Journal of Environmental Management 271 (2020) 111030

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Journal of Environmental Management

journal homepage: http://www.elsevier.com/locate/jenvman

Review

Fate and toxicity of pharmaceuticals in water environment: An insight on

their occurrence in South Asia
Hudda Khaleeq Khan, Muhammad Yasir Abdur Rehman, Riffat Naseem Malik *
Environmental Health Laboratory, Department of Environmental Sciences, Quaid-i-Azam University, Islamabad, Pakistan

A R T I C L E I N F O A B S T R A C T

Keywords: Pharmaceutically active compounds are newly recognized micropollutants which are ubiquitous in aquatic
Pharmaceutical compounds environment mainly due to direct discharge of treated and untreated wastewater from wastewater treatment
Fate plants. These contaminants have attracted mounted attention due to their toxic effects on aquatic life. They
Toxicity
disrupt biological processes in non-target lower organisms upon exposure. Biodegradation, photo-degradation,
Risk assessment
and sorption are key processes which determine their fate in the environment. A variety of conventional and
Antibiotic resistance
South-Asia advanced treatment processes had been extensively investigated for the removal of pharmaceuticals from
wastewater. However, due to structural complexity and varying operating parameters, complete removal seems
ideal. Generally, due to high energy requirement of advanced treatment technology, it is considered cost inef­
fective. Transport of pharmaceutical compounds occurs via aquatic channels whereas sediments and aquatic
colloids play a significant role as sinks for these contaminants. The current review provides a critical under­
standing of fate and toxicity of pharmaceutical compounds and highlights their vulnerability and occurrence in
South Asia. Antibiotics, analgesics, and psychiatric drugs were found predominantly in the water environment of
South Asian regions. Despite significant advances in understanding pharmaceuticals fate, toxicity, and associated
risks since the 1990s, still substantial data gaps in terms of monitoring, human health risks, and legislation exist
which presses the need to develop a more in-depth and interdisciplinary understanding of the subject.

1. Introduction
Pharmaceutically active compounds are emerging contaminants
whose presence in water bodies has become a growing environmental
concern. Varying levels of pharmaceutical compounds have been re­
ported so far across different environmental matrices worldwide i.e.
drinking water, surface water, wastewater, sediments and biota (aus der
Beek et al., 2016). Pharmaceutical compounds include a diverse group
of chemicals together with their metabolites and transformation prod­
ucts. They become persistent in the environment by their use and
dispose practices (Wilkinson et al., 2017). Direct discharge of untreated
and treated wastewater becomes the primary source of these contami­
nants in aquatic environments (Daughton, 2003). Among secondary
source is terrestrial runoff from livestock farms, agricultural fields, and
aquaculture facilities (Hong et al., 2018). Moreover, these compounds
are managed and used differently, therefore, an important source in one
geographical region may not be as important in another (Boxall et al.,
2012). Transport of these contaminants occurs via aquatic channels and
their lipophilic nature is responsible for bioaccumulation. However,
lipophilicity is not the only parameter to understand bioaccumulation
(Ebele et al., 2017). Recent studies have explained other processes
including metabolism (Gomez et al., 2011), inhalation exposure (Du

abbreviations: Advanced oxidation processes, AOPs; Antibiotic resistance bacteria, ARB; Antibiotic resistance genes, ARGs; Antibiotic resistance genes database,
ARDB; Antibiotic resistance genes online, ARGO; Antibiotic resistance gene-annotation, ARG-ANNOT; Beta-lactamase database, BLDB; Centre for Disease Dynamics,
Economics and Policy; CDDEP, Comprehensive antibiotic resistance database; CARD, Conventional activated sludge process; CAS, Defined daily doses; DDD, Drug
Resistance Index; DRI, Environmental Protection Agency; EPA, Food and Agriculture Organization; FAO, High-performance liquid chromatography; HPLC, Hori­
zontal gene transfer; HGT, Human metabolites; HMs, Measured environmental concentrations; MEC, Membrane bioreactor; MBR, Metagenomics rapid annotation
using subsystems technology; MG-RAST, Microbubble; MB, Predicted environmental concentrations; PECs, Predicted no-effect concentration; PNEC, Quantitative;
PCR, qPCR; Suspended particulate matter, SPM; SILVA small subunit, SSU; Transformation products, TPs; Wastewater treatment plants, WWTPs; World Health
Organization, WHO.
* Corresponding author. Environmental Health Laboratory, Department of Environmental Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
E-mail address: r_n_malik@qau.edu.pk (R.N. Malik).

https://doi.org/10.1016/j.jenvman.2020.111030
Received 11 March 2020; Received in revised form 12 June 2020; Accepted 28 June 2020
Available online 2 July 2020
0301-4797/© 2020 Elsevier Ltd. All rights reserved.
H.K. Khan et al.
et al., 2014) and animal homeostasis to better understand the accumu­
lation of these contaminants in marine biota (Franzellitti and Fabbri,
2014). Conventional wastewater treatment plants are inefficient in
completely removing pharmaceutical compounds. This raised concern
for their possible risks to aquatic organisms and humans. Potential toxic
effects have been identified for aquatic organisms as evidenced by bio­
accumulation studies. These contaminants were measured in different
fish tissues such as gills (Tanoue et al., 2015), muscles (Zhao et al.,
2015), blood plasma (Muir et al., 2017), liver (Ojemaye and Petrik,
2019) and brain (Arnnok et al., 2017). Numerous studies have also
measured antibiotics in algae (Ali et al., 2017), bivalves (Burket et al.,
2019) and aquatic invertebrates (Meredith-Williams et al., 2012).
Concomitantly, for human health, antibiotic resistance is a major threat
and has been given special attention during the past decades. Numerous
studies on fate and toxicity of pharmaceutical compounds have been
reported so far. Monitoring data is well-established for developed
countries whereas developing countries are still struggling to detect,
measure, and manage the abundance of pharmaceutical compounds in
water environment. Particularly, Asia and Africa which are the largest
and populous continents in the world with a majority of developing
countries. Further, the risk of contamination by pharmaceuticals in
these geographical regions is more likely due to poor sanitation, irre­
sponsible use and disposal of pharmaceutical compounds, and lack of
advanced wastewater treatment facilities. Although scientists from these
regions have managed to develop baseline monitoring data for phar­
maceutical compounds but still huge voids exist in data availability in
many regions. Several reviews had been published previously evaluating
contamination status in Europe (Fekadu et al., 2019) southeast Asia
(Menon et al., 2020) and Africa (Madikizela et al., 2017) (Fekadu et al.,
2019; Madikizela et al., 2017; Menon et al., 2020), but no review had
been published so far discussing contamination status of pharmaceuti­
cals in South-Asia, except two reviews discussing emerging contami­
nants in Indian environment (Balakrishna et al., 2017; Philip et al.,
2018). South Asia houses one fourth of the world’s population. The
relocation of pharmaceutical manufacturing from west to Asia has made
China, India, Bangladesh, and Pakistan emerging pharmaceutical in­
dustries (Rehman et al., 2015). Low production cost and the growing
pharmaceutical market makes these countries large consumers of
pharmaceuticals in the world (Mathew and Unnikrishnan, 2012). The
socio-economic indicators of the pharmaceutical industry in South Asian
region have been provided in Table S1 Thus, with growing pharma­
ceutical market, low socio-economic conditions, and no legislation to
ensure responsible use of drugs in health care facilities South Asia re­
mains an underappreciated region of contamination. Hence, this review
aims to provide insights into current knowledge of pharmaceuticals in
Fig. 1. Natural attenuation processes of pharmaceuticals in water environment. (Source: Online Drafting Tool; Biorender (https://biorender.com/)
2
Journal of Environmental Management 271 (2020) 111030
terms of fate and toxicity in water environment considering the recent
literature. It also provides new insights to be considered as important
research prospects for future. Further, it systematically evaluates envi­
ronmental monitoring data of pharmaceutical compounds in surface and
wastewater of South Asian regions.
2. Environmental fate and transport
Biotic and abiotic processes shape the fate of pharmaceutical com­
pounds in the environment. Biodegradation, photo-degradation and
sorption are the key processes involved in attenuation of these con­
taminants in water environment (Fig. 1) (Caracciolo et al., 2015). There
are certain key factors which influence the fate and transport of these
contaminants in water-sediment matrices which include their physico­
chemical properties (solubility, vapour pressure and lipophilicity),
environmental conditions (pH, temperature, irradiation and redox
conditions) and the microbial community (Luo et al., 2014). Knowledge
about the fate of pharmaceuticals is limited to several compounds, and
lab experiments under controlled conditions mimicking the natural
environment. Only a few data sets are available focusing field studies (Li
et al., 2016). Thus, sufficient data gaps exist regarding pathways of
degradation and transformation processes which makes it difficult to
understand the fate of these compounds in natural complex systems.
2.1. Transformation processes in the natural environment
The transformation process is associated with detoxification of con­
taminants, resulting in transformation products (TPs). The information
on occurrence of TPs and human metabolites (HMs) of pharmaceuticals
in different environmental matrices is incipient. Table 1. summarize TPs
of pharmaceutical compounds formed during degradation and their
respective toxic effects. The nature of TPs is indeterminate; some TPs
may be more toxic or persistent than their parent compounds for
instance transformation of antiviral drug acyclovir produces two toxic
byproducts during wastewater treatment which showed decreased
reproduction in Daphnia magna by 40% and inhibited the growth of
green algae (Schlüter-Vorberg et al., 2015). Direct photolysis of cepha­
losporin antibiotics forms byproducts which displayed increased toxicity
to green algae (Wang and Lin, 2012). An anticonvulsant drug carba­
mazepine which is persistent in aquatic environment and poses toxicity
to aquatic organisms such as algae, bacteria, and fish. Its several human
metabolites and transformation products might pose a risk for increased
genotoxicity (Brezina et al., 2017). Some TPs or HMs might convert back
to their parent compounds under suitable conditions as evidenced by
back-transformation of TPs and HMs of antibiotic sulfamethoxazole in
H.K. Khan et al. Journal of Environmental Management 271 (2020) 111030

Table 1
TPs formed during degradation of pharmaceuticals and their respective toxic effects.
Parent Compound Transformation Transformation products Ecotoxic effects References
process

Acetaminophen Photocatalysis 1,4-benzoquinone, Hepatotoxicity, genotoxic & mutagenic Chang et al. (2015)
Chlorination N-acetyl-p-benzoquinone-amine effects in humans Vo et al. (2019)
Acyclovir Ozonation Carboxy-acyclovir, Increased reduction in reproduction levels of Schlü;ter-Vorberg et al.
N-(4-carbamoyl-2-imino-5-oxoimidazolidin)- Daphnia magna (2015)
formamido-n-methoxy-acid
Carbamazepine Biodegradation 2-Hydroxy carbamazepine, Luminescence inhibition in V. fischeri Kaiser et al. (2014)
3-Hydroxy carbamazepine
Carbamazepine Biodegradation carbamazepine-10,11-epoxide Population decrease in the non-biting midge Heye et al. (2016)
Chironomus riparius
Cefazolin Photolysis 5-methyl-1,3,4-thiadiazole-2-thiol Luminescence inhibition in V. fischeri Wang and Lin (2012)
Diclofenac Biodegradation 4-Hydroxydiclofenac Luminescence inhibition in V. fischeri Grabarczyk et al. (2020)
Gemfibrozil Chlorination Chloro- & bromo-gemfibrozil Increased anti-androgenic activity in Bulloch et al. (2012)
Japanese medaka
Ibuprofen Ozonation Hydroxy-ibuprofen Increased growth inhibition in S. capricornium Quero-Pastor et al.
alga (2014)
Metoprolol Biodegradation Metoprolol acid Growth inhibition in Ganoderma lucidum Ja�
en-Gil et al. (2019)
Phenazone Ozonation Aniline Increased growth inhibition in Daphnia magna Miao et al. (2015)
Propranolol Photolysis 4-hydroxy-propranolol, Cytotoxicity towards V. fischeri Menz et al. (2017)
5-hydroxy- propranolol
Sulfamethoxazole Biodegradation N4Acetylsulfamethoxazole Growth inhibition in duckweed and algae Grabarczyk et al. (2020)

water/sediment environment where photo-transformation occurs dur­
ing daytime and reformation occurs at night under certain abiotic con­
ditions via biodegradation (Su et al., 2016). Similar back-transformation
has also been observed for photo-products of steroid trenbolone acetate
(Qu et al., 2013). Transformation products are thus secondary pollutants
which are released into the environment from their parent compounds
with their eco-toxic potential largely unknown.
2.1.1. Transformation mechanism
Photolysis and biodegradation are major transformation processes in
aquatic environment. However, these processes are dependent on
boundary conditions. Favorable boundary conditions for example,
shallow depth, low total organic carbon content, sandy sediments, and
low turbidity makes the processes efficient (Baena-Nogueras et al.,
2017). Surface water which receive high waste discharge containing
co-emitted wastewater bacteria could also establish well-adapted com­
munities at the water-sediment interface that might increase the effi­
ciency for biodegradation (Li et al., 2016). However, no sweeping
statement can be made as different attenuation patterns have been
observed for different compounds in different aquatic environment.
Seasonal variations may affect transformation processes in aquatic
environment for instance during winters low irradiance and low tem­
perature reduces the potential for photo-degradation and
microbial-degradation thereby increasing the threat of pharmaceutical
contamination in aquatic ecosystem during winters (Bernot et al., 2019).
Soil, sediments, colloids, and suspended solids in aquatic environment
play a significant role as sinks which determines the transport of phar­
maceutical compounds via sorption. Many studies have shown the
adsorption ability of pharmaceutical compounds onto sediments, soils
(Biel-Maeso et al., 2018), and biosolids (Walters et al., 2010). Fixation of
these contaminants to sediments or biosolids can inhibit their degra­
dation thereby they become sinks of these contaminants (Beretta et al.,
2014). Primarily, sorption involves cation-exchange and complexation
on surface and interlayers. Sorption affinity of compounds differs greatly
according to sediment material, ionic strength, pH, and cation type
(monovalent or divalent). Colloids are known as strong sorbents due to
their large surface area and reactive surfaces (Xing et al., 2015).
Adsorption potential of five pharmaceutical compounds (propranolol,
sulfamethoxazole carbamazepine, indomethacin, and diclofenac) to
sediments, aquatic colloids and suspended particulate matter (SPM)
revealed high sorption affinity of pharmaceuticals to aquatic colloids
than sediments and SPM suggesting colloids can act as powerful sorbents
for pharmaceutical compounds (Maskaoui and Zhou, 2010).
Beta-blockers (metoprolol, propranolol, and sotalol) seem to possess
great sorption affinity with sediments and aquatic colloids (Li et al.,
2016). Colloids include clay minerals, organic particulates, metal oxides
and bio-colloids (e.g. bacterium, protozoans and viruses). Colloidal
interaction is important for understanding the transport of pharmaceu­
ticals in the environment. In the soil environment, pharmaceuticals
transport is facilitated through irrigation, uptake by plants, erosion and
leaching subsequently reaching groundwater. Nevertheless, under un­
favorable conditions, the mobility of colloids might be reduced (Li,
2014). Particles attached to sediments might also release back into water
compartment under some conditions such as alteration in pH, ionization
of adsorbate, and surface charges (Martínez-Hern� andez et al., 2014).
However, as much as this mobility promotes pharmaceutical compounds
pervasiveness in the environment, sorption is also evidenced as a sig­
nificant process in eliminating them from the environment (Leal et al.,
2013). As adsorption phenomena has been studied in WWTPs as capable
of removing pharmaceuticals from wastewater. Moreover, sorption
could assist in developing antibiotic resistance by domesticating anti­
biotic resistance genes and microbes, pharmaceuticals adsorbed to
sediments and aquatic colloids may become gentle to microorganisms
thereby resisting degradation and promoting microbial acclimation
(Azuma et al., 2019a).
2.2. Fate in wastewater treatment plants
In wastewater treatment plants (WWTPs), true mineralization or
complete removal of pharmaceutical compounds is hard to achieve. The
water treatment technologies which have been investigated to remove
pharmaceutical compounds were either conventional or advanced sys­
tems. The conventional techniques include physical–chemical and bio­
logical systems, such as sedimentation, coagulation, filtration,
adsorption/bio-adsorption on activated carbon, activated sludge pro­
cess, and chemical disinfection. Whereas, the advanced techniques
include membrane filtration and advanced oxidation processes (AOPs)
such as, ozonation, UV photolysis, photocatalysis, and Fenton reaction
(Blair et al., 2015). Huge disparities have been observed in removal
efficiencies of pharmaceutical compounds due to the treatment applied
at individual WWTPs. Also contaminants physicochemical properties
and varying operating parameters such as pH, solids retention time,
hydraulic retention time and microbial activity influence removal effi­
ciency (Petrie et al., 2015). Table S2. provides removal efficiencies of
pharmaceutical compounds in WWTPs.

3
H.K. Khan et al.
2.2.1. Advanced oxidation processes
Studies have demonstrated the potential of AOPs in efficiently
removing a wide spectrum of pharmaceutical compounds. These pro­
cesses vary in performance and treatment efficiency. Generally, due to
the high energy requirement of AOPs, they are deemed non-cost effec­
tive. Further, the additional transformation products formed by these
processes can result in higher toxicity, for example, some oxidative TPs
have a high polarity which increases their environmental mobility and
thus the risk of contaminating groundwater resources (Brezina et al.,
2017). Activated carbon adsorption, however, does not form any TPs
(Funke et al., 2016). Ozonation is the most widely studied advanced
oxidation process for the removal of pharmaceutical compounds. Its
combination with UV, hydrogen peroxide (H2O2), TiO2 has been
explored and is known to improve removal efficiencies. One study
investigated simultaneous ozonation and photocatalysis (O3þTiO2þUV
system) in a model reactor for the removal of pharmaceutical com­
pounds. Complete mineralization was achieved for carbamazepine,
diclofenac and ketoprofen within a relatively short time (6–8 min)
(Jankunaite et al., 2017). In recent years, microbubble (MB) based
technologies have been developed in Japan for the removal of envi­
ronmental pollutants. MBs due to their big surface-to-volume ratio and
longer stability were used for ozonation to remove pharmaceutical
compounds. Removal rates were enhanced by using ozonated micro­
bubbles (O3-MB) as compared to O3. Further, recalcitrant properties of
all contrast media pharmaceuticals (iohexol, ioversol, iopromide,
iomeprol and iopamidol) disappeared by combined treatment with UV,
and removal rates became 94–99% from 0% to 52%. Thus, O3-MB sys­
tem could serve as a promising treatment for pharmaceuticals removal
(Azuma et al., 2019b). UV/H2O2 is the conventional advanced oxidation
process which utilizes UV to produce hydroxyl radical via H2O2. This
process is energy-intensive and hydroxyl radical can easily be scavenged
by other co-existing components in water such as dissolved organic
matter therefore excessive H2O2 dosing is required making it
non-economical (Yu et al., 2015). Reactive chlorine species (Cl�, ClO�,
Cl�-
2 ) and sulphate radical (SO4 ) based advanced oxidation processes
�-
have also been proposed. They are more selective, economical and have
a longer half-life (Guo et al., 2018; Liu et al., 2013). However, oxidation
products formed by these processes remains an area of concern as their
toxic potential is largely unknown and in some cases, more toxicity than
parent contaminant has been reported (Yang et al., 2019). Nevertheless,
owing to the structural diversity of compounds, the simultaneous pres­
ence of different compounds, and intricacy of natural systems, single
AOP might not be sufficient to remove all pharmaceutical compounds.
Further, AOP technologies can be energy-intensive, thus,
cost-effectiveness is another important factor to take into consideration
while deciding on the best-suited treatment process. A combination of
treatment processes seems more promising. For instance, a combination
of O3/H2O2 and UV/H2O2 was shown superior abatement of pharma­
ceutical compounds with less energy requirement and less formation of
by-products (Lee et al., 2016).
2.2.2. Membrane technology
Reverse osmosis membrane filters seem promising as they can
remove a broad range of pharmaceutical compounds. Moreover, the
integration of membrane technology with oxidation processes have
more potential for efficient removal as membrane technology only
separate contaminants for degradation (Abdelmelek et al., 2011). Con­
structed wetlands and micro-algae based technologies are thought as
promising sustainable alternatives in removing pharmaceutical com­
pounds (Zhang et al., 2014). Micro-algae are used for biodegradation,
photodegradation and sorption. It contains certain enzymes which can
metabolite a variety of xenobiotics. It also accelerates photodegradation
by extracellular secretions (Wang et al., 2017b). Certain pharmaceuti­
cals were also found to accumulate in algae cells (Maes et al., 2014).
Constructed wetlands as a tertiary treatment have also shown significant
removal efficiency for pharmaceutical compounds by utilizing aquatic
4
Journal of Environmental Management 271 (2020) 111030
macrophytes (single or multispecies). Comparatively, they have low cost
and energy requirements and are easy to maintain (Rabello et al., 2019).
Enzyme assisted biodegradation is considered another environmental
friendly, cost-effective, and highly efficient technology for the removal
of wide array of environmentally relevant pollutants. Lignin peroxidases
(LiPs), laccases, horseradish peroxidases (HRPs), manganese dependent
peroxidases (MnPs), and tyrosinases are the most commonly used bio­
catalysts (Bilal et al., 2019). A study developed a novel hybrid
bio-reactor by combining cross-linked laccase and tyrosinases enzyme
aggregates with microfiltration membrane for removal of pharmaceu­
tical compounds. Complete removal of all pharmaceutical compounds
was achieved after five days of operation (Ba et al., 2018).
3. Toxicity and ecotoxicological effects
Pharmaceutical compounds are intended to produce a biological
response in specific organisms but exposure to environmental concen­
trations might also produce a biological response in non-specific or­
ganisms. Considering most pharmaceutical compounds exist for longer
periods at low concentration in aquatic environment and their lip­
ophilicity, the toxic effects are more likely to be chronic rather than
acute. Also, aquatic biota is exposed to these contaminants throughout
their life cycle making their prenatal stage more susceptible to toxic
effects (Wilkinson et al., 2016). Both, in vitro and in vivo assays are used
to determine toxic potential of pharmaceutical compounds, however,
the latter is predominant. Common endpoints for toxicity testing had
been growth, mortality, and reproduction. But, only recently much
attention has been given to investigate potential effects on develop­
mental, molecular, histological, and behavioral level (Godoy and
Kummrow, 2017). Primary producers (microalgae), invertebrates
(aquatic crustaceans, molluscs and worms) and vertebrates (fish) are
more investigated as compared to amphibians and other vertebrates
(Gunnarsson et al., 2019). The toxicity of pharmaceutical compounds
varies depending on the contaminant, species, exposure duration, con­
centration and developmental window in which organisms are exposed
(Gerbersdorf et al., 2015).
3.1. Ecotoxicological effects
Toxic effects of analgesics are mostly reported for diclofenac,
ibuprofen, paracetamol, and naproxen (Lonappan et al., 2016). Envi­
ronmental exposures of diclofenac caused gill alterations and renal le­
sions in rainbow trout at 5 μg/L concentration (Schwaiger et al., 2004).
It also caused acute renal failures in vultures feeding on diclofenac
treated dead livestock, the reason for their great decline in population
reported in Pakistan and India (Oaks et al., 2004). There is no significant
proof of reproduction abnormalities caused by analgesics at environ­
mentally relevant concentrations. However, one study observed diclo­
fenac (at concentration 1000–2000 μg/L) to cause a delay in Zebrafish
hatching (Hallare et al., 2004). For antibiotics, the ecotoxicological
potential is incipient. The commonly reported effects are related to
growth inhibition in cyanobacteria and green algae (Xiong et al., 2019)
and development of antibiotic resistance (Berglund, 2014). Acute
exposure of erythromycin (0.0002–200 μg/L) increased gill histopath­
ological index and chronic exposure of oxytetracycline (0.0004–400
μg/L) increased pathological index in gilthead seabream (Rodrigues
et al., 2019c). Oxidative DNA damage was also observed upon exposure
to erythromycin in rainbow trout and gilthead seabream (Rodrigues
et al., 2016, 2019a, 2019b). Besides, presence of other contaminants
particularly heavy metals can increase the toxicity of antibiotics as
evidenced by oxytetracycline and ciprofloxacin complexes with copper,
cadmium, and zinc which exhibited highest algal growth inhibition as
compared to individual antibiotics. Ignoring such associations might
underestimate risks therefore must be taken into account in environ­
mental risk assessment (Zhang et al., 2012). Beta-blockers and Blood
lipid regulators are known to generate similar effects in non-target
H.K. Khan et al.
organisms as in target organisms. For instance, atorvastatin, a globally
prescribed blood lipid regulator at 1.2 μg/L led to depletion of lipid,
carbohydrate, and protein pools, and suppressed transcription of key
enzymes involved in mitochondrial biogenesis and fatty acid meta­
bolism in the digestive gland of keystone specie bivalve (Mytulis edulis)
(Falfushynska et al., 2019). Similarly, Heart rate of Daphnia magna was
greatly affected upon exposure to beta-blocker propranolol (Jeong et al.,
2018). Just like in humans, the presence of beta-2 receptors in fish
reproductive, heart, and liver tissues increases their likelihood of eco­
toxic action caused by beta-blockers. Mostly data is reported for pro­
pranolol and atenolol. Reproductive abnormalities are also reported for
beta-blockers and blood lipid regulators. However, generally,
beta-blockers are thought to pose little risk to aquatic organisms because
their high sorption affinity to sediments reduces their bioavailability
(Maszkowska et al., 2014). Neurotoxicity and behavioral changes are
the common effects reported for psychiatric drugs. Mostly toxic effects
are studied for Fluoxetine and Carbamazepine. For some environmen­
tally concerned pharmaceutical classes little is known for their toxic
effects in non-target organisms, for example, anti-cancer compounds
and X-ray contrast media. However, they affect conserved biological
pathways in lower organisms in similar ways to that of humans (Too­
laram et al., 2014). Cyclophosphamide and 5-fluorouracil are the most
used anti-cancer drugs. Environmental concentrations (0.2–123 μg/l) of
these contaminants influenced visual acuity and produced mutagenic
effects for example formation of micronuclei and binuclei as well as
development of melanocytes in gastrointestinal tract of tadpoles (Lith­
obates catesbeianus) after 30 days exposure (da Costa Araújo et al., 2019).
Growth inhibition in algae (Pseudokirchneriella subcapitata) and cyano­
bacteria (Synechococcus leopoliensis) was also observed for 5-fluorouracil
at concentration 0.13 mg/l and 1.20 mg/l respectively (Brezov�sek et al.,
2014). Endocrine disruptors (natural and synthetic hormones) are
generally known to disrupt reproductive system. They have great po­
tential to bio-concentrate because of their ability to freely pass through
the gills and affinity for sex steroid binding proteins in aquatic organ­
isms. However, only small number of these molecules are covered in
investigating their toxic effects (Runnalls et al., 2010). Only recently, a
study reported that over the counter use of Ibuprofen induced a repro­
ductive disorder in human males called compensated hypogonadism
(Kristensen et al., 2018). This evidence could serve as a basis to further
investigate human health effects upon environmental exposures to such
contaminants. Further, ecotoxicological effects frequently reported for
different classes of pharmaceutical compounds is given in Supplemen­
tary Table S3.
4. Biomonitoring
Biomonitoring studies have gained much attention in recent times
for their significance in identifying exposure and hazard of pharma­
ceutical compounds particularly in aquatic organisms. There are two
ways to approach bio-monitoring. The one which examines the potential
effects of pollutants on individual organisms at lower levels (cell or
tissue level). And the other which examines potential effects of pollut­
ants at higher levels (population or community level). It is more
ecologically relevant as it provides a holistic view of changes occurring
within a community or population. However, comparatively, from the
perspective of pharmaceutical compounds the latter one is understudied
(Pomfret et al., 2020). Both, active and passive biomonitoring have been
used in studies. In active biomonitoring caging of the organisms is done.
Whereas, passive bio-monitoring of effects upon exposure to pollutants
is done in-situ. Comparatively, active bio-monitoring is more prevalent,
and it provides better results whereas passive biomonitoring might un­
derestimate results due to the possibility of organism’s adaptation to
pollutants. However, active biomonitoring approach hinders our un­
derstanding of species adaptive phenomena under stress conditions
(Wang et al., 2011). Bio-marker is an efficient tool by which responses of
living organisms upon exposure to toxic pollutants are measured.
5
Journal of Environmental Management 271 (2020) 111030
Multiple-bio marker approach is commonly utilized to better understand
exposure to environmental hazards (Gavrilescu et al., 2015). A suite of
biomarkers is used to determine the bioeffects of pharmaceutical com­
pounds. Most commonly used biochemical markers include acetylcho­
linesterase for neurotoxic effects, glutathione-S-transferase,
reduced/oxidized glutathione, catalase (CAT), glutathione peroxidase,
lipoperoxidation (LPO), and malondialdehyde (MDA) for oxidative
stress (Ghelfi et al., 2016). Whereas, genetic biomarkers include DNA
breaks (comet assay), frequency of micronuclei (MN) and erythrocytic
nuclear abnormalities (ENA) (Vieira et al., 2017). There are limited
studies determining exposure and consequent health risks of pharma­
ceutical compounds based on biomonitoring. Human biomonitoring
studies are comparatively less. However, lately, few studies have
monitored pharmaceuticals in urine and assessed their associated health
risks. Antibiotics had been monitored in the urine of children and
pregnant women from Korea (Ji et al., 2010) and China (Wang et al.
2016, 2017a). Recently, a study monitored 18 antibiotics in the urine of
adults (21–75 years of age) the findings of the study indicated sub­
stantial exposure to multiple antibiotics at low dose. Some adults also
showed health risk due to disturbance of gut microbiota (Wang et al.,
2018). Commonly used analgesic, paracetamol was found in the urine of
individuals with no clinical exposure suggesting environmental expo­
sure to be the reason for ubiquity of paracetamol in the German popu­
lation (Modick et al., 2014). Another study reported paracetamol in the
urine of Danish mothers and children with no clinical exposure of
paracetamol (Nielsen et al., 2015).
5. Risk assessment and modelling approaches
Risk assessment involves identifying risks associated with a given
compound, in the environment and on human health. A reliable and
relevant prospective risk assessment procedure is the backbone of an
effective and successful environmental policy (Ågerstrand et al., 2015).
Most commonly, environmental risk assessment of pharmaceutical
compounds is done following EU standard method known as risk quo­
tient approach by calculating the ratio of predicted environmental
concentrations (PEC) or measured environmental concentrations (MEC)
and predicted no-effect concentration (PNEC) (EU, 2003). This process
helps in screening compounds with potential environmental risks. For
calculating PNECs, chronic toxicity endpoints such as no observed effect
concentration (NOEC) or lowest-observed effect concentration (LOEC)
are required. In the absence of chronic data, acute toxicity endpoints
such as median effective concentration (EC50) or median lethal con­
centration (LC50) are used. PNECs of the compounds and organisms can
also directly be obtained from published literature or can be searched in
toxicity databases such as ECOTOX (http://cfpub.epa.gov/ecotox/) and
EnviroTox (https://envirotoxdatabase.org/). If data is not available in
published literature or databases, acute and chronic toxicity data of
compounds can also be predicted using models QSAR toolbox 3.3 or
ECOSAR (Zhou et al., 2019). Similarly, due to sophisticated analytical
procedures, MECs are either not available or available for a limited
number of compounds for risk assessment studies of pharmaceuticals.
Therefore, alternative computational methods have gained much
importance to fill data gaps and to ease risk assessment and monitoring
of pharmaceuticals.
5.1. Modelling approaches
Different models have been proposed to understand environmental
occurrence, fate, and risks of pharmaceuticals. However, multimedia
(water, soil, air) fate models have been widely adopted. They are based
on mass balance equations and assume homogenous distribution of
chemical within compartments (Chen et al., 2018). Fugacity-based
multimedia modelling is more commonly used in predicting environ­
mental concentrations and fate of pharmaceutical compounds (Kim
et al., 2017). The model inputs information on chemical emissions,
H.K. Khan et al.
physicochemical properties of chemicals and environmental parame­
ters. The model also amounts distribution of chemicals as well as their
partitioning, transfer and transport pattern between environmental
compartments (Wang et al., 2015). Recently, an updated version of
multimedia fugacity model FATEMOD-Q has been applied in Finland to
simultaneously predict concentrations of three pharmaceutical com­
pounds and their transformation products at various depths in a strati­
fied lake. This new version was developed to include arbitrary
intrasystem flows and support assessment of transformation products
while requiring a modest number of parameters (Nurmi et al., 2019).
Multimedia models do not account for spatial variations. There are
geo-referenced single media models for spatial variations such as
GREAT-ER (Aldekoa et al., 2013), PhATE (Hosseini et al., 2012),
GWAVA (Liu et al., 2015), LF2000-WQX (Williams et al., 2012) and
iSTREEM (Kapo et al., 2016). They are catchment-scale models and have
been applied to estimate PECs in many river catchments worldwide.
They require input variables such as contaminant consumption, human
metabolism, contaminant load released by wastewater treatment plant
(WWTP), local population served by WWTP, removal in WWTP, dilution
and dissipation in receiving waters. These models have limited appli­
cability in regions where such data is unavailable. However, recently
China has been successful in overcoming data barriers and implemented
GREAT-ER model to predict environmental concentrations of pharma­
ceutical compounds in river catchments (Jackson, 2018). Recently,
another GIS-based model GLOBAL FATE has been developed which
utilize some input variables but predicts environmental concentrations
of pharmaceutical compounds at global river network including lakes
and reservoirs. It is computationally efficient and flexible. Users can
define the working spatial resolution and extent just by adapting the
resolution of the raster inputs and the region of interest (for instance, a
single continent or subcontinent). It displays the output as a global map.
However, it models lakes and reservoirs with no spatial heterogeneity.
This may fail to capture likely gradients of contaminant concentration in
large lakes and reservoirs (Font et al., 2019). Other spatially explicit
models include exposure to pharmaceuticals in the environment (ePiE)
(Oldenkamp et al., 2018) and an unnamed model (Zhu et al., 2019).
Both models are constructed in R software and utilize consumption data,
emissions from WWTP and removal rate in WWTP, among other pa­
rameters. They predict environmental concentrations at high spatial
resolution with limited computational and data requirements. In addi­
tion, these models also allowed risk prioritization of compounds.
6. Antibiotics and antibiotic resistance
Antibiotics helped revolutionized medical treatments by combating
infectious diseases which were formerly considered fatal. Antibiotics
have been in use since the 1940s and since then it has become essential
in human therapy to organ transplants to the treatment of common
communicable diseases, without antibiotics modern medicine could fall
apart (Levy, 1982). Antibiotics have caught increased attention as
environmental pollutants since they were frequently found to occur and
persist in different environmental media (rivers, groundwater, sedi­
ments, soils and wastewater) worldwide, and their potential to wield
toxic effects in non-target organisms at environmentally relevant con­
centrations, as well as their entry in the food chain and drinking water
supply systems (Zhang et al., 2017). Their residues had been detected in
vegetables, milk, aquatic products and pork (Hao et al., 2015). Despite
being warned by medical experts, the increased and inconsiderate use of
antibiotics continues to grow and not only in developing countries but
developed countries like OECD countries where inappropriate use of
antibiotics in some general practices is estimated to be as high as 90% of
the total consumption (OECD, 2016). Similarly, in the UK approximately
50% of individuals between 15 and 24 years have consumed antibiotics
not meant for them (Honigsbaum, 2018). In the United States, 70% of
the antibiotics used in animals are medically important for humans
(Dall, 2016). An estimate suggests that the global use of antimicrobials
6
Journal of Environmental Management 271 (2020) 111030
in meat production is expected to grow by 67% between 2010 and 2030
(Van Boeckel et al., 2015).This intemperate use has jeopardized the
effectiveness of antibiotics as bacteria’s have retaliated by developing
resistance against even the strongest antibiotics (carbapenems) putting
medicine at stake and raising concerns over public health (Honigsbaum,
2018). As antibiotic resistance reportedly cause 700,000 deaths per year
globally and is projected to be 10 million in 2050 (O’Neill, 2016).
Recently, World Health Organization (WHO) published its first ever
antibiotic resistant priority pathogens list which includes twelve species
of bacteria which pose the greatest threat to human health for which
new antibiotics are immediately needed (WHO, 2017).
6.1. Mechanisms of antibiotic resistance
Antibiotic resistance is an evolutionary comeback, by the virtue of
Darwinian natural selection, microbes develop robust processes to avoid
obliteration from toxic compounds. Even though some microbes, plants,
and fungi naturally produce antibiotics, there is less evidence which
suggests that this is a significant selection pressure to develop antibiotic
resistance among microbes in their native environment (Martinez,
2009). A recent study has proposed that bacterial persistence can
generate and accelerate the evolution of resistant mutants from persister
population via chromosomal mutations during antibiotics treatment by
providing an increased number of viable cells for mutation (Windels
et al., 2019). Resistance has evolved through two distinct mechanisms:
vertical evolution whereby de-novo mutations that increase antibiotic
tolerance occur in the bacterial genome and are subsequently trans­
ferred to the progeny; or horizontal evolution which is the horizontal
gene transfer (HGT) between microorganisms via phage transduction,
natural transformation, and bacterial conjugation. However, horizontal
evolution has shown to contribute majorly in current antibiotic resis­
tance crisis (Sommer et al., 2017). Among other resistance mechanisms,
resistance mutation is considered as a core mechanism. These mutations
alter the target protein, for instance, by inactivating the
antibiotic-binding site but leaving the cellular function of the protein
unharmed (Holmes et al., 2016). Particularly, modifications in the
DNA-gyrase which cause resistance to fluoroquinolones, multidrug
resistance efflux pumps (these pumps export a drug out of the micro­
organism), inactivation of the drug by covalent modification of the
antibiotic such as fluoroquinolone inactivation by an aminoglycoside
N-acetyltransferase (Allen et al., 2010). Various anthropogenic activities
are thought to significantly promote antibiotic resistance selection in the
environment (OECD, 2016). Co-resistance is one such underlying
mechanism whereby one or more resistance genes are located next to
each other on mobile genetic elements and due to genes close arrange­
ment combined transfer via horizontal gene transfer occurs. For
instance, heavy metal pollution in the environment co-selects for anti­
biotic resistance (Seiler and Berendonk, 2012). Further, non-antibiotic
drugs could also encourage acquired multiple antibiotic resistance via
mutations. Recent studies have revealed underlying mechanisms of
multiple antibiotic resistance induced by non-antibiotics. For instance,
antidepressant fluoxetine triggered multiple antibiotic resistance in
Escherichia coli via reactive oxygen species (ROS) mediated mutagenesis
in DNA binding transcriptional regulators which resulted in over­
expression of multiple drug efflux system promoting antibiotic efflux via
AcrAB-TolC pump and decrease in outer membrane porin OmpF which
helped in blocking antibiotics from entering the cell (Jin et al., 2018). A
similar mechanism was also proposed for antibacterial agent triclosan
(Lu et al., 2018). Another study revealed, exposure to antiepileptic drug
carbamazepine promotes the dissemination of antibiotic resistance via
horizontal gene transfer by the up-regulation of pili formation genes on
the RP4 plasmid in E. coli (Wang et al., 2019).
6.2. Molecular methods to study antibiotic resistance
Various methods exist to study the diversity of antibiotic resistance
H.K. Khan et al.
bacteria (ARB) and antibiotic resistance genes (ARGs) in a specified
environment either in terms of their abundance (per mass or volume of
sample) or prevalence (per total bacteria). Three main approaches have
been in use, two targeted (culture-based and quantitative PCR) to
investigate a particular bacterial group or gene and one non-targeted
(metagenomics) (Manaia et al., 2018). Culture-based methods deter­
mine resistance phenotypes. With the development of
culture-independent methods, culture-based methods became unpopu­
lar as they are time-consuming, requires experienced operators and
there is a risk for biohazards contamination (McLain et al., 2016).
However, culture-independent methods depend on the extraction of
genetic material, mostly DNA and seldom RNA. Analyses based on DNA
are used for gene survey whereas analyses based on RNA are utilized to
investigate gene expression. The extraction efficiency of genetic mate­
rial varies with the protocol utilized (Li et al., 2017). The qPCR tech­
nique is designed to follow in real-time the amplification of a specific
gene fragment using specific primers and the development of fluores­
cence. However, an important limitation is the challenges to design
primers for unidentified genes (Rocha et al., 2020). Metagenomics is an
appropriate method to overcome this limitation as this technique offers
sequencing the whole metagenome present in the sample. A key aspect
of metagenomics is that it can provide information about the known
ARGs, their variants, relative roles of intrinsic resistance, mutation and
the mobilome (Oulas et al., 2015). However, the availability of repre­
sentative databases, from which possible reliable information can be
extracted constitutes a bottleneck, due to the limited size and phyloge­
netic and geographic coverage of the databases (Arango-Argoty et al.,
2018). High throughput sequencing is now a trend which is further
encouraged by a progressive cost reduction and increasing read length
offered by Oxford Nanopore Technologies and Pacific Biosciences
(PacBio) (Goodwin et al., 2016). Illumina Hiseq and Miseq platforms are
widely used to perform high throughput sequencing.
6.2.1. Molecular Databases
Based on annotation range and, numbers and types of ARGs covered,
numeral databases have been established for analyzing antibiotic
resistance genes. Comparative analysis of these databases is provided in
Table S4. These include structured ARG reference database (SARG)
(Yang et al., 2016), comprehensive antibiotic resistance database
(CARD) (Jia et al., 2016), antibiotic resistance gene-annotation
(ARG-ANNOT) (Gupta et al., 2014), antibiotic resistance genes online
(ARGO) (Scaria et al., 2005), antibiotic resistance genes database
(ARDB) (Liu and Pop, 2009), beta-lactamase database (BLDB) (Naas
et al., 2017), ResFinder (Zankari et al., 2012), repository of antibiotic
resistance cassettes (RAC) (Tsafnat et al., 2011) and sequence database
of ARGs (SDARG) (Wei et al., 2019). These databases utilize protein and
nucleic acid sequences of known antibiotic resistance genes from the
National Center for Biotechnology Information (NCBI) GenBank re­
pository (Luby et al., 2016). ARDB and CARD databases have been used
widely and provide most of the publicly available ARG sequences.
Nevertheless, limited online analysis capabilities are provided by ARDB
database whereas genomic data can efficiently be analyzed using online
resources provided by CARD, but it lacks to provide information about
the number of genes and their locations in the genome (Alcock et al.,
2020). Manual categorization of ARGs can be avoided by using SARG,
but not all ARG sequences are facilitated in this database (Yin et al.,
2018). ARGO only provides information regarding resistance genes of
vancomycin and β-lactam antibiotics. While BLDB provides insights on
beta-lactamase mediated antibiotic resistance (Naas et al., 2017).
ARG-ANNOT has originally been designed to analyze ARGs in bacterial
genomes instead of environmental samples. However, it is a promising
tool to search for putative new ARGs in a given sequence (Gupta et al.,
2014). ResFinder performs ARG detection functions but needs longer
query reads. For a sequence to be detected as an ARG in ResFinder, it
must be at least two-fifths of the length of the matching ARG in the
database with no less than 50% identity (Zankari et al., 2012).
7
Journal of Environmental Management 271 (2020) 111030
Additionally, to characterize the structure of microbial community
SILVA small subunit (SSU) database and MG-RAST (metagenomics rapid
annotation using subsystems technology) interface is commonly used
(Chen et al., 2016).
6.3. Environmental reservoirs of resistance determinants
In general, antibiotic resistance arises when antibiotics are used in
clinical settings to treat human pathogens. But numerous studies have
revealed that the use of antibiotics outside clinical settings have, to some
extent, exerted selective pressure for resistance (Fig. 2). However, the
surge of resistance caused by antibiotic use is specific to individual
drugs. As in clinal settings, antibiotic use in an agricultural setting, such
as the farm-wide application of prophylactic antibiotics in feed and
water selects for antibiotic resistance. Zoonotic pathogens such as
Campylobacter and Salmonella serovars species are affected by antimi­
crobial resistance in animal husbandry (Laws et al., 2019). In nature,
living organisms including animals, birds and humans provide a bio­
logical mechanism to disseminate ARGs. For instance, African apes and
baboons living near human settlements had more antibiotic-resistant
enteric bacteria than those away from humans (Rwego et al., 2008).
Wild birds inhabit diverse environments from isolated lakes and
mountains to agricultural lagoons and can transmit ARGs at long dis­
tances while travelling (Bonnedahl and Ja €rhult, 2014). Physical forces
for example watershed and wind, also play an important role in
disseminating ARGs. Even bacteria from environments which are
considered stationary such as soil can be moved by the forces of nature
(Holmes et al., 2016). Antibiotic resistance is also transmitted through
human-human interactions. Faecal-oral transmission is of particular
importance as it occurs due to poor sanitation. This highly impacts
resistant Enterobacteriaceae species (Wellington et al., 2013). Trans­
mission can also take place via sexual encounters, for example, Neisseria
gonorrhoeae have led to extensive dissemination of resistant clones
(Lewis, 2013). Despite the barriers, ARGs have been spread to even the
remotest human populations. The only environments which are wholly
exempted from the impact of human antibiotic use existed before the
antibiotic era (Allen et al., 2010).
6.4. Controlling antibiotic resistance – strategies and legislation
Antibiotic resistance has been most efficiently and timely controlled
by countries which implemented comprehensive national strategies. For
example, the UK for control of Methicillin-resistant Staphylococcus aureus
and Clostridium difficile. Similarly, Israel controlled carbapenem-resistant
Klebsiella pneumoniae by a national approach (Schwaber et al., 2011).
These strategies include limiting drug marketing, scrutinizing antibiotic
consumption, implementing measures to detect resistance, development
of standardized infection control guidelines and antibiotic stewardship
programs in hospitals and health-care services. However, successful
implementation of these strategies needs time and patience, as well as
support from the governments (Laxminarayan et al., 2013). Compara­
tively, developing countries have made less progress even though China
and India made significant steps towards controlling antibiotic resis­
tance. For instance, India issued its Chennai declaration (Ghafur et al.,
2013) and the Chinese Government has indorsed guidelines to limit the
use of antibiotics in hospitals and animals, together with the initiation of
an antibiotic resistance campaign (Gould et al., 2014). Recently, re­
searchers at the Center for Disease Dynamics, Economics & Policy
(CDDEP) have developed a Drug Resistance Index (DRI) which measures
the ability of antibiotics to treat infections with the extent of their use in
clinical practice. This can serve as a powerful tool for communicating
problems of antibiotic resistance to policymakers (Pulcini et al., 2019).
6.4.1. Controlling antibiotics consumption
Controlling antibiotic use is a key strategy for controlling antibiotic
resistance. Recently, a concept of “antibiotic footprint” has been
H.K. Khan et al.
Fig. 2. Selection pressures and spread of antibiotic resistance genes in the environment.
proposed by Limmathurotsakul et al. (2019) to inform people of the
extensive and needless usage of antibiotics. The author utilized carbon
foot-printing as a model to explain how the antibiotic footprint can be
calculated by attributing antibiotic consumption to different human
activities. This includes direct consumption of antibiotics at community
and hospital levels, and indirect consumption, for example via animals
and food industry. The antibiotic footprint can then be calculated by
combining the total amount of direct and indirect consumption. This
tool could help visualize data and track the reduction in antibiotic usage
as well as monitor the excessive use of antibiotics locally and globally. It
can also calculate antibiotic footprint per capita (Limmathurotsakul
et al., 2019). People, therefore, can lessen their antibiotic footprint by
changing their consumption patterns and behavior such as ensuring to
take vaccinations to lower the risk of infections and advancing hand and
food hygiene (Patrick and Hutchinson, 2009).
6.4.2. Strengthening health care systems
Strengthening health-care systems is indispensable to controlling
antimicrobial resistance. A number of policy actions have been under­
taken to tackle antibiotic resistance through structural reforms, national
campaigns and antibiotic stewardship programs in health care systems.
For instance, responsible use policies in inpatient and outpatient settings
have shown effectiveness in reducing antimicrobial consumption in
several countries, including USA, Sweden, South Korea, France and
Vietnam (Huttner et al., 2014). Thailand’s Antibiotic Smart Use program
has revealed that alternate prescribing choices e.g., oral rehydration and
zinc for diarrheal ailments, and herbal drugs for viral infections of the
upper respiratory tract were significant in curbing prescription of anti­
biotics in outpatients and inpatients (Sumpradit et al., 2012). Delayed
prescribing seems to be a promising possibility in reducing antibiotic use
in primary care, whereas, in secondary care antibiotic prescription
guidelines were an effective option (Dar et al., 2016). Strong govern­
ment regulations and national restrictions on antibiotic subsidies can
encourage responsible use of antibiotics (Xiao et al., 2013). Recently,
8
Journal of Environmental Management 271 (2020) 111030
researchers at the Center for Disease Dynamics, Economics & Policy
(CDDEP) have developed checklist items feasible to adopt globally in all
healthcare facilities regardless of the resource availability to encourage
implementation of antibiotic stewardship programs in less resourceful
countries (Pulcini et al., 2019). Lack of knowledge and diagnostics,
enticements and marketing from industry are the main reasons for ir­
rational prescription of antibiotics by doctors in most developing
countries. Global Action Plan for developing countries promotes
evidence-based prescribing through effective and low cost diagnostic
tools and educational programs on correct diagnosis and management of
common infections for all health care workers, veterinarians, prescribers
and dispensers to optimize the use of antibiotics (W.H.O, 2017). The
GAVI Alliance finances vaccines in low-income countries. It provides
vaccines for ailments which would otherwise require antibiotic treat­
ment e.g., pneumococcal, rotavirus and Haemophilus influenzae (Berkley,
2014).
6.4.3. Policies in animal and food sector
Antibiotic use in food production can be lowered by promoting good
animal husbandry standards. General guidance spanning regulatory
needs and prudent use of antimicrobials is provided by all international
organizations: The World Organization for Animal Health (OIE), World
Health Organization (WHO), and the UN Food and Agriculture Orga­
nization (FAO). However, the implementation relies on the daily work of
farmers and veterinarians. Legitimate conflicting interests can surround
this implementation e.g. production economy and the ethical obligation
to care for diseased animals. In low- and middle-income countries
awareness in farmers is low, therefore, awareness campaigns are needed
to help educate them. Some governments have enacted the reduction of
veterinarian profit from antibiotic sales which proved effective in
reducing consumption. To compensate veterinarians for income loss,
new advisory roles were created (e.g., provision of technical support to
farmers for animal health and biosecurity without antimicrobials)
(Bowen, 2013). In March 2015, a new bill was introduced that required
H.K. Khan et al.
the US Food and Drug Administration to withdraw product approval for
antimicrobial use in animals if a manufacturer cannot show that its drug
poses no risk to human health (Silverman, 2015). Further, robust pol­
icies are needed for infection prevention and control in veterinary set­
tings such as the adoption of all-in-all-out farming systems i.e.,
production systems whereby animals are prevented from commingling
and reformulation of animal diets (Dar et al., 2016). Nevertheless, all in
all, monetary aid from government or funding agencies is essential in
curbing antibiotic consumption in both, humans, and animals.
6.4.4. Drug development
A crucial part of the global strategy to combat antibiotic resistance is
actions to develop new antibiotics and vaccines. Antibiotic development
has slowed considerably during the past 30 years. Historical data show
that, generally, only 1 out of 5 infectious disease drugs that reach the
initial phase of testing in humans will receive approval from the Food
and Drug Administration (Renwick et al., 2016). Reasons for this decline
include scientific challenges such as generation of new chemical matter,
lack of diversity regarding target pathogens, indications, and microbi­
ological approaches, barriers to successfully conducting clinical trials,
and lack of better understanding of cellular defenses of drug-resistant
Gram-negative bacteria, which cause some of the most
difficult-to-treat infections (Talkington et al., 2016). Markets also do not
provide incentives to discover new classes of antibiotics (Kållberg et al.,
2019). A recent study shows 42 new antibiotics are in development, out
of which at least 16 of the antibiotics have the potential to treat in­
fections caused by Gram-negative pathogens (Trusts, 2019). Addressing
fundamental gaps in scientific research and economic incentives are
important in developing new antibiotics. World Health Organization
(WHO) has developed a list of priority pathogens. This work is crucial in
developing an organized R&D approach, allowing for the identification
of and discrimination between current and future resistance threats
(WHO, 2017).
7. Pharmaceuticals: The South Asian scenario
7.1. Socio-economic demography
Developing countries are becoming a hub for pharmaceutical
manufacturing, as well as consumption which can lead to significant risk
of contamination by pharmaceuticals in its environment. Globally,
China is among the largest producers of pharmaceutical compounds
along with Japan and the USA. It is one of the most populous developing
countries in the world with 1.4 billion residents which has increased
significant consumption of pharmaceuticals in the region as well (Liu
and Wong, 2013). Moreover, Southeast Asia has also attracted phar­
maceutical market in recent years. For instance, Singapore’s economy is
largely dominated by exports from the pharmaceutical industry (Hashim
et al., 2012). Similarly, a middle-income country, Malaysia has made
considerable efforts to invest in medical technology and pharmaceuti­
cals manufacturing (Menon et al., 2020). The African region has also
seen a rise in pharmaceutical consumption in recent years due to its
better spending on health care than before (Dong and Mirza, 2016).
However, mortality rates due to acute diseases continue to increase in
this region. It is the second-largest and populous developing geograph­
ical region after Asia, which accounts for 13% of the global population
with poor sanitation and unavailability of modern sewerage systems in
majority African countries (Lu et al., 2011). The South Asian region is
the most densely inhabited in the world, with a total population of 1.814
billion (WorldBank, 2018). Despite its increasing population its econ­
omy remains low comprising mostly of low to lower-middle-income
countries. Further, South Asia’s urban population is on the rise, but
the growth has been messy, sprawled, and hidden. A population of 130
million resides in informal urban dwellings, with people in most of the
cities living below the line of poverty. As seen in the widespread prev­
alence of slums, poor infrastructure and lack of access to basic amenities
9
Journal of Environmental Management 271 (2020) 111030
of life (Ellis and Roberts, 2015). South Asia’s ability to bring improve­
ments in both livability and prosperity in urban areas remains chal­
lenging. However, Bhutan and Sri Lanka have seen huge progress in
eradicating extreme urban poverty. While India, Pakistan, and
Bangladesh have urban poverty share of 13.7%, 13.1% and 21.3%,
respectively. Whereas, in Afghanistan 1 in 4 while in Nepal 1 in 6 people
live below the poverty line (Mathur, 2013). Besides, due to resource
constraints, these developing countries mostly fail to practice appro­
priate health care waste management, most of the hospital waste is
dumped in the landfills. Only very few hospitals incinerate hazardous
medical waste (Khan et al., 2019). Similarly, unused, or expired drugs at
the consumer end are commonly disposed of in municipal bins or
washed down via sinks or toilets. There is no practice of returning drugs
to the pharmacies for safe disposal (Ahmed et al., 2013). According to a
recent survey, the most common unused drugs found in households of
India and Pakistan are antibiotics, such practices raise concern over
antibiotic resistance in these regions (Nipa et al., 2017). Moreover, in
many developing countries municipal wastewater treatment facilities
are often not widely available. In addition, the wastewater treatment
plants, if any, use primary treatment and at the very best utilize sec­
ondary treatment. Tertiary treatment and advance treatment technolo­
gies are unavailable. Huge capital and operating costs of technologically
advanced wastewater treatment plants are major bottlenecks for
developing countries. Screening, sedimentation, filtration, and disin­
fection are the most common wastewater treatment processes in
Pakistan. There is no prevailing concept of treatment at secondary and
tertiary level. Only one treatment plant which is the biggest in the
country employ conventional activated sludge process, that too is not
fully functional (Murtaza and Zia, 2012). On the contrary, in India, there
are 234 sewage treatment plants mostly employing conventional acti­
vated sludge process (secondary treatment). Other technologies include
up-flow Anaerobic Sludge Blanket reactor and waste stabilization ponds.
Bangladesh is also facing water treatment and sanitation challenges.
Most of the treatment facilities include filtration, sedimentation, and
disinfection (Kaur et al., 2012). The socio-economic demographic data
of South Asia has been provided in Supplementary Table S1.
7.2. Pharmaceutical consumption
To the best of our knowledge, no evaluation of pharmaceutical
consumption has been done in developing regions. Nevertheless, the
Centre for Disease Dynamics, Economics and Policy (CDDEP) provides
information on global antibiotic consumption between 2000 and 2015
obtained from IQVIA MIDAS database for developed and developing
regions of the world. Human consumption was estimated by utilizing
antibiotics sales data in retail and hospital sector expressed in defined
daily doses (DDD) per 1000 inhabitants. For South Asian region, data for
only Pakistan, India, Bangladesh, and Sri Lanka is available. For the year
2015, Pakistan, India, Bangladesh, and Sri Lanka had annual antibiotics
consumption of 7138, 4950, 4123, and 3841 DDDs per 1000 inhabitants,
respectively. Overall, the South Asian region has seen an increasing
trend in annual antibiotics consumption. The highest consumption was
seen for cephalosporins antibiotics in India and Bangladesh 1822 and
1433 DDDs per 1000 inhabitants, respectively. Whereas, in Pakistan and
Sri Lanka broad-spectrum penicillin were highly consumed, 2421 and
1492 DDDs per 1000 inhabitants, respectively (CDDEP, 2018b). CDDEP
also provides information on global trends in antibiotic resistance by
utilizing data from multiple sources. Antibiotic resistance data of
Pakistan, India, and Sri Lanka is only included in this database.
Description of percentage resistance occurring for important human
pathogens in south Asian regions is provided in Table 2. For all three
countries of surveillance, some important pathogens such as Escherichia
coli, Klebsiella pneumoniae, Salmonella typhi and Acinetobacter baumannii
were resistant to most of the antibiotics tested with varying percentages.
Species were resistant to fluoroquinolones, cephalosporins (3rd gen) and
aminoglycosides antibiotics at high levels (CDDEP, 2018a). Lack of data
H.K. Khan et al. Journal of Environmental Management 271 (2020) 111030

Table 2 Table 2 (continued )

Percentage resistance of antibiotics tested in important human pathogens. Country Pathogens Antibiotics tested Resistant
Country Pathogens Antibiotics tested Resistant (%)
(%)
Amikacin 24
Pakistan Acinetobacter Amikacin 69 Ceftazidime 34
baumannii Salmonella paratyphi Fluoroquinolones 92
Aminoglycosides 70 Aminopenicillins 22
Carbapenems 63
*Data was taken for the latest year which was 2017; Data source: CDDEP https
Glycylcyclines 31
Polymyxins 57 ://resistancemap.cddep.org/AntibioticResistance.php.
a
Escherichia coli Aminoglycosides 63 Data for Sri Lanka was available for the year 2009.
Aminopenicillins 97
Amoxicillin-clavulanate 96
availability and bias hampers our true understanding of resistance and
Carbapenems 10
Cephalosporins (3rd gen) 86
consumption of antibiotics as well as other pharmaceutical compounds
Fluoroquinolones 59 in developing countries.
Polymyxins 73
Piperacillin-tazobactam 10
Klebsiella pneumoniae Aminoglycosides 74 7.3. Occurrence of pharmaceuticals in developing regions: General
Carbapenems 43 consideration
Amoxicillin-clavulanate 97
Fluoroquinolones 58
Among developing countries, China and Africa have made significant
Cephalosporins (3rd gen) 84
Piperacillin-tazobactam 51 efforts in generating monitoring data of pharmaceutical compounds in
Polymyxins 82 water environment. Data on the occurrence of pharmaceuticals in
Salmonella typhi Fluoroquinolones 92 aquatic environment of China has been thoroughly and systematically
Trimethoprim- 46 provided in previously published reviews (Nkoom et al., 2018; Bu et al.,
sulfamethoxazole
Staphylococcus aureus Oxacillin 63
2013). China is the only country with well-established literature on the
India Acinetobacter Amikacin 75 occurrence and fate of pharmaceuticals in the environment. With a
baumannii particular focus given to antibiotics, accounting for 50% of the most
Aminoglycosides 81 reported pharmaceutical compounds (Zhao et al., 2016). Whereas, in
Carbapenems 77
Africa pharmaceutical compounds have been reported in 44 publica­
Glycylcyclines 24
Fluoroquinolones 58 tions. Of which, antibiotics constitute 43%, analgesics 38%, psychiatric
Ceftazidime 84 drugs 36%, and anti-retrovirals 26% (K’oreje et al., 2020). Diclofenac,
Ampicillin-sulbactam 79 ibuprofen, and sulfamethoxazole were the most frequently studied
Enterococcus faecalis Aminoglycosides 60 compounds in the African region due to limited availability of analytical
Aminopenicillins 41
Escherichia coli Aminoglycosides 17
techniques to study other compounds. Studies had been reported from 9
Carbapenems 18 African countries only, with majority of the data originating from South
Cephalosporins (3rd gen) 77 Africa this could be because South Africa is comparatively more devel­
Fluoroquinolones 84 oped than other African countries (Madikizela et al., 2020). The moni­
Piperacillin-tazobactam 28
toring data on pharmaceutical compounds in South Asia is scarce.
Klebsiella pneumoniae Aminoglycosides 59
Carbapenems 59 Considerable data was available for India as compared to Pakistan and
Cephalosporins (3rd gen) 68 Sri Lanka while data for Bangladesh was scant. No data has been re­
Fluoroquinolones 69 ported for other South Asian countries. Data was obtained by thoroughly
Piperacillin-tazobactam 59 searching literature using search engines web of science and Google
Polymyxins 15
Salmonella paratyphi Fluoroquinolones 53
scholar. Data from SWTPs influent and sediments was not considered,
Trimethoprim- 35 only surface water and wastewater effluents remained our focus. Phar­
sulfamethoxazole maceutical compounds detected in the South Asian region belonged to a
Salmonella typhi Fluoroquinolones 37 variety of classes (Fig. 3). Total, ninety compounds belonging to 21
Trimethoprim- 23
different classes of pharmaceuticals were detected. Different analytical
sulfamethoxazole
Streptococcus Macrolides 32 technologies were used to detect and measure these contaminants
pneumoniae summarized in Table 3.
Staphylococcus aureus Oxacillin 39
Sri Acinetobacter Amikacin 31
Lankaa baumannii 7.4. Occurrence of antibiotics
Aminoglycosides 48
Carbapenems 44 The most frequently detected antibiotic groups in both surface and
Ceftazidime 54
Fluoroquinolones 33
wastewater samples from China were sulfonamides, macrolides and
Escherichia coli Aminoglycosides 40 fluoroquinolones (Liu and Wong, 2013). Whereas, sulfamethoxazole
Cephalosporins (3rd gen) 18 was the most frequently detected compound in surface water of Africa,
Fluoroquinolones 59 with highest concentration (53828 ng/L) reported in Mozambique
Piperacillin-tazobactam 13
(Segura et al., 2015). Sulfamethoxazole was also detected in surface
Aminopenicillins 83
Amoxicillin-clavulanate 38 water of Malaysia at a concentration of 0.86 ng/L (Omar et al., 2019). In
Klebsiella pneumoniae Aminoglycosides 72 South Asia, 24 antibiotics were detected in Pakistan whereas 19 were
Amoxicillin-clavulanate 52 detected in India, 7 in Bangladesh and 15 in Sri Lanka. Total nine classes
Cephalosporins (3rd gen) 47 of antibiotics have been investigated. Amongst them, fluoroquinolones,
Fluoroquinolones 49
Pseudomonas Aminoglycosides 36
sulfonamides, and macrolides were detected in both surface and
aeruginosa wastewater samples from all four countries. Mean concentrations in
ng/L of pharmaceutical compounds in surface and wastewater of south
Asian region is given in Table 4. Ciprofloxacin is the most common

10
H.K. Khan et al. Journal of Environmental Management 271 (2020) 111030

Fig. 3. Major classes of pharmaceutical compounds measured in South Asian region.

Table 3
Analytical approaches used to quantify parmaceuticals from water environment
in South-Asian Region.
Country Sample Analytical instrumentation
treatment
Bangladesh Solid-phase High-performance liquid
extraction chromatography (HPLC) with
(SPE) Micromass Quattro Ultima mass
spectrometer
India SPE Liquid chromatography with
triple quadrupole mass
spectrometer (LC-MS/MS)
SPE LC with quadrupole time of
flight mass spectrometer (LC-Q-
ToF-MS)
SPE Ultraperformance liquid
chromatography (UPLC) with
Orbitrap Fourier Transform
mass spectrometer
SPE Gas chromatography with dual-
stage quadrupole mass
spectrometer (GC-DSQ)
SPE High-resolution liquid
chromatograph tandem mass
spectrometry (HR-LC-MS/MS)
SPE HPLC with photodiode array
detector
Pakistan SPE LC-MS/MS
Liquid-liquid HPLC with UV detector
extraction
Liquid-liquid GC/MS
extraction
Srilanka SPE HPLC with diode array and
fluorescence detector
SPE Ultra-fast liquid
chromatography (UFLC) with
Qtrap mass spectrometer
antibiotic prescribed in Indian hospitals. It was detected at the highest
concentration in surface water (356.052 μg/L) and wastewater
(2830.658 μg/L) of India (Larsson et al., 2007). The high levels in sur­
face water indicate hospital wastewater and untreated effluent from
Patancheru Enviro Tech Ltd. (PETL) treatment plant discharged into
surface water (Diwan et al., 2010; Fick et al., 2009). In Pakistan sulfa­
methoxazole was detected at the highest concentration in surface water
(Khan et al., 2013). Whereas, oxytetracycline, ampicillin and amoxi­
cillin were measured at high levels in surface water of Sri Lanka
Reference (Liyanage et al., 2014). High levels of ofloxacin and sparfloxacin were
also detected in wastewater samples of Pakistan near a pharmaceutical
Hossain et al. industrial area. This indicates lack of pharmaceutical waste treatment by
(2018)
manufacturers in Pakistan (Ashfaq et al., 2017). Low levels of antibiotics
were detected in surface water in Bangladesh. There are widespread
Subedi et al. facilities of aquaculture near surface water of Bangladesh, and presently
(2017) they are being strictly monitored by the government authorities,
because majority of the produced are exported to USA and EU countries.
Khalid et al.
(2018)
This might be a prominent reason for the less contamination of antibi­
otics in surface water (Hossain et al., 2018). Moreover, tylosin, peni­
Kumar et al. cillin, and metronidazole antibiotics were only analyzed and detected in
(2019) Bangladesh (Hossain et al., 2017). As penicillin and metronidazole are
among the essential drugs used for humans in Bangladesh. Nonetheless,
Mutiyar et al. metronidazole is also used in veterinary and aquaculture practices in
(2018) Bangladesh despite its ban in USA and EU due to its mutagenic and
carcinogenic toxic properties which might affect aquatic organisms
Mohapatra (DGDA, 2016). Antibiotics residues found in the environment can vary
et al. (2016)
according to the use patterns in each country.
Mutiyar and.
Mittal (2014)
Khan et al.
7.5. Occurrence of other pharmaceutical compounds
(2018)
Ashfaq et al. In sewage wastewater of China, androgens were found to dominate
(2016) in both influent and effluent samples (Chang et al., 2011) with highest
Scheurell et al.
concentration (1778 ng/L) reported in influent of sewage treatment
(2009)
Liyanage and plant in Guangdong province (Liu et al., 2012). Whereas, in Malaysia
Manage ethinylestradiol (EE2) was detected at a concentration of 77 ng/L in
(2014) sewage effluent (Al-Odaini et al., 2016). In addition, Diclofenac,
Guruge et al. ibuprofen, carbamazepine and caffeine were also detected in China in
(2019)
sewage wastewater with high frequency and concentrations (Liu and
Wong, 2013). Carbamazepine was also detected in surface water of
Singapore. Carbamazepine has widespread use in treatment of child­
hood epilepsy in Singapore (Bayen et al., 2013). Diclofenac was also
measured in surface water of Malaysia and Singapore at high concen­
tration of 105 ng/L and 81.1 ng/L, respectively (Al-Odaini et al., 2016;
Tran et al., 2014). In South Asia, compounds belonging to analgesics,
benzodiazepines, anti-depressant, and anti-convulsant were detected in

11
H.K. Khan et al. Journal of Environmental Management 271 (2020) 111030

Table 4 Table 4 (continued )

Mean concentrations (ng/L) of pharmaceuticals in surface and wastewater of Compounds Country Surface Wastewater References
South Asia. detected water
Compounds Country Surface Wastewater References India – 115.076 (Subedi et al.,
detected water 2015, 2017)
Acetaminophen India 1470.81 632.5 (Kumar et al., Codeine India 45.66 65.17 (Mutiyar et al.,
2019; Subedi 2018; Subedi
et al., 2017) et al., 2015)
Pakistan 169 12774 Ashfaq et al. Cyclophosphamide Pakistan – 0.325 Ashfaq et al.
(2019) (2019)
Alprazolam India – 20.84 (Subedi et al., Danafloxacin Pakistan 16 20 Ashfaq et al.
2015, 2017) (2019)
Amlodipine Pakistan – 16800 Ashfaq et al. Sri Lanka 10.7 – Guruge et al.
(2017) (2019)
Amoxicillin Sri Lanka 101000 4090 (Liyanage and Diazepam Pakistan 14.16 15.412 (Ashfaq et al.,
Manage, 2014, 2019; Khan et al.,
2016b; Liyanage 2018)
and Pathmalal, India 39 43.155 (Subedi et al.,
2017) 2015, 2017)
Ampicillin India 1283.3 6341.583 Mutiyar and Sri Lanka 0.17 – Guruge et al.
Mittal (2014) (2019)
Sri Lanka 345000 2261.75 (Liyanage and Diclofenac Pakistan 905.03 72710.6 (Ashfaq et al.,
Manage, 2014, 2017; Khan et al.,
2016b; Liyanage 2018; Scheurell
et al., 2014) et al., 2009)
Antipyrine Pakistan 3.7 165.5 Ashfaq et al. India 11.75 818 (Mutiyar et al.,
(2019) 2018; Sharma
Aspirin India 344 – Mutiyar et al. et al., 2019; Singh
(2018) et al., 2014)
Atenolol India 0.0928 610.172 (Mohapatra et al., Diltiazem Sri Lanka 0.13 – Guruge et al.
2016; Subedi (2019)
et al., 2015) India – 3.4 Subedi et al.
Pakistan 2 361 Ashfaq et al. (2017)
(2019) Doxycycline Pakistan 50.22 146.05 Khan et al. (2013)
Atorvastatin India – 310 Subedi et al. Erythromycin Pakistan 36.2 364.23 Khan et al. (2013)
(2017) India 38.6875 35.91 (Prabhasankar
Azithromycin Pakistan 2.638 14.91 Khan et al. (2013) et al., 2016;
Bromazepam Pakistan 7.4 10 Khan et al. (2018) Ramaswamy
Carbamazepine India 118.67 406.95 (Ramaswamy et al., 2011)
et al., 2011; Singh Bangladesh 0.76 – (Hossain et al.,
et al., 2014) 2017, 2018)
Bangladesh 1.51 – Hossain et al. Sri Lanka 6501.1 849 (Guruge et al.,
(2018) 2019; Liyanage
Sri Lanka 12.5 – Guruge et al. and Manage,
(2019) 2016b; Liyanage
Cefotaxime Pakistan 2.42 11.1 Khan et al. (2013) et al., 2014)
Cefuroxime India 230 200 Mutiyar and Enalapril India 313 2200 Fick et al. (2009)
Mittal (2014) Enoxacin Pakistan 0.492 17.38 Khan et al. (2013)
Cephalexin India – 1300 Mohapatra et al. India 51745 Fick et al. (2009)
(2016) Enrofloxacin Pakistan 0.353 1.775 (Ashfaq et al.,
Cetirizine Sri Lanka 6.44 – Guruge et al. 2019; Khan et al.,
(2019) 2013)
Chloramphenicol India 3.125 6.793 Prabhasankar India 9826.27 210000 Fick et al. (2009)
et al. (2016) Fenofibric acid Sri Lanka 1.36 – Guruge et al.
Sri Lanka 0.48 – Guruge et al. (2019)
(2019) Fenoprofen Pakistan 0.4 115.5 Ashfaq et al.
Chlorpheniramine Sri Lanka 1.36 – Guruge et al. (2019)
(2019) Fluoxetine Sri Lanka 0.15 – Guruge et al.
Ciprofloxacin Pakistan 19.2 447.16 (Ashfaq et al., (2019)
2016, 2017, Pakistan 5.1 10.75 Ashfaq et al.
2019) (2019)
India 356052 2830658 (Archana et al., Gatifloxacin India – 1220 Mutiyar and
2016; Mutiyar Mittal (2014)
and Mittal, 2014; Gemfibrozil India – 100 Mohapatra et al.
Sharma et al., (2016)
2019) Sri Lanka 3.12 – Guruge et al.
Sri Lanka 3.12 – Guruge et al. (2019)
(2019) Pakistan 0.29 211 Ashfaq et al.
Citalopram India 13718.1 430,000 Fick et al. (2009) (2019)
Clarithromycin Pakistan 19.81 100.2 Khan et al. (2013) Glibenclamide Pakistan – 7 Ashfaq et al.
India – 50 Mohapatra et al. (2019)
(2016) Ibuprofen Pakistan 41.9 219147.8 (Ashfaq et al.,
Sri Lanka 11.1 – Guruge et al. 2019; Khan et al.,
(2019) 2018)
Clenbuterol Pakistan 0.6 0.81 Ashfaq et al. India 232.2 648.396 (Mutiyar et al.,
(2019) 2018; Singh et al.,
Clindamycin Pakistan 4.34 0.9 Khan et al. (2013) 2014; Subedi
et al., 2017)
(continued on next page)

12
H.K. Khan et al. Journal of Environmental Management 271 (2020) 111030

Table 4 (continued ) Table 4 (continued )

Compounds Country Surface Wastewater References Compounds Country Surface Wastewater References
detected water detected water

Sri Lanka 6.83 – Guruge et al. (Ashfaq et al.,

(2019) 2019; Khan et al.,
Indomethacin Sri Lanka 0.45 – Guruge et al. 2013)
(2019) Sri Lanka – 253350 (Liyanage and
Pakistan 0.16 18 Ashfaq et al. Manage, 2014,
(2019) 2015, 2016a)
Ketoprofen India 10.41 362.8 (Shanmugam Paracetamol Pakistan 23808 27900 (Ashfaq et al.,
et al., 2014; 2017; Khan et al.,
Sharma et al., 2018)
2019) India 445 – Mutiyar et al.
Pakistan 68 122 Ashfaq et al. (2018)
(2019) Pefloxacin Pakistan 0.484 11.13 Khan et al. (2013)
Levofloxacin Pakistan 7.646 910.68 Khan et al. (2013) Penicillin Bangladesh 0.275 – Hossain et al.
India – 2600 (Diwan et al., (2017)
2010; Mohapatra Phenytoin Sri Lanka 6.44 – Guruge et al.
et al., 2016) (2019)
Sri Lanka 0.86 – Guruge et al. Pirenzepine Pakistan – 5.45 Ashfaq et al.
(2019) (2019)
Lincomycin Pakistan 54.3 1075.2 Khan et al. (2013) Primidone India 34.165 – Archana et al.
India – 170.442 (Subedi et al., (2016)
2015, 2017) Progesterone India 8.32 – Archana et al.
Sri Lanka 0.26 – Guruge et al. (2016)
(2019) Propranolol Pakistan – 1.15 Ashfaq et al.
Lomefloxacin Pakistan 0.43 2.89 Khan et al. (2013) (2019)
India 142.27 8800 Fick et al. (2009) Sri Lanka – 0.39 Guruge et al.
Lorazepam India – 16.018 Subedi et al. (2019)
(2015) India – 43.608 (Subedi et al.,
Sri Lanka 0.28 – Guruge et al. 2015, 2017)
(2019) Propyphenazone Pakistan 0.67 0.95 Ashfaq et al.
Losartan Pakistan – 10.25 Ashfaq et al. (2019)
(2019) Rosuvastatin Pakistan – 27800 Ashfaq et al.
Sri Lanka 15.7 – Guruge et al. (2017)
(2019) Roxithromycin Pakistan 17.23 57.74 Khan et al. (2013)
Mefenamic acid India 680 – Khalid et al. Sri Lanka 0.1 – Guruge et al.
(2018) (2019)
Pakistan 20 2506 Ashfaq et al. Sparfloxacin Pakistan – 7200 (Ashfaq et al.,
(2019) 2016, 2017)
Sri Lanka 15 – Guruge et al. India 350 140 Mutiyar and
(2019) Mittal (2014)
Metoprolol India 529.84 4000 (Fick et al., 2009; Sulfadiazine Pakistan 8.35 45.9 Khan et al. (2013)
Khalid et al., Bangladesh 0.505 – (Hossain et al.,
2018) 2017, 2018)
Pakistan 0.575 303 Ashfaq et al. Sri Lanka – 169.8 Liyanage and
(2019) Manage (2016b)
Metronidazole Bangladesh 2.74 – Hossain et al. Sulfamethoxazole Pakistan 325.83 7745 (Ashfaq et al.,
(2018) 2019; Khan et al.,
Miconazole Pakistan 0.57 0.93 Ashfaq et al. 2013)
(2019) India 90.78 343.79 (Prabhasankar
India – 16.5 Subedi et al. et al., 2016;
(2017) Sharma et al.,
Moxifloxacin Pakistan – 320 (Ashfaq et al., 2019; Subedi
2016, 2017) et al., 2017)
Nalidixic acid Pakistan 13.78 127.9 Khan et al. (2013) Bangladesh 2.95 – (Hossain et al.,
Naproxen Pakistan 14 140819 (Ashfaq et al., 2017, 2018)
2017, 2019) Sri Lanka 525 1000 (Guruge et al.,
India 3.014 147.75 (Shanmugam 2019; Liyanage
et al., 2014; and Manage,
Sharma et al., 2016b; Liyanage
2019) et al., 2014)
Norfloxacin Pakistan 3.73 20.95 Khan et al. (2013) Sulfamethizole Bangladesh 1.055 – (Hossain et al.,
India 98138 19850 (Diwan et al., 2017, 2018)
2010; Fick et al., Sulfamethazine Bangladesh 0.77 – (Hossain et al.,
2009) 2017, 2018)
Ofloxacin Pakistan 12.77 9143.28 (Ashfaq et al., Pakistan 1.4 2.5 Ashfaq et al.
2017, 2019; (2019)
Khan et al., 2013) Sri Lanka 0.15 – Guruge et al.
India 4283.6 29700 (Diwan et al., (2019)
2010; Fick et al., Sulfapyridine Sri Lanka 1.5 – Guruge et al.
2009) (2019)
Oxazepam Sri Lanka 0.38 – Guruge et al. Temazepam Pakistan 16.9 48 Khan et al. (2018)
(2019) Terbinafine India 1765.18 120 Fick et al. (2009)
India – 45.78 (Subedi et al., Tetracycline Pakistan 10.33 29.45 (Ashfaq et al.,
2015, 2017) 2019; Khan et al.,
Oxytetracycline Pakistan 58.37 2397.6 2013)
Sri Lanka – 1658.49
(continued on next page)

13
H.K. Khan et al. Journal of Environmental Management 271 (2020) 111030

Table 4 (continued ) is a system proved well suited for developing countries.

Compounds Country Surface Wastewater References
detected water 8. Conclusion and future directions
(Liyanage and
Manage, 2015, Recently, environmental residues of pharmaceutical compounds
2016a; Liyanage have been identified as problematic, of which, their presence in aquatic
and Pathmalal, environment is crucially important. Evidence suggests that physico­
2017)
chemical characteristics and structural complexity of pharmaceutical
Theophylline India 979.25 – Kumar et al.
(2019) compounds hinder their complete removal in conventional WWTPs
Tramadol Sri Lanka 5.07 – Guruge et al. which highlights their inadvertent persistence in environmental me­
(2019) diums. This review culminates that knowledge on the toxicity of phar­
Trimethoprim Pakistan 147.9 4066.1 Khan et al. (2013)
maceutical compounds is essential since it serves as the basis to reduce
India 212.7 1214.37 (Mohapatra et al.,
2016; Singh et al.,
their use through legal enforcement. There is mounting evidence which
2014; Subedi suggests that aquatic life is more vulnerable to involuntary and
et al., 2015) continuous exposure of pharmaceutical compounds. As of yet, little
Bangladesh 4.035 – (Hossain et al., evidence is found to suggest pharmaceuticals detrimental impacts on
2017, 2018)
humans at environmentally relevant concentrations. There is limited
Sri Lanka 3.85 – Guruge et al.
(2019) understanding of pharmaceutical compounds fate in natural habitats.
Tylosin Bangladesh 2.66 – Hossain et al. They are transported unhindered through waterbody to reach subsur­
(2017) face which complicates their attenuation. Evidences suggest that sedi­
Venlafaxine India 20.382 (Subedi et al.,
–
ments, soils and biosolids serve as reservoirs of pharmaceutical
2015, 2017)
compounds as well as for their transformation products (Ebele et al.,
2017). Among pharmaceuticals, antibiotics have been given special
both surface and wastewater. Statins were also detected in wastewater attention due to the growing threat of antibiotic resistance. Further, for
samples from India and Pakistan and a considerably high concentration comprehensive risk assessment in the absence of monitoring data
of rosuvastatin (27800 ng/L) was measured in Pakistan. Amlodipine is a different models are discussed to facilitate implementation and valua­
calcium channel blocker which was also detected at high concentration tion of regulatory policies and risk management. Our analysis suggests
(16800 ng/L) in the wastewater of Pakistan. The presence of these imbalances in monitoring data of developing countries, in terms of
contaminants might indicate their production and use in the region compounds as well as the regions because these countries differ in their
(Ashfaq et al., 2017). Gemfibrozil is a blood lipid regulator which was stages of development. Prescription drugs and hormones being less
detected in Sri Lanka and India (Guruge et al., 2019; Mohapatra et al., represented whereas antibiotics and analgesics, particularly in South
2016). Citalopram which is an anti-depressant had the highest concen­ Asia. While our analysis mainly considers contamination in the dis­
tration (430000 ng/L) in wastewater which was measured in India (Fick solved phase (surface water and wastewater) other matrices such as
et al., 2009). Theophylline, terbinafine, losartan, miconazole and sediments, soils and biosolids could also be evaluated for a better rep­
cyclophosphamide are some other pharmaceutical compounds which resentation of contamination. This review provides an integrated
were also detected in India (Kumar et al., 2019) and Pakistan (Ashfaq knowledge of pharmaceutical compounds in aquatic environment.
et al., 2019). However, few data gaps still need to be addressed. Data on acute toxicity
testing is more prevalent than chronic testing. Therefore, chronic
toxicity at environmentally relevant concentrations needs more evalu­
7.6. Future challenges for South Asia ation. The issue of mixture toxicity or synergistic effects of pharma­
ceutical compounds is still pressing, and the toxicity mechanisms are not
The existing insufficient data does not give a clear picture of the fully understood and require more in-depth knowledge. Studying
status of pharmaceutical contamination in south Asia. There is also a toxicity mechanism across species and taxa, particularly of amphibians,
fundamental lack of data on ecotoxicological effects and overall fate and mammals, and birds, is important to better understand possible toxic
distribution of these contaminants. There is a need to expand knowledge effects. Further, endpoints and species based on highly conserved bio­
on the occurrence of these contaminants. Therefore, monitoring studies logical mechanisms must be evaluated to understand toxicity mecha­
at a local and national level are required particularly in highly populated nisms in humans. Moreover, human epigenome and the endocrine
countries of South Asia. Controlling antibiotic resistance is a current system have the prospective to be explored in terms of pharmaceuticals
global challenge. A strategic and comprehensive surveillance program is toxicity to humans. LC-MS/MS remains the most sensitive technique to
needed to monitor and prevent the emergence of antibiotic resistance in detect pharmaceutical compounds. However, alternate point-of-care
South Asia. Investigation of more pharmaceutical compounds in surface detection techniques are becoming increasingly valuable. Electro­
water is pivotal in carrying out proper risk assessment studies. Research chemical, optical, enzymatic, oligonucleotides and immunochemical
networks and capacity build-up among governments and private in­ biosensors are of particular interest and must be evaluated for successful
stitutions is essential for the development and optimization of analytical detection of pharmaceutical compounds as they hinge on the benefit of
protocols as well as for the availability of advanced detection instru­ low sample volume and high detection capability at low concentrations.
mentation. Specific guidelines and legislation for tackling antibiotics There is a pressing need for human biomonitoring programmes, pref­
prescription practices at hospitals, waste disposal practices and collec­ erably at the national level to identify environmental exposure and
tion of unused or expired drugs from households must be developed and hazards of pharmaceuticals and to support risk communication and
regulated. The problem of antibiotic consumption in animals cannot be management. Typically, samples were collected using active sampling.
overlooked. A coherent approach to regulate the use of antibiotics in the However, passive samplers such as polar organic chemical integrative
animal sector should be a priority. Design and number of wastewater samplers (POCIS) are becoming important economical tools for under­
treatment plants is a major challenge for low and lower-middle-income standing the transformation process and to determine time-integrated
countries. Considering conventional treatment plants are mostly ineffi­ concentrations of pharmaceutical compounds. Additionally, another
cient in removing pharmaceutical compounds, advanced treatment appealing research avenue is the search for novel materials and
technologies must be given consideration. Recently, constructed wet­ bio-nano-catalysts for effective removal of pharmaceutical compounds.
lands have shown efficiency in removing pharmaceutical compounds. It Due to accelerating progress on the occurrence of pharmaceuticals in the

14
H.K. Khan et al.
environment, the pharmaceutical industry in part shares the re­
sponsibility to manage their wastewater at point-source. Implementing
the following guidelines is necessary to minimize pharmaceutical
contamination in the environment. (i) Recovery of valuable products
which could considerably reduce raw materials requirement and waste
disposal cost (ii) Investing in sustainable production by introducing
green chemistry initiatives (iii) Phasing out chemicals used in the
manufacturing process listed under critical substances of EU REACH
(Registration, Evaluation and Authorization of Chemicals) (iv) Ensuring
safe disposal of products in reverse distribution (v) Defining legal limits
for active pharmaceutical ingredients in the effluent.
Funding
This research did not receive any specific funding.
Declaration of competing interest
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jenvman.2020.111030.
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