports of infected patients confirming RNA of SARS-CoV-2 in their feces have risen up the concern for inactivation at sources like hospitals effluent only [125] . Liquid chlorine, chlorine dioxide, and sodium hypochlorite are some of the mostly used disinfectants at health facilities [126, 127] . All these chlorine based disinfectants offer several advantages over UV/Ozone and other inactivation processes like i) low power consumption ii) low toxicity iii) simple equipment iv) need no skilled labor v) low set-up and operational cost [128] . The effective product which inactivates the pathogen during chlorine-based disinfection is HClO [125] . Also, due to 80% similarity between SARS-CoV-2 and SARS-CoV-1, the disinfection process of the latter could be well approximated to the former one. Chen et al. (2006) studied the complete inactivation of SARS viruses by adding free Cl (0.5 mg/L) or ClO 2 (2.9 mg/L) after a heat treatment of 30 o C for half an hour. Therefore, it can be an effective inactivation for the COVID-19, too [129] . Heat treatment for virus inactivation has been in use for decades. involves denaturing viral capsid proteins, which in turn creates gaps in the viral particles making it more vulnerable to proteinase K and RNase treatment [78] . Recently, Hu et al. (2020) studied the thermal inactivation of SARS-CoV-2 by heating human serum contaminated with the virus at 56 o C for 30 min [97] . In another approach, 90% inactivation of the virus was achieved within 7 and 14 min when experiments were conducted in simulated saliva and culture media, respectively [130] . Several studies have reported instances of using microorganisms as an important tool for inactivating enterovirus [75] . Toranzo et al. (1982) reported the antiviral properties of isolated marine bacteria [131] . Photocatalysis is an alternative to chemical disinfection. He with an expected 12 to 18 months of timeline for production and delivery. In the meantime, researchers are also exploring potential antiviral drugs to minimize the mortality rate caused by SARS-COV-2. Figure 3 shows repurposed antiviral drug targets for SARS-CoV-2 infection. Development of drugs starts with the identification of interactions between a target virus and host receptor [133] , as polymerase inhibition, budding inhibition, target sites for the virus, human-drug interaction, and a better strategy [134] . Drug repurposing is one of the most crucial steps in finding the drug from the already existing drugs, which saves both time and cost during drug development [135] . Table 3 summarizes various human viruses, including SARS-CoV-2, and their effective antiviral drugs. The drugs were mesalazine, toremifene, eplerenone, paroxetine, sirolimus, dactinomycin, irbesartan, mercaptopurine, melatonin, quinacrine, carvedilol, colchicine, camphor, equaline, oxymetholone, and emodin. Additionally, a combination of sirolimus and dactinomycin, toremifene and emodin, and mercaptopurine and melatonin were found to be potential drug combinations against SARS-CoV-2 [135] . Some of the old drugs (such as J o u r n a l P r e -p r o o f 19 ribavirin, interferon, lopinavir, and ritonavir), formerly used for SARS and MERS, are currently under trial repurposing against SARS-CoV-2 [134] . Hydroxychloroquine (HCQ) was reported to be effective against COVID -19 [137] .The production of cytokine was often observed in severely-ill COVID -19 patients [138] and HCQ was found to be successful in inhibiting the production of cytokine [137] . Wang et al. Immediately after consumption, antiviral drugs undergo series of biotransformation such as glucuronidation, sulfoxidation, dimethylamine N-demethylation, and sulfate conjugation and finally excreted from the human body to the greater extent as metabolites, including active ones, mostly in urine [14] . Therefore, the drug residues and metabolites can be continuously transported through hospital and household wastewater to WWTPs and may pose additional challenges in their detection in complex environmental matrices [142] . Since WWTPs are not specifically designed to remove such drug residues, WWTPs become a major source of antivirals and their metabolites in the surface water bodies, especially during the J o u r n a l P r e -p r o o f 20 pandemics [14] . In this section, fate, transport, and occurrence of antiviral drugs with their seasonal variation, and ecotoxicological effects in the environmental waters are discussed In general, pharmaceuticals are expected to be attenuated via hydrolysis, sorption photodegradation, and biodegradation in the natural environment [143] . Similar months [144] . Except for favipiravir, laninamivir, and laninamivir octanoate, most of the studied antivirals were found to be persistent and could travel from upstream to downstream in chemically unchanged form. While the majority of antivirals are resistant to photodegradation, favipiravir, which is under clinical trial against SARS-CoV-2, is reported to be removed through photodegradation [144] . Most of these antiviral drugs were weakly adsorbed to sediment and sludge samples, indicating removal via sorption is not the primary removal mechanism. Except for laninamivir and oseltamivir, no other antivirals were found to be removed through biodegradation. While there is no extensive study reported on the transport of antiviral drugs in the natural environment, available data on other drugs suggests that river's hydrogeological conditions, J o u r n a l P r e -p r o o f 21 dissolved organic matter, and physical conditions prevailing in an aquatic environment may control the attenuation of antivirals [133] . However, it would be difficult to predict the actual attenuation of such drugs in surface water receiving active antiviral drugs from the manufacturing industries along the river course as reported elsewhere [145] . The occurrence of antiviral drugs in environmental waters is largely affected by seasonality [148, 149] . The drug acyclovir was detected at the highest concentration in winter (17 ng L -1 ) than in spring (14 ng L -1 ), summer (11 ng L -1 ), and fall (7 ng L -1 ). Its J o u r n a l P r e -p r o o f 22 concentration in the effluent did not show statistically significant seasonal variation over one year of sampling. An anti-influenza drug oseltamivir, and its metabolite oseltamivir carboxylate were detected in a river during the flu epidemic in Japan [150] . The maximum concentration of oseltamivir carboxylate was found to be 288 ng L -1 , and the concentration trend corresponded with the number of influenza patients obtained from sentinel surveillance [150] . In the case of Nairobi River in Kenya, the highest concentration for zidovudine (9 μg L -1 ) was detected due to high consumption of this drug during HIV-AIDS outbreak [151] . Unlike the Pearl River, acyclovir was not found in the Nairobi River, indicating the importance of drug usage patterns, consumer habits, and prescription patterns, which varies significantly across the globe. The seasonal variation of pharmaceuticals has been well studied, but similar study for antiviral drugs is still lacking [152] . studied the seasonal trend in the occurrence of fluoroquinolone drugs viz., levofloxacin, norfloxacin and ciprofloxacin in Kelani and Brahmaputra rivers from Sri Lanka and India, respectively [153] . It was found that concentration of drugs declined significantly in summer compared to the winter season. Similarly, the occurrence of naproxen, diclofenac, ibuprofen, bezafibrate, and ketoprofen was studied in the influent and effluent streams of a WWTP and nearby drinking water treatment plant (DWTP), as well as at downstream of a river in summer, spring and winter seasons [152] . Poor removal for the pharmaceuticals was noticed during the winter season (~25%) attributed to slow microbial activity compared to summer and spring seasons. The mean concentration of the studied drugs was found to increase by 3 to 5 times in the winter season compared to other seasons. These results suggest that cold/winter seasons J o u r n a l P r e -p r o o f 23 adversely elevate the probability of pharmaceutical contamination in environmental water and escalate the chances of their occurrence in drinking water [152] . Collectively, in winter, human immunity tends to be low, especially in colder countries, thus viral infection cases and consumption of antiviral drugs increases. Together with the low flow rate in winter, antiviral concentration levels in environmental waters are typically high in winter. Additional studies may be conducted as a priority basis, especially during this pandemic, to understand occurrence, fate, persistence, transport, and seasonal variation of antivirals, including the ones considered for the application to COVID-19 patients, in the environment. Like several other pharmaceuticals, antiviral drugs are prognosticated to be one of the most perilous among the therapeutic group, with the help of quantitative structure activity relationship (QSAR) modelling, in terms of their toxicity with regard to fishes, crustaceans, common water fleas and algae [146, 154] . The ecotoxicological effects of various antiviral drugs, together with their side effects on human are summarized in Table 3 . Aliivibrio fischeri bacteria [163] . Diverse reports are available on the ecotoxic nature of antiviral drugs, nonetheless, antiviral drugs for the treatment of influenza are of major concern [159, 164, 165] . Tamiflu or oseltamivir ethyl ester was reported to be even more toxic than its hydrolysis metabolite oseltamivir acid, towards algae (: Desmodesmus subspicatus, Chlorella vulgaris and Pseudokirchneriella subcapitata), bacteria (Vibrio fischeri), water flea (Daphnia magna) and fish (Cyprinus carpio, Pimephales promelas and Danio rerio) [166] ; Oseltamivir and oseltamivir carboxylate was studied by Mestankova et al. (2012) , and reported that for daphnia, algae and fish the no observed effect concentration (NOEC) were higher than 1 mg L -1 [167] . It has been asserted that the influenza drug amantadine does not pose any harm even in serious influenza pandemic situations, however an unaccustomed ecotoxicity was observed even at concentrations 0.1 mM. Inhibition of D. magna, S. capricornutum and P.phosphoreum was reported between 15 min to 72 h of exposure to amantadine and rimantadine [168, 169] . In another study, major freshwater bacteria viz., Planctomycetes, α, β and γ-Proteobacteria, and Cytophaga-Flavobacterium-Bacteroides, was observed with Fluorescence In-Situ Hybridization (FISH) technique for the comparative toxic effect of Tamiflu and its metabolite oseltamivir carboxylate and reported lower survival of bacteria in the presence of the parent compound [170] . Antiretroviral drugs like abacavir shown prodigious toxic effects on green algae, crustaceans and diatoms, with half maximal effective concentration (EC50) values ranging from 50 to 100 mg L -1 [171] . Green algae containing chlorophyll, are considered to be the primitive first degree producers in an aquatic ecosystem and hence, toxicity towards it, is of pivotal concern [172] . Furthermore, subjection to efavirenz (20.6 ng L -1 ) elicited hepatocyte cell damage and even caused death in O. mossambicus [173] . Ecotoxicity assay for acyclovir Some of these drugs discovered previously for other viral diseases and now under trial to treat the novel coronavirus showed acute toxicity to microalgae: Pseudokirchneriella subcapitata, crustacean: Daphnia magna, zebrafish: Danio rerio [161, 162] . Thus, these drugs may prove to be a perilous menace to the aquatic ecosystems, and their toxicity and actual environmental conditions needs to be studied in depth. J o u r n a l P r e -p r o o f 26 Antiviral drugs released to the environment are of substantial concern, owing to potential transformation in the ecosystem as well as plausible threat of viral resistance development [176] . In general, WWTPs become major source of the antiviral drugs in the surface water bodies especially during the pandemics. As mentioned above, conventional wastewater treatment at WWTPs doesn't lead to the complete mineralization of the parent antiviral drugs, but results in residues and formation of metabolites and oxidation/transformation products; those compounds can be as biologically active as their parent compounds. This gives rise to the major concern of the development of antiviral drug-resistant viruses within wild animals, such as bats, pigs, camels, etc., which are natural reservoirs of the viruses [177] . The potential pathways and origins of antiviral drug-resistant viruses through environmental waters are depicted in Figure 6 . In the case of influenza virus, water fowls are known animal reservoirs [178] . As for SARS-CoV-2, bats and pangolins are considered as wild animal reservoirs [177, 179] . Recently, the novel coronavirus has also been detected in eight lions and tigers at New York's Bronx Zoo [180] . Development of antiviral drug-resistant viruses are concerned when those animals with viruses ingest the contaminated environmental waters, then the viruses are continuously exposed to the high loads of antiviral drug residues and their metabolites/transformation products and, thus gain resistance through mutations. This potential development of antiviral drug-resistant viruses within animal reservoirs and their subsequent transmission to humans will compromise the treatment of the viral disease [177] . This all will cause more severity to human being for the current and future pandemic control. When the antiviral resistance is suspected, proper management in terms of clinical treatments, therapies, and laboratory testing can minimise the risk of severe consequences [181] . To guide the therapeutic decisions, an accessible and authorised database about the mutations of drug resistant viruses should be developed [181] . Less toxic and potent antiviral drugs should be developed which can reduce the risk of cross-resistance and simultaneously target the different aspects of viral replications. Understanding the kinetics of emergence of antiviral resistance in the host population (from minor to predominant) is now possible due to the contemporary next-generation sequencing [182] . Administration of genetic screening for pre-existing resistant mutants with respect to the particular drugs before the onset of treatments proves to be beneficial as observed in the case of HIV and HCV [8] . Such genomic data obtained for screening helps to scan the already known mutants and to detect new resistant mutations. Moreover, for management of antiviral resistant viruses, following actions can be summarised: 1) Discontinuation of ongoing monotherapies: If the ongoing drug therapy is stopped, then generally the resistant virus returns to its wildtype, which can be then easily treated with new drugs or vaccination. 2) Switching to a new antiviral agent or therapy: This will help when the virus is resistant against some particular drug. 3) Adding another drug to the current treatment: New drugs can be more effective against the known resistant mutants than repurposed drugs. 4) Using combination chemotherapies: patient with advanced critical disease/infections can be treated with proper combinations of antiviral agents [183] . Effective wastewater treatment facilities: The wastewater treatment facilities should adopt advanced treatment technologies, such as advanced oxidation processes, adsorption, membrane separation processes, and/or hybrid treatment systems, [14, [185] [186] [187] , which can completely degrade or reduce the concentrations of such drugs and their harmful metabolites/transformation products in the effluents. While vaccine development againt SARS-CoV-2 is underway, the number of confirmed cases has globally crossed 20 million, as of the second week of August, 2020. In such an unprecedented scenario where several countries have already experienced the second wave, the use of chemical, alcohol, and chlorine-based disinfectants found to be promising to inactivate the virus. Compared to UV-based disinfection, chlorination seems to be the best way to inactivate the virus in underdeveloped countries due to low cost and ease of handling. Currently, there is no publication related to persistence and transport of SARS-CoV-2 in surface and subsurface medium. However, it is essential to research those aspects of SARS-CoV-2, which is critical for developing countries where open defection and management of irregular dumping of biomedical wastes are yet to be addressed. It is also imperative to take presumptive action to find the answer of questions like: What will be the J o u r n a l P r e -p r o o f 30 different scenarios in case of such a high use of antivirals during this ongoing pandemic of SARS-CoV-2? Can we deny the possibility of the development of stronger viruses, causing severe pandemics than COVID-19 in the near future? What will be the occurrence scenarios of antiviral drugs and antiviral resistance in different parts of the world? Will there be any correlation of drug prevalence and antiviral resistance in the ambient water and infected person reported from that region or it will be affected by capabilities of WWTP infrastructure present in that country? What will be the consequences of higher concentration of antiviral drug and their metabolites? Finally, how to minimise these antiviral drug concentrations to go the ambient waters like river especially in developing countries where WWTPs are scarce and not even integrated in the hospital effluent? The authors declare no competing financial interest. R References [1] M. Kumar Antiviral drug resistance as an adaptive process Current emerging SARS-CoV-2 pandemic: potential direct/indirect negative impacts of virus persistence and related therapeutic drugs on the aquatic compartments Viral mutation rates Why are RNA virus mutation rates so damn high? 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