Chemosphere 263 (2021) 128285

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Chemosphere
journal homepage: www.elsevier.com/locate/chemosphere

Threat and sustainable technological solution for antineoplastic drugs

pollution: Review on a persisting global issue
Ankush Yadav a, Eldon R. Rene b, Mrinal Kanti Mandal c, Kashyap Kumar Dubey a, d, *
a
Bioprocess Engineering Laboratory, Department of Biotechnology, Central University of Haryana, Mahendergarh, 123031, Haryana, India
b
Department of Water Supply, Sanitation and Environmental Engineering, IHE Delft Institute for Water Education, Westvest 7, 2611AX, Delft, the
Netherlands
c
Department of Chemical Engineering, NIT Durgapur, Durgapur, 713209, West Bengal, India
d
Bioprocess Engineering Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India

h i g h l i g h t s g r a p h i c a l a b s t r a c t

Role of antineoplastic agents as

emerging water contaminants has
been discussed.

The health implications of antineo-
plastic compounds were reviewed.

Strategies for the treatment of anti-
neoplastic compounds were
analyzed.

The role of stringent discharge regu-
lations and its implementation were
identified.

a r t i c l e i n f o a b s t r a c t

Article history: In the past 20 years, the discharge of pharmaceuticals and their presence in the aquatic environment
Received 30 April 2020 have been continuously increasing and this has caused serious public health and environmental con-
Received in revised form cerns. Antineoplastic drugs are used in chemotherapy, in large quantities worldwide, for the treatment of
31 August 2020
continuously increasing cancer cases. Antineoplastic drugs also contaminate water sources and possess
Accepted 6 September 2020
Available online 8 September 2020
mutagenic, cytostatic and eco-toxicological effects on microorganisms present in the aquatic environ-
ment as well as on human health. Due to the recalcitrant nature of antineoplastic drugs, the commonly
Handling Editor: Derek Muir used wastewater treatment processes are not able to eliminate these drugs. Globally, various anticancer
drugs are being consumed during chemotherapy in hospitals and households by out-patients. These anti-
Keywords: cancer agents enter the water bodies in their original form or as metabolites via urine and faeces of the
Antineoplastic out-patients or the patients admitted in hospitals. Due to its high lipid solubility, the antineoplastic drugs
Wastewater accumulate in the fatty tissues of the organisms. These drugs enter through the food chain and cause
Cyclophosphamide adverse health effects on humans due to their cytotoxic and genotoxic properties. The United States
Toxicity
Environmental Protection Agency (US-EPA) and the Organization for Economic Cooperation and
Food chain
Development (OECD) elucidated new regulations for the management of hazardous pharmaceuticals in
Treatment
the water environment. In this paper, the role of antineoplastic agents as emerging water contaminants,
its transfer through the food chain, its eco-toxicological properties and effects, technological solutions
and management aspects were reviewed.
© 2020 Elsevier Ltd. All rights reserved.

* Corresponding author. Bioprocess Engineering Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India.
E-mail address: kashyapdubey@gmail.com (K.K. Dubey).

https://doi.org/10.1016/j.chemosphere.2020.128285
0045-6535/© 2020 Elsevier Ltd. All rights reserved.
A. Yadav, E.R. Rene, M.K. Mandal et al.
1. Introduction
The presence of pharmaceutical compounds (i.e. chemicals or
drugs) in the aquatic environment is one of the most critical and
persisting issues in the world due to an increase in the disease
burden and demand for pharmaceuticals (Mir-Tutusaus et al.,
2018). The presence of pharmaceuticals in water bodies is due to
the continuous increase in the level of consumption of various
medicinal drugs. After administration in the body, antineoplastic
compounds get metabolized and the un-metabolized form of the
drugs is excreted out from the body to the environment (Santana-
Viera et al., 2016; Dubey et al., 2017; Biel-Maeso et al., 2018). These
residual metabolites, after ADME (adsorption, distribution, meta-
bolism and excretion), are usually treated with domestic sewage
waste and enters the water bodies due to lack of facility in sewage
treatment plants (STPs) thereby causing water pollution. The
presence of these pharmaceutical active compounds varies in
different natural environments as they can interact with other
pollutants (i.e. chemicals or ions) present in water and become
more toxic to the living beings (Nussbaumer et al., 2011).
Antineoplastic (L01) compounds are a class of chemicals which
is commonly used to treat cancer patients. These compounds can
inhibit cell proliferation by blocking DNA replication during the cell
cycle. At present, the consumption of antineoplastic compounds is
exceedingly high because the number of cancer patients is globally
increasing (Franquet-Griell et al., 2017; Bray et al., 2018; Cristo
va
~o
et al., 2020). The presence of these chemicals in water bodies can
also cause mutagenic, carcinogenic and genotoxic effects to the
living beings present in aquatic environments, as well as for
humans (Kümmerer, 2001; Turci et al., 2006; Besse et al., 2012;
Mater et al., 2014; da Costa Araújo et al., 2019).
The source of antineoplastic drugs in various water resources
includes irresponsible domestic discharge (out-patient getting
treatment by chemotherapy), hospital discharge (excretion of
hospitalized cancer patients) and drug manufacturing industries
effluents (Gebhardt and Schro €der, 2007; Pe
rez-Moya et al., 2010;
Ferrando-Climent et al., 2014; Guichard et al., 2017; Cristo
va~o et al.,
2020). However, these drugs are functionally effective to supress
the growth of any tumour cell, however, they are not very much
selective towards specific tumour cells. Thus, they may be
responsible for DNA damage of normal dividing cells and cause a
mutagenic effect on an organism (Xie, 2012; Balcerzak and Rezka,
2014). When these compounds enter into the aquatic environ-
ment through the food chain, they may undergo biomagnification
and increase their concentration in the next trophic levels.
Conventional wastewater treatment plants (WWTPs) are not
effective/efficient for the removal of these pharmaceutical pollut-
ants due to the recalcitrant nature of these compounds (Franquet-
Griell et al., 2017). There are advanced biological and physi-
ochemical processes to effectively mineralize antineoplastic com-
pounds present in wastewater; typical examples include
photocatalytic degradation, electrocoagulation and fungal enzy-
matic degradation, etc, among others (Franquet-Griell et al., 2017;
Castellet-Rovira et al., 2018; da Rosa et al., 2019; Zaied et al., 2020).
The World Health Organization (WHO), the American Society of
Hospital Pharmacists (ASHP) and the National Institute for Occu-
pational Safety and Health (NIOSH) have stipulated precautionary
guidelines for handling, storage and management of pharmaceu-
tical chemicals, i.e. before and after the use of these compounds, in
order to minimize their harmful effect on human health and the
environment (Bernabeu-Martinez et al., 2018). This review focuses
on the following objectives: (i) to analyse and describe the occur-
rence and fate of antineoplastic compounds in water bodies (i.e. in
different aquatic ecosystems), (ii) to identify and explain the health
2
Chemosphere 263 (2021) 128285
effects of different antineoplastic compounds on aquatic organisms
and human life, (iii) to suggest and illustrate the different techno-
logical options available for the treatment of antineoplastic com-
pounds present in water, and (iv) to examine the sustainable/
practically feasible solutions for the management of antineoplastic
compounds in the environment.
2. What are antineoplastic drug pollutants?
Antineoplastic drugs are a class of pharmaceutical compounds
that are used as a chemotherapy agent for the treatment of cancer.
These are organic compounds that inhibit the proliferation in
rapidly dividing cells or abnormal growth of any cell in tissue that
potentially acts like a cancer cell. This property of antineoplastic
drugs is known as “cytostatic”. Antineoplastic (cytostatic) agents
circulate in the human body and destroy the cancer-causing cells.
However, because of their very low selectivity towards some target
cancer cells or due to its non-specific nature, these drugs also have a
lot of negative effects on the normal dividing cell of a healthy
person if the person is in contact with any of these compounds.
These drugs block DNA replication in the cell cycle by inhibiting the
topoisomerase activity. These compounds can also cause muta-
genic, carcinogenic and genotoxic changes in aquatic life, even if
they are present at trace levels in treated hospital wastewater
(Negreira et al., 2014; Kümmerer et al., 2016; Novak et al., 2017).
These antineoplastic drugs are divided into five sub-categories
according to their functional therapeutic operations: (i) alkylating
agents (L01A), (ii) antimetabolites (L01B), (iii) plant alkaloids
(L01C), (iv) cytotoxic antibiotics (L01D), and (v) other antineoplastic
agents (L01X). As shown in Table 1, the physiochemical properties
of antineoplastic drugs could also determine their fate, accumula-
tion and transport in the environment (Zhang et al., 2013b; Azuma,
2018).
Surprisingly, the alkylating agents are the dominating sub-
category of antineoplastic compounds. Presently, more than 100
types of antineoplastic drugs are using worldwide and in all these
compounds mainly around 20 to 30 compounds are used widely to
cure malignant neoplasm according to the “World Cancer Report”
published by WHO in the year 2018. The consumption of these
drugs has been reported worldwide in cancer hospitals and the
other reported concentrations of these drugs in water bodies are
listed in Table 2. These antineoplastic compounds are much
different from each other in terms of their physiochemical prop-
erties (Kosjek and Heath, 2011).
According to the IARC-GCO (International Agency for Research
on Cancer - Global Cancer Observatory) report published in the year
2018, Asian countries had the highest new cancer patient popula-
tion in the world (Bray et al., 2018; Ferlay et al., 2018). As the
number of patients are high, the consumption of antineoplastic
drugs also becomes high. Thus, the metabolites of the consumed
drugs are excreted from the patient’s body to the sewage treatment
plants (Besse et al., 2012; Habibzadeh et al., 2018). The native/
original form of these drugs also makes their way to the sewage
treatment plants because of mishandling, household discharge,
ampoules, cleaning and testing of the drugs. The average dose for a
patient varied from 1 to 1000 mg m2, depending on the type of
cancer, drug type and age of the patient. This average dose suggests
that even a trace amount of these drugs can be very harmful to the
normal cells of any living species (Power and Coyne, 2018).
3. Global issue
The worldwide average of 18.07 million new cases and about 36
new types of cancers were reported in the year 2018 (Fig. 1) and it is
expected to increase up to 29.5 million in the year 2040 (IARC, WHO
A. Yadav, E.R. Rene, M.K. Mandal et al. Chemosphere 263 (2021) 128285

Table 1
Physiochemical properties of some commonly used antineoplastic drugs.

Name of the Applications Chemical class Molecular weight pKa Solubility (mg.ml1 in Log Koc BCF UVmax (nm)
compounds (g.mol1) water) Kow

CP
Lymphomas Alkylating agent 261.08 2.84 40 0.63 59 2.1 200

Brain cancer

Neuroblastoma

Leukemia

Some solid tumours
IF
Testicular cancer Alkylating agent 261.08 1.45 3.8 0.86 62 2.2 <290

Breast cancer

Lymphoma (Hodgkin and Non-
Hodgkin)

Soft tissue sarcoma

Osteosarcoma or bone tumour

Lung cancer

Cervical cancer

Ovarian cancer
Etoposide
Lung cancer Plant alkaloid 588.57 9.8 Insoluble 0.60 51 3 283/229

Testicular cancer

Lymphoma

Nonlymphocytic leukemia

Glioblastoma multiforme
Paclitaxel
Ovarian Plant alkaloid 853.93 11.99 Insoluble 3.95 3355 591 227/273

Breast and lung

Bladder

Prostate

Melanoma

Esophageal

Other types of solid tumour cancers
5-FU
Anal cancers Antimetabolite 130.08 8.02 11.1 0.89 8 3 266

Breast cancers

Colorectal cancers

Esophageal cancers

Stomach cancers

Pancreatic cancers

Skin cancers (especially head and
neck cancers)
Tamoxifen
Breast cancer Hormonal 371.515 8.87 0.167 7.88 DNF 827 205
antagonist
Methotrexate
Uterus cancer Antimetabolite 454.44 4.7 >1 1.85 1 3.2 244/290

Lung cancer

Breast cancer

Leukemia

Head and Neck cancers

Lymphoma
Capcetabine
Colon or rectal cancer Antimetabolite 359.354 1.9 26 0.6 4.5e8.0 1.3 310

Metastatic breast cancer e3.0

Ovarian cancer

Fallopian tube cancer

Pancreatic cancer
Gemcitabine
Lung cancer Antimetabolie 263.198 3.6 .546 2.01 DNF DNF 232

Pancreatic cancer

Bladder cancer
Vincristine
Thyroid cancer Plant alkaloid 824.958 11.99 .0227 2.82 DNF DNF 252/293/

Brain tumour 218/285

Acute leukemia

Multiple myeloma
Doxorubicin
Lung cancer Antitumor 543.52 8.22 26 1.27 6000 0.5 290

Breast cancer antibiotic

Leukemia

Ovarian cancer

Stomach cancer
Docetaxel
Breast cancer Plant alkaloid 807.90 12.02 .00274 2.83 1.9  106 19 283

Head and Neck cancer

Stomach cancer

Prostate cancer

Lung cancer

Note: *CP (Cyclophosphamide), IF (Ifosfamide), 5-FU (%-Fluorouracil), pKa (Acid dissociation constant), Kow (Octanol-water partition coefficient), Koc (Organic carbon-water
partition coefficient), BCF (Bioconcentration factor), DNF (Data not found).
Sources: PubChem (https://pubchem.ncbi.nlm.nih.gov); Chem ID Plus Advanced (http://chem.sis.nlm.nih.gov/chemidplus/); Drug Hazardous Substances Data Bank (http://
toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB); ChemSpider (http://www.chemspider.com).

3
A. Yadav, E.R. Rene, M.K. Mandal et al. Chemosphere 263 (2021) 128285

Table 2
Occurrence of some commonly used antineoplastic compounds (ng$L1) drugs in aquatic environment.

Antineoplastic compounds Hospital effluent (ng$L1) STP influent (ng$L1) STP effluent (ng$L1) References

Bicalutamide - - Nd- 254 Azuma (2018)

IF Nd-228 Nd-130 e Ferrando Climent (2016)
e Nd-27.9 Nd-15.9 Negreira et al. (2014)
Tamoxifen e 110e147 Nd-180.6 Negreira et al. (2014)
e e Nd-9 Azuma (2018)
26e170 Nd-58 11e42 Ferrando Climent (2016)
Methotrexate Nd-19 Nd-26 Nd-6 Ferrando Climent (2016)
CP e Nd-43.8 Nd-25 Negreira et al. (2014)
e e Nd- 20 Azuma (2018)
Blq-200.7 Nd-26 7e25 Ferrando Climent (2016)
Cytrabine e 9.2 14 Martín et al. (2011)
Etoposide e 15 3.4 Martín et al. (2011)
Nd-714 Nd-175 e Ferrando Climent (2016)
Docetaxel Nd-98 Nd-219 e Ferrando Climent (2016)
Epirubicin e 24800
mez-Canela et al. (2012)
Go
Azathioprine Blq-188 Nd-20 e Ferrando Climent (2016)
Capcitebine e 8.2e27 e Negreira et al. (2013)
e Nd-72.6 Nd-36 Negreira et al. (2014)
e e 2e11 Azuma (2018)
Vincristine Nd-49 Nd-23 e Ferrando-Climent et al. (2014)
Doxifluridine e e Nd-8 Azuma (2018)
Tegafur e e Nd-49 Azuma (2018)
Hydroxy-tamoxifen e e Nd-5.8 Negreira et al. (2014)
4-hydroxy-N desmethyltamoxifen e e 91.6 Negreira et al. (2014)
Paclitaxel Blq-100 Nd-18 e Ferrando Climent (2016)
Irinitecan e Nd-21.3 Nd-16.8 Negreira et al. (2014)
Hydroxy-paclitaxel e Nd-18.5 Nd-3.7 Negreira et al. (2014)

Note: # Blq (Below limit of quantification).

Nd (Not detected).
The FDA and EMA proposed acceptable limit for the antineoplastic drugs in the environment are 0.01 mg$L1 (FDA) and 0.1 mg$L1 (EMA), respectively.

[GCO]). Therefore, the use of antineoplastic compounds will also
continue to increase in the coming years and subsequently, the risk
of water pollution due to antineoplastic contaminants will also
continue to increase (Cristo
va
~o et al., 2020). Chemotherapy is a
slow, but reliable treatment technique to treat cancer cells even
after surgery or radiation therapy to remove any leftover cancer
cells.
The most commonly used anticancer drugs are CP, tamoxifen, IF,
methotrexate, etoposide and paclitaxel (Nassour et al., 2019). The
concentration of antineoplastic compounds in different environ-
mental samples ranged from 0.1 to 86200 ng.L1. Azuma (2018)
described the occurrence of biocalutamide and a total of six drugs
were detected in the Yodo river of Japan, out of which the highest
concentration was found to be 254 ng.L1. The domestic waste-
water discharged from hospitals usually makes their way to the
sewage treatment plants and further to the water bodies. In many
Asian countries, the hospitals are not well equipped with adequate
WWTPs to treat/remove these pollutants. In conventional sewage
treatment plants, different treatment trains combining physico-
chemical and biological processes are used to treat wastewater.
These methods only partially degrade antineoplastic compounds,
while a majority of the non-treated pollutant is discharged to water
bodies.
After the release of antineoplastic drugs into water bodies, both
the parent compounds and their derivatives may further undergo
physical and chemical interactions in water through the process of
hydrolysis, photolysis, dilution, adsorption, chemical/biological
accumulation, etc. among others. Due to the very low vapour
pressures, most of these antineoplastic drugs are present in the
liquid or solid forms in activated sludge or suspended solids. The
low value of octanol-water partition coefficient (Kow¼103) sug-
gests that the compound will have low adsorption onto the solids
present in water. Besides, the high value of carbon-water partition
4
coefficient (Koc) provides information about the compounds
mobility in solids in comparison to water. The value of Kow and Koc
for each antineoplastic compound varies significantly, for example,
the Kow value of CP is 0.630 and IF is 0.860 (Table 1). The antineo-
plastic drugs will also be degraded by photolysis, while high values
of bioconcentration factor (BCF) indicate their accumulation in
organic matter.
Based on the physiochemical properties of a particular anti-
neoplastic drug, they are present in different water environments
(e.g. surface water, groundwater, rivers, lakes, oceans), at varying
concentrations, including WWTPs (Table 2). Their degradation
profiles should be monitored periodically in aquatic environments.
These compounds are not degraded easily and have a long half-life;
besides, their metabolites can pass from one food chain to another
through aquatic species such as fish and seafood (El-Kady and
Abdel-Wahhab, 2018).
4. Antineoplastic compounds from humans to the
environment
Antineoplastic drugs are carcinogenic in nature and dangerous
to the normal cells of living beings (Kümmerer et al., 2016; Novak
et al., 2017). There are various ways in which antineoplastic drugs
multiply in the environment (Fig. 2) (Besse et al., 2012; Habibzadeh
et al., 2018). The low vapour pressure of anticancer drugs lead to
non-volatile nature under normal conditions; this property in-
creases the solubility of antineoplastic drugs in water. The excretion
product of the patient may be one of the reasons for the dispersion
of the drugs in the surroundings because of the high solubility of
antineoplastic drugs (Pruijn and DeWitte, 2004).
It is noteworthy to mention that, depending on the mode of
excretion, patient’s gender and improper management practices
during urine accession can simply disperse the antineoplastic drugs
A. Yadav, E.R. Rene, M.K. Mandal et al.
Fig. 1. Population of new cancer incidence in the year 2018 (Source: GLOBCAN, 2018).
in the environment. Nevertheless, anticancer drugs are excreted in
a stable form along with urine (Polovich and Martin, 2011; Santana-
Viera et al., 2016). The results of a recent contamination survey
done at a hospital indicated the presence of anticancer drugs on the
toilet seat and floor (Sato et al., 2014). Many other surveys have also
mentioned that hospital staffs and family members have more
chances to be exposed to these drugs via unanticipated contact
with the patient’s body fluids. Besides, there are numerous path-
ways for antineoplastic drugs to reach the nearby water
environments.
As discussed previously, hospitals are the main source of anti-
neoplastic drugs pollution in the aquatic environment. It also de-
pends on the persistency of the parent compound, its
physiochemical property and administration mode. The con-
sumption rate of antineoplastic drugs varies from country to
country every year according to the population of cancer patients. A
study conducted by Kümmerer et al. (2016) has shown that the
consumption of different antineoplastic drugs differs from one
country to another (unit: mg.d1.P1), e.g. 0.013 in France, 0.012 in
Germany, 0.003 in Austria, 0.56 in Switzerland and 0.002 in
Denmark respectively. In Germany, the total consumption of these
drugs was 22000 kg in the year 2001, 42000 kg in the year 2008
and 50000 kg in the year 2012. Cristo
va
~o et al. (2020) has reported
the consumption of several antineoplastic drugs in cancer hospitals
of Portugal, Belgium and India and their PEC (predicted environ-
mental concentration) values. According to this study, the con-
sumption rate in Portugal was 177.2 kg in 2012 and 260.9 kg in 2016
for 101 antineoplastic drugs, respectively. However, in Belgium, the
value was 2897.4 kg in 2012 and 3004.2 kg in 2015 for 99 anti-
neoplastic drugs, while in India it was 6364 kg in 2016 for 33
antineoplastic drugs. These statistics clearly indicate that most of
the antineoplastic drugs administered to cancer patients at hospi-
tals are also excreted in hospital wastewater.
Verlicchi et al. (2020) reviewed the literature data for the
presence of ~35 antineoplastic drugs in different water compart-
ments, from the year 1990e2017, in eighteen different countries.
According to this literature information, Aherne et al. (1990)
5
Chemosphere 263 (2021) 128285
monitored the levels of bleomycin in wastewater samples from
the UK, while Steger-Hartmann et al. (1996) reported the levels of
CP and IF in hospital wastewater samples of Germany. On the other
hand, ~28 antineoplastic drugs were detected in hospital waste-
water, with their concentrations ranging from 2 to 266000 ng.L1.
These included alkylating agents (0.85e266,000 ng.L1), antime-
tabolites (0.24e124000 ng.L1), plant alkaloids
(2.75e99.70 ng.L ), hormonal agents (0.2e133.40 ng.L1) and
1
antitumor antibiotics (5e21000 ng.L1), respectively. The following
drugs were also reported: CP, IF, 5-FU, azathioprine, capcetabine,
gemcitabine, methotrexate, tegafur, epirubicin, etoposide, irinote-
can, docetexal, paclitaxel, vincristine, tamoxife, anastrazole, letro-
zole, erlotinib, etc., among others. Besides, some of these patients
who were receiving treatment at home (outpatients) contributed to
the release of these drugs in household effluents. In France, about
86.2% of the antineoplastic drugs were released from household
effluent, while the rest (~13.8%) were from the hospitals (Besse
et al., 2012). Based on the review done by Verlicchi et al. (2020),
25 antineoplastic drugs were also reported to be present in
municipal wastewaters and 22 in WWTP effluents, in a range of
0.12e144000 ng.L1 (Steger-Hartmann et al., 1996; Kümmerer
et al., 1997; Mahnik et al., 2004, 2006, 2007; Tauxe-Wuersch
et al., 2005; Lenz et al., 2007; Catastini et al., 2008; Weissbrodt
et al., 2009; Liu et al., 2010; Yin et al., 2010; Verlicchi et al., 2012;
Ferrando-Climent et al., 2013; Kosjek et al., 2013; Ferrandso-
Climent et al., 2014; Go
mez-Canela et al., 2014; Negreira et al.,
2014; Vyas et al., 2014; Azuma et al., 2016; Isidori et al., 2016). As
expected, the concentration of these drugs in hospital wastewater
was higher when compared to municipal wastewater. On the other
hand, the municipal wastewater contained higher concentration of
these drugs when compared to EETP effluents.
5. Impact of antineoplastic drugs and their metabolites on
the environment
Antineoplastic drugs have an adverse effect on the genetic
makeup and cell cycle of aquatic flora and fauna because of chronic
A. Yadav, E.R. Rene, M.K. Mandal et al.
Fig. 2. Sources of antineoplastic compounds and its pathway to enter the water bodies.
exposure (Johnson et al., 2008; Rowney et al., 2009; Booker et al.,
2014). Many authors acknowledge the fact that these drugs are
pseudo-persistent pollutants (Jones, 2005; Hernando et al., 2006).
A recent study has suggested that a lower concentration of anti-
neoplastic drugs in the pollutant mixture will have the same toxic
effect as a single dose in higher concentration (Elersek et al., 2016).
The bioaccumulation and biomagnification processes may lead to
high levels of antineoplastic drugs in the aquatic environment.
Several studies have reported the toxicity of various antineoplastic
drugs on different aquatic organisms and cell lines. The results are
usually reported in the form of LOEC (lowest observed effect con-
centration), EC50 (effective concentration), LD50 (lethal dose) and
IC50 (inhibitory concentration) values (Zounkov
a et al., 2007). The
mixture of antineoplastic drugs causes more potent DNA damage to
non-target cells, even at low concentrations, when compared with
the parent drug itself (Novak et al., 2017). EC50 value of bleomycin
and vincristine was found to be < 10 mg.L1 and in the range of
10e100 mg.L1, respectively (Jureczko and Przysta
s, 2019). Plat-
inum based drugs such as cisplatin and carboplatin are commonly
present in hospital effluents and they are considered to be highly
toxic to aquatic organisms (Ghafuria et al., 2018; Aldossary, 2019).
Similarly, CP and 5-FU have reported to cause mutagenic effects in
tadpoles (da Costa Araújo et al., 2019). 5-FU, imatinib and cisplatin
are the most potent drugs to cause transgenerational effects on
certain aquatic species (Misík et al., 2019). The recalcitrant property
of antineoplastic drugs leads their passage from sewage treatment
plants to the surface water in its active form (Kümmerer, 2001). The
native or parent compounds, as well as the by-product form of
6
Chemosphere 263 (2021) 128285
these drugs can induce adverse effects on both aquatic species and
human life, e.g. direct physiological effects, genetic material dam-
age and immune system damage (Zounkova et al., 2010; Filipic,
2014; Yadav et al., 2020). The organism present in aquatic envi-
ronment would come in contact with the residue of antineoplastic
pollutants throughout its life span and it will tend to accumulate
the biomagnified pollutant within its body (Ghafuri et al., 2018;
Jureczko and Przysta
s, 2019; Jureczko and Kalka, 2020). Zounkova
et al. (2010) studied the ecotoxicity effects of three antineoplastic
drugs and their metabolites, namely 5-FU, gemcitabine and cytar-
abine on Daphnia magna, Desmodesmus subspicatus and Pseudo-
monas putida and genotoxicity effect on Salmonella choleraesius.
The metabolite of 5-FU is FBAL (a-fluoro-b-alanine), while the
metabolite of cytarabine is AraU (uracil-1-b-D-arabinofuranoside)
and that of gemcitabine is dfdU (2, 2 - difluorodeoxyuridine),
respectively. According to this study, the native/parent forms of
these antineoplastic drugs were able to cause higher toxicity when
compared to their metabolites. The metabolites showed less or no
toxicity and among these metabolites only FBAL showed significant

toxic effect on the aquatic organisms. Cesen et al. (2016a) investi-
gated the genotoxicity and ecotoxicity effects of CP, IF and their
metabolites, as a single compound and in mixtures. The ecotoxicity
effects of the three metabolites of CP, namely Nedechloroethyl-
cyclophosphamide, keto-cyclophosphamide and carboxy-
cyclophosphamide were tested on Pseudokirchneriella subcapitata
and Synecococcus leopoliensis, while the genotoxicity effect was
tested on Salmonella typhimurium. According to the authors,
interestingly, among these three metabolites, only carboxy-
A. Yadav, E.R. Rene, M.K. Mandal et al.
cyclophosphamide showed toxicity and the EC50 value for com-
pound was 17.1 mg.L1 (low value: 14.4 mg.L1; high value:
20.2 mg.L1).
In another study (Calza et al., 2014), the degradation of meth-
otrexate, doxorubicin and the toxicity of their transformed prod-
ucts were tested on Vibrio fischeri. During degradation, eight by-
products (M1-M8) of methotrexate and twelve by-products (D1-
D12) of doxorubicin were formed. In the case of methotrexate and
doxorubicin, the initial transformed products showed high toxicity,
while the other end-products of degradation showed less toxicity
on Vibrio fischeri. Similarly, toxicity studies of the parent antineo-
plastic drug and their metabolites have also been reported in the
literature for capecitabine, CP, methotrexate and 5-FU on different
microorganisms (Lutterbeck et al., 2015b, 2016; Barışçı et al., 2018;
Chen et al., 2019; Huo et al., 2020).
The dispersion of antineoplastic drugs via drinking water has
also been reported (Aherne et al., 1990). As an example, if a preg-
nant woman is undergoing chemotherapy, the antineoplastic drugs
would have negative impact on the foetus with craniofacial and
digital abnormalities because the anticancer drugs can cross the
placenta (Paskulin et al., 2005; Jureczko and Kalka, 2020). There are
very authentic rules which stipulate that the health care staff under
the pregnancy period should be boycotted from the preparation
and management of the cytotoxic drugs (Allwood et al., 2002).
Every beneficiary of the earth’s food chain is a consumer of
water and many of them directly depend upon the natural water
bodies such as lakes, rivers, bore wells and ponds (Bai et al., 2018).
These water bodies are often contaminated with untreated do-
mestic sewage (Zounkova et al., 2010). Researchers have found
traces of numerous pesticides and other pharmaceutical com-
pounds in the food chains, i.e. food crops, fishes and seafood.
Similar to these pesticides and pharmaceutical compounds, the
antineoplastic drugs may also find their way to our food chain
through fish or any kind of direct water body dependent foods.
Antineoplastic agents work their way through the food chain by
accumulating in the body of living organisms and becoming more
concentrated as they move from one organism to another through
the process of “biomagnification”. The pharmaceutical compounds
contaminate the surface water and extricate with time in a different
niche of the aquatic food webs. However, there are very few sci-
entific documents that report the presence of antineoplastic drugs
in the food web. According to several imitated/custom-designed
food web experiments, the gathering of antineoplastic drugs oc-
curs at a greater magnitude in the life, ensuing at the lower tropic
levels (e.g. algae) when compared to the higher trophic levels (e.g.
fish) (Du et al., 2014; Ruhí et al., 2016). However, Xie et al. (2017)
reported conflicting outcomes, i.e. their study shows no accretion
and tropic biomagnification of the drugs in the aquatic food webs.
Hence, in order to understand the generic motif of pharmaceutical
compounds transmission in aquatic environments, long-term
studies should be carried out because the bioaccumulation of
these drugs depends on the species (Heynen, 2016; Lagesson et al.,
2016).
6. Sustainable technological solutions
Table 3 reports the important results reported in different lit-
eratures wherein the authors have used conventional treatment
techniques/technologies for removing antineoplastic drugs,
together with their operating conditions (Zhang et al., 2013a).
6.1. Biological treatment
The biological treatment process involves the use of microor-
ganisms (mixed or pure cultures) for the removal of persistent
7
Chemosphere 263 (2021) 128285
pharmaceuticals from water. Currently, researchers have reported
that the conventional biological wastewater treatment processes
are not able to efficiently remove or degrade these compounds
(Franquet-Griell et al., 2017; Castellet-Rovira et al., 2018; da Rosa
et al., 2019). On the other hand, the white-rot fungi can secrete
extracellular and intracellular ligninolytic enzymes, e.g. laccase,
lignin peroxidase, manganese peroxidase and versatile peroxidase
(Table 4). These enzymes can effectively degrade a wide variety of
antineoplastic compounds (Haroune et al., 2014; Ferrando-Climent
et al., 2015; Castellet-Rovira et al., 2018; Singh et al., 2018; Pereira
et al., 2020). Ferrando-Climent et al. (2015) ascertained the
removal of tamoxifen, etoposide, CP and IF by the fungi Trametes
versicolor and Ganoderma lucidum in a synthetic solution and non-
sterile hospital wastewater, respectively. The authors reported that
the removal of tamoxifen was 48% in non-sterile hospital waste-
water and 99% in the synthetic solution, respectively. In the case of
IF and etoposide, the removals were 40 and 100% from non-sterile
hospital wastewater. In another similar study, Castellet-Rovira et al.
(2018) tested the removal of CP and IF using Trametes versicolor and
reported very less removal of the drugs (i.e. ~ 40%). Membrane
bioreactors (MBR) with high biomass concentration and retention
time have also proven to be effective for the biotransformation and
mineralization of pharmaceutical drugs (Martín et al., 2011). Seira
et al. (2016) tested the efficiency of a MBR for the removal of a
cytostatic drug (e.g. CP) and characterized the mechanism
(adsorption/biodegradation) of pollutant removal. The authors
operated a 20 L MBR for 153 days, at an inlet CP concentration of
5 mg.L1 and reported ~60% CL removal. For the removal of trace
levels of antineoplastic drugs from water, stand-alone technologies
are rather not very efficient and therefore, conventional biological
technologies should be combined with a post-treatment technol-
ogy (e.g. AOPs) to completely remove these drugs from wastewater.
6.2. Physiochemical treatment
The physiochemical treatment process involves membrane
filtration and AOPs for the removal of antineoplastic compounds
from wastewater. Membrane filtration involves both membrane
separation and adsorption for the removal of pharmaceuticals
compounds. Reverse osmosis (RO) membrane is one of the most
comply used membrane separation process (Wang et al., 2009).
While, in adsorption based separation processes, the use of PAC
(powder activated carbon) is more efficient for long term column
operations when compared to activated carbon loaded columns
(Kovalova et al., 2013). This treatment strategy has the advantage of
separating the water from the contaminants, thereby providing
both water treatment and fulfilling the water demand. The per-
formance of PAC and GAC (granulated activated carbon) depends on
the Kow value of the antineoplastic compounds and dose of adsor-
bent. Verlicchi et al. (2015) reported the removal of CP and IF by PAC
from hospital wastewater, while Lenz et al. (2007) tested the
removal of 5-FU and capcitabine from oncological ward effluent of a
hospital by GAC and showed the superiority of using GAC when
compared to the use of PAC. For the removal of pharmaceutical
drugs from wastewater, RO and NF membranes have also proven to
be efficient (Ankush et al., 2019). Wang et al. (2009) studied the
removal of CP by RO and NF and observed a rejection of around 90%,
which indicated that both NF-MBR and RO-MBR were highly effi-
cient to remove CP from contaminated water. Besides membrane
filtration, AOPs have also been tested for the removal of pharma-
ceutical/antineoplastic drugs present in wastewater, e.g. electron
beam radiation, UV photolysis, and photocatalytic oxidation.
The removal efficiency of a particular treatment process for
antineoplastic compounds varies and each method has its own
specific advantage and limitation for a particular drug. For example,
 Table 3

A. Yadav, E.R. Rene, M.K. Mandal et al.

Different strategies used to mitigate antineoplastic drugs from wastewater.

Strategies Drugs Source Operating parameters Conclusion Reference

Biological treatment by WRF 10 common drugs (Ciprofloxacin HCl, CP, IF, Hospital Kirk medium, 25  C temperature, 4.5 pH and Tamoxifen removed totally but CP and IF remains as Ferrando-
(Trametes versicolor) methotrexate, azathioprine, etoposide, docetaxel, wastewater 130 rpm for 9 days such Climent
paclitaxel, vincristine sulphate and tamoxifen et al.
citrate) (2015)
CP and IF Synthetic solution Kirk medium þ other nutrient source, 25  C Removal percentage for both CP and IF was less than Castellet-
temperature, 4.5 pH and 135 rpm for 6 days 40% Rovira
et al.
(2018)
1
Membrane Bioreactor CP Semi-synthetic MBR volume 20 L, WWPF were 13.3 L d , HRT was 60% removal efficiency Seira et al.
wastewater 36 h, SRT was 20 days, DO level was kept between n (2016)
0 and 4.5 mg O2 L1, temperature varied between 25
and 32  C and pH varied between 7 and 8
Enzymatic degradation Various antineoplastic compounds such as Mixed sources Growth medium þ other nutrient elements, More potential than WRF Pereira
(secreted by WRF) tamoxifen, If, CP, etoposide etc. temperature range from 25  C to 35  C, pH range et al.
from 4 to 6 and degradation time period from 6 days (2020)
to 30 days
Mixed approach (biological and 16 antineoplastic compound (cytarabine, Hospital WWTPs For photochemical e 22  C temperature, 6.5 pH and UV-H2O2 (eliminate all) > UV-C (not Franquet-
photochemical) gemcitabine, capecitabine, IF, CP, melphalan, 48 h degradation time effective) > aerobic biodegradation (not capable) Griell et al.
chlorambucil, doxorubicin, daunoribicin, For biodegradation- 22  C temperature, 7.5 pH and (2017)
etoposide, irinotecan, vincrisne, vinblasne, 48 h degradation time
megestrol, prednisone and mycophenolic)
Activated sludge batch Vincristine Synthetic 9 days degradation time period, pH from 5 to 8 and 90% removal of parent compound Kosjek
biotransformation wastewater used AS concentration 0.24e1.9 g$L1 et al.
(2018)
MBR-Pilot (HRT- 24 h) 5-FU and anthracyclines (doxorubicin, epirubicin, Oncologic MBR tank size 1000 L, HRLe260 L d1, UV radiation - 5-FU was readily biodegradable and adsorption to Lenz et al.
daunorubicin) wastewater 254 nm and monitoring time period was 18 months sludge was marginal, it could be completely (2007)
eliminated from the liquid phase; over 90% of
8

anthracyclines were removed mainly due to

adsorption of suspended solids.
MBR-Pilot Cisplatin, carboplatin Oncologic MBR tank size 1000 L, HRL (hydraulic load)-100- Moderate elimination efficiency (51%e63%) of total Mahnik
wastewater 200 L d1, HRT- 20e24 h and monitoring time period platinum was achieved; carboplatin showed et al.
was 98 days relatively low adsorption to activated sludge and (2007)
was mainly present as an intact drug in both influent
and effluent.
 
CP and its human metabolites Domestic MBR volume 20 L, 25 C to 32 C temperature, 7e8 CP removal was up to 80%, however, residue Delgado
wastewater with pH, SRT- 50 and 70, HRT- 48 and 32 and aeration cytotoxicity was measured in permeate. et al.
inoculated cycle 2 min (2011)
activated sludge
NF, NF/Granular activated CP Pre-treated Pre-treatment time periode 100 days, 7.5 pH and NF rejection > 90% when water recovery is only 10% Verliefde
carbon surface waters 6.7, DOC- 6 and 12, conductivity e 530 and 920, but at 20% water recovery only 30% rejection for CP. et al.
pump pressure- 25 bars and treatment time period- (2007)
4 days
NF/RO CP, IF, paclitaxel and etoposide Ultrapure water MBR volume - 400 ml, HRT- 48 h, SRT- 50 days, 7.5 RO performed with more than 90% rejection in (Wang
and MBR effluent, e8 pH, room temperature and trans-membrane compare to NF’s poor rejection of 20e40%. et al.,
synthetic urine pressure range between 5$10þ5 to 25$10þ5 Pa Rejection in NF for etoposide was maximum i.e., 97.7 2009;
and real 250 ml feed solution, minutes, 300 rpm, room and 98.7% in ultrapure water and secondary effluent Cristo
v~
ao

Chemosphere 263 (2021) 128285

secondary temperature and treatment time period was 30 min as compare to paclitaxel and IF. et al.,
effluent 2019)
Electrolysis (anodic oxidation) Epirubicin, irinotecan, vincristine, mitomycin-C, Clinic wastewater Two platinum-irridium electrodes (gap 5 mm), Cytotoxicity, mutagenicity and antibacterial activity Hirose
paclitaxel, methotrexate, cisplatin 100 mA constant current and current density was of epirubicin were ~100% eliminated after et al.
4 A dm2 electrolysis (6 h), 72e100% for other investigated (2005)
cytostatics.
The cost-effective apparatus can be adapted to treat
clinical wastewater.
Electrolysis (anodic oxidation) Methotrexate Urine Platinum-irridium electrodes, 1 A constant current, Electrolysis generates active chlorine and Kobayashi
3.5e4 V voltage and electrolysis time period was 4 h decomposes methotrexate et al.
(2012)
A. Yadav, E.R. Rene, M.K. Mandal et al. Chemosphere 263 (2021) 128285

the removal efficiency of capcitabine in a UV irradiation process

Note: # NF (Nanofiltration), AOPs (Advanced oxidation processes), HRT (Hydraulic retention time), SRT (Sludge retention time), DO (Dissolved oxygen), DOC (Dissolved organic carbon), HRL (hydraulic load), AS (Activated
Garcia-Ac
Kim et al.
was 100%, but the toxicity in aquatic system after treatment
Buerge

(2006)

(2009)

(2010)

(2011)
increased significantly due to the production of more toxic me-

Lester
et al.

et al.

et al.
tabolites (Guo et al., 2015). 5-FU treated by UV/H2O2 process ach-
ieved 99.6% degradation (Kosjek et al., 2013), while the CP
UV dose decreased from 5201 to 1695 mJ cm2 (UV/

kOH
¼ 1.3  109 M1s1 (CP þ OH
). H2O2/O3 show

conditions, followed by ozone treatment alone. H2O2

organic matters might act as scavengers of both OH

(10 mg$L1 O3) spiked with hydrogen peroxide (2.5 natural water matrix effects; reaction of CP with OH

Elimination efficiency was 80% and 60% for CP and IF.

(ko3 ¼ 3.3 ± 0.2 M1s1, pH 8.1) without significant

concentration (oxidant dose  contact time) value of

natural water. By comparison, methotrexate reacted

~45 mg min/L was required to remove 96% CP from
effective to less readily- degraded PPCPs. Dissolved

quickly with O3 (ko3 ˃ 3.6  103 M1s1) at typical

degradation was only 90% (Ferre-Aracil et al., 2016). In another

10 mg$L1 H2O2), buffered ultrapure water (8.10 pH) was much easier (k ¼ 2.0  109 M1s1). A high
Increased OH
by adding nitrate enhanced the

highest degradation rate among different AOP

H2O2) for 90% CPedegradation. H2O2 addition

dosages applied in drinking water treatment.

significantly enhanced CP degradation by UV

study, the degradation of cytarabine was compared in different UV

concentration was found to be an important

radiation. The H2O2 enhancement was more

irradiation based technologies and the following results were

achieved: UV/S2O2 2
8 ¼ 96%, UV/H2O2 ¼ 81%, UV/(OH)4B2O4 ¼ 65%,

Reactor volume e 1 L, 0.45 kW medium pressure, ko3 ¼ 2.5 M1s1 (CP þ O3 in excess);
Natural water (10 mg$L1 O3), natural water spiked CP degradation rate with O3 was low

and UV/C3H9COOH ¼ 48% (Ocampo-Pe
rez et al., 2016). Meanwhile,

the removal of methotrexate and doxorubicin by UV was only 60%
and 10%, respectively, although both the compounds were removed
degradation of CP and IF.

completely by UV/TiO2 (Calza et al., 2014).

Lai et al. (2015) studied the removal of CP and IF by UV/TiO2 and
reported that, although the removal was ~100%, the by-products
and UV energy.

formed during the treatment process showed higher toxicity

parameter.
when compared to the parent compound. These results were
similar to the results achieved by Guo et al. (2015) for capcitabine
degradation. In two different studies, 5-FU and CP degradation was
compared in a UV/H2O2, UV/TiO2 and UV/H2O2/Fe2þ system and the
concentration was 6e8.2 mg$L1, 20  C temperature

authors reported no toxicity of the treated effluent even when the

pH 8.8, 2.51 mM alkalinity, 1.6 mg.L1 dissolved

8 W low-pressure mercury lampe254 nm, H2O2

with tert-butanol (10 mg$L1 O3), natural water

organic carbon, 22  C temperature foe light and

removal efficiencies of 5-FU and CP were not >99% (Lutterbeck

spiked with tert-butanol (10 mg$L1 O3) and


polychromatic UV lamp- 200e300 nm and

et al., 2015a, 2015b). Cesen et al. (2016b) ascertained the removal

of CP and IF in a UV/O3/H2O2 process and removal efficiencies > 98%
was reported for both CP and IF. Li et al. (2016) reported the
degradation of busulfan, chlorambucil, CP, dacarbazine, flutamide,
IF, tamoxifen and methotrexate by ozonation and the authors
observed 100% removal of chlorambucil, dacarbazine, flutamide,
temperature was 20  C

temperature was 25  C

tamoxifen and methotrexate was achieved, 70% removal for CP and

IF, and no removal of busulfan. In a combined O3/H2O2 process,
Ferre-Aracil et al. (2016) reported complete removal of a mixture of
20  C for dark

pharmaceutical drugs, namely gemcitabine hydrochloride, temo-

and 7 pH

zolomide, methotrexate, hydroxymethotrexate, irinotecan, imati-

nib, mesylate, IF, CP, erlotinib hydrochloride, etoposide, doxorubicin
hydrochloride, capecitabine, endoxifen, 4- hydroxytamoxifen and
Deionized water

tamoxifen citrate. Ferrando-Climent et al. (2017) demonstrated

Pure water and

Drinking water
treated water

100% removal of tamoxifen in an UV/O3 process and observed that

biologically
Lake water

the by-products formed during the degradation was more toxic

compared to tamoxifen. As a novel treatment technique, the
electro-degradation of CP and IF by boron doped diamond elec-
trode was tested by Fabian
ska et al. (2015). In that study, the au-
thors tested the effect of current density (4.8e16.0 mA cm2), IF
concentration (5e55 mg.L1), and pH (4.0e9.5) and observed that
the current density has a significant effect on the removal efficiency
of both CP and IF, while pH did not affect the performance of the
electro-degradation process.

6.3. Chemical treatment

CP, methotrexate

The removal of antineoplastic drugs by chemical treatment

sludge), WWPF (Wastewater and permeate flow).

processes was previously used in hospitals and pharmaceutical

industries; however, they have been replaced recently by AOPs. In
chemical treatment, different oxidising agents such as sodium hy-
CP, IF

CP

CP

pochlorite, potassium and sodium permanganate, Fenton reagent

and hydrogen peroxide are used to remove various antineoplastic
processes (i.e. UV, UV/H2O2,

drugs like doxorubicin, epirubicin, CP, IF melphalan and idarubicin

UV/H2O2/O3 and its sub-

(Hansel et al., 1996; Castegnaro et al., 1997). During the chemical

Indirect photochemical

UV/O3, O3, H2O2/O3)

transformation of antineoplastic drugs, several by-products or in-

termediate chemicals are formed and these by-products are
UV and UV/H2O2
degradation

mutagenic in nature (Lutterbeck et al., 2015b). The conventional

chemical treatment process includes methods such as neutraliza-
Ozonation

tion, precipitation, ion exchange, disinfection (ozone, chlorine and

UV) and adsorption (Tripathi et al., 2020).
In recent years, AOPs are commonly used for the removal or
9
A. Yadav, E.R. Rene, M.K. Mandal et al.
Table 4
Comparison between different treatment techniques for antineoplastic drugs, their removal performance and mechanisms.
Treatment methods
Advanced (Photo catalytic)
oxidation (UV/TiO2), (UV/H2O2), methotrexate and
(UVeC/TiO2)
UV photolysis
Ozonation
Chlorination
Electron beam radiation
Photo Fenton oxidation (UV/Vis/
H2O2/Fe2þ)
Membrane Technology
Adsorption
Hybrid Technology
Whole cell fungal culture
Purified and crude enzymes
Immobilised Enzymes
Enzymatic membrane reactors
Chemosphere 263 (2021) 128285
Removed Degradation mechanism References
antineoplastic
drugs
Doxorubicin, In photo catalytic oxidation processes UV light or sunlight in the presence of TiO2 (Calza et al., 2014; Lutterbeck
and H2O2 form oxidising hydroxyl radical. Hydroxyl radical react with oxygen and et al., 2015b; Janssens et al.,
etoposide water molecule to form reactive oxygen species and covert antineoplastic 2020)
pollutant into by-product, H2O and CO2
5-FU UV photolysis process involves the use of emission of UV beam of a particular Lutterbeck et al. (2016)
wavelength for the breakdown of antineoplastic drugs. This process use UV light
from sun or light emitting lamp such as Hg and Xe lamp. The removal rate
depends on the maximal absorption wavelength of light. While indirect
photolysis process occurs through the formation of free radical in this process
which is check by the measurement of H2O2 concentration
CP Ozonation process also involves the formation of hydroxyl radical by the Lin et al. (2015)
decomposition of ozone and form reaction cascade with antineoplastic drugs.
Hydroxyl radical act as highly reactive species during degradation of
pharmaceutical in ozonation process
Erlotinib Chlorination process involves use of free chlorine molecule for removal at (Negreira et al., 2015)
particular pH for removal of pharmaceuticals. At pH 7, reactive chlorine molecules
get converted into OClˉ and HOCl which degrade antineoplastic drug molecule
Capecitabine This process use AOPs with electron radiation beam for the removal of Huo et al. (2020)
antineoplastic drugs. In electron beam gamma radiation are very effective for the
degradation of antineoplastic drugs molecule. In this process radiation generate
reactive species i.e., OH
, H
and e aq. Involvement of H2O2 increase the rate of
degradation during reaction. S2O2ˉ 8 also increase the rate of reaction during
degradation by producing SO
ˉ 4
5-FU, doxorubicin Photo-Fenton process also work on the degradation of recalcitrant compounds Governo et al. (2017)
formation of OH
and O
2 in the presence of light. The ions (positive or negative)
generated from catalyst during oxidation process also react with water molecule
to form active radical and increase the rate of degradation.
CP, IF, etoposide Membrane technology is advanced treatment for removal of pharmaceutical
va
(Cristo ~o et al., 2019;
and paclitaxel compound from wastewater. This process involves membrane bioreactor, Janssens et al., 2019)
ultrafiltration, microfiltration, NF and RO. Electrostatic exclusion is the main cause
of removal of charged pharmaceuticals and the elimination of uncharged
compounds is based on size exclusion approach.
Electrodialysis is another membrane based technology that is operated under
electric field in which ions are bound to pass through the semi- permeable
membrane
Irinotecan, Activated carbon is a recent advanced technology for treatment of wastewater. It Lutterbeck et al. (2020)
tamoxifan and CP is use for removing pharmaceutical constituents and residual disinfection in
water supplies. Many polar and non-polar antineoplastic compounds present in
wastewater effluents can be eliminated by using activated carbon either in
powdered form or granulated form
CP, IF, Ibuprofen Hybrid technology is an emerging technology for treatment of wastewater, this (Ofiarska et al., 2016; Janssens
and naproxen process involve combination of two technologies such as combination of fungal et al., 2017)
media with Fenton system etc.
The combination of biofilm with suspended biomass can largely improves the
biodegradability of pollutants
Tamoxifen, IF, CP, Treatment of wastewater by using microorganism such as fungi, bacteria, algae (Ferrando-Climent et al., 2015;
and etoposide and their extracellular or intracellular enzymes. Pereira et al., 2020)
In whole cell culture particularly white rot fungus (WRF) are mainly used in the
removal of recalcitrant antineoplastic drugs from the wastewater. Several species
that belongs to different genera of WRF have been utilised and studied for the
degradation purpose of recalcitrant compounds such as Ganoderma lucidum,
Bjerkandera adusta, Trametes versicolor. Fungi Fungi remove antineoplastic drugs
by adopting bioadsorption, biomineralisation, biotransformation and
biodegradation mediated by both intracellular and extracellular enzymatic
systems.
Different reactor configuration have been explored for the treatment of
pharmaceuticals based on WRF systems such as stirred tank bioreactor, bubble
column bioreactor, fluidized bed bioreactor etc
Naproxen In this process different enzymes such as manganese peroxidase, lignin Pereira et al. (2020)
peroxidase, versatile peroxidase and laccase have been used in purified or crude
extract forms to remove recalcitrant pharmaceuticals with high rate of
effectiveness. These enzyme degrade the antineoplastic drugs by its substrate
specificity and transfer of electron from substrate to molecular oxygen
Diclofenac In this process, immobilised enzymes can be used with support of membranes Pereira et al. (2020)
and nanoparticles. They can be used in continuous mode of reactors avoiding
biocatalyst loss
IF, tamoxifen In this process, enzymes remain in the reactor during continuous feeding and (Asif et al., 2017; Pereira et al.,
effluent removal. Better enzyme dispersion takes place in the reactor, high 2020)
enzymatic retention period with easily replenishment of enzymes
10
A. Yadav, E.R. Rene, M.K. Mandal et al.
degradation of antineoplastic drugs. Typical examples of AOPs are
ozonation, photo-assisted degradation, electrochemical oxidation
and Fenton based degradation (Pieczyn
ska et al., 2017). These
methods involve the use of free radicals for the degradation or
transformation of the antineoplastic drug (Janssens et al., 2017).
Briefly, the mechanism/steps of hydroxyl based AOPs can be sum-
marized as follows: (i) the first step if the production of highly
reactive free radicals (e.g. OH
), (ii) the OH
has electrophilic
functions and it can react with the antineoplastic drugs present in
water, (iii) during the process, there is transfer of hydrogen ions and
interaction of radicals, (iv) the OH
have a very short lifetime and
they are produced In-situ using oxidising agents such as H2O2 and
O3, irradiation (e.g. UV light source or ultrasound), and catalysts
(e.g. Fe2þ), and (v) this process mineralizes the antineoplastic
agents and it is transformed into less or non-toxic products in the
water phase. In AOPs, many combined techniques have been
developed for treating pharmaceutical compounds present in wa-
ter: UV (O3/UV), H2O2 (O3/H2O2), and both (O3/UV/H2O2) (Table 4).
AOPs have proven to be effective in treating hospital wastewater
(Lutterbeck et al., 2015b; García et al., 2020). Many researchers have
tested electrochemical oxidation (Hirose et al., 2005; Lazarova and
Spendlingwimmer, 2008), ozonation, H2O2 and UV induced photo-
oxidation for treating numerous recalcitrant pollutants present in
water and wastewater (Roberts and Thomas, 2006; Brose
us et al.,

2009; Zhang et al., 2013b; Cesen et al., 2015).
Evidently, the literature reports have proven the effectiveness of
different treatment processes, both as standalone and combined/
integrated systems, and depending on the nature of the drug, var-
iations in removal efficiencies has been observed. The operational
parameters of the treatment system/reactor also affects the treat-
ment efficiency, e.g. treatment time, concentration of the drug,
initial pH, catalyst/adsorbent dose, nature of the oxidant, applied
voltage/current intensity, etc, among others. However, the oper-
ating conditions and the degree of treatment achieved decides the
final quality of the treated water, its toxicity and treatment costs.
For example, although ozonation has proven to be efficient for
removing a wide variety of pharmaceutical drugs, persisting
organic pollutants, pesticides, insecticides/herbicides and volatile
organics present in water, in most of the cases, the toxicity of the
treated water is somewhat high than the initial pollutant (Lin et al.,
2015). For the treatment of antineoplastic drugs, photo-assisted
treatment has also shown promising results. In few studies, UV/
H2O2 process has achieved 100% removal, reduced toxicity of the
treated water and increased biodegradability of the transformed
products (Lutterbeck et al., 2015b, 2016; Koltsakidou et al., 2017).
On the other hand, in some studies, although the photo-assisted
process has shown 100% efficiency for removing antineoplastic
drugs, the toxicity of the by-products were shown to be high
(Ocampo-Pe
rez et al., 2010; Lin and Lin, 2014; Ferrando-Climent
et al., 2017).
Biological treatment systems have also been tested for the
removal of pharmaceutical drugs present in water. Although, the
operating costs for biological processes are less compared to
physico-chemical processes, they are not completely efficient to
mineralize the antineoplastic compounds due to the following
reasons: (i) the activity of the microorganism, (ii) acclimation of the
microorganism to the target drugs, (iii) complex structure of the
drug and its ring cleavage mechanism, (iv) the pathway that re-
quires several enzymes and co-enzymes, and (v) sensitiveness to
environmental and reactors operating conditions, e.g. temperature,
pH, oxygen and reduction potential (ORP), reactor configuration,
salinity and the presence of competing ions or other pollutants
present in wastewater (Ferrando-Climent et al., 2015; Castellet-
Rovira et al., 2018). In order to achieve 100% removal of the
11
Chemosphere 263 (2021) 128285
pharmaceutical drugs present in water, some laboratory scale
studies have shown that, a combination of one or two technologies,
e.g. UV/O3 þ biodegradation or UV/H2O2 þ biodegradation, will be
more efficient to meet discharge/regulatory limits (Lutterbeck et al.,
2020).
7. Safety guidelines
The exposure of people living in the vicinity of the patients to
the anticancer drug is becoming a health hazard risk. Biosafety
cabinets, closed system and personal protection equipments (PPEs)
such as masks, double pairs of gloves and disposable gowns should
be used during the preparation and management. During the
process of chemotherapy, the person in the surrounding environ-
ment should use PPEs to protect themselves. In case, an anticancer
drug solution is dispersed on the floor, benefits of spill kit along
with PPEs and inactivating agent should be taken to forbid the
contamination and diffusion. The antineoplastic drug preparation
area should be cleaned using sodium hydroxide, sodium hypo-
chlorite and ozone waters but the use of these chemicals may
create other issues like the destruction of the tiles, toilet stool and
other problems related to the laboratory. Researchers have devel-
oped active carbon sheets that can adsorb the anticancer drugs
(Sato et al., 2014). The advanced version of this active carbon sheet
is named as HD safe sheet-U. It can also be used to adsorb the
antineoplastic drug from urine (Fig. 3). That’s the reason why HD
safe sheet-U might play an important role in decreasing the
exposure of hospital staff and relatives of patients to the antineo-
plastic drugs present in the urine.
Specific isolator technology was introduced in France in order to
prevent the exposure to antineoplastic drugs. This specific isolator
acts as a physical barrier and it provides a closed working place to
evade direct contact between the operator and the antineoplastic
drug. Specific isolators are also useful to avert the inhalation
inconvenience of anticancer drugs. Thus, the isolator technology
helps to develop a small and protective environment for health care
workers. All pharmaceutical companies should follow the defined
decontamination procedures during the process of drug manufac-
ture (Crauste-Manciet et al., 2005). The process of ozonation should
be performed for the purification of freshwater, i.e. to remove the
colour and many antineoplastic drugs like CP and pentoxifylline.
For the management of antineoplastic drugs pollution in the
environment, several regulatory bodies have enunciated guide-
lines. Example of these agencies are the following: the USEPA
(United States Environmental Protection Agency), DEA (Drug
Enforcement Administration), DOT (Department of Trans-
portation), OSHA (Occupation Safety And Health Administration),
FDA (Food and Drugs Administration), SEPA (State Environmental
Protection Agencies), WHO (World Health Organization), OECD
(Organization for Economic Cooperation and Development), EMA
(European Medical Agency), State pharmacy boards, State Pollution
Control Boards (PCB) and POTW (Local publicly Owned Treatment
Works). Each organization has its own guidelines and policy based
on the prevailing local conditions; however, some specific rules/
acts framed by the USEPA are used by organizations in developing
countries.
The USEPA proposed guidelines or regulations for the manage-
ment of hazardous pharmaceutical wastes in the year 2008 (vol-
ume 73 of FR - Federal Register). However, due to certain limitations
(facility generation, handling, transport and lack of tracking), this
was not finalized. Hence, in the year 2015, the USEPA articulated
another regulation (80 FR 58014) for healthcare facilities and
reverse distributors for the management and disposal of hazardous
pharmaceutical waste. After this, the USEPA involved stakeholders
and states for many years by evaluating the performance of states,
A. Yadav, E.R. Rene, M.K. Mandal et al.
Fig. 3. Mechanism of HD safe seat-U (activated carbon adsorption sheet) to adsorb urine and urinary antineoplastic drugs.
healthcare facilities, environmental organizations/departments,
retailers, reverse distributors and facilitate public participation.
Through the evaluation, significant changes were made in proposed
guidelines and they were subsequently implemented. The new
guideline entitled “Management standards for hazardous waste
pharmaceutical and amendment to the P075 listing for nicotine”
was enunciated in the year 2018 and published as ‘40 CFR’ (code for
federation regulation) by the Federal Register in the year 2019
(Mehta and Lau, 2019). The EMA and FDA has also developed
guidelines for monitoring the occurrence of antineoplastic drugs in
different aquatic ecosystems based on health and environmental
risk assessment studies. The values set by the EMA and FDA were
0.01 mg$L1 and 1 mg$L1, respectively (Russo et al., 2020).
Antineoplastic drugs are regulated as hazardous waste under
the RCRA (Resource Conservation and Recovery Act) when dis-
carded. Under this regulation, the healthcare facility and reverse
distributor will manage hazardous pollutants such as antineo-
plastic agents and antibiotics, and also prohibit the direct release of
antineoplastic drugs into the drainage/sewer system from hospitals
and household. The RCRA determines the hazardous levels of
different pharmaceutical compounds including antineoplastic
drugs on the basis of their toxicity (categorized by EPA as P, U and
D). The pharmaceutical compounds categorized under ‘P’ category
are highly or acutely toxic and which comes under hazardous
waste, while the pharmaceutical compounds that are categorized
under ‘U’ category are toxic but less than the ‘P’ category. Some
antineoplastic drugs are placed under the ‘U’ category, while some
are in the ‘P’ category. According to these categories, these drugs are
disposed in specific containers (e.g. antineoplastic drugs are
disposed in black coloured containers).
The OECD has also developed new guidelines for the manage-
ment of hazardous pharmaceutical pollutants in water. In these
guidelines, the OECD recommends the government of countries to
start a collective, life cycle approach using the “act, plan, do and
check” strategy for the management of pharmaceutical pollutants
through the collaboration between different government de-
partments, local authorities and stakeholders (OECD, 2019). These
OECD guidelines are responsible for the cost-effective management
of hazardous/toxic pollutants and protect the aquatic environment.
The five strategies can be summarized as follows:
12
Chemosphere 263 (2021) 128285
(i) Knowledge gap - Improve the existing scientific knowledge
of these chemicals and reduce the gap in understanding the
occurrence, fate and risk caused due to the presence of
antineoplastic drugs in water bodies.
(ii) Source directed approach - This helps to reduce the direct
release of antineoplastic drugs into water bodies and this
approach directly targets the pharmaceutical industries.
Typical source directed approaches include change of raw
materials, change of unit operations, process optimization
and waste minimization strategies in the pharmaceutical
industry.
(iii) Use/user orientated approaches - This helps to reduce the
inappropriate consumption of antineoplastic drugs. This
approach is directly linked to the change in existing practice
(e.g. drug overdose) and behaviour of doctors and patients.
(iv) End of pipe measures - This strategy mainly focus on the
improvement of treatment technologies for the removal of
antineoplastic drugs or their residue before or after their
release into the water environment. However, the removal
efficiencies of the different treatment processes depend on
the various physicochemical properties of antineoplastic
drugs and their metabolites/by-products such as hydropho-
bicity, reactivity, molecular size and charge and biodegrad-
ability. In some developed nations, preventative approach
(e.g. cleaner production, waste minimization) has been rec-
ommended and given priority over end-of-pipe treatment
technologies. Depending on the type and composition of
antineoplastic drugs present in wastewater, the end-of-pipe
measures are usually limited by their removal efficiencies,
high capital/operation costs and high energy demand.
(v) Life cycle approach and policies - This strategy involves
drafting guidelines and action plans for the above-
mentioned four strategies. Besides, life cycle analysis of
pharmaceutical products such as precursor chemicals (e.g.
enzymes), synthetic, speciality and fine chemicals used, and
the assessment of different antineoplastic drug production/
synthesis routes and their reactor configurations should be
evaluated.
A. Yadav, E.R. Rene, M.K. Mandal et al.
8. Conclusions and future perspectives
Globally, the consumption of antineoplastic drugs is increasing
rapidly and it is expected to increase further in the next 15e20
years. The presence of antineoplastic drugs in different aquatic
environments has drawn attention of the scientific community and
the policymakers. The present review discussed the key sources of
antineoplastic drugs and their pathway which are majorly
responsible for the occurrence of these drugs in the natural
ecosystem. In some countries, antineoplastic compounds have been
found in the surface water and wastewater treatment plant of
hospitals. The contamination of water bodies with antineoplastic
drugs possesses severe toxic effects on aquatic organisms, human
health and the environment. In aquatic environments, even trace
quantities of antineoplastic compounds can easily enter the food
chain; however, the mechanism of biomagnification, biological
interaction at the species level and transport of antineoplastic
compounds from lower to higher trophic levels is still unclear. It is
necessary to continuously monitor the presence of these drugs,
their metabolites and toxicity levels and upgrade/retro-fit the
existing facilities to achieve high removal performance. The health
and environmental organizations/departments of developing
countries should formulate policies, guidelines and create aware-
ness among the general public, hospital staffs and industrial asso-
ciations to protect people from the identified toxicological risks
associated with the exposure to antineoplastic drugs.
Credit author statement
Ankush Yadav, Writing - original draft, Writing - review and
editing. Eldon R Rene, Writing - review and editing. Mrinal Kanti
Mandal, Writing - review and editing. Kashyap Kumar Dubey,
Writing - review and editing, Visualization, Supervision.
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgements
The authors would like to thank the Ministry of Science and
Technology, Department of Biotechnology (DBT), Government of
India for providing financial support under the grant agreement BT/
IN/INNO-INDIGO/26/MKM/2015e16 to support this research. ERR
thanks IHE Delft, The Netherlands for providing staff time support
to collaborate with researchers from India, under the project
“Support to Society”.
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