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Biotechnology and Genetic Engineering Reviews
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Recent advancements in toxicology, modern
technology for detection, and remedial measures
for arsenic exposure: review
Bibha Kumari & Vijay K. Bharti
To cite this article: Bibha Kumari & Vijay K. Bharti (2022): Recent advancements in toxicology,
modern technology for detection, and remedial measures for arsenic exposure: review,
Biotechnology and Genetic Engineering Reviews, DOI: 10.1080/02648725.2022.2147664
To link to this article: https://doi.org/10.1080/02648725.2022.2147664
Published online: 21 Nov 2022.
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REVIEW ARTICLE
Recent advancements in toxicology, modern technology
for detection, and remedial measures for arsenic
exposure: review
Bibha Kumari
a
and Vijay K. Bharti
b
a
Department of Zoology, Magadh Mahila College, Patna University, Patna, India;
b
DRDO-Defence
Institute of High-Altitude Research (DIHAR), Leh, UT Ladakh, India
ABSTRACT
Arsenic toxicity has become a major global health concern
for humans and animals due to extensive environmental and
occupational exposure to arsenic-contaminated water, air,
soil, and plant and animal origin food. It has a wide range
of detrimental eects on animals, humans, and the environ-
ment. As a result, various experimental and clinical studies
were undertaken and are undergoing to understand its
source of exposures, pathogenesis, identify key biomarkers,
the medical and economic impact on aected populations
and ecosystems, and their timely detection and control mea-
sures. Despite these extensive studies, no conclusive infor-
mation for the prevention and control of arsenic toxicity is
available, owing to complex epidemiology and pathogenesis,
including an imprecise approach and repetitive work. As a
result, there is a need for literature that focuses on recent
studies on the epidemiology, pathogenesis, detection, and
ameliorative measures of arsenic toxicity to assist researchers
and policymakers in the practical future planning of research
and community control programs. According to the preced-
ing viewpoint, this review article provides an extensive ana-
lysis of the recent progress on arsenic exposure to humans
through the environment, livestock, and sh, arsenic toxico-
pathology, nano-biotechnology-based detection, and cur-
rent remedial measures for the benet of researchers,
academicians, and policymakers in controlling arsenic eco-
toxicology and directing future research. Arsenic epidemiol-
ogy should therefore place the greatest emphasis on the
prevalence of dierent direct and indirect sources in the
aicted areas, followed by control strategies.
ARTICLE HISTORY
Received 20 August 2022
Accepted 15 October 2022
KEYWORDS
Arsenic toxicity; toxicology;
human health; fish; mice
1 Introduction
The presence of inorganic arsenic (As) of geological origin is widespread in
water drawn from very deep wells in plain area, hilly area, and even shallow
wells in endemic areas. The global scenario for arsenic pollution has
CONTACT Bibha Kumari bibhak136@gmail.com Department of Zoology, Magadh Mahila College, Patna
University, Patna, 800001, India
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS
https://doi.org/10.1080/02648725.2022.2147664
© 2022 Informa UK Limited, trading as Taylor & Francis Group
changed with the discovery of new locations and sources, so more and more
people are being affected. Around 230 million people are currently living
with arsenicosis worldwide, a number that has dramatically increased over
the past ten years and is now 10 parts per billion (ppb) above the WHO’s
safe drinking water standard (Shaji et al., 2021). According to a recent
report, natural exposure to arsenic from groundwater is one of the most
serious concerns for human and animal health in over 103 countries,
including Bangladesh, India, Vietnam, Taiwan, China, Thailand, Pakistan,
Iran, Australia, Argentina, Brazil, Chile, Bulgaria, Canada, Czech Republic,
Egypt, and parts of the United States (Sanyal et al., 2020; Shaji et al., 2021).
Therefore, human exposure is widespread through the soil, air, water, and
food in different parts of the world, leading to arsenic poisoning (Sanyal et
al., 2020).
The other significant source of arsenic exposure is the anthropogenic
origin, like agrochemicals, wood preservatives, mineral processing, drainage
from acid mines, burning of fossil fuels, etc. (Bundschuh et al., 2021; Kumari
et al., 2017). Arsenic in water and other sources is present in three common
forms, e.g. inorganic salt, organic salt (monomethyl arsenic, common in
aquatic food sources), and gaseous form (arsine) (Kuivenhoven & Mason,
2021). Moreover, arsenic presence in drinking water is imperceptible, taste-
less, and odorless (Viscusi et al., 2015). Therefore, prolonged excessive
exposure to inorganic arsenic from drinking water and food is inevitable
for large populations who consume untreated water, causing endemic
arsenicosis (Oza et al., 2021; Sanyal et al., 2020). In addition, exposure to
other metals and environmental toxicants with arsenic is also of consider-
able public concern due to its strong interactions and complex pathogeni-
city, particularly with fluoride and lead in contaminated groundwater
(Kumar et al., 2020; Mondal & Chattopadhyay, 2020).
Therefore, the control and prevention of arsenic-induced disorders are
dependent on how early they are detected, as well as epidemiology and
toxicopathology. Numerous studies have shown that exposure to various
concentrations of arsenic in humans and animals can negatively affect their
bodies’ physiological processes and general health (Alvarado-Flores et al.,
2019; Bharti & Srivastava, 2009; Bharti et al., 2012a, 2012b; Tchounwou et
al., 2019). So, modern arsenic toxicology is, therefore, more specialized in
toxicity testing, molecular mechanisms on how arsenic interacts with cells
and other physiological systems, arsenic-other trace minerals interactions,
basic cellular, and developmental biology (Hahn & Sadler, 2020).
Furthermore, depending on its species effect, age, location, the form of
arsenic, feeding habits, etc., arsenic toxicity affects humans and animals
differently (Sanyal et al., 2020). Recent reports revealed that continued
exposure to arsenic also significantly increases the risk of illness and death
from cancer and heart, lung, kidney, and liver disease (Rahman et al., 2019).
2B. KUMARI AND V. K. BHARTI
The association between arsenic exposure and abnormal obstetric effects
like spontaneous abortion, stillbirths, embryonic death, pregnancy hyper-
tension, and gestational diabetes has also been observed in many developing
countries (Amadi et al., 2017). In addition, it is an independent risk factor
for cognitive impairment. Further, chronic arsenic exposure may affect
adult cognitive function dose-dependently (Wang et al., 2021a). Therefore,
there is a need to use modern arsenic detection and removal techniques and
establish a proper epidemiological database for effective preventive and
control measures of arsenic toxicity.
Although there are studies on arsenic’s toxic effects on different species
and remediation techniques, however, the specific epidemiology of arsenic
exposures, effective detection methods, and remediation are poorly under-
stood (Sage et al., 2017). Therefore, the current state of sources of arsenic
exposure, arsenic toxicopathology, health effects, therapeutic agents, mod-
ern techniques of nano-biotechnology-based detection, and remedial mea-
sures and crucial areas for future research are thoroughly reviewed in this
review paper. All the database . . . google, pubmed . . . cabi . . . etc are
reviewed from 2014–2021
2 Abiotic sources of human exposure to arsenicals
Arsenic (As) is a toxic metalloid element of the earth’s crust and is present
abundantly in the air, water, and soil in different valence states, viz. As(0),
As(III), As(V) and arsine gas (−3 oxidative state). The abiotic sources of
arsenic in the environment include geogenic (underground water, minerals,
and geothermal processes) and anthropogenic like mining operations,
industrial processes, agricultural activities, etc. (Nadiri et al., 2018, 2021;
Palma-Lara et al., 2020; Sanyal et al., 2020). Arsenic-contaminated soil is a
major source of arsenic exposure in humans by consuming plant-based food
cultivated on these soils (Dahlawi et al., 2018). These contaminated soils also
contribute arsenic to groundwater and surface water resources through
leaching and runoff mixed with the river, pond, etc. The geogenic contam-
ination can be further extended by unintended human and industrial
activities (Nadiri et al., 2018, 2021). So, polluted groundwater for drinking
and other household activities is a major source of arsenic exposure to
humans.
High arsenic level equal to or greater than 50 µg/L in groundwater has
been reported, especially in Southeast Asia and parts of India and
Bangladesh, which is alarming for society (Chakraborti et al., 2018). Other
studies indicated that the outside Asia population is also affected by arsenic
exposure through groundwater (Shahid et al., 2020; Shaji et al., 2021).
Interestingly, Bharti et al. (2017), Giri et al. (2017, 2019, 2020) reported
that water from high-altitude is also contaminated with arsenic and other
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 3
heavy metals. River sediment is another important source of arsenic in the
ground and river water (Shaji et al., 2021). These reports indicate wide-
spread arsenic contamination in water resources from high-mountain to
plain areas, irrespective of industrialization and other anthropogenic
sources.
The gaseous form of arsenic (arsine) is the most toxic form, and inhala-
tion of over 10 ppm to 25 ppm is lethal even in less than an hour. The
mining activities and burning of contaminated charcoal are causing air
pollution with arsenic (Zhao et al., 2019a). Arsenic does not cause tissue
irritation and is odorless; hence exposure to this arsine is unrecognizable.
To regulate water arsenic levels, earlier, the WHO set 50 parts per billion
(ppb) arsenic levels in drinking water throughout the exposure period but
revised it in 1993 to a lower level when it is considered to pose an unac-
ceptably high risk of cancer death. The current WHO guideline value is
temporarily set at 10 ppb due to arsenic detection and removal limits
(Cheng et al., 2016), although this is still considered an unacceptably high
health risk. So, every country should establish its own recommended level of
arsenic in drinking water; so far, various countries have set it from 50 ppb to
less than 10 ppb (Altowayti et al., 2021). So, it emphasized that more studies
are still required to evaluate arsenic in different abiotic sources for better
epidemiological study and control measures of arsenic toxicity and asso-
ciated health hazards.
3 Arsenic exposure through aquatic life
The high concentrations of arsenic in fish, crabs, shrimps, bivalves, and
other seafood have also been reported (Liu et al., 2019). These food animals’
products are the primary sources of organic arsenic for humans (Feng et al.,
2020). Several arsenic-based chemicals are used in the agricultural field,
wood industry, pharmaceutical industry, etc., which go into the river,
ponds, lakes, etc., and are exposed to aquatic animals (Kumari et al., 2017;
Tuteja et al., 2021). These aquatic contaminations by arsenicals are further
increased due to the high disposal of untreated sewage (Baeyens et al., 2007),
posing widespread arsenic toxicity in aquatic organisms and bioaccumula-
tion into their bodies. According to international water quality standards,
arsenic levels above 0.010 mg/L exposure result in bioaccumulation, mainly
in the muscles, liver, and kidneys of freshwater organisms, including fish
(Cui et al., 2021). One recent report observed very high biomagnifications
up to 2.05 ± 0.30 mg Kg − 1 in freshwater fish, although water contained
very low arsenic concentrations of 0.001 to 0.003 ppm (Alvarado-Flores et
al., 2019). These findings indicate that aquatic animal-based food should be
regularly monitored for arsenic concentration irrespective of harvesting or
culture sources.
4B. KUMARI AND V. K. BHARTI
There are many reports on algae aggravated arsenic exposure to aquatic
animals since algae additively act with arsenic to increase arsenic uptake and
assimilation in aquatic animals (Byeon et al., 2021; Milan et al., 2021).
Furthermore, algae retain arsenic, so consumption of these algae and plants
further magnifies the arsenic bioaccumulation in aquatic foods (Hussain et
al., 2021). Hence, water systems having high algae and arsenic are posing
more bioaccumulation in aquatic animals. So, increased algal biomass in
ponds, lakes, etc., is directly related to increased arsenic content in the
aquatic animal compared to ponds and lakes having lesser algal mass. The
other factors are the metabolic role of organs and their relationships with
arsenic, which affect the concentration of arsenic in aquatic organisms
(Juncos et al., 2019). Therefore, aquatic animals’ products obtained from
arsenic-contaminated ponds, rivers, etc., are an important source of arsenic
to human consumers.
However, Juncos et al. (2019) reported that despite high arsenic levels
in fish do not represent any health risk to consumers. Similarly, Liu et al.
(2020) found less arsenic in Chinese mitten crabs collected from different
locations in China and said that the intake of Chinese mitten crabs had
not posed any appreciable danger to human health. These findings could
be due to specific food habits of those human populations around the
study areas and other dietary factors. Hence, more studies are required to
correlate arsenic exposure to humans through aquatic animal origin
food.
4 Arsenic exposure through plant origin food
Other routes of arsenic exposure include food from those crops irrigated
with arsenic-contaminated water, as more arsenic is absorbed into plants
irrigated with arsenic-contaminated water (Allevato et al., 2019; Kaur et al.,
2017). So, plants are considered one of the most vulnerable matrices of
short- and long-term exposure to arsenic (Navazas et al., 2019). The top
layer of soil irrigated with arsenic-contaminated water acts as an arsenic
reservoir which can affect plants for longer periods even after irrigation has
stopped (Rehman et al., 2021). The contamination of vegetables and edible
grains is considered a significant exposure pathway by which arsenic enters
the food chain of livestock and human beings (Kumar et al., 2019). So,
agricultural fields should not be irrigated with polluted water to avoid
entering arsenic into the food cycle.
It has been well known that arsenic is also toxic to plants (plant toxins),
and higher soil arsenic levels affect crop yield (Dahlawi et al., 2018). Zeng et
al. (2021) investigated 157 crop varieties, including rice, vegetables, and
corn, and their risk of arsenic accumulation in edible parts with the help of
pot and field experiments. They found that rice has greater accumulation
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 5
even in low concentrations of arsenic in soil (56.7 mg/kg) but green tender,
cabbage, rapeseed, and amaranth appeared with the risk of exceeding the
limit for arsenic when the arsenic from the soil reached 238.3 mg/kg (severe
contamination). However, they reported that corn and tubers or fruit
vegetables had the lowest arsenic content in their edible parts, and sweet
potatoes, peanuts, peppers, and potatoes had less variation in arsenic accu-
mulation among varieties of the same crop. Paddy plant (Oryza sativa L.) is
particularly effective in absorbing arsenic from the soil due to its unique
mineral utilizing mechanism (Zheng et al., 2021). So, flooded paddy fields
may cause an increased accumulation of arsenic in rice and could become a
new catastrophe for the population of Southeast Asia (Thielecke & Nugent,
2018; Yan et al., 2021). Rasheed et al. (2018) found very high inorganic
arsenic concentrations in Pakistan, which were 92.5 ± 41.88μgkg
−1
, 79.21 ±
76.42μgkg
−1
, and 116.38 ± 51.38μgkg
−1
for raw rice, cooked rice, and wheat,
respectively. Thus, in addition to these crops, barley, vegetables, fodders,
etc., can also absorb arsenic and transport it to different ranges using similar
transporters (Zheng et al., 2021). More studies are required to understand
soil-water-plant interactions on bioaccumulation of varying levels of arsenic
to plant origin food and human exposure through soil and water.
5 Arsenic exposure through livestock origin food
Large amounts of arsenic have been reported in poultry and livestock origin
foods such as milk, boiled egg yolks, egg whites, liver, and meat (Das et al.,
2021). Generally, animals are exposed to arsenic through drinking water,
feed, grass, vegetables, and other contaminated foliage. In endemic arsenic
areas, irrigation with arsenic-contaminated water leads to soil contamina-
tion and subsequent transport of arsenic to forage grown on it and then to
livestock, resulting in excessive bioaccumulation of arsenic in livestock
products (Das et al., 2021; Zubair et al., 2018). A recent report revealed
that bio-concentration of arsenic occurs more rapidly in water compared to
rice straw, and when used as fodder, it manifests itself mainly in the excreta
and tail hair of cattle (Das et al., 2021). Cow dung and tail hair are other
apparent pathways for the biotransformation of arsenic in the environment
(Rehman et al., 2021). So, arsenic-contaminated edible vegetables and grains
are believed to be the main route of arsenic exposure into the food chain of
livestock and humans (Kumar et al., 2019). Giri et al. (2016, 2020) studies on
blood minerals status in dairy cattle and water quality at high-altitude have
revealed the arsenic presence in blood, which could be due to high arsenic
levels in fodder and water sources in that region. Therefore, contaminated
fodder, grains, and drinking water are considered important sources of
arsenic exposure to livestock population and livestock origin food, e.g.
meat, milk, and eggs.
6B. KUMARI AND V. K. BHARTI
According to reports, higher estimated daily intakes of arsenic from
livestock origin food exceed the recommended safe limits (Bala et al.,
2018;). Though chronic exposure to low levels of arsenic in livestock often
shows no external signs or symptoms, although the concentration of arsenic
(or its metabolites) in the blood, fur, hooves, and urine of animals from
contaminated areas remains high (Mondal, 2017). Importantly, due to
phosphoserine units in milk casein, arsenic in milk is mainly concentrated
in casein (83%) (Das et al., 2021). The severity-adjusted margin of exposure
(SAMOE) risk thermometer was calculated by Das et al. (2021) for the most
commonly eaten foods in the region. It displayed human health risks in
precise order: drinking water> rice grains> milk> chicken> eggs> lamb,
from level 5 to level 1. Njoga et al. (2021) reported a high level of arsenic
(0.53 ± 0.10 mg/kg kidney, 0.57 ± 0.09 mg/kg liver, and 0.45 ± 0.08 mg/kg
muscle) in goat meat collected from Enuga state of Nigeria. The United
States Environmental Protection Agency (USEPA) health risk assessment
model shows that adults face a higher risk than children (Sheng et al., 2021)
because eating animal protein foods that cannot be ignored in children has a
continuing risk of serious health hazards. Hence, more studies on the
arsenic level in livestock products and their toxicity in these food animals
are essential to understand human arsenic epidemiology in affected popula-
tions to overcome the severe arsenic crisis in the human community.
6 Toxic eects of arsenic
Understanding arsenic-induced diseases and carcinogen requires
research into toxic effect mechanisms, including identifying early diag-
nostic markers and drug development. As evident from the review of
the previous section, arsenic is everywhere in the soil, water, air, and
food chain and is considered a high-risk priority pollutant in various
parts of the world, even at low concentrations. The Environmental
Protection Agency (EPA) and the WHO have established less than
0.010 mg/L of the safe limit of arsenic in drinking water. In contrast,
the National Institute for Occupational Safety Health (NIOSH) has
recommended 2 µg/m
3
of air for no more than 15 minutes as a safe
exposure limit (Marcotte et al., 2017). Therefore, a higher arsenic
concentration than the recommended limit in drinking water and
food leads to acute and chronic arsenic poisoning and adverse cellular
metabolism changes in humans and animals (Sanyal et al., 2020).
Various toxicologists, biochemists, cell biologists, and other related
scientists have observed changes in physiological function and imprecise
signaling pathways in response to arsenic (Cardoso et al., 2020; Palma-
Lara et al., 2020; Wang et al., 2019). Due to high arsenic exposure, these
physio-pathological changes affect our body metabolism, reproductive
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 7
health, embryonic development, cancer incidence, cognitive function,
aging, immunity, and our symbiotic microbiome, summarized in an
illustrative manner (Figures 1, 2, & 3).
Many toxicokinetic reports revealed that arsenic is highly toxic in its
inorganic form than the organic form, especially the trioxide form (arsenite)
than the pentoxide (arsenate) (Dahlawi et al., 2018; Li et al., 2018; Polak-
Juszczak & Szlinder-Richert, 2021; Raman et al., 2021). Total of two-thirds
of ingested inorganic arsenic absorption occurs through the gastrointestinal
tract and is distributed in the hepatic, kidney, muscle, skin, brain, and other
Figure 1. Arsenic affecting the metabolic pathways.
8B. KUMARI AND V. K. BHARTI
parts of the body (Aribam et al., 2021; Cui et al., 2020). However, the
particulate form of arsenic is absorbed through respiratory routes and
later mixed with blood, causing hemolysis and affecting oxygen transport
to cells (Figure 2). While dermal absorption is significantly less and not
causing acute toxicity, however, caution should be maintained to avoid
dermal exposure as it may pose chronic toxicity (Sohrabi et al., 2021).
Arsenic excretion from the body is very slow and primarily occurs
through the renal system and depends upon valence state, the form of
arsenic, and body fat deposition (Sharma et al., 2020). Furthermore, the
elimination of inorganic arsenic in urine can be monitored up to the first
week of possible exposure, an important tool for epidemiology and clinical
studies (Srivastava and Flora, 2020). Serum arsenic concentration is not an
effective or reliable indicator of arsenic toxicity due to the rapid removal of
arsenic from the blood to tissues (Kuivenhoven & Mason, 2021). Further,
arsenic is teratogenic, can cross the placenta, and affects fetal development
(Gangopadhyay et al., 2019).
All the absorbed arsenic is distributed to bone, hair, blood, and hepatic,
renal, and connective tissues. After that, binding with the iron part of
hemoglobin, interacts with serum and cellular minerals, sulphydryl moieties
of protein, phosphate molecules, and transcriptional factors. The metabo-
lism of inorganic arsenic progress mainly through a sequence of repetitive
reduction and oxidative methylation (Thomas, 2021), the latter mediated by
arsenic methyltransferase (CYT19) (Hayakawa et al., 2005). Arsenic-
glutathione complexes are substrates for human CYT19. These cellular
and molecular changes lead to cascades of various pathological changes,
like impairment of cellular respiration, energy metabolism, protein synth-
esis, enzyme function, the oxygen-carrying ability of erythrocytes, aerobic
respiration (Figure 3), DNA repair, cell cycle, etc. These above arsenic-
induced pathological changes are flared up with other disease conditions,
oxidative stress, and deficiency of the antioxidant system (Prabu &
Sumedha, 2014).
These pathological changes ultimately lead to increased cellular and
tissue damage reported in various studies on arsenic toxicity. There may
be relevant environmental co-exposures of arsenic with other inorganic
compounds leading to a combined effect, with questions about the
mechanisms involved. Therefore, the epidemiology of arsenic toxicity
and its clinical signs is complex and needs a multidimensional collec-
tion of information on disease history, food habits, environment, clin-
ical laboratory reports, etc. This will help correct and timely diagnose
arsenic toxicity, excluding other similar clinical conditions and proper
control and preventive measures.
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 9
7 Experimental advancement in detection of arsenic toxicity
The animal models used in studying human disease by toxicants are often
chosen because they are genetically, anatomically, and physiologically simi-
lar to humans. Therefore, bio-medical research using laboratory animals
like mice, guinea pigs, zebrafish, and fruit flies has significantly contributed
Figure 2. Arsenic absorbed by the blood cells causing hemolysis and affecting oxygen transport
to cells.
10 B. KUMARI AND V. K. BHARTI
Figure 3. Arsenic induced cellular respiration impairment and other pathological changes.
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 11
to many important scientific and medical advances (Norberg-king et al.,
2018). Short-term in-vitro tests have been helpful in screening for a wide
variety of potentially toxic compounds of arsenic, safety assessment, and
carcinogenicity testing (Tsuji et al., 2019). Additionally, animal models are
generally preferred for research work for toxicology due to their ease of
handling and testing hypotheses about how a disease develops; however, an
appropriate number of subjects should be used to test the experiment’s
outcome statistically (Smith, 2020). These animal models have currently
used in arsenic toxicological studies as indicators of human health problems
and environmental monitoring. Hence, in this section, recent studies are
reviewed to provide experimental advancement in detecting arsenic toxicity
and mechanistic information to validate other alternative testing methods in
a wide range of studies.
7.1 Utilizing sh as an aquatic animal model
Although it is widely recognized that aquatic ecosystems serve as the
ultimate reservoir for many chemicals, including arsenic (Kumari &
Ahsan, 2011b; Rand et al., 2020), water serves as the ultimate vehicle for
exposure to many toxic substances. Fish is currently a well-known biological
model for toxicological research (Boudou & Ribeyre, 2018; Denizeau, 2018)
and can be used as a study model for arsenic toxicity to elucidate the
molecular mechanism. Indeed, the establishment of zebrafish, medaka
fish, and other schools of fish is probably at the forefront of biomedical
research (Hirata & Iida, 2018). Zebrafish have great potential for mechan-
istic study for arsenic and could be used more in the future.
Many biochemical processes have been studied in fish, including hetero-
logous metabolism, DNA damage, and repair induction, membrane trans-
port, disruption of ion homeostasis, oxidative stress, metallothionein
expression, and protein stress (Huggett, 2018). The effect of foreign bodies
on specific cellular functions, particularly those of immune cells and their
response to estrogenic compounds, has also received some attention. This
review has summarized the various studies on the effect of arsenic on
different fish species, and how this information can be utilized for toxico-
logical studies is presented in Table 1.
Arsenic has a high metabolic action in accumulation in various tissues
and organs of different fish species, such as O. mykiss, S. trutta, and Danio
rerio (Juncos et al., 2019; Wang et al., 2020). The toxic effects are dose-
dependent and through various mechanisms (Mekkawy et al., 2020; Tuteja
et al., 2021), being chronic exposures at low doses to higher doses for acute
exposure. Arsenic has a good effect at an extremely low amount (1-5ppb)
(Kumari & Ghosh, 2012a), while the same concentrations are lethal in other
fish species. Acute arsenic exposure causes symptoms like increased mucus
12 B. KUMARI AND V. K. BHARTI
Table 1. Arsenic toxicological research works on fish (arranged in chronological order). As
indicating Arsenic; iAs –inorganic Arsenic; As III- Trivalent Arsenic; AsV- pentavalent Arsenic,
As2o3- Arsenic tri-oxide; NaAso2- Sodium arsenite; Cu- copper.
SN Sp. Of Fish
Arsenic/
compound Parameters References
1Cyprinus carpio As Hematological, biochemical and
histomorphological
Tuteja et al. (2021)
2Danio rerio As Alteration in stress marker and
apoptotic gene
Mondal et al. (2021)
3Onchorhincus mykiss As Oxidative stress Milan et al. (2021)
4Gambusia affinis As III Nucleotide polymorphism Park et al. (2021)
5Clarias batrachus As2O3 Behaviour and Morphology Sahu and Kumar (2021)
6Curassius auratus iAs Biotransformation and
bioaccumulation in muscles
Cui et al. (2021)
7 Twelve fish As Bioaccumulation Raman et al. (2021)
8Scyliorhinus canicula As Accumulation Marques et al (2021)
9Morone saxatilis +
Esox lucius
As Lipid and protein level of muscles Charette et al. (2021)
10 Cyprinus carpio As Apoptosis pathway Wang et al. (2021a)
11 C. harengus,+S.
fuegensis +P.
dentatus
As As speciation Polak-Juszczak and
Szlinder-Richert
(2021)
12 Group of fishes In- vitro Bio accessibility Lin et al. (2021)
13 Mystus vittatus As Serum Biochemicals Prakash and Verma
(2020)
14 Curassius auratus i As Biotransformation Cui et al. (2020)
15 Clarias garipenus As Hemato- Biochemical Mekkawy et al. (2020)
16 Oryzias melastigma As Physiological based pharmacokinetics
model
Zhang et al. (2020c)
17 Pangasianodon
hypophthalmus
As III Stress biomarker Kumar et al. (2020)
18 Danio rerio As III & As V Bioaccumulation and
Biotransformation
Wang et al. (2020)
19 Salmo trutta As As in muscles tissue Shakeri et al. (2020)
20 Clarias garipenus As Hepatopathology Moneeb et al. (2020)
21 Clarias batrachus As2O3 Biochemical Pichhode and Gaherwal
(2020)
22 Platichthys stellatus As Growth and hematology Han et al. (2019)
23 O. mykiss & S. trutta As Bioaccumulation Juncos et al. (2019)
24 C. carpio As Bioconcentration Ghadersarbazi et al.
(2019)
25 O. mykiss As As speciation and accumulation Erickson et al. (2019)
26 Six fish As As accumulation Quintela et al. (2019)
27 O. melastigma As Bioaccumulation and antioxidant
responses
Chen et al. (2019)
28 Oryzias latipes As Cytotoxic and genotoxic Sayed et al. (2019)
29 C. carpio As Cardiotoxicity Zhao et al. (2019b)
30 Channa punctatus As Genotoxicity Singh et al. (2019)
31 Mystus vittatus As Lipid metabolism Prakash and Verma
(2019)
32 Anabas testidunes As Digestive enzymes Kole et al. (2018)
33 D. rerio As Neurobehavioral alteration Dipp et al. (2018)
34 O. mykiss As Oxidative stress response Kopp et al. (2018)
35 Mugilogobius chulae As Bioaccumulation of As in benthic fish Zhang et al. (2017a)
36 Callionymus
richardsonii
As Bioaccumulation & transformation Zhang et al. (2017b)
37 Heteropneustes
fossilis
As + Cu Hepatosomatic and Gonadosomatic
index
Singh and Srivastava
(2017)
38 Channa punctatus NaAsO2 Hematology Amsath et al. (2017)
39 Labeo rohita As Biomarker of Hepatoroxicity Banerjee et al. (2017)
40 S. trutta As Bioaccumulation, oxidative stress and
Antioxidant enzymatic defence
Greani et al. (2017)
(Continued)
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 13
secretion, defects in gill epithelial, and asphyxiation. In contrast, chronic
exposure led to bioaccumulation and various histopathological changes, e.g.
renal and hepatic degeneration, focal hepatic necrosis, bile duct obstruction,
proliferation in parenchymal hepatocytes (Kumari & Yashmin, 2018;
Moneeb et al., 2020). Furthermore, the increased arsenic accumulation
induces hyperglycemia, adverse changes in other biochemical and hemato-
logical parameters, down-regulation of antioxidant defense, inhibition of
enzymatic activities, immune system dysfunction, and reduced breeding
ability in fish (Han et al., 2019; Kumari & Ahsan, 2011b; Mekkawy et al.,
2020; Prakash & Verma, 2020; Tuteja et al., 2021). Later it causes poor
growth, behavioral changes, and death in fish and other aquatic organisms.
The other pathological markers of arsenic toxicity in fish are apoptosis of
brain cells (Wang et al., 2021b), an indicator of arsenic as a neurotoxin.
Milan et al. (2021) observed that arsenic toxicity adversely affected the
quality of rainbow trout (O. mykiss) fillets by inducing oxidative stress and
affecting the level of antioxidant enzymes. In another study on Clarias
batrachus, high blood glucose and tissue glycogen levels were low in mus-
cles, liver, and brain were observed (Kumari & Ahsan, 2011a, 2011b; Kumari
et al., 2012, 2015). The recent research by Han et al. (2019) and Mekkawy et
al. (2020) also supported these findings that arsenic affects glucose levels.
The effect of arsenic on fish’s skin and their pigmentation was noticed by
Kumari et al. (2013) when fish was exposed to arsenic for a week. Han et al.
(2019) reported the toxic effects of arsenic on Platichthys stellatus (P.
stellatus), which were higher at the highest temperature. They observed a
decrease in hematological and growth parameters with increasing arsenic
concentration, while higher concentrations of the plasma components were
detected. Kumari and Ghosh (2012b) observed the cellular damage in
erythrocytes of fresh water fish. These results indicate that exposure to
arsenic in water at high water temperatures may exert more toxic effects
on growth, hematological parameters, and plasma components
The arsenic contained in bottom sediments is biologically available to
benthic fish and their food and causes bioaccumulation. The body level of
Table 1. (Continued).
SN Sp. Of Fish
Arsenic/
compound Parameters References
41 Heteropneustes
fossilis
As + Cu Hepatosomatic and Gonadosomatic
index
Singh and Srivastava
(2017)
42 Heteropneustes
fossilis
As + Cu Hepatosomatic and Gonadosomatic
index
Singh and Srivastava
(2017)
43 Oreochromis sp. As Cortisol level Thang and Phuong
(2017)
44 Channa punctatus NaAsO2 Hematology Amsath et al. (2017)
45 S. trutta As Bioaccumulation, oxidative stress and
Antioxidant enzymatic defense
Greani et al. (2017)
14 B. KUMARI AND V. K. BHARTI
arsenic is positively correlated with the concentration of arsenic in sediment
but is not significantly related to water-soluble arsenic (Zhang et al., 2017b,
2018). Although nutrition is an essential means of uptake of arsenic in
benthic fish, most studies on the toxicity and metabolism of arsenic in
benthic fish have investigated how the absorption of arsenic contained in
water through gills and its consequences on their health (Hua et al., 2017;
Juncos et al., 2019). The scarcity of data and findings suggests that more
research is needed to investigate the toxicological effects and metabolism of
arsenic in fish to identify vital signs that can be used as reliable and sensitive
biomarkers of arsenic toxicity in environmental monitoring programs.
7.2 Using rodents as a small animal model
Biologically, rats and mice are very similar to humans and undergo many
similar physiological disorders and genetic expressions, so they can be
genetically engineered to mimic any disease or human condition
(Perlman, 2016). Rats or mice can be bred to produce genetically identical
lines, and this uniformity allows us for more accurate and repeatable
experiments (Zhang et al., 2019b). Hence, rodent species (rats and mice)
are ideal animal models for experimental toxicology, including arsenic
toxicity (Rydell-Törmänen & Johnson, 2019; Smith, 2020).
Arsenic toxicity is partly due to its electrophilic nature, so when absorbed,
it readily binds to the electronic sulfhydryl groups of proteins and then
modulates the activity of the protein (Patel et al., 2020). There are various
reports that observed a positive correlation between arsenic exposure levels
with arsenic accumulation in liver and kidney tissue (Garla et al., 2021; Patel
et al., 2020). Arsenic exposure lowers the reduced glutathione (GSH),
increasing kidney and liver function test parameters and histological
abnormalities (Dkhil et al., 2020). The various histopathological changes
are necrosis, the appearance of vacuoles, and degenerative nuclear changes
in experimental animals. So, the pathology of metabolically active organs
like renal and hepatic tissues is a good experimental tool to study arsenic
toxicity. Furthermore, arsenic is also responsible for damaging the male
reproductive function in rats and mice and, after that, causing reduced
spermatogenesis, sperm counts, and motility (Liu et al., 2021; Souza et al.,
2021). It also inhibits testosterone release, the function of the testicular
enzyme, and the atrophy of male genital organs. Several experimental
studies have been performed on arsenic exposure. Its effects on various
parameters, such as physiology, biochemistry, genotoxicity, histopathology,
etc. are presented in Table 2, which could be useful in designing experiments
on arsenic toxicity for more data on regulatory and exploratory toxicology.
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 15
8 Current understanding on arsenic-induced medical conditions in
humans
Millions of people worldwide are regularly exposed to arsenic from various
sources, mainly through drinking water. The human health risk comes from
the (i) anthropogenic activities caused by unprecedented population
growth, urbanization and industrialization (Wang et al., 2019; Zhai et al.,
2017) and (ii) geogenic processes often resulting from long-term hydro-
geochemical reactions (Beiyuan et al., 2017; Singh et al., 2018). Sarret et al.
(2019) reported that in Latin America, millions of people are chronically
exposed to the high concentration of arsenic (>50 µg/L drinking water),
with extremes up to 2000 µg/L. Humans are primarily exposed to arsenic via
contaminated drinking water, while inhalation and dermal absorption are
secondary routes of exposure (Shih et al., 2019). The human health risks
were also affected by consuming plant origin food grown over the soil
irrigated with arsenic-contaminated water (Figure 4).
There is recent report on the implications of various environmental
factors in diagnosis of arsenic toxicity related diseases in humans, which
Table 2. Arsenic toxicological works on rat/mice. As indicating Arsenic; As III- Trivalent Arsenic;
AsV- pentavalent Arsenic, As2o3- Arsenic tri-oxide; Na3aso4- Sodium arsenate.
SN As exposure Parameter Organs Reference
1. As2O3 Cytotoxicity Pulpal cells Nassar et al. (2021)
2. As Biochemical and histopathological Liver and kidney Garla et al. (2021)
3. Chronic As Intestinal flora and testicular
autophagy
Intestine and testis Liu et al. (2021)
4. Chronic As Neurotoxicity Brain Abdollahzade et al.
(2021)
5. Sub-chronic As Inflammatory response Liver Dong et al. (2021)
6. Chronic As DNA methylation, genotoxicity Gonad, WBC Nava-Rivera et al. (2021)
7. Chronic As Oxidative stress Liver mitochondria Mozaffarian et al. (2021)
8. Chronic As Carcinogenicity effect Bladder Cohen et al. (2021)
9. Na3AsO4 (21
days)
Reproductive effect Testis Souza et al. (2021)
10. As (28 days) Hepatotoxicity Liver Al Aboud et al. (2021)
11. As (30 days) Histological alteration Liver Alam et al. (2021)
12. As III & As V Accumulation and Liver, kidney,
muscles
Yi et al. (2020)
13. As DNA methylation Pancreatic islets Khan et al. (2020)
14. As Reproductive effect Testis Couto-Santos et al.
(2020)
15. Na3AsO4 (28
Days)
Oxidative stress and apoptosis Liver Dkhil et al. (2020)
16. As Oxidative/Nitrosative damage RBC Panghal et al. (2020)
17. As Cardiac hypertrophy Cardiomyocites Samanta et al. (2020)
18. As III Insulin expression Pancreas islets Huang et al. (2019)
19. As Neurotoxicity Brain Chandravanshi et al.
(2019)
20. As (Chronic) Sex dependant pathogenic effect Kidney Zhang et al. (2019b)
21. As (40 days) Glucose nephrosis Renal tissue Sertorio et al. (2019)
22. As (30 days) Glucose metabolism Hematology Rahman et al. (2018)
23. As (28 Days) Oxidative stress Liver Mahajan et al. (2018)
24. As (56 days) Fertility effects Gonads Lima et al (2018)
16 B. KUMARI AND V. K. BHARTI
are highly relevant to public health in many countries, e.g. keratosis, hyper-
keratosis, melanosis, black foot disease, peripheral vascular disease, leuco-
melanosis, dorsum, nonpetting edema, and gangrene (Altowayti et al.,
2021). Keratosis and melanosis are the most common manifestations in
affected people (Singh et al., 2021). Now a day, arsenic toxicity has become a
global public health problem because of its association with various cancers
and other pathological effects of vital organs through cytotoxicity and
genotoxicity mechanism (Bjørklund et al., 2018; Tchounwou et al., 2019;
Tsuji et al., 2021; Zhou & Xi, 2018). Exposure to arsenic can lead to various
systemic diseases like hepatic, renal, and neuronal systems. Several experi-
mental and clinical studies brought considerable evidence, which indicates
that arsenic adversely affects the antioxidant defense system, apoptosis, and
other physio-biochemical changes, as shown in Figure 2 (Flora, 2011; Giri et
al., 2016) however, its specific mechanism is poorly understood. Recently,
arsenic exposure has been implicated in the incidence of various skin
cancer, gall-bladder, lung, and hepatocellular carcinoma (Abdollahzade et
al., 2021; Fujioka et al., 2020). The estimated lethal dose of inorganic arsenic
for humans is 0.6 mg/kg, which leads to death within 1–4 days of ingestion
(Kuivenhoven & Mason, 2021).
However, long-term exposure to inorganic arsenic can cause various
dysfunctions of vital organ systems such as the digestive system, respira-
tory system, cardiovascular system, hematopoietic system, endocrine sys-
tem, kidney system, nervous system and reproductive system, and
eventually lead to cancer (Ahmad et al., 2021; Palma-Lara et al., 2020).
Inhalation
Occupational
Arsenic
Air
Grains/ Pulses / Oils/
Fruits/ Vegetables etc.
Water Soil
Human
Contact
Food/ Drink
Terrestrial
Animal
products
Plant
products
Aquatic
Milk, Meat, Fish,
Eggs, etc.
Figure 4. Various routes of exposure of arsenic to human.
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 17
The various experimental and clinical kinds of research brought numer-
ous pieces of evidence and are presented in Table 3. Despite the magni-
tude of this potentially fatal toxicity, there is no effective treatment for
the disease, so affected patients may not recover even after the restoration
of arsenic-contaminated water. There is peripheral neuropathy that may
disappear with As exposure cessation (Kuivenhoven & Mason, 2021).
However, research data on absorption, distribution, metabolism, and
excretion (ADME) of arsenic species/compounds are lacking. Therefore,
more studies are required on how age, sex, food habits, co-morbidity,
etc., affect human arsenic toxicity.
9 The intervention of biotechnology and nanotechnology in arsenic
control measures
The efficient detection and removal of arsenic are crucial for effective
arsenic control measures in the community. In recent decades, many che-
mical methods and instrumental techniques, using e.g. oxidation,
Table 3. Arsenic toxicity to human. As indicating arsenic; As2o3- arsenic tri-oxide; NRF2- Nuclear
related Factor-2; DNA- Deoxyribonucleic acid; DNMTs-DNA methyltransferases; miRNA- Micro
Ribonucleic acid; mRNA- Messenger RNA; KRAS- Kirsten rat sarcoma virus; ROS- Reactive oxygen
species; NF-kB-nuclear kappa- light- chain- enhancer of activated B cells; PBMC- Peripheral
mononuclear blood cells; ROR- Regulator of reprogramming.
S.N. Affected organs Analytical methods Reference
1 Bladder/Kidney cancer DNA damage Tsai et al. (2021)
2 Cancer risk assessment Soil water analysis Orosun (2021)
3 Dermal/Oral hazards As concentration in ground water Patel et al. (2021)
4 Carcinogenesis NRF2- mediated transcription and
epigenetic regulator
Bi et al. (2021)
5 Skin Modification of DNMTs gene Chanda et al. (2021)
6 Breast cancer cell Cell proliferation and gene expression Kim et al. (2021)
7 Skin cancer mi RNA and mRNA expression profile Banerjee et al. (2021)
8 Gall bladder cancer Immunological marker Singh et al. (2021)
9 Lung cancer cell In vivo & In Vitro Cell cycle genes Sun et al. (2021)
10 Prostate cancer KRAS-retroviral fusion transcripts and gene
amplification
Merrick et al. (2020)
11 Bladder cancer As level in drinking water & mortality rate López-Carrillo et al.
(2020)
12 Bladder cancer Clinico-pathological characteristics Fernández et al.
(2020)
13 Lung cancer As induced transformation Chang et al. (2020)
14 Prostate cancer ROS in the cytotoxicity of As2O3. Doroshow and Gaur
(2020)
15 Breast cancer Attenuation of NF-kB signaling pathway Nasrollahzadeh et al.
(2020)
16 Skin cancer immunological dysfunction and
Histopathological analysis
Zeng and Zhang
(2020)
17 Carcinogenesis PBMC gene expression profile Chen et al. (2020)
18 Growth factor, cancer related
disease pathways
Transcriptome responses in blood Rehman et al. (2020)
19 Liver cancer cell Resistance of As2O3 by Long non coding
RNA ROR
Li et al. (2020)
20 Breast cancer Immuno-histo-chemical López et al. (2020)
18 B. KUMARI AND V. K. BHARTI
coagulation, adsorption, electrocoagulation, etc., have been developed for
arsenic detection and removal. However, these conventional and chemical
approaches allow the identification of arsenic in simple matrices; further,
these methods have low sensitivity, detection limit, and high cost-
maintenance (Xu et al., 2020). Therefore, studies on arsenic removal using
biotechnological and nanotechnological tools are gaining pace (Mostafa &
Hoinkis, 2012; Verma et al., 2020).
Biosensors contain a major promise for the rapid detection of arsenic
(Mao et al., 2020), especially the nanomaterials-based aptamer sensors that
have drawn considerable attention due to their simplicity, high sensitivity,
and speedy action. For this reason, in recent years, there has been active
research on developing nanomaterials-based biosensors to detect inorganic
arsenic (Table 4). A study by Rosales et al. (2020) reported that a few-layer of
Mxene nano-sheets are capable of efficiently oxidizing the highly toxic As
(III) to the less harmful As (V) and further excellent absorption capacity for
both species [approximately 44% for (III) and 50% for (V)]. So, these Mxene
nano-sheets layers could be a promising candidate for effective arsenic
removal using adsorption and photo-oxidation effect. Polymer-, polymer
composite-, and polymer nanocomposite-based nanofilter membranes of 1-
10 nm pore size are also promising effective tools of arsenic removal from
water (Siddique et al., 2020). These membranes are suitable for removing
Table 4. Detection of arsenic through nano-particles. Au indicates gold; Nps- Nanoparticles;
AgNps- silver nanoparticles; Cu: Copper; SNPs- Silica nanoparticles; Pbs- Lead; SERS- surface-
enhanced raman spectroscopy.
SN Nano Particle Detection methods Reference
1 Au NPs SERS Li et al. (2021)
2 Au NPs Colorimetric assay Pu et al. (2021)
3 Au NPs Rapid colorimetric Zheng et al. (2021)
4 Au NPs Voltammetric detection Sullivan et al. (2021)
5 Au NPs Electrochemical detection Sedki et al. (2021)
6 Au NPs Ultra-sensitive Electrochemical detection Jijana et al. (2021)
7 Au NPs Selective and sensitive colorimetric Harisha et al. (2021)
8 Au NPs Absorption based detection Karakuzu et al. (2021)
9 Au NPS Voltammetric analysis Salunke et al. (2021)
10 Cu2O-Ag NPs Chemometric SERS sensor Barimah et al. (2021)
11 Prussian Blue NPs Fluorescence Sensing Pandey et al. (2021)
12 Au-Cu Nps Electrochemical sensing Fuletra et al. (2021)
13 Mn3O4 NPS Colorimetric chemosensor Wang et al. (2021a)
14 AuNPs Voltammetric analysis Bu et al. (2020)
15 Au NPs Colorimetric Shrivas et al. (2020)
16 Zirconia NPs Absorption based detection Tokuyama et al. (2020)
17 Au-Cu NPs Electrochemical aptanser Mushiana et al. (2019)
18 Ag NPs Colorimetric detection Boruah et al. (2019)
19 Au NPs Electrochemical Gu et al. (2018)
20 Au NPs Colorimetric detection Yang et al. (2018)
21 Ag NPs Electrochemical detection Sonkoue et al. (2018)
22 S NPs Sensor based Taghdisi et al. (2018)
23 Ag Nps Multimodal assay Wen et al. (2018)
24 Pbs Nps Absorption based Priyanka et al. (2017)
25 AuNPs Electrochemical detection Idris et al. (2017)
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 19
multivalent ions from monovalent ions and can be adjusted at different
permeability of water and arsenic rejection, hence superior for water filtra-
tion. Nowadays, there are several nanofilter membranes are commercially
available (Siddique et al., 2020; Uddin et al., 2007). Nanometals, nanometal
oxides, magnetic nanoparticles, etc., are other composite materials that can
be integrated in existing water technologies for arsenic removal from water.
Among them, nano iron hydroxides are excellent abrasion-resistant adsor-
bents with a large specific surface area, enabling high arsenic adsorption
from contaminated water (Aredes et al., 2012). ArsenXnp (SolmeteX Inc.,
Philadelphia, PA, USA) is a commercially available hybrid of iron oxide
nanoparticles and polymers for arsenic removal. However, standards and
guidelines on nanomaterials-based water filtration technologies are required
for an easy decision for their application.
The role of microorganisms in the degradation and detoxification of
arsenic-contaminated lands and water areas has become important in recent
years under the process of bioremediation (Patel et al., 2021). Some of the
research findings have described the mechanisms of arsenic detoxification
in microalgae, including cell surface absorption, intracellular As (III) oxida-
tion, As (V) reduction and thiol (−SH) complexation, and vacuole seques-
tration (Huang et al., 2021). Hence, biological treatment of arsenic-
contaminated water with aquatic algae should be carried out, considering
the effects on the entire ecosystem. These algae enhance arsenic bioaccu-
mulation in aquatic animals, so algal removal is good for controlling arsenic
accumulation in aquatic animal origin food (Hussain et al., 2021).
Therefore, a multidisciplinary approach should be considered for bioreme-
diation considering their cross-taxon integrating behavioural and other
effects of arsenic toxicity, which also need restoration of aquatic and terres-
trial ecosystems. Recent studies on microbial biotechnology revealed that
various bacteria and fungi could be used for arsenic elimination from soil
and water (Upadhyay et al., 2018). Some of the species from pseudomonas,
aeromonas, ancylobacter, rhodoferax genera of soil bacteria utilize arsenate
and have arsenic metabolizing activities. Therefore, these microbial con-
sortia can be used in soil and water treatment for arsenic removal.
10 New therapeutic agents for controlling arsenic toxicity
In recent years, most in-vivo and in-vitro studies have shown that ROS
generation, oxidative stress, DNA damage, mutations, and cytotoxicity are
the important molecular changes in arsenic toxicity (Firdaus et al., 2018;
Perker et al., 2019; Rehman et al., 2020; Wu et al., 2019). This means that
arsenic induces oxidative stresses and cytotoxicity in different cell lines
through ROS generation, which triggers NADPH oxidation and leads to
adverse cellular changes. Glutathione is an important antioxidant that
20 B. KUMARI AND V. K. BHARTI
maintains the antioxidant/pro-oxidizing balance and plays a vital role in
protecting cells from oxidative stress (Rao et al., 2017). Hence, controlling
oxidative stress and up-regulation of body antioxidant defense is an impor-
tant strategy for controlling and treating arsenic toxicity.
Plant extract is rich in antioxidant content due to the presence of various
flavonoids, alkaloids, trace minerals, etc., which could be helpful to antiox-
idant-based therapeutic agents in arsenic toxicity. Mohajeri et al. (2017)
reported curcumin has beneficial effects against arsenic-induced toxicity
without any side effects. Another study on the extract of Ginkgo biloba
(GBE), obtained from leaves contains ginkgo flavone glycosides, terpene
lactones, and other active components, which has shown beneficial effects
through modulating antioxidant functions, anti-inflammatory effects, inhi-
bition of platelet aggregation, and immune regulation (Zeng et al., 2021).
Xia et al. (2020) observed that GBE has consequences for arsenicosis
through the law of balance of pro-inflammatory and anti-inflammatory T
cells, whereas the pathogenesis of arsenicosis induces an imbalance of pro-
inflammatory and anti-inflammatory T cells. Yao et al. (2017) found that
GBE can reduce the accumulation of arsenic in the liver and liver injury
through ameliorating lipid peroxidation in rats. Recently, several reports
(Perker et al., 2019; Rahman et al., 2018; Rehman et al., 2020; Susan et al.,
2019) showed that Natural bioactive compounds exhibit antioxidant prop-
erties and effectively mitigate arsenic-induced toxicity by modulating the
antioxidant defense system. These studies advocate that antioxidant treat-
ment is comparatively safe and cost-efficient preventive therapeutics in
arsenic toxicity and other human diseases and disorders. Numerous studies
on different therapeutic materials to control arsenic toxicity are reviewed in
detail and summarized in Table 5.
Although chelating therapy is also considered an effective and well-
known treatment of arsenic toxicity, however, it has shown several
unwanted effects due to the limited safety of chelating agents (Nurchi et
al., 2020). Further, it is suggested that arsenic is incorporated by cells in
mammals and other organisms, after which it can be bio-transformed, and
its metabolites also exert toxic effects (Hirano, 2020). Thus, the inhibition of
bio-transformation of arsenic should be considered a prime pathway for
arsenic bio-inactivation and reduction of arsenic toxicity in the body. This
would be a vital point for developing many future therapeutic agents.
Recently, nano metal oxides have been increasingly used to solve this
global problem in various biomedical applications. The nanomaterials like
liposomes, polymeric micelles, and phospholipid complexes have emerged
as a few promising therapeutic tools for reducing arsenic toxicity (Edis et al.,
2021). These materials have a large surface area, specificity for their custom
substrates, and different shapes. Several metal oxide nanoparticles (NPs)
such as iron (hydro) oxides, aluminium oxide, titanium dioxide, zinc oxides,
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 21
and copper oxide have been used as nano adsorbents to remove heavy
metals from various sources (Pillai & Dharaskar, 2020). Naqvi et al. (2020)
reported a better protective effect of solid lipid nanoparticles loaded with
monoisoamyl-2,3-dimercaptosuccinic acid (NanoMiADMSA) compared to
its volume of MiADMSA in the treatment of neurological and other bio-
chemical abnormalities induced by arsenic. The results suggested that the
size of NanoMiADMSA ranged between 100 and 120 nm and has better
chelating properties than MiADMSA in bulk. These findings encourage
future investigation on identifying effective nanomedicine in arsenic toxi-
city having higher efficacy and safety.
Table 5. Various therapeutic agents of arsenic toxicity. DNA- Deoxyribosenucleic acid; MiADMSA
– Monoisoamyl 2,3 dimercaptosuccinic acid; Chk1– Checkpoint kinase 1; p53 −53 Kilodalpton
protein product-; H3K18- acetylation of histone H3 at the lysine-18 residue; JHDM2A- JmjC-
domain-containing histone demethylase 2A; ERCC1 – Excision repair cross complementation
group 1) and ERCC2- Excision repair cross complementation group 2).
SN Treatment agent Methods References
1 N-Acetylcysteine (NAC) Density Functional theory Das et al. (2021)
2 Antibiotic cefoperazone Blood chemistry Roggenbeck et
al. (2021)
3Ginkgo biloba extract DNA damage assay Ding et al
(2021)
4Rosa roxburghii Tratt (RRT) hepatic oxidative damage assay Xu et al. (2021)
5Ginkgo biloba extract Skin damage assay Zheng et al.
(2021)
6 melatonin DNA damage, inflammation and apoptosis
assay
Abdollahzade
et al. (2021)
7 Lycopene Kidney marker damage assay Ramadan et al.
(2021)
8 Epididymal vascular endothelial
growth factor (VEGF)
Gene therapy Dai and Gao
(2021)
9 Selenium Assessment of oxidative damage and
neurotransmitter-related parameters
Ren et al (2021)
10 Ginkgo biloba extract Chk1-p53 pathway assessment Yang et al.
(2021)
11 Spirulina and vitamin E haematological parameters Khatun et al.
(2020)
12 acetylated histone H3K18 Chromatin immunoprecipitation (ChIP-
qPCR) analysis
Zhang et al.
(2020a)
13 Histone demethylase JHDM2A DNA damage repair pathway Zhang et al.
(2020b)
14 Monoisoamyl dimercaptosuccinic acid
(MiADMSA)
Chelation therapy Sau et al. (2020)
15 BAL (dimercaptopropanol), DMPS
(dimercapto-propane sulfonate)
Chelation therapy Nurchi et al.
(2020)
16 Turmeric and Passiflora foetida powder Biochemical, haematological, antioxidant
parameters
Maji et al.
(2020)
17 Nano curcumin & nano MiADMSA Chelation therapy Kushwaha et al.
(2018)
18 Gingko biloba Liver function indices Yao et al. (2017)
19 Hypermethylation of ERCC1 and ERCC2 Methylight and bisulfite sequencing (BSP)
assays
Zhang et al.
(2017a)
20 2,3-dimercaptopropane −1-sulphonate
(DMPS)
Chelation therapy Lu et al. (2017)
22 B. KUMARI AND V. K. BHARTI
11 Future research and policy guidelines for eective control of
arsenic toxicity
With the current understanding of the mechanistic view of arsenic toxicity,
it is concluded that multifaceted research interventions are required for the
development of sustainable technology and the framing of policy guidelines;
among them, the following are some critical priority areas:
(i) Experimental toxicological studies in different species considering
their developmental stages, age, sex, habitats, climates, and fat-
muscle body mass index for developing species signature of arsenic
toxicity.
(ii) Histopathology of active metabolic organs like liver, kidney, skin,
brain, lungs, and gonads for ascertaining tissues and cellular toxi-
cities, metabolomics for developing biomarker index of arsenic
toxicity.
(iii) Identification of biochemical and molecular biomarkers of acute,
sub-acute, and chronic toxicity for developing severity, endemic,
etc., the status of arsenic exposure.
(iv) Immunohistochemistry to understand initiation, promotion, and
progression of arsenic-induced cancer;
(v) Ameliorative measures targeting various sources of arsenic, e.g.
water arsenic removal, food fortification, chelating and neutraliza-
tion techniques, nutraceuticals for animals and human, and specific
community-based health preventive measures in endemic areas.
(vi) Intervention of biotechnology and nanotechnology tools for arsenic
detection and their removal from various sources.
(vii) Epidemiological studies at an in-country and regional level along
with other health programs for developing large-scale preventive
strategies.
(viii) Evaluation of genetic and epigenetic factors affecting arsenic-
induced health hazards to understand their epidemiology in differ-
ent areas and populations.
(ix) Studies on the association of reproductive, embryonic develop-
ment, and metabolic diseases in endemic arsenic areas to under-
stand pathophysiology and differential diagnosis of arsenic-induced
diseases.
(x) Regulatory studies and monitoring of arsenic and other metals in
water, soil, air, and food system at the community level.
These are some important research areas where immediate interventions are
required to develop better control and preventive strategies for arsenic toxicity.
BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 23
12 Summary
In recent days, the increase of arsenic in the human body poses a serious
global health risk to the human population. Extensive studies indicated
that arsenic exposure has become common in various food chains, and
therefore widespread toxicity is reported in multiple species of livestock,
aquatic animals, and human beings. So, arsenic epidemiology should
focus on the dominance of different direct and indirect sources in the
affected areas, and then only control measures and implementation of
public health policy could be successful. Various research reports
revealed that arsenic is a known human carcinogen and interacts with
various cellular molecules. Additionally, experimental research on
arsenic toxicokinetics, toxicodynamics, and mode of toxic action are
high priority areas to address arsenic toxicity and related disease condi-
tions. Nanotechnology and biotechnology-based detection measures
have proven good and promising in control measures of arsenic toxicity.
Hence, extensive regular epidemiological studies on arsenic-induced
toxicity are extremely important for identifying exposure sources and
choosing suitable detection methods and therapeutic strategies.
Disclosure statement
Both authors have read the journal’s policy and declare that they have no competing
interests that might be perceived to influence the content of this article. Authors also
declare that they have no proprietary, financial, professional, or any other personal
interest of any nature or kind in any product or services and company that could be
construed or considered a potential conflict of interest that might have influenced views
expressed in this manuscript. Further, the opinions expressed in this article are those of
the authors and do not necessarily represent the official views of their affiliated
institutions.
Author contributions
All the authors contributed equally to this work and met authorship criteria based on the
ICMJE guidelines. After literature search and analysis, BK and VKB have conceived the
ideas, designed and wrote the initial draft. Both authors (BK, VKB) have reviewed and
accepted the final version of the paper before submission. No writing assistance was utilized
in the production of this manuscript.
Funding
The author(s) reported there is no funding associated with the work featured in this article.
24 B. KUMARI AND V. K. BHARTI
ORCID
Bibha Kumari http://orcid.org/0000-0002-4898-0138
Vijay K. Bharti http://orcid.org/0000-0001-6072-8704
Data availability statement
This article does not contain any new data collected from experiments conducted by any of the
authors. This review’s research and associated data are based upon the information available in
the peer-reviewed scientific publications and or public domain that can be publicly accessed.
The citations and or web links details are provided in the bibliography list of this publication.
Ethical approval and compliance with ethical standards
This article does not hold any studies with human or animal subjects performed by any of
the authors. Hence, no ethical approval for animal and human experimentation was needed
for this work. No primary data have been reported in this study.
Pre - print availability
The pre-print of an earlier version of this manuscript is available on Research Square as
entitled ‘Environmental toxicology of arsenic: Current understanding of toxicity,
detection, and remedial strategy’. DOI :https://doi.org/10.21203/rs.3.rs-1351038/v1.
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