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Molecular Mechanism of Fluoride Induced Oxidative Stress and Its Possible

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Research and Reviews: A Journal of Toxicology
Volume 3, Issue 2, ISSN: 2231- 3834
__________________________________________________________________________________________

Molecular Mechanism of Fluoride Induced Oxidative

Stress and Its Possible Reversal by Chelation Therapy
S. Thangapandiyan, S. Miltonprabu*
Faculty of Science, Annamalai University, Annamalai Nagar, Tamilnadu, India

Abstract
Fluorine (Fl) a member of the halogen family is the most electronegative and reactive of all
the elements of Periodic table. Chronic and acute exposures of fluoride leads to
cardiovascular disease (hypertension and atherosclerosis), neurological disorders,
gastrointestinal disturbances, liver disease, renal disease, reproductive effects, other health
disorders and also affects the antioxidant system in the body. Furthermore, reactive oxygen
species (ROS)-mediated oxidative damage is a common malady in fluoride pathogenesis.
Formation of free radical due to cascade mechanism combined with glutathione-depleting
agents increases the oxidation process in the cells and cause damage. Formation of
ROS/RNS including peroxyl radicals (ROO•) the superoxide radical, singlet oxygen and
hydroxyl radical (OH•) via the Fenton reaction direct DNA damages when both humans
and animals are exposed to fluoride. In addition, fluoride induces the formation of oxidized
lipids which in turn generate several bioactive molecules (ROS, peroxides and
isoprostanes), of which aldehydes [malondialdehyde (MDA) and 4-hydroxy-nonenal
(HNE)] are the major end products. Various synthetic antidotes were recommended for the
present study such as DMSA (meso-2, 3-dimercaptosuccinic acid), and BAL (2, 3-
dimercapto-1-propanol) for fluoride toxicity. However, it may cause side effect when used
alone. Recently, phyto-antidotes from plants or vegetables like flavonoid and polyphenols
have played a major role in Fl induced oxidative stress related diseases. In this thought we
included the various phytochemical used till now for mitigating fluoride induced toxicity in
different organs. Eventually, this review suggests that combination with natural and
synthetic antidotes revealed a good strategy for chelating fluoride toxicity.

Keywords: Toxicity, oxidative stress, glutathione (GSH), chelation therapy

*Author for Correspondence: E-mail smprabu73@gmail.com, +91 9842325222

INTRODUCTION fluorides, representing approximately 0.06–

Fluorine is the ninth element on the periodic
table. It is the lightest and most reactive
member of the halogen family. It has an
atomic weight of 18.9984. The physical and
chemical property of fluorine has been given
in Table 1. Fluorine reacts with other elements
to produce ionic compounds such as hydrogen
fluoride (HF), sodium fluoride (NaF),
aluminium fluoride (AlF) and many others.
When these ionic compounds are dissolved in
water, the ions dissociate and fluorine is
present as the negatively charged fluoride ion.
It is derived from the element fluorine, a gas
that never occurs in a free state in nature.
Fluoride is abundant in the environment and
exists as minerals in rocks and soil. Elemental
fluorine does not exist in nature but forms
inorganic and organic compounds called
0.09% of the Earth’s crust. Fluorides are
released into environment through a
combination of natural and anthropogenic
processes include the weathering and
dissolution of fluoride rich minerals, emissions
from volcanoes, geothermal activity, and
marine aerosols [1, 2]. Fluoride levels in
surface waters depend on geographical
location and proximity to emission sources but
are generally low, ranging from 0.01 to
0.3 mg/L in freshwater and from 1.2 to 1.5
mg/L in seawater. However, high fluoride
concentrations (3 mg/L and greater) are
common in the ground waters at many
geographical areas due to rich fluoride-
containing rocks. These regions include East
African Rift system (from Jordan in northern
Africa to Kenya and Tanzania in east Africa),

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Molecular Mechanism of Fluoride Induced Oxidative Stress Thangapandiyan and Miltonprabu
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Middle East (Iran, Iraq, and Syria), Indian
subcontinent (India, Pakistan, Sri- Lanka),
parts of the USA, China, Argentina, and some
regions of Central Europe [3–5]. In addition
the core of fluoride existence in the nature is
foodstuffs and water, i.e., fluoridated water
(usually at 1.0 mg/l), fluoride supplements
(such as fluoride tablets), fluoride dentifrices
(containing on average 1000 mg/kg), and
professionally applied fluoride gel (containing
on average 5000 mg/kg).

Table 1: Chemical Properties of Fluorine.

Atomic number 9
Atomic mass 18.998403 g.mol-1
Electronegativity according to Pauling 4
Density 1.8*10-3 g.cm-3 at 20°C
Melting point -219.6 °C
Boiling point -188 °C
Vanderwaals radius 0.135 nm
Ionic radius 0.136 nm (-1); 0.007 (+7)
Isotopes 2
Electronic shell [ He ] 2s22p5
Energy of first ionisation 1680.6 kJ.mol -1
Energy of second ionisation 3134 kJ.mol -1
Energy of third ionisation 6050 kJ mol-1
Standard potential - 2.87 V
Discovered by Moissan in 1886
Source: http://www.lenntech.com/periodic/elements/f.htm#ixzz2Zqcdg4xg

The main source of fluoride for humans is the
intake of groundwater contaminated by
geological sources (maximum concentrations
reaching 30–50 mg/l). Fluoride concentrations
in water are limited by fluorite solubility, so
that in the absence of dissolved calcium,
higher fluoride solubility should be expected
in the groundwater of areas where fluoride-
bearing minerals are common and vice versa
[6]. Excessive fluoride intake over a long
period of time may result in a serious public
health problem called fluorosis, which is
characterized by dental mottling and skeletal
manifestations such as crippling deformities,
osteoporosis, and osteosclerosis. The symptom
of the fluoride toxicity was given in Table 2.

Table 2: Symptoms of Fluoride Toxicity.

Fluoride symptoms Blood Brain Heart
Gastric symptoms Electrolyte Neurological effects Cardiovascular effects
Nausea abnormalities Headache Widening of QRS
Vomiting Hyperkalemia Tremors Various arrhythmias
Diarrhoea Hypoglycemia Titanic concentration Shock
Abdominal Pain Hypocalcemia Hyperactive reflexes Cardiac arrest
Dysphasia seizures
Mucosal injury Muscular pain

Endemic fluorosis is now known to be global
in scope, occurring on all continents and
affecting many millions of people [7]. In some
regions, artificial fluorides used to fluoridate
community water supplies (mostly at around
1mg/l) include silicofluoride compounds
(sodium silicofluoride and hydrofluosilicic
acid) and sodium fluoride (NaF). At neutral
pH, silicofluoride is dissociated to silic acid,
fluoride ion, and hydrogen fluoride (HF) [8].
The primary benefit associated with fluoride
supplementation is linked to the potential to
reduce the risk of dental caries due to the
cariostatic effects of fluoride. Even in the past,
fluoride was considered an essential element
[9]. Additional risks of increased fluoride
exposure are known; the most significant are
effects on bone cells (both osteoblasts and

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Research and Reviews: A Journal of Toxicology
Volume 3, Issue 2, ISSN: 2231- 3834
__________________________________________________________________________________________
osteoclasts) that can lead to the development
of skeletal fluorosis. It is now recognized that
fluoride also affects cells from soft tissues, i.e.,
renal, endothelial, gonadal, and neurological
cells [10]. The minimal risk level for daily oral
fluoride uptake was determined to be 0.05
mg/kg/day [11], based on a non-observable
adverse effect level (NOAEL) of 0.15 mg
fluoride/kg/day for an increased fracture rate.
Estimations of human lethal fluoride doses
showed a wide range of values, from 16 to 64
mg/kg in adults and 3 to 16 mg/kg in children
[11]. Moreover, there are no convincing
evidences on the role of fluoride as essential
element for normal human growth and
development. In contrast, during recent
decades, numerous investigations have
established the toxicity of fluoride for cells of
different tissues both in vitro and in vivo.
The present review is paying attention on the
effects of fluoride with respect to potential
physiological and toxicological implications. It
addresses the current understanding of the
pathways and mechanisms underlying the
sensitivity of various organs and tissues to
fluoride. This review provides information and
described special chelating antidotes used
against fluoride induced toxicity in different
organs.
SOURCES OF FLUORIDE AND
HUMAN EXPOSURE
Anthropogenic fluoride sources include the
release of processed waters and waste from
various industrial sites including, steel,
aluminum, copper and nickel production,
phosphate ore processing, phosphate fertilizer
Fig. 1: Environmental Sources of Fluoride Exposures.
RRJoT (2013) 1-11 © STM Journals 2013. All Rights Reserved
manufacturing and use, and glass, brick, and
ceramic manufacturing [3, 4]. Phosphate ore
production and aluminum manufacture are the
major industrial sources of environmental
fluoride pollution. The use of fluoride
containing pesticides and combustion of the
coal and fuel also contribute to fluoride
dispersion. These processes result in
accumulation of fluoride compounds in the
surface waters and groundwater reserves, air,
soils, and in the living organisms. The most
common inorganic fluorides are hydrogen
fluoride (HF), calcium fluoride (CaF2),
sodium fluoride (NaF), sulfur hexafluoride
(SF6), and silico fluorides. Nowadays
organofluoride compounds (carbon–fluoride
bond) are increasingly used, because it has a
wide range of functions in many fields such as
agrochemicals, pharmaceuticals, refrigerants,
pesticides, surfactants, fire extinguishing
agents, fibers, membranes, ozone depletors,
and insulating materials [12]. An estimated
20% of pharmaceuticals and 30–40% of
agrochemicals are organofluorines [13].
However, environmental and health issues are
still a problem for many organofluorines.
Because of the strength of the carbon–fluoride
bond, many synthetic fluorocarbons and
fluorocarbon-based compounds are persistent
global contaminants and may be harming the
health of human and wildlife [12]. Their
effects on human health are unknown.
However, the toxicity of fluorinated organic
chemicals is usually related to their molecular
characteristics rather than to the fluoride ions
that are metabolically displaced. Figure 1
represents the various environmental sources
of fluoride exposures.
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Molecular Mechanism of Fluoride Induced Oxidative Stress
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Air
Fluoride can enter the air from sea spray, and
therefore might be expected highest near the
coast [14]. No data were found on fluoride
levels in ambient air or residential soil. Human
exposure to fluoride from ambient air has been
estimated to be only about 1 to 4 mg/day [14].
This is insignificant compared to other sources
of exposure [15, 16]. The use of fluoridated
water for watering of lawns and gardens might
be expected to add fluoride to air and soil, but
this does not appear to have been
systematically studied.
Fluorides are widely distributed in the
atmosphere but air is responsible for only a
small fraction of total fluoride exposure. In
non-industrial areas, the concentration of
fluoride is quite low, whereas in areas where
phosphate fertilizers are used or fluoride-
containing coal is burned then the
concentration in air increases [17]. But
recently koblar et al., [18] has been reported
the air bone fluoride from aluminium smelter
factory causes severe damages to the soil and
vegetation through which affect the human
health.
Water
Fluorides are naturally present in water
sources and drinking water as they are released
from the runoff of fluoride-containing rocks
and soils and leach into groundwater [19]. In
some areas drinking water is artificially
fluoridated, therefore drinking water is
typically the largest contributor to daily intake.
Fl has been estimated that children drinking 1
liter (L) of water per day may drink up to 1.2
mg fluoride per day [17].
Most consumers use water from their tap for
drinking water. In addition they use this water
for preparing beverages such as juices, coffee
and tea. The estimated intake of one to two
liters per day includes beverages as well as
drinking water. Some sources of drinking
water, especially surface water, are naturally
low in fluoride (< 0.3 mg/L). In many
communities fluoride is added to the water
supply in order to bring its concentration into
the range of 0.7 to 1.2 mg/L, which is deemed
optimal for prevention of dental caries [14].
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Thangapandiyan and Miltonprabu
In other communities fluoride need not be
added because it is naturally present in this
range, or even higher, up to about 3 mg/L.
Table 3 shows the estimated levels of daily
fluoride intake drinking water for children and
adults. Because water consumption is higher in
areas with higher ambient temperatures, the
recommended amount of fluoride to be added
to drinking water has been made temperature-
dependent.
Toothpaste, Mouthwash and Fluoride
Supplements
Over 80% of the toothpastes sold in the India
are fluoridated, with fluoride concentrations
ranging from 1 mg/gram to 1.5 mg/gram [20].
When a person brushes with fluoride
toothpaste, some of the fluoride is absorbed
directly into the tooth enamel. Children may
swallow 0.2 to 0.8 grams of toothpaste per
day, whereas adults are estimated to swallow
only approximately 0.02 to 0.1 grams per day
[21]. The ranges of fluoride exposures from
toothpaste shown in Table 3 were calculated
by multiplying the amounts swallowed by the
fluoride concentration of the toothpaste.
Mouthwashes contain 0.23 to 0.97 mg/gram
fluoride [20]. These are probably used, and
swallowed, more frequently by adults than by
children. Office of Environmental Health
Hazard Assessment (OEHHA) is estimating
that an adult would swallow about 1 gram of
mouthwash per day, and a child would
swallow about 0.5 grams. The range of
fluoride exposures from mouthwashes
indicated in Table 3 are based on these
estimates of the amount swallowed multiplied
by the range of fluoride concentrations found
in mouthwashes.
Fluoride tablets are used to provide fluoride
for children who live in areas with non
fluoridated water. These tablets provide 0.5
mg/day of fluoride to the child. Fluoride
supplements are not recommended for children
in areas with fluoridated water, or for adults
[14].
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Table 3: Estimated Fluoride Intakes for Children and Adults from Various Sources.
Fluoride Intake (mg/kg)
Fluoride in Drinking
Food Toothpaste Mouthwash Supplement Total
drinkingwater(mg/ Water
Children<0.3 0.1 to 0.3
0.1 to 0.5 0.2 to 1.2 0.1 to 0.5 0.5 1.0 to 3.0
0.7 to 1.2 0.7 to 1.2
0.1 to 1.7 0.2 to 1.2 0.1 to 0.5 0 1.1 to 4.6
0.2 to 0.6 0.3 to 1.0 0.02 to 0.15 0.3 to 1.0 0 0.7 to 2.8
Adults< 0.3 0.7 to 1.2
1.4 to 2.4 0.3 to 3.4 0.02 to 0.15 0.2 to 1.0 0 1.9 to 7.0
Source from: Public Health Goal for Fluoride in Drinking Water, California Environmental
Protection Agency, December 1997.

Food can also release small amounts of fluoride into

The major source of fluoride in the diet is
added to foods when they are cooked or
processed with fluoridated water. Although
raw foods contain some fluoride, among the
foods that are high in fluoride are tea and
ocean fish containing bones or bone meal.
However, the consumption of tea in larger
quantities can represent a potential health risk
because tea plant (Camellia sinensis) is known
to uptake Fl from the soil, and to accumulate
in the leaves, from where it is easily released
during infusion. Case reports, epidemiological
observations and animal studies on fluorosis
induced by tea drinking have been reviewed
[22, 23]. Based on market basket diet studies
the amount of fluoride in a typical adult's diet
has been estimated by several researchers [24,
25]. For communities with low fluoride levels
in drinking water the food contribution to
fluoride exposure for adults ranges from 0.3 to
1 mg/day. For adults in communities with
fluoridated water the corresponding fluoride
intakes are 0.3 to 3.4 mg/day. To estimate the
intakes for children, the adult intakes were
divided approximately in half to yield intakes
ranging from 0.1 to 0.5 mg/day and 0.1 to 1.7
mg/day for non-fluoridated and fluoridated
communities, respectively.
Through Community
Communities near previous or current
agricultural or fertilizer industrial sources may
be exposed to fluoride. Facilities such as wood
preservative and glass factories may
contaminate nearby air, soil, and water.
Communities near smelters, or near fields or
orchards where fluoride contaminated source
were used, may also have contaminated soil.
Burning fossil fuels (such as coal) and tobacco
the air.
Mechanism of Fluoride Toxicity
The toxicity of fluoride is associated with its
high chemical and biological activity. Fluoride
freely and rapidly migrates across the
biological membranes, primarily in the form of
HF via passive nonionic diffusion in response
to differences in the acidity of adjacent body
fluid compartments. The permeability
coefficient of HF is more than one million
times greater than that of ionic fluoride and
close to water permeability [26, 27]. After
ingestion, fluoride is rapidly and virtually
absorbed into the blood. Ingested fluoride
appears in the plasma 30 to 60 min after
ingestion. Fluoride is present unbound in the
plasma and does not appear to be any
homeostatic control of plasma fluoride levels.
Fluoride is taken up into all the tissues of the
body, but is retained and accumulated only in
the bones and teeth. Ninety-nine percent
(99%) of the “body burden” of fluoride resides
in these tissues, tightly but reversibly bound
into the crystalline structure [28]. The exact
mechanism of fluoride toxicity is unknown.
But it has been suggested that oxidative stress
can be a possible mechanism through which
fluoride induces damage to the various tissues.
Fluoride leads to cause toxicity as follows;
Fluoride binds calcium ions and may lead to
hypocalcemia which could further lead to
osteoid formation. It disrupts oxidative
phosphorylation, glycolysis, coagulation, and
neurotransmission (by binding calcium). It
inhibits Na+/-K+/-ATPases, which may lead to
hyperkalcemia by intracellular release of
potassium and decrease acetyl cholinesterase,
which may be partly responsible for hyper
salivation, vomiting and diarrhea (Cholinergic

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Molecular Mechanism of Fluoride Induced Oxidative Stress Thangapandiyan and Miltonprabu
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signs) and causes other metabolic disorders. biomolecules. The mechanism of fluoride
Due to high electronegativity, fluoride (F) has toxicity on the antioxidant status has been
a proclivity to form strong hydrogen bonds, shown on Figure 2.
especially with –OH and –NH moieties in

Fig. 2: Mechanism of Fluoride Toxicity.

Fluoride is able to exert powerful influences
on various enzymes and endocrine gland
functions that affect or control the status of
oxidant/antioxidant systems in living
organisms. Fluoride has a dense negative
charge and is biochemically very active
compound lead direct effect on DNA due to
strong affinity with uracil and amide bonds by
–NH---F- interactions leads to genotoxicity
[29]. Fluoride can combine stably with DNA
by covalent bonding, affecting the normal
structure of DNA, and induce the production
of free radicals, which can damage DNA
strands directly or by lipid peroxidation
initiated by free radicals [30]. Fluoride may
depress the DNA polymerase enzymes which
might further affect the process of DNA
replication or repair and thereby damage DNA
[31]. Fluoride was reported to be an equivocal
carcinogen by the National Cancer Institute
Toxicological Program [32]. International
Agency for Research on Cancer (IARC)
evaluated that there is limited data, which
provide inadequate evidence about fluoride
induced carcinogenicity. But recent study
revealed that rats and mice given sodium
fluoride in drinking water at 11, 45, or 79
mg/L have shown the occurrence of
osteosarcomas in bones of male rats [33].
ORGAN TOXICITY BY FLUORIDE
Dental fluorosis
Dental fluorosis is defined as a hypo-
mineralization of enamel, characterized by
greater surface and subsurface porosity than is

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Research and Reviews: A Journal of Toxicology
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found in normal enamel, and results from
excess fluoride reaching the growing tooth
during its developmental stages [34]. It has a
great affinity for the developing enamel
because tooth apatite crystals have the
capacity to bind and integrate fluoride ion into
the crystal lattice [35]. The recommended
level for daily fluoride intake is 0.05–0.07 mg
F/kg/day, which is considered of great help in
preventing dental caries, acting in
remineralization. A daily intake above this
safe level leads to an increased risk of dental
fluorosis. Excessive intake of fluoride during
enamel development can lead to dental
fluorosis, a condition of the dental hard tissues
in which the enamel covering of the teeth fails
to crystallize properly, leading to defects that
range from barely discernible markings to
brown stains and surface pitting. The severity
of the dental fluorosis has been demonstrated
in the Figure 3A.

Fig. 3A: Severity of Dental Fluorosis.

The mechanism of dental fluorosis (Figure 3B)

has been demonstrated by Aoba and Fejerskov
[36] suggested that dental fluorosis effects are
associated with precipitation of hydroxyapatite
by fluoride ions, altering enamel
mineralization. Alternatively, several authors
concluded that these clinical signs are
associated with the action of fluoride on the
secretory functions of ameloblasts epithelial
cells responsible for enamel development [37].

The life cycle of these cells has three stages:

secretory, transition and maturation. In the
secretory phase there is an extensive
endoplasmic reticulum (ER) that secretes large
amounts of matrix proteins. In the transition
phase, rough ER and Golgi complexes
decrease. Finally, during the maturation phase
the ameloblasts secrete serine proteases that
induce protein degradation and removal.
Several decades ago, morphological studies
[38] showed that fluoride affects the secretory
stage in ameloblasts cells and leads to
formation of dental fluorosis.

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Molecular Mechanism of Fluoride Induced Oxidative Stress Thangapandiyan and Miltonprabu
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substituting hydroxyl groups in the carbonate

apatite structure to produce
Fig. 3B: Pathological Mechanism Involved in fluorohydroxyapatite, thus altering the mineral
Fluoride Induced Dental Fluorosis structure of the bone, unlike hydroxyl ions,
Skeletal Fluorosis fluoride ions reside in the plain of calcium
Skeletal fluorosis is a painful crippling ions, resulting in a structure that is electro
pathological condition, which can occur on statically more stable and structurally more
long term exposure to high levels of fluoride. compact.
The risks of increased fluoride exposure are
known fluorosis. The most significant effects
are on bone cells (both osteoblasts and
osteoclasts) that can lead to the development
of skeletal fluorosis (Figure 4A) [39]. Chronic
ingestion of drinking water containing 3–6
mg/lit/day fluoride can produce skeletal
fluorosis [40]. It is now recognized that
fluoride also affects cells from soft tissues, i.e.,
renal, endothelial, gonadal, and neurological
cells [10]. The mechanism of fluoride toxicity Fig. 4A: Skeletal Fluorosis Affected Bone.
of skeletal fluorosis (Figure 4B) suggest that,
fluoride ions are incorporated into bone

Fig. 4B: Pathological Mechanism Involved in Skeletal Fluorosis.

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Research and Reviews: A Journal of Toxicology
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Because bone strength is thought to derive
mainly from the interface between collagen
and minerals, alteration in mineralization
affects bone strength and finally causes
unstable bone or soft bone called skeletal
fluorosis.
Effect of Fluoride on Brain
Fluoride is a powerful central nervous system
toxin and adversely affects the brain
functioning even at low doses. It is able to
induce neuron apoptosis [41] and decreased
cerebral functions, impaired memory and
learning ability [42, 43]. Fluoride is a
chemically activated ionized element, it may
affect oxygen metabolism and induce oxygen
free radicals which appears to play a role in
diminishing cognitive ability process such as
learning and memory [44]. The mechanism of
fluoride toxicity in the brain demonstrated
Figure 5A. Fluoride ions bind with antioxidant
N-acetyl cysteine (NAC), glutathione (GSH)
and other free radical destroying enzymes,
triggering oxidative stress that leads to cell
damage and even cell apoptosis [45]. Absence
Fig. 5A: Pathological Mechanism Involved in Fluoride Induced Neurotoxicity.
The distribution of IQ scores from the females
in the two villages (Wamiao and Xinhuai) is
shown in Figure 5B. The number of children
in Wamiao with scores in the higher IQ ranges
was less than that in Xinhuai. There were
corresponding increases in the number of
RRJoT (2013) 1-11 © STM Journals 2013. All Rights Reserved
of compensatory antioxidant system with the
presence of oxidative stress due to increased
free radicals plays a great role in the initiation
of damage of nerve cells membrane especially
via increased lipid peroxidation [46]. Several
studies have reported the effects of fluoride in
drinking water on cognitive capacities [47–
49]. Among the studies, the one by Xiang et
al. [50] had the strongest design of fluoride
neurotoxicity. This study compared the
intelligence of 512 children (ages 8–13) living
in two villages with different fluoride
concentrations in the water. The IQ test was
administered in a double-blind manner. The
high-fluoride area (Wamiao) had a mean water
concentration of 2.47 ± 0.79 mg/L (range
0.57–4.50 milligrams per liter [mg/L]), and the
low-fluoride area (Xinhuai) had a mean water
concentration of 0.36 ± 0.15 mg/L (range
0.18–0.76 mg/L). The populations studied had
comparable iodine and creatinine
concentrations, family incomes, family
educational levels, and other factors. The IQ
scores in both males and females declined with
increasing fluoride exposure.
children in the lower IQ range. Fluoride has
alter the total brain phospholipids after chronic
exposure for seven months, the main species
of phospholipids influenced by fluorosis is
phosphatidyl ethanolamine, phosphatidyl
choline, and phosphatidyl serine. Rats exposed
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Molecular Mechanism of Fluoride Induced Oxidative Stress
__________________________________________________________________________________________
to fluoride showed a number of
histopathological changes in the brain,
including demyelination, a decrease
Effect of Fluoride on Lung
Lung is one of the target organs for the
toxicity of inhalated Fl compounds. The
respiratory tract is frequently exposed to
elevated concentrations of Fl compounds and
become the primary target site for toxicity.
Occupational, accidental or prolonged
exposure to a great variety of chemicals may
result in acute or delayed injury to cells of the
respiratory tract [51]. The most fundamental
adverse effect of fluorides is the inhibition of
Kreb’s cycle enzymes. Thus they affect the
metabolic pathways of carbohydrates, lipids
and proteins. The impact of fluorides upon
carbohydrate metabolism occurs via the
inhibition of glycolysis, whereas the influence
of fluorides upon protein metabolism causes a
decrease of protein levels in serum, skeletal
muscles and lungs [52]. Pieta et al. [52] who
reported that, administration of NaF
2.5mg/kg/day/bw for five weeks (35 days)
exhibit severe damage in the alveolar region of
lungs. Figure 6 shows the mechanism of
fluoride induced pulmonary toxicity.
Yamamoto et al. [53] who reported, that
inhalation of fluoride can cause cellular
alterations in the lung that diminish the ability
to respond to infectious bacteria. Human
exposure to inhaled fluoride is implicated in
acute respiratory failure-inducing
inflammatory reactions in the respiratory tract
[54]. In addition, rat lung tissues presented
emphysema and lung parenchyma
inflammation associated with loss of alveolar
architecture in the second generation of adult
rats exposed to 50 or 100 mg/l of NaF via the
drinking water. Interleukin 8 (IL-8) has a
pivotal role in several pathological conditions,
such as chronic inflammation, fibrosis and
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Thangapandiyan and Miltonprabu
disappearance of dendrities, swelling of
mitochondria, and dilation of endoplasmic
reticulum in neurons [50].
cancer [55]. The inflammatory effect of
fluoride exposure was evaluated in human
lung epithelial cells, and an increase in the
activity of IL-8 was found (with a 5–7-fold
increase after 20 h exposure to 3.75 and
5 mMNaF, respectively) [56].
Effect of Fluoride on Heart
Heart is a muscular pumping organ, mainly
involved in the purification and circulation of
blood in the body. Heart sickness like
myocardial infarction (MI) is one of the main
causes related to sudden death in the world
and it continues to cause substantial morbidity
and mortality [57]. It is believed to increase in
coming years and a complex phenomenon
affecting the mechanical, electrical, and
structural and biochemical properties of the
heart [58]. Heart failure results from sudden
reduction in coronary blood flow to a segment
of the myocardium, which initiates a
continuum of progressively more severe
cellular changes that, unless interrupted by
early reperfusion inevitable culminate in cell
death and tissue necrosis [59]. Fluoride
induced oxidative stress plays an important
role in progression of a variety of cardiac
disorders such as cardiac failure and ischemia
[60]. nicotinamide adenine dinucleotide
phosphate-oxidase (NADPH oxidase) (Nox),
an important source of ROS in the vasculature,
is activated by high levels of fluoride
exposure. Nitric oxide synthase (NOS) is
involved in the formation of NO, a highly
reactive, uncharged, membrane-permeable
molecule that functions as a signal in many
regulatory processes such as blood vessel
dilation, immune responses and
neurotransmission. Fluoride can stimulate the
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__________________________________________________________________________________________

Nox expression and activity has implications dysfunction in coronary heart disease could be
in endothelial dysfunction and vascular related to the chronic inflammation that
disorders. It is possible that endothelial coexists with atherosclerosis [61].

Fig. 6: Pathological Mechanism Involved in Fluoride Induced Lung Toxicity.

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Molecular Mechanism of Fluoride Induced Oxidative Stress Thangapandiyan and Miltonprabu
__________________________________________________________________________________________

Fig. 7: Pathological Mechanism Involved in Fluoride Induced Cardio toxicity.

However, Catecholamine plays an important
role in normal cardiac function. Nevertheless,
excess release of catecholamine is responsible
for the development of various cardiac
dysfunctions such as myocardial cell death,
lipid peroxidation, and heart failure.
Peroxidation of endogenous lipids has been
shown to be a major risk factor in cardio toxic
action of fluoride (Figure 7) [62].
Thangapandiyan and Milton Prabu has been
reported that, fluoride induce severe damage to
the heart tissue at a dose of 25 mg/kg/bw for
four weeks. The report showing that free
radicals produced by fluoride may possibly
initiate peroxidation of membrane-bound
polyunsaturated fatty acids, leading to cause
both functional and structural integrity of heart
[63].
Effect of Fluoride on Stomach
Fluoride occurs in drinking water primarily as
free fluoride. The stomach is a target organ for
the adverse effects of fluoride. Among the soft
tissues of the body, the propensity of gastric
mucosa exposed to the highest concentrations
of the Fl ion is immense. The mechanism of Fl
on stomach toxicity is given in Figure 8. The
ingested fluorides combine with hydrogen ions
to form hydrogen fluoride (HF), depending on
the pH of the contents of the stomach (2.4%
HF at pH 5; 96% HF at pH 2).

Fig. 8: Pathological Mechanism Involved in Fluoride Induced Stomach Toxicity.

HF easily crosses the gastric epithelium, and is
the major form in which fluoride is absorbed
from the stomach. Upon entering the
interstitial fluid in the mucosa where the pH
approaches neutrality, HF dissociates to
release fluoride and hydrogen ions which can
cause stomach epithelial damage [64]. The
damage has been occurs depends on the
concentrations of these HF ions in the tissue. It
appears that an HF concentration somewhere

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__________________________________________________________________________________________
between 1.0 and 5.0 mmol/L (20 and100
mg/L), applied to the stomach mucosa for at
least 15 min, is the threshold for effects on the
function and structure of the tissue [65].
Several functional and structural changes
might be associated with ingestion of fluoride
such as, increased mucus secretion, followed
by patchy or widespread loss of the mucus
layer, hyperemia, edema, and hemorrhage
[66]. The mechanism of Fl involved in the
stomach remain unknown but fluoride has
ability to activate guanine nucleotide
regulatory proteins (G proteins) [67] in the gut
epithelium even at very low doses (e.g., from
fluoridated water at 4.0 mg/L) by which
damage gut cells.
Effect of Fluoride on Liver
Liver, responsible for maintaining the body
metabolic homeostasis has been considered as
the target organ for the toxic effects of fluoride
[68]. It is the largest repository of softy tissue
followed by kidney [69]. Several mechanisms
RRJoT (2013) 1-11 © STM Journals 2013. All Rights Reserved
have been proposed to explain the fluoride
induced toxicity. One possible mechanism is
the disturbance of prooxidant and antioxidant
balances by generation of reactive oxygen
species cause liver damage. Liver is one of the
active site of metabolism susceptible to
fluoride induced toxicity. Previous studies
realized on adult rats, have shown that fluoride
could produce abnormalities in the liver
including degenerative, inflammatory, dilation
of sinusoids, and hepatic cellular hyperplasia
[70]. Chronic fluoride consumption shows
abnormal function and metabolism and
histopathological changes have been found in
liver of rat, sheep, calves, mice by several
research groups [71]. Pieta et al. [72] has been
reported that, administration of NaF changed
the biochemical and morphological structure
of liver due to over production of free radicals
leads to lipid and protein oxidation. The
mechanism of fluoride induced hepatotoxicity
has been given in Figure 9.
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Molecular Mechanism of Fluoride Induced Oxidative Stress Thangapandiyan and Miltonprabu
__________________________________________________________________________________________

Fig. 9: Pathological Mechanism Involved in Fluoride Induced Hepatotoxicity.

Effect of Fluoride on Kidney
The kidney is the potential site of acute
fluoride toxicity because kidney cells are
exposed to relatively high fluoride
concentrations. Fluoride concentrations in the
kidney show an increase in gradient of
concentration, the lowest concentrations
occurring in the renal cortex and the highest in
the papilla [73]. Mechanism behind Fl induced
renal toxicity represented on Figure 10.
Fluoride oral administration is rapidly
absorbed into the blood. Approximately 50%
of the daily intake of fluoride is cleared by the
kidneys. Consequently, the kidney is thought
to be a target organ for any adverse effects of
fluoride because of the bioconcentration and
kinetics of fluoride metabolism and excretion
patterns.

Fig. 10: Pathological Mechanism Involved in Fluoride Induced Nephrotoxicity.

A few experimental studies have examined the
effects of fluoride exposure on rodent kidney.
Nabavi et al. [74] reported that, single
intraperitoneal dose of fluoride at 600 ppm for
one week to rats observed that increased
excessive generation of nitric oxide, oxygen
free radicals, decreased CAT, SOD,
Glutathione (GSH) and increased lipid
peroxidation which may leads to severe
damages in the nephron structure and
functions and also biomacromolecules, such as
proteins and nucleic acids [75, 76]. There are
many reports showed that, there was increased
concomitant oxidative stress through
nitrosative stress, peroxynitrite and nitric
oxide in the kidney of fluoride intoxicated rats
[77].
Effect of Fluoride on Reproductive Systems
Male Reproductive System
Fluoride toxicity led to a significant inhibition
of fertility in male rats. Fluoride compounds
could alter the internal milieu of testis and
epididymis causing functional and structural
changes [78]. The decline in male reproductive
health and fertility for the past 30 years has
been linked to environmental toxicants and
xenobiotics [79]. One of the toxicants that
have harmful effects on male reproductive
function is fluoride. The metabolism and
morphology of spermatozoa were also altered
in the fluoride exposed rat due to enhanced

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lipid peroxidation. Long et al. [80] reported
that, fluoride significantly declined the
weights of caput and cauda epididymus in rats.
However, weights of seminal vesicle and vas
deferens were not affected. The motility of
cauda epididymal sperm, sperm count in cauda
dpididymus and cauda epididymal sperm
viability decreased significantly. The protein
Fig. 11: Pathological Mechanism Involved in Fluoride Induced Reproductive Toxicity.
According to Hodge and Smith [82] reported
that, sodium fluoride toxicity involves
inhibition of enzyme activity, particularly
those in which divalent metal cations act as
cofactors; the alterations in ATPases activity
might be related to the fact that it is either a
Ca2+ or Mg2+ activated enzyme. Sialic acid is
an important constituent of
mucopolysaccharides and sialomucoproteins
which are essential for the maturation of
spermatozoa in epidiymis and maintenance of
the structural integrity of their membranes
[83]. Structural integrity of acrosomal
membrane of the sperm is also altered in Fl
intoxicated rat testes. A significant
accumulation of glycogen in the vas deferens,
suppression of vas deferens phosphorylase
activity, increase in fructose levels in seminal
vesicle and altered carbohydrate metabolism
RRJoT (2013) 1-11 © STM Journals 2013. All Rights Reserved
levels, activity of Atlases and levels of silica
acid in the caput, cauda epidiymus and vas
deferens decreased significantly after sodium
fluoride exposure [81]. This decreased in
protein levels might be due to impairment of
protein metabolism or synthesis. The
mechanism of Fl toxicity on reproductive
system elucidate in Figure 11.
mainly by causing inhibition of some key
enzymes in glycolysis and tricarboxylic acid
cycle were reported after exposure to fluoride.
Female Reproductive System
An epidemiological study to evaluate whether
fluoride could affect human birth rates using a
U.S. database of drinking water systems
showed an association of decreasing total
fertility rate with increasing fluoride levels
[84]. Sharma et al [85] has been reported that,
female rats exposed to sodium fluoride (6
ppm) for 15 and 30 days revealed that the
reproductive organ weights of ovary, uterus,
vagina and adrenal gland were declined
significantly due to over production of reactive
oxygen species with increased lipid
peroxidation. Animals exposed to 200, 400
and 600 ppm of fluoride could produce
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Molecular Mechanism of Fluoride Induced Oxidative Stress Thangapandiyan and Miltonprabu
__________________________________________________________________________________________

significant reduction in number of viable body removing them from intracellular or

fetuses, increased number of resorptions, an
increase in both the absolute and relative
weights of the ovaries, relative uterine weights
and kidney weights. Increased oxidative stress,
lipid peroxidation, and apoptosis were found
in the endometrium of rats treated with the
fluoride [86].
CHELATION THERAPY
Chelation therapy is the preferred medical
treatment for reducing the toxic effects of
metals. The mechanism of chelating agents
with toxic compounds has been given in
Figure 12. Chelating agents are capable of
binding to toxic metal ions to form complex
structures which are easily excreted from the
extracellular spaces. Many of synthetic
antidotes, like 2, 3-dimercaprol (British anti-
lewisite) and meso 2, 3-dimercaptosuccinic
acid (DMSA), have been used in the
management of metal induced toxicity [87].
These chelating agents compete with
sulfhydryl groups in tissues or enzymes for
binding fluoride, which results in the
elimination of fluoride induced free radicals.
Because most conventional metal-chelating
agents have toxic side effects or
disadvantages, the possibility of dietary
intervention of or supplementation with
naturally occurring dietary nutrients, to
prevent the effects of fluoride in populations at
risk of Fluoride intoxication [88].

Fig.12: The Mechanism of Combinational Chelating Therapy.

Apart from synthetic chemical chelators,
studies have been carried out to explore
natural antioxidants against toxic substance or
elements. Antioxidants (AOX) are substances,
which inhibit or delay oxidation of a substrate.
Antioxidant molecules are thought to play a
crucial role in counteracting free radical-
induced damage to macromolecules.
Nutritional antioxidants act through different
mechanisms directly neutralize free radicals,
reduce the peroxide concentrations and repair
oxidized membranes and quench iron to
decrease ROS production via lipid
metabolism, short-chain free fatty acids and
cholesterol esters neutralize ROS [89–92].
There is a wide range of antioxidants which
can counteract the condition of oxidative
stress. It includes vitamins, phenolic
compounds (flavonoids), carotenoids and etc.,
in addition, minerals such as selenium, zinc,
manganese, magnesium and copper are also
involved in hundreds of antioxidant roles in
the body. Apart from the free radical
scavenging property, antioxidants are known

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Research and Reviews: A Journal of Toxicology
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__________________________________________________________________________________________
to regulate the expression of number of genes
and signal regulatory pathways and thereby
may prevent the incidence of cell death [93].
The following natural antioxidant was used
against fluoride induced oxidative stress
mediated toxicity in various organs in rat.
Epigallocatechin Ggallate
Epigallocatechin gallate (EGCG) also known
as Epigallocatechin 3-gallate, is the ester of
epigallocatechin and gallic acid. EGCG is the
most abundant polyphenols in tea but is also
found in other plants. It is one of the most well
studied polyphenols in relation to oxidative
stress mediated diseases. EGCG has been well
studied antioxidant, owing to its free radical
scavenging property and ability to chelate
transition metal ions. The results of earlier
studies suggest that regular intake of EGCG
can reduce oxidative stress, which decreases
the risk of disorders associated with oxidative
stress [94]. Thangapandiyan and Milton prabu
[95] has been reported that, the antioxidant
efficacy of EGCG in an in-vitro and in-vivo
study against sodium fluoride intoxicated rat.
Moreover EGCG was proved a good in vivo
antioxidant against NaF induced oxidative
stress in rat liver with significant restored the
enzymatic, non-enzymatic antioxidant in rat
[68]. It has been reported that, EGCG is one of
the main catechins, extracted from green tea,
and was associated with a wide range of
physiological effects including antioxidant
activities [96], free radical scavenging [97,98],
ion chelating [99,100], and anti-inflammatory
properties [101]. Numerous studies have
revealed that polyphenolic compounds of tea
extract catechins are implicated in decreasing
the development of tumor and cardiovascular
conditions [102–104], and inhibiting
carcinogen-induced tumors [105].
Curcumin
Curcumin is the bioactive natural product in
Curcuma longa Linn. Curcumin extracted
from Curcuma longa Linn is widely used as a
food additive [106] and has a long history as a
food additive in Chinese, Indian and Iranian
traditional medicines [107, 108]. In the
traditional medicine of India, a cream of
Curcuma longa Linn called “Ayurveda” is
used for the treatment of eye diseases, wounds,
bites, burns and various dermal diseases. In
India Curcuma longa Linn powder is taken
RRJoT (2013) 1-11 © STM Journals 2013. All Rights Reserved
with milk and used as an antitussive and cure
of respiratory damage. Roasted Curcuma
longa Linn is a component used for protection
against intestinal diseases in children [109]. In
food technology, curcumin is used as a yellow
food additive to flavor different types of
curries and mustards [110]. Recent reports on
the use of natural products in Western
medicine have drawn the attention of food
scientists to this polyphenolic compound.
Research has shown that curcumin has
different beneficial effects such as anti-
inflammatory, antioxidant, chemo preventive
and chemotherapeutic [111]. Nabavi et al. [74,
112, 113] who reported recently the
antioxidant potential of curcumin against NaF
induced toxicity in kidney, heart, and RBC in
rat models. This is showed the ability of
curcumin scavenge the free radical during
oxidation of biomolecules induced by fluoride.
Silymarin
Silymarin is isolated from the fruits and seed
of the plant Silybum marianum L. Gaertn
(milk thistle). Milk thistle belongs to the
family of Asteraceae and is indigenous of the
Mediterranean area and southwest Europe
[114]. The natural product of this plant is
classified as a benzopyranone compound
containing polyphenols such as silybin,
silydianin and silychristin [115].
Milk thistle extract has centuries-old history of
use in folk medicine to treat a variety of
illnesses including jaundice, gallstones,
hemorrhage, bronchitis or varicose veins. Its
beneficial effects have been attributed to the
antioxidant, anti-proliferative and anti-
inflammatory effects based on the regulation
of specific signaling pathways, transcription
factors and gene expression. Although it has
been evidenced the potential benefits of
silymarin, the protective actions towards the
neural systems as well as its mechanisms of
action need to be examined [116]. Nabavi et
al. [117, 118] who reported that, NaF caused
severe damage to the heart and brain after
administration it is due to the alteration of
enzymatic, nonenzymatic antioxidant with
increased lipid peroxidation markers.
Administration of curcumin recovered all the
changes caused by fluoride. However,
innovation work has been going on with
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Molecular Mechanism of Fluoride Induced Oxidative Stress
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silymarin antioxidant against various heavy
metals toxicity.
Quercetin
Quercetin is one of the most well-studied plant
polyphenols found in onions, apples, berries,
tea, and red wine [119]. Quercetin, a member
of the flavonoid family, is one of the most
prominent dietary antioxidants. The preventive
effects of quercetin from apoptosis have been
reported in several kinds of cells such as
macrophages [120], retinal pigmented
epithelial cells [121], and glomerular
mesangial cells [122]. Furthermore, quercetin
has been recently reported to mediate
cytoprotection through induction of heme
oxygenase (HO)-1, which has a potent
antioxidant property [123]. Recent evidences
have indicated that HO-1 plays a key role in
defence mechanisms against oxidative
damages [124]. Nrf2 is a noted cellular
regulator of antioxidant and stress response
because of its affinity for antioxidant response
elements (ARE) [125]. Quercetin enhanced
antioxidant reactive elements (ARE) binding
activity with Nrf2 and Nrf2-mediated
transcription activity in human HepG2 cells
[126]. Recently, Chouhan et al. [127] reported
that, Silymarin and Quercetin synergistically
abrogates fluoride induced oxidative toxic
effect in rat liver and kidney via activation of
phase I antioxidant enzymes such as SOD,
CAT, GPx.
Fisetin
Fiestin (3,4,7-tetrahydroxyflavone) is a
flavonoid found in fruits, vegetables, nuts and
wine at concentrations of 2–160 lg/g with an
average daily intake estimate of 0.4 mg [128].
Fiestin is also added to nutritional supplements
at very high concentrations and has a variety
of pharmacological effects [129] including
antioxidant [130] and anti-inflammatory
activity acting mainly as a free radical
scavenger [131]. Fiestin was reported a good
antioxidant against fluoride induced oxidative
damage in brain hippocampal cells of rat
[132]. Fiestin are a class of natural biological
products that have evolved to protect the
oxidative damage caused by fluoride.
Caffeic Acid
Caffeic acid is a widely studied natural
flavonoid like compounds, which is one of the
major components of honey bee propolis. It is
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Thangapandiyan and Miltonprabu
used for many years in Middle East countries
in the folk medicine. Guney et al. [133]
reported that, caffiec acid offered protection
against fluoride induced oxidative stress and
apoptosis in rat endometrium. This report
strongly suggests that caffeic acid has strong
antioxidant, and anti-inflammatory [134]
property against fluoride induced oxidative
stress toxicity.
Arjunolic Acid
Arjunolic acid is a triterpenoid saponin and
one of the major constituents present in the
plant of terminalia arjuna. It has long history
of medicinal application primarily in the
preparation of ayurvedic formulations for over
three centuries [135]. Arjunolic acids are
active components of many medicinal plants
and possess a wide range of biological
activities [136]. Recently Ghosh et al. [137]
reported that, arjunolic acid has cytoprotective
effect against sodium fluoride mediated
oxidative stress and cell death in rat
hepatocytes. This is due to protective role of
arjunolic acid inhibiting ROS and
inflammatory process via necrotic pathway.
Proanthocyanidin
Proanthocyanidin is one of the flavonoid,
richly found in grapes, especially grape seeds.
It is contain important secondary metabolite
and hydroxylated groups. Hence, it has strong
antioxidant activity [138]. El-Demerdash et al.
[139] reported that, supplementation of grape
seed proanthocyanidin (75 mg/kg/BW) to
fluoride intoxicated rat (18 mg/kg/BW) for 30
days significantly increased enzymatic, non
enzymatic antioxidant and decreased oxidative
stress parameters and MDA, NO levels in the
fluoride treated rats testes.
Tamarind
Tamarind (Tamarindus indica L.) is found all
over India and has been used in the treatment
of pain, diabetes, urinary problems, infection
and stress in man and animals [140]. Use of
powdered tamarind fruit pulp for amelioration
of metal poisoning is mentioned in the
literature [141]. Dey et al. [142] who reported
that, administration of fluoride orally at a dose
of 200 mg/kg/BW daily for 14 weeks showed
an increased oxidative stress like lipid
peroxidation, protein oxidation in the blood
and tissue of rats. Administration of Tamarind
fruit pulp extract at three doses 25, 50,
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__________________________________________________________________________________________
100 mg/kg/BW orally shows a significant
decreased level of those ROS mediated
oxidative stress in the rat. Hence, tamarind
was proved to be a good antioxidant against
fluoride induced ROS, and other toxic
rudeness in rats.
Mangiferin
Mangifera indica L. (F: Anacardiaceae) fruit is
well known throughout the world and, in India
this fruit is used in preparation of pickles and
salads. Mango fruit is considered a
cardiotonic, hypotensive, hepato- and gastro-
protective agent and is reported to possess
antidiabetic, hypolipidemic, antioxidant, anti-
viral, antibacterial, anti-fungal, anthelminthic,
anti-parasitic and anti-inflammatory properties
[143]. The mango peel extracts have been
shown to contain mangiferine, polyphenols
and carotenoids and prevent the RBC
membrane spectrin degradation thereby
protecting the RBCs from oxidative stress
[144]; the flavonoids of the fruit are reported
to decrease tissue lipid peroxidation and
improve antioxidant profiles [145,146]. Rupal
et al. [147] reported that administration of
fluoride through drinking water at 100ppm to
the rat showed elevated levels of lipid
peroxidation with decreased antioxidant status
in the liver and kidney. Administration of
mango fruit powder reduced both hepatic and
renal tissue lipid peroxidation, with a
significant increase in antioxidant profiles
(SOD, CAT, GSH and GPX). Ultimately,
Mangifera indica fruit proved its chelating
efficacy with having considerable
antiperoxidative and antioxidant potential to
mitigate the fluoride toxicity.
CONCLUSION
In this review, we discuss the various sources
of fluoride exposure and related to different
organs toxicity. The molecular mechanism of
the fluoride toxicity is still unclear but even
though it has been suggested some mechanism
are clear in particular organs. We also
discussed the absorption, distribution and
elimination of fluoride after ingested in to
body. We have been intended to identified the
fluoride induced oxidative stress mediated
organ toxicity such as, brain, lung, heart,
kidney, liver, and reproductive organs.
Chelation therapy is the removal of excess or
toxic metal from the system rendering it
RRJoT (2013) 1-11 © STM Journals 2013. All Rights Reserved
immediately nontoxic and reducing the late
effects. Most chelators have the disadvantages
of copious adverse side effects, non-specific
binding and administration inconvenience. In
the world, increasing fluoride exposure
although chelation therapy is an important tool
in fighting fluoride induce disorders yet lack
of clinical trials still offers controversy on its
clinical therapeutic benefits. However, the
combination therapy (co-administration of
structurally different chelating agents,
supplementation of an antioxidant with
chelating agent) or co-administration of
antioxidants with moderate synthetic chelating
antidotes provide better clinical recoveries, but
combinational therapies with antioxidants like
n-acetylcysteine, α-lipoic acid, EGCG,
silymarin, curcumin, quercetin etc., also some
herbal extracts have shown considerable
promise in improving clinical recoveries. Our
group has also reported that co-administration
of naturally occurring vitamins like vitamin E
or vitamin C along with the administration of a
thiol chelator like DMSA or MiADMSA may
be more beneficial in the restoring altered
biochemical variables although it has only
limited role in depleting fluoride burden.
Ultimately, we suggest from this review
combination therapy has a major role to play
in future approach towards finding a safe,
suitable and effective treatment for fluoride
poisoning.
ACKNOWLEDGEMENTS
We thank the Professor and Head, Department
of Zoology and UGC-SAP for their generous
support towards this review.
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