Abstract
Emerging
occupational and environmental health problems are currently major priorities
that need to be tackled along with existing traditional public health
problems like communicable diseases, malnutrition, poor environmental
sanitation, and inadequate medical facilities. Although toxicologists have
expressed deep concern and have prioritized these issues, public awareness,
toxicological databases, suitable early diagnosis, specific preventive and
therapeutic measures are some of the major issues which requires major
attention. Among various strategies which may address these issues include
use of modern technologies, amenities, and resources for detecting toxic
substances or their derivatives at nanogram (ng) levels.These steps will be
important to specifically quantify various toxicants and facilitate future research
in order to (i) safe and specific therapeutic or preventive measures and (ii)
early diagnosis/ biomarkers to examine effects at the molecular level. It has
recently been realized that most of the diseases related to toxicants are
incurable; therefore, the best course of action in dealing with them is
prevention (Flora, 2008).
Heavy
metal induced toxicity and its associated complications have become a major
issue in the medical world. Heavy metals accumulation in the environment and
their associated health hazards still need to be extensively studied as there
are many unanswered questions like early diagnosis and specific treatment
particularly in case of chronic exposure. Exposure to heavy metals (like
lead, cadmium and mercury) or metalloids like arsenic come from a variety of
sources, including gasoline, fertilizers, paints, sewage sludge, ground
water, wastewater irrigation, pesticides, coal burning residues, domestic and
industrial effluents, and petrochemicals. Heavy metals are characteristic representatives
of toxic substances which are not biodegradable, enter the food chain, and
accumulate in living systems. Increased concentrations and accumulation of
Heavy metals can cause severely damaging effects and associated complications
in living organisms and can even lead to the death of the organism. Heavy
metals toxicity generally lessens energy levels and can severely damage and
decrease the function of the brain, kidney, lungs, and liver. Frequent and
continuous exposure to heavy metals or metalloids leads to physical,
muscular, and neurological degeneration, emulating disorders such as
Parkinson's disease, Alzheimer's disease, Wilson's disease, muscular
dystrophy, and multiple sclerosis etc. Exposure to lead toxicity causes ionic
and oxidative stress conditions in living organisms, occurring due to an
imbalance in free radical production and antioxidant levels which normally
neutralize or detoxify the reactive intermediates. Antioxidants can protect
against free radical mediated damage, providing its reducing equivalents from
sulphur groups of cysteine to reactive oxygen species (ROS) and making them
stable (Flora et al., 2013). Elevated levels of ROS damages the cells
and cellular components, which results in a harassed condition at the
cellular level. The ionic mechanism of lead or arsenic toxicity also causes
substantial deviations in apoptosis, ionic transportation, cell adhesion,
inter- and intra-cellular signalling, protein folding and maturation, the
release of neurotransmitters, and enzyme regulation (Pachauri et al.,
2013).
Arsenic
contamination in ground water in the Ganga-Brahmaputra fluvial plains in
India and Padma-Meghna fluvial plains in Bangladesh has been found to have a
huge impact on human health and its consequences have been reported as the
world's biggest natural ground water calamities (Flora, 2011). In India, West
Bengal, Jharkhand, Bihar, Uttar Pradesh in the flood plains of the Ganga,
Assam and Manipur in the flood plains of the Brahmaputra and Imphal rivers
Rajnandgaon village in Chattisgarh state have been reported to be affected by
arsenic contamination in ground water (National Rural Drinking Water Program,
2013); The maximum permissible limit of arsenic recommend by WHO in potable
safe drinking water is 0.01 mg l-1; however, in India the
acceptable level is 0.05 mg l-1 due to the absence of potable
drinking water. Subsequent to its high level in drinking water arsenic gains
it's entry in our body, leading to chronic multi system disorder known as
arsenicosis.
The
scope of arsenic contamination of drinking water, and the threat it poses to
global health, is much more widespread than previously believed. As many as
140 million people worldwide may have been exposed to drinking water with
arsenic contamination levels higher than the World Health Organization's
(WHO) provisional guideline of 10 μg l-1. Arsenic poisoning is
worst in Bangladesh, where an estimated 35-77 million people are at risk from
drinking groundwater contaminated by naturally-occurring arsenic. Another 6
million are at risk in West Bengal, India. However, numerous cases have now
been reported from China, Chile, Cambodia, Laos, Burma, Pakistan, Nepal,
Vietnam, Taiwan, Iran, Argentina, Finland, the United States and several
other Indian States. Groundwater in Australia are also known to be
contaminated with arsenic, and the landscape contains 'hot spots' from its
former widespread use as an insecticide to protect livestock and crops nearly
a century ago. Researchers are currently working to understand the pathology
and various approaches for the management of arsenic poisoning worldwide.
However, there are very few studies currently being done or in progress as
far management of arsenic poisoning are concerned. With all the available
literature it has been proved that arsenic is a potent toxic substance for
which safe and specific counter measures are required to overcome its
poisoning. Chelation therapy has been suggested treatment of arsenic
poisoning (Flora and Pachauri, 2010). Several chelating drugs have been
studied to understand the chelation of arsenic but they have been compromised
with shortcomings/ limitation. These drugs include British anti-lewisite
(BAL): It is a lipophilic drug which can be distributed both intra and
extracelluarly. It has been used since World War II. It contains two
sulfhydryl groups to form a stable non-toxic five membered ring with arsenic.
Due to its instability and ability to oxidize soon it is difficult to store.
One of its major drawbacks is the significant elevation of brain lead and
arsenic level due its rapid mobilization. Other shortcomings include allergic
conditions, extremely painful intramuscular injection. D-Penicillamine - It
is a penicillin degrading product which has been used as a chelator
(particularly against lead and copper) since long. It has the ability to
chelate arsenic too. Studies have found that it is effective against acute
arsenic toxicity. It also possesses many adverse effects such as nausea,
vomiting, hematuria, rashes etc. which has led to the development of thiol
chelators such as DMSA and DMPS. Meso-2, 3-Dimercaptosuccinic Acid (Succimer,
DMSA): It is an orally active and less toxic analogue of dimercaprol. Its
major drawback has been its extracellular distribution which makes it
incapable to remove arsenic from its intracellular sites. Other side effect
includes skin reaction, elevated liver enzymes, gastrointestinal discomfort
etc., 2, 3-Dimercaptopropane-1-Sulfonic Acid (DMPS): It is a sodium salt of
2, 3 dimercaptopropane-1-sulfonic acid, and a derivative of BAL. DMPS is
water soluble. DMPS has a highly specific effect on MMA metabolism or urinary
excretion in humans, although the mechanism by which DMPS reduces arsenic
burden is not fully established. Minor symptoms like headache, fatigue, nausea,
taste impairment, pruritus, and rash have been observed due to it.
The
side effects or shortcomings associated with conventional chelating drugs
have led researchers to develop less toxic analogue. Hydrophilic chelators
like meso-2, 3-dimercapto succinic acid effectively promote renal metal
excretion, but as indicated above their ability to access intracellular
metals is weak. Monoisoamyl 2,3-Dimercaptosuccinic acid (MiADMSA) was
developed by our group as a potential drug candidate that is still in its developmental
phase. Studies till date highlight the efficacy and safety of new molecule in
chronic arsenic toxicity in experimental animals. The brain targeted
polymeric based nanoparticles loaded with MiADMSA could also be more
effective than bulk MiADMSA alone and reduce the required dose of chelating
agent (Naqvi et al., 2020). Another future approach to tackle the issue of
developing a safe and effective antidotes could be surface modification of
MiADMSA loaded polymeric nanoparticles which may provide an excellent
strategy to overcome the blood brain barrier and hence, can be used further
to enhance the therapeutic efficacy of MiADMSA in reducing the arsenic burden
from the brain and prevent the impairment of cognitive function.
MiADMSA
is being a newer chelating agent for the chronic arsenic poisoning treatment
and currently in clinical phase I study (Flora et al., 2022). The novelty of
the proposed work is to reduce the dose of MiADMSA utilizing
nanotechnological approach and hence, reducing the undesirable side effects
of MiADMSA. Elimination half-life of MiADMSA was found to be approximately 4
hr post oral administration in rats (Flora et al., 2012). The drug candidates
having the elimination half-life of 2-8 hr are ideal candidate for the design
of sustained release drug products. The release of MiADMSA can be extended by
its encapsulation in the polymeric nanoparticles. The prolonged release of
MiADMSA from nanoparticles could be beneficial in the treatment of chronic
arsenic poisoning as it requires long term treatment. Thus, it will be
interesting to develop and multifunctional polymeric nanoparticles loaded
with MiADMSA to improve its therapeutic efficacy for improved treatment of
chronic arsenic poisoning and therapeutic monitoring (Yadav and Flora, 2016).
Ayurvedic
therapies is also an area which need to be explored against toxicity of
metals. It may provide relief with reduced adverse effects, even after
prolonged administration. In Ayurvedic medicine, ingredients of natural
origin, including whole plants or certain portions of the plant, animal
sources, and minerals, are used for therapeutic purposes as medicines, both
alone and in combination. Nowadays, alternative medicines are being used
extensively to reduce heavy metal-induced toxicity (Flora, 2011, Flora et
al., 2022). The aim of suggesting phytomedicine as alternative systems of
medicine can help to neutralize and overcome metal/ metalloid induced
toxicity. Studies using animal models (mice, rats, and hamsters), cell
culture studies using various cell lines, in vitro studies, including docking
studies and bioinformatics tools, and human clinical trials will help to
understand the mechanisms and associated complications.
In
brief, I suggest few potential research areas which include but are not
limited to; studying mechanisms of action of phytoconstituents to neutralize
metal-induced toxicity, understanding the pathogenesis and alternative
therapy of heavy metal toxicity, heavy metal/ metalloid toxicity and
diagnosis using molecular, genetic, and biochemical biomarkers of oxidative
stress-related diseases, including Alzheimer's disease, Parkinson's disease,
multiple sclerosis, and muscular dystrophy, environmental and occupational
exposure to heavy metals, risk assessment, and dietary modifications to
reduce toxicity, phytochemicals in heavy metal toxicity and therapy, animal
models, cell cultures, and bioinformatic tools to study and understand the
toxicity and healing mechanisms, neurotoxicity, nephrotoxicity,
hepatotoxicity and lung toxicity of heavy metals and possible remedies.
Finally,
few words about Journal of Environment Biology. It has been an honour
to be associated with this journal for last 30 years as Member Editorial
Board, Reviewer and as an author. I have seen its journey from a regional
journal to an international journal of repute. This would not have possible
but for the passionate and single handed efforts of Professor R.C. Dalela,
the Editor-in-Chief of the journal. The popularity of the journal has grown
manifold and it's so heartening to see number of interesting articles being
published from researchers abroad. The impact factor of the journal has shown
a steady upward growth but it is still need to travel miles before it achieve
the rank among the top 10 in the area of Environmental Biology. I feel we
need to have more special issues and minimum 2-3 review article every issue
by experts of varied fields. We also need to consider a separate section on
Toxicology, phytomedicine/ phyto-toxicology, in addition to emphasis on
environment pollution.
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