ISSN: 2641-2969
Annals of Environmental Science and Toxicology
Review Article       Open pjestcess      Peer-Reviewed

Fluoride Sources, Toxicity and Its Amelioration: A Review

Vijay K Bharti*, Arup Giri and Krishna Kumar

Defence Institute of High Altitude Research (DIHAR), DRDO, Leh-Ladakh, Jammu & Kashmir, India
*Corresponding author: Dr. Vijay K Bharti, Scientist - D, Defence Institute of High Altitude Research (DIHAR), DRDO, Ministry of Defence, Leh-Ladakh-194101, India, Tel: +91-9779618799; Fax: +91-172-2638500; E-mail: vijaykbharti@rediffmail.com
DOI: 10.17352/aest.000009
Received: 30 December, 2018 | Accepted: 17 January, 2018 | Published: 21 January, 2018
Keywords: Ameliorative measures; Fluoride toxicity; Human Health; Oxidative stress

Cite this as

Bharti VK, Giri A, Kumar K (2017) Fluoride Sources, Toxicity and Its Amelioration: A Review. Ann Environ Sci Toxicol 2(1): 021-032. DOI: 10.17352/aest.000009

In recent scenario, fluorosis is now going to be a severe problem throughout the globe due to toxic effects of fluoride (F) on both plants and animals. F presents in the halogenated group of the periodic table and has the characteristics of electronegativity. Natural geological sources and increased industrialization have contributed greatly to the increasing incidence of fluoride-induced human and animal health issues. In animals and human beings, it exerts adverse effects mainly through the attenuation of antioxidant defense mechanism and chelation of enzymatic cofactors. Thereafter, it causes metabolic disorders through interacting with various cellular processes such as gene expression, cell cycle, metabolism, ion transport, hormonal secretion, endocytosis, apoptosis, necrosis, and oxidative stress. These effects lead to dental mottling, skeletal dysfunctions including crippling deformities, osteoporosis, and other vital organs dysfunction. It was found that, water is the main source of fluoride intake to plants and animals, which further may go into food chain of human beings through consumption of high fluoride content plant and animal origin food. Several preventive and control measures have been developed to ameliorate the fluoride toxicity, like application of synthetic chemicals, plants bioactive molecules, and plant products like fruit pulp, seed mixture, and plant buckle products. Therefore, this article presents up-to-date information on the fluoride sources, toxicity and different amelioration measures to reduce fluoride level directly from water as well as application of different natural/synthetic products/molecules to ameliorate the toxic effects of fluoride in in-vivo models.

Introduction

In the halides group of the periodic table, fluoride (F) has great importancy due to its smallest size and most electro negativity. Although the mechanisms of F in biological forms are remains unclear but it has the unique chemical and biochemical properties for the size and reactivity [1-3]. It is ubiquitously present in soil, water, plants and air. In the animal body, F makes its presence through water and food. But, some of the recent studies indicate that, most of the F comes from pharmaceutical drugs (20%) and through agrochemicals (30-40%) [4,5]. The variability and presence of fluoride depends upon the location. It was found that F is present in the soil within the range of 10-1000 parts per million (ppm). However, in water it ranges from 0.5 to 2000 ppm. This incident depends upon the sources of water [6,7]. According to World Health Organization (WHO), F exposure to animals above the 1.5 ppm, set at chronic fluoride toxicity. Through water exposure, this type of toxicity is going to endemic in most of the countries across the world [8]. In USA, the normal level of F in drinking water is 4 mg/L [9]. But, in the European country, it is 0.8 ppm [10]. In India, most of the states are showing the greater level of F in drinking water [11]. Fluoride exerts its effects on plants also [12]. It attenuates all the cells and tissues, impaired the stomatal conductance. Simultaneously, it acts as the metabolic and reproductive inhibitor, impaired photosynthesis and respiration pathways. Ultimately, F caused even to plants death [13-18]. In animals, fluoride intoxication causing skeletal impairment, called as skeletal fluorosis. Recently, high fluoride intake has been associated with dental cancer and tumors of other organs. First clinical symptoms appeared like reduced in food intake and loss of body weight gain. After attenuating the antioxidant defence mechanism, F also affect to the gastrointestinal tract, brain, muscle etc.. [19-22]. To ameliorate these effects, several types of synthetic chemicals, herbal drugs, plant bioactive molecule, and plant natural products have been incorporated in the medicinal documentary. For example, melatonin, pineal proteins (epiphyseal proteins), quercetin, curcumin, ascorbic acid, lipoic acid, flavonoids, polyphenols have been found great role against the F toxicity [23-26]. The present review critically discusses on the fluoride sources, worldwide levels and its toxic effects on plants and animals. Furthermore, the article discusses the recent ameliorative steps developed through synthetic chemicals, plant bioactive molecules, and plant natural products.

Biochemistry of fluoride

In the halides group of the periodic tables (group VII), among all other molecules, fluoride has the great importancy due to it’s smallest size and most electro negativity. Although, the mechanisms of F in biological forms are remains unclear but it has the unique chemical and biochemical properties for the size and reactivity [1-3]. It is 13th most abundant element and distributed widely throughout the earth in soil, water, and food. F, a pale yellow colored gas, has atomic number 9 and atomic weight of 18.9984 at standard temperature and pressure [27]. The brief about the F, have been mentioned in the Figure 1 [28]. It has the tendency to exist in the Free State as diatomic molecules. Due to electromotivity characteristics, these can react with less electromotive elements or chemical groups. Fluoride compounds are formed when the element fluoride combines with other chemical elements. It does not occur in a free state in nature [28]. Fluoride however has many unique chemical properties. These properties had a great impact on the special biochemical physiological effects. For these reason, F can affect the metabolism and mechanisms of action within the living system [29]. In addition to the chemical properties and isotopic nature of fluorine has had an important impact on our understanding of the metabolism, toxicity, and therapeutic effects of fluoride. 19-F is one of the isotopes of F and occurs naturally. This isotope has the extremely short half-life.

Figure 1: Basic properties of Fluoride [Source: 28].
Sources of fluoride

Natural and anthropogenic sources are the two main ways through which F entered in the environment [30].

Natural sources

Soil: The normal total fluoride content of soil ranges from 150-400 mg/kg. F level in the clay soil is 1000 mg/kg [31]. F contamination to soil is because of the utilization of phosphorus fertilizers which have total 1-1.5% fluorine [32]. Contaminated soil with F, show it’s toxicity after the inhalation of soil contaminants which have vapourized or through the contaminated ground water after the F leaching from the soil [33-35].

Water: Water containing the F concentration up to 1.0 mg/L is safe. Whereas, the F levels in between 1.1 and 2.5 mg/L are marginally contaminated. However, above 2.6 mg/L F level is determined as the highly contaminated [31]. It was found that the level of F in ground water is higher than the surface water as the F percolates from the soil to ground water through leaching process. There are several factors which are responsible for the presence of F in natural ground water from the soil. Among them, geological factors, consistency of the soil, nature of rocks, pH and temperature of the soil, chelating action of other elements, depth of wells, leakage of shallow groundwater, and chemical and physical characteristics of water [36]. Water is an important source of F exposure to human beings and animals.

Forage, grasses and grains: At the vicinity of industrialized area, it was found that forages and grasses contain the higher level of F than the other area. Some studies also found that, grasses and forages has the higher level of F than the industrialized area. It is due to the fluoride rich dust, ash, raining factors for which plants could be affected far from the industry. Plants contamination depends upon several factors like the amount of F released in to the atmosphere, distance between the F source and contaminated area, type of vegetation, height of plants, atmospheric condition, and seasons etc. [37-39]. It has been established the relationship between the F level in soil and plants of F will be increased by 3 ppm for each 100 ppm increase in soil F up to the 2200 ppm [39].

Volcanic activities: Due to volcanic eruption, animals and plants kingdom have been affected throughout the globe (Table 1). Volcanic ash contains high level of F and contaminations of F to the geochemical cycle are frequent. From the volcanic eruption, F has been released in the form of hydrogen fluoride. Erupted F may covered several places and stay for many years. After decaying and leaching, F caused severe casualty to domestic and wild animals [6,40,41].

Table 1:Volcanic eruption leads to increase in Fluoride exposure.
Sl. No. Country Casulty References
01 Hekla volcano, Iceland F concentration was 350–4300 μg/g. [42]
02 Lonquimay volcano, Chile Affected more than 10,000 farm animals. Death occurred of more than 4000 livestock animals. [43]
03 Ruapehu volcano, Mexico Livestock and wild animals dead. [44]
04 Puyehue–Cordon Caulle volcano, Argentina Severe fluorotic dental lesions were observed in died wild red deer. [45]
05 Hekla volcano, Iceland Livestock and wild animals died. [44]
*Sl. No.-serial number.
Anthropogenic sources

Anthropogenic fluoride contamination happens by human activities like industrialization, motorization, fluoride containing pesticides, fluoridation of drinking water supplies, dental products, refrigerants, and fire extinguishers [46,47]. F contamination due to airborne sources also occurred. The mean F concentration in normal areas (unpolluted/non-industrialized) is generally less than 0.1 μg/m3. The levels may be slightly higher in the vicinity of industries, but should not exceed 2–3 μg/m3 [6]. In many countries, coal burning for household purposes was documented as the main source of F causing endemic fluorosis [48,49]. Industrial release fluoride-rich fumes and effluents into the environment also caused casualty in livestock sector like cattle, buffaloes, sheep, goats, camels etc. [50-55]. There are several reports documenting mineral mixture supplements as a major source of fluoride toxicity in livestock [56]. Moreover, incorporation of modern creation and utilization of chemicals in different sectors like hydrogen fluoride (HF), calcium fluoride (CaF), sodium fluoride (NaF), fluorosilicic corrosive (H SiF), sodium hexafluorosilicate (Na SiF), sulfur hexafluoride (SF), and phosphate manures are the main sources of fluoride.

Global scenario of fluoride levels

Around the globe, twenty three nations are belongs to the critical region regarding the fluoride level. Among them India is also present. Billions of people are affected due to fluoride exposure. In India, twenty million people are severely affected by fluorosis and 40 million people are exposed to risk of endemic fluorosis [57]. Level of fluoride in drinking water throughout the globe has been tabulated in the Table 2.

Table 2:Fluoride level in drinking water sources throughout the globe.
Sl. No. Country Name Fluoride level References
01 Pilanesberg and Western
Bushveld, South Africa		 30 mg/L [20]
02 Sanddrif, Kuboes and
Leeu Gamka, South Africa		 30 mg/L [58,59]
03 Ivory coast, Africa Above permissible limit [60]
04 Bongo, Ghana 0.11-4.6 mg/L [61]
05 Lakes Elmentaita and Nukuru, Kenya 2–20 mg/L [62-64]
06 Tibiri, Nigeria 4.7–6.6 mg/L [65]
07 Senegal 4.6-7.4 mg/L [66]
08 Tanzania 8.0-12.7 mg/L [67]
09 Rift Valley, Uganda 0.5-2.5 mg/L [68]
10 Abu Deleig and Jebel Gaili, Sudan 0.65–3.2 mg/L [69,70]
11 Hail, Saudi Arabia 2.8 mg/L [71]
12 Mecca, Saudi Arabia 2.5 mg/L [72]
13 Middle and eastern part of Turkey 13.7 mg/L [46]
14 Alberta, Canada 4.3 mg/L [46,73,74]
15 Saskatchew, Canada 2.3 mg/L [73]
16 Quebec, Canada 2.5 mg/L [73]
17 Rigolet, Canada 0.1–3.8 mg/L [73]
18 Coronel Dorrego,Argentina 0.9–18.2 mg/L [75]
19 Olho D’Agua, Brazil 2–3 mg/L [76]
20 Wonji-Shoa sugar estates, Ethiopia 1.5–177 mg/L [77,78]
21 Hermosillo and Abasolo, Mexico 1.5 to 2.8 mg/L [79]
22 Illinois, USA 1.06-4.07 mg/L [80]
23 Texas, USA 0.3-4.3 mg/L [81]
24 Czech republic >3 mg/L [82]
25 Munster, Germany 8.8 mg/L [83]
26 Pohang and Gyeongju, Korea >5 mg/L [84]
27 Hordaland, Norway 0.02–9.48 mg/L [85]
28 Northern and Central Poland >3 mg/L [86]
29 Tenerife, Spain 2.50-4.59 mg/L [87]
30 Kuitan, Chaina 21.5 mg/L [7,88]
31 Finland >3 mg/L [89]
32 Japan 1.4 mg/L [90]
33 Indonesia 0.1–4.2 mg/L [7]
34 Thailand >0.9 ppm [91]
35 North Central Province, Sri Lanka 10 mg/L [92]
35 India 0.5-69.7 mg/L [7,93-95]
37 Naranji, Pakistan 8–13.52 mg/L [96]
Fluoride toxicity

In Animals: Chronic exposure to F induces an array of deleterious impacts in livestock animals, experimental animals, as well as humans also [6,97,98]. First symptoms of chronic F toxicity in animals are reduced feed intake and body weight gain (BWG) loss [19,22]. Prolonged exposure to F causes fluorosis, leading to a progressive degenerative disease, dental mottling and several types of skeletal dysfunctions [4]. Main mechanism of these deformities, after exposure of F is mainly the generation of different types of ROS production (Table 3). Experimental evidence (Tables 4,5) has indicated that exposure to fluoride results in oxidative stress both in vitro and in vivo in soft tissues such as liver, kidney, brain, lungs etc. Fluoride inhibits the activities of antioxidant enzymes like superoxide dismutase, glutathione peroxidase and catalase and reduces levels of glutathione. Glutathione reduction leads to overproduction of reactive oxygen species at the mitochondrial level, resulting in damage of cellular components. Besides, production of excessive reactive oxygen species results in oxidation of macromolecules, membrane phospholipid breakdown, lipid peroxidation, mitochondrial membrane depolarization and apoptosis (Tables 4,5). Neurodegeneration also occurred due to the F exposure. Several studies indicated that hippocampus of rat brain can lead to the degenerate due to the imbalance between oxidant– antioxidant balance. F crossed the blood brain barrier (BBB) easily and induces neural cell degeneration [24,99-101]. All the effects of fluoride are summarized in the Tables 4,5.

Table 3: Summary of reactive oxygen and nitrogen species [Source: 28]
Reactive Oxygen Species   Reactive Nitrogen Species
Free Radicals Other Substances   Free Radicals Other Substances
Superoxide anion radical O2• − Hydrogen peroxide H2O2   Nitric oxide radical NO• Peroxynitrite ONOO−
Hydroxyl radical HO• Hypochlorous acid HOCl   Nitric dioxide radical NO2• Nitrites NO2-
Alkoxyl radical RO• Ozone O3       Nitrates NO3-
Peroxyl radical ROO• Singlet oxygen 1O2       Nitrosyl NO+
Table 4: Modulation of different oxidative biomarkers during hepatic oxidative damages occurs on high exposure of fluoride.
Type of the study Model & Dosage End point* References
In-vitro
(Animal cells)		 Mouse pancreatic beta-cells (ßTC-6) at 1.35 and 2.5mM for 12 h ↑Generation of O2−,
↓activity of SOD,
↓Δψ m		 [102]
Primary rat hippocampal neurons at 20, 40, and 80 mg/l, equivalent to 1.05, 2.1 and 4.2mM for 24 h ↑Generation of ROS,
↓level of GSH,
↓activities of GSH-Px, and SOD,
↑lipid peroxidation		 [103]
Murine hepatocytes at 100mM for 1 h ↑Generation of ROS,
↓level of GSH,
↓GSH:GSSG ratio,
↓activities of SOD, and catalase,
↑lipid peroxidation, and oxidation of proteins		 [104]
In-vitro
(Human Cells)		 Hepatocellular carcinoma (HepG2) cells at 3mM for 6 and 24 h ↓GSH/GSSG ratio,
↑gene expression of Mn-SOD		 [105]
Neuroblastoma (SH-SY5Y) cells exposed at 0.05–5mM for 24 h ↑Lipid peroxidation, and ↑protein oxidation [106]
In vivo
(Animals)		 Male albino guinea pigs exposed at 250mg NaF/kg subcutaneously and sacrificed 8 h later ↑Generation of NO in blood [107]
Male Wistar rats exposed at 5mg/kg body mass/day, orally for 8 weeks ↑Generation O2−,
↓activity of SOD,
↓Δψm,
↑lipid peroxidation in
spermatozoa		 [108]
Male Swiss mice exposed at 50 mg/l in drinking water for 10 weeks ↑Generation of ROS,
↑lipid peroxidation,
↓activities of SOD, and catalase,
↑activities of GST, and GSH-Px,
↓ratio GSH:GSSG in brain		 [109]
  Albino rats exposed at 100 mg/l in drinking water for 4 months ↑Level of ascorbic acid
↓ level of uric acid in plasma
↑Lipid peroxidation,
↑level of GSH,
↑activity of GSH–Px,
↓activity of SOD in erythrocytes
↑Lipid peroxidation,
↑activities of GSH-Px, and GST,
↑GSH in brain and liver		 [109]
Male albino Wistar rats exposed at 1, 10, 50, and 100 mg/l in drinking water for 12 weeks ↑Generation ROS, changes in levels of GSH in blood,
↑generation ROS in liver, kidney, and brain		 [110]
Second generation of Male Albino adult Wistar rats exposed at 10, 50, and 100 mg/l in drinking water for 180 days ↑Lipid peroxidation,
↓activities of SOD, catalase, and GSH-Px in lung		 [111]
Chicks exposed by diet to 100, 250, or 400mg F/kg for 50 days ↑Generation of NO,
↑lipid peroxidation,
↓activities of SOD, catalase, and GSH-Px in serum		 [112]
Male albino rats exposed at 10.3mg NaF/kg body weight/day, orally for 5 weeks ↑Lipid peroxidation,
↑generation NO,
↓activities of SOD, and catalase,
↓Total antioxidant capacity, and
↓level of GSH in liver		 [113]
Pig exposed to food supplemented with 250mg F/kg for 50 days ↓Expression of gen Cu/Zn SOD in liver [114]
Male rats exposed at 20 mg/kg/day for 29 days by oral gavage ↑Level of conjugated dienes in the testis, epididymis, and epididymal sperm pellet.
↓activities of GDH-Px, and catalase in the sperm		 [115]
Male Wistar rats exposed at 50 and 100 mg/l in drinking water during 4 months ↓Activity of CuZn-SOD in pancreas [116]
Male and female Wistar rats exposed at 50, 100, and 150 mg/l in drinking water during 3 months ↑Lipid peroxidation,
↓activities of SOD, and GSH-Px in liver		 [116]
Barrows exposed at 250 and 400 mg/kg (from NaF) in their diets for 50 days ↑Generation of NO,
↑lipid peroxidation,
↓activities of GSH–Px, and SOD in serum
↑Lipid peroxidation,
↓activities of GSH-Px, and SOD in thyroid, liver,
and kidney		 [117]
Male Swiss mice exposed at 5mg/kg body mass/day, orally for 8 weeks ↑ROS in erythrocytes,
↓level of GSH in blood,
↓activities of SOD, catalase, and GSH-Px,
↑lipid peroxidation, in kidney and liver		 [118]
Female rats exposed at 100 mg/l in drinking water for 60 days ↑Lipid peroxidation,
↓activities of SOD, catalase, and GSH-Px in
endometrium		 [119]
  Swiss albino male mice exposed at 50 mg/l in drinking water for 3 weeks ↑Generation of ROS,
↓GSH level,
↓activity of SOD in blood,
↑activity of catalase in liver		 [120]
Male albino rats exposed at 10, 50 and 100 mg/l in drinking water for 10 weeks ↑Generation ROS in blood, liver, kidney, and brain
↓GSH/GSSG ratio in liver, kidney, and brain		 [121]
Female Albino mice exposed 5mg/kg body weight/day, orally for 30 days ↓Activities of SOD, catalase, and GSH–Px,
↓level of GSH,
↓total, dehydro and reduced ascorbic acid,
↑lipid peroxidation in ovary		 [122]
Male Balb/c mice exposed at 200 mg/l, in drinking water for 7 days ↓Activities of SOD, GSH-Px, and catalase,
↑lipid peroxidation, in erythrocytes, and liver		 [123]
Female Wistar rats exposed at 150 mg/l in drinking water for 28 days ↓Level of GSH,
↓activities of SOD, GPx, catalase and, glutathione reductase,
↑lipid peroxidation in brain		 [101]
Wistar albino pups placentally and lactationally exposed from mother rats at 50, and 150 mg/l in drinking water ↑Lipid peroxidation,
↑protein oxidation in developing central nervous
system		 [124]
In-vivo
(Human Cells)		 Residents from China-endemic area (mean urine concentration of 2mg F/l) ↓Activities of SOD, catalase, and GSH-Px
↑Lipid peroxidation, in serum		 [125]
Children with skeletal fluorosis from Indian-endemic area (mean water concentration of 5.53mg F/l) ↑Level of ascorbic acid,
↓level of uric acid in plasma
↑Lipid peroxidation,
↓GSH,
↓activities of SOD and GSH–Px in erythrocytes		 [126]
*Arrows refer to increases (↑) or decreases (↓) regulation [Source: 28].
Table 5: Regulation of apoptotic and cytokines related gene expression by fluoride exposure [Source: 28].
Type of the study Model & Dosages End point References
In vitro
(Human cells)		 Neuroblastoma (SH-SY5Y) cells at 40, and 80 mg/l, equivalent to 2.1, and 4.2mM for 24 h ↑Apoptosis molecules Fas, Fas-L, and caspases 3 and 8. [127]
In vivo
(Humans)		 Peripheral blood mononuclear cells from Mexican individuals drinking water with levels of 1.9–4.02mg F/l ↓Inflammatory Chemokines (CCL1, CCL18, CCL19), ↓cytokines (IL-11; IL-2), ↓pro- and anti-inflammatory molecules (LTA, TNF-a, TGF-a, TGF-b1,and TGF-b3), ↓Apoptosis molecules (TNF-a, FasL, CD30L, 4-IBBL, TANK, TRAIL, DR3, Casp-2, Casp6, CIDE-A and CIDE-B), ↑survivine [128]
Arrows refer to increases (↑) or decreases (↓) genes regulation.
Amelioration of fluoride toxicity

Recently, various studies have been conducted in various fields like development of different techniques to reduce the fluoride level from the water sources directly, use plant metabolites on the experimental animals, and use of different chemical/molecule (melatonin, pineal protein, quercetin etc.). In case of different techniques, several natural and chemical adsorbents such as red soil, charcoal, brick, Waste tea ash, fly-ash, serpentine, alum, Activated carbon, Al-Fe (hydr) oxides, sulfate-doped Fe3O4/Al2O3 nanoparticles, aluminum salts etc have been used (Table 6). On the other hand, use of leaves, seeds, fruit pulps, plant juices of Azadirachta indica, Ficus religiosa, Acacia catechu, Peltiphyllum peltatum and tamarind seeds etc. are also using to reduce the toxic effects of fluoride and summarized in the Table 7. Additionally, some synthetic chemical molecules like melatonin, pineal protein, lycopene, and quercetin, etc. also have the great role to reduce the fluoride induced toxicity. All are summarized in the Table 8.

Table 6: Available technologies for removal of fluoride in water.
Sl. No. Technique for water defluoridation Component Used References
01 Adsorption Al-Fe (hydr)oxides [129]
02 Adsorption Sulfate-doped Fe3O4/Al2O3 nanoparticles [130]
03 Adsorption Waste tea ash [131]
04 Adsorption Neem charcoal [132]
05 Adsorption Calcined bauxite, gypsum, magnesite and their composite filter [133]
06 Adsorption Activated alumina [134-136]
07 Adsorption Bone char [67,137]
08 Adsorption Activated carbon [138,119]
09 Adsorption Palm
kernel shell-based adsorbent		 [140]
10 Adsorption Rice husk and activated
charcoal		 [141]
11 Anion Exchange Leaf Biomass [142]
12 Electrochemical method - [143]
13 Coagulation Aluminum salts [144]
14 electro- dialysis - [145]
15 Reverse osmosis - [146]
16 Nanofiltration - [147]
17 Membrane processes - [148]
Table 7:Experimental studies on plant based natural products in amelioration of fluoride toxicity.
Sl. No. Species of experimental animals Fluoride dose and route of administration Duration of study Dose and route plants Effect on studied parameters References
01. Adult male Wistar albino rats 10.3 mg/kg bw/day; Oral 35 days Black berry juice, 1.6 g/kg bw administered perorally ↑Glutathione level, total anti-oxidant capacity and superoxide dismutase activity [149]
02. Adult albino mice 600-ppm NaF; Oral 45 days Ginseng Extract, 50, 150, and 250 mg/kg bodyweight/day, administered perorally ↑ of TCA enzymes (ICDH, SDH,
and aconitase) were noted in brain regions  		 [150]
03. Adult albino mice 600-ppm NaF; Oral 45 days Banaba Extract, 50, 150, and 250 mg/kg bodyweight/day, administered perorally ↑ of TCA enzymes (ICDH, Succinate dehydrogenase (SDH),
and aconitase) were noted in brain regions		 [151]
04. Adult female albino mice 1030.675 mg m3; Oral 14 day Gallic acid
of Peltiphyllum peltatum.10-20 mg/kg bw/day, i.p.		 ↑Succinate dehydrogenase (SDH), Catalase and superoxide dismutase enzyme activities and glutathione levels [152]
06. Male Swiss albino mice NaF at a dose of 600 ppm; Oral 14 days Ethanol extract of the bark of Terminalia arjuna. 50 mg/kg of body weight, administered perorally ↑Heart SOD,
↑GPx, ↑GR, ↑GSH, ↑ CAT ↓SGOT, ↓ ALP 		[153]
07. Colony-bred male albino rats NaF at a dose of 100 ppm; administered perorally 30 days Tamarindus indica leaf powder, 2.5 to 10 g% of feed administered through diet ↓Plasma glucose, ↓Lipid levels, ↓Lipid peroxidation,
↑Hepatic glycogen content, ↑Hexokinase activity, ↑ Cholesterol excretion, imrovement in
antioxidant profiles of both hepatic and renal tissues		 [154]
Table 8:Experimental studies supporting protective effect of melatonin, epiphyseal (pineal) proteins, quercetin, and lycopene in amelioration of fluoride toxicity.
Sr. No. Species of experimental animals Melatonin dose and route of administration Duration of study Dose and route of fluoride exposure Effect on studied parameters References
Melatonin
01. Adult female albino mice 10 mg/kg bw/day; i.p. 30 days 10 mg/kg bw/day, administered perorally ↑Liver ALP, ACP, SDH, SGOT, SGPT, liver weight, body weight, Liver protein content [155]
02. Young Wistar rats 10 mg/kg bw/day; administered perorally 60 days NaF 4 mg/kg bw/day; administered perorally ↓TBARS and ROS in brain tissues , ↑ GSH and GPx brain tissue, attenuation of NaF induced rise in brain levels of TNF-α [156]
03. Adult female Wistar rats 10mg/kg bw/day; i.p. 28 days 150 ppm in drinking water, administered perorally ↓MDA (LPO)
levels in cardiac, hepatic, and renal tissues, ↑CAT, ↑SOD, ↑GPx, and ↑GR activities and ↑GSH		 [157]
04. Adult female Wistar rats 10 mg/kg, bw/day; i.p. 28 days 150 ppm in drinking water, administered perorally ↓ [Na+], [K+], and ALP levels, ↑plasma glucose. [158]
05. Adult female albino mice 10 mg/kg bw/day; i.p. 30 day 10 mg NaF/kg bw/day, administered perorally ↑Succinate dehydrogenase (SDH), ↑ protein and creatinine levels, ↑Acid phosphatase (ACP) and ↑ alkaline phosphatase (ALP), ↓ Lipid peroxidation (LPO) and Glutathione (GSH) [159]
06. Adult female Wistar rats 10 mg/kg bw/day; i.p. 28 days 150 ppm in drinking water, administered perorally ↑plasma glucose, ↓Plasma creatinine, ↓urea, ↓BUN,
↓cholesterol, ↓K+,  ↓Na+ ,↓ SGPT, ↓SGOT, ↓ ALP
plasma ↓Na+, ↓ALP, and ↓cholesterol 		[160]
07. Adult female Swiss-strain albino mice 10 mg/kg bw/day; i.p. 30 days 10 mg/kg bw/day, administered perorally Lowered the level of lipid peroxides and enhanced the antioxidant status. [161]
08. Adult female Wistar rats 10 mg/kg
bw/day; i.p. 		28 days 150 mg/L administered perorally ↓Brain MDA , ↑SOD,
↑GPx, ↑GR, ↑GSH, ↑ CAT 		[101]
09. Mature male Wistar rats 10 mg/kg bw/day; i.p. 60 days 5 and 10 mg NaF/kg bw, administered perorally ↑Lipid peroxidation (LPO),
↑glutathione peroxidase (GPx), ↑glutathione (GSH),
↑total ascorbic acid (TAA), ↑glutathione-S-transferase (GST), ↑glutathione reductase
(GR), ↑superoxide dismutase (SOD), and ↑catalase (CAT) in the testiculare cells		 [162]
10. Human red blood cells (Male) 5 μg/mL and 10 μg/mL 4 hr at 37ºC 50–500 μg NaF/mL in a final normal saline volume of 4.0 mL Significant reduction in F-induced hemolysis with maximum amelioration occurring at 10 μg/mL [163]
Epiphyseal (pineal) proteins
01. Adult female Wistar rats 100 µg/kg bw/day; i.p. 28 days 150 ppm
administered perorally 		↓MDA (LPO)
levels in cardiac, hepatic, and renal tissues, ↑CAT, ↑SOD, ↑GPx, ↑GR and ↑GSH		 [156]
02. Adult female Wistar rats 100 μg/kg, bw/day; i.p. 28 days 150 ppm,
administered perorally 		Plasma reduction of [Na+], [K+], and ALP levels, increases in the plasma glucose [157]
03. Adult female Wistar rats 100 μg/kg bw/day; i.p. 28 days 150 ppm administered perorally ↑Plasma glucose, ↑Plasma creatinine, ↑urea, ↑BUN,
↑cholesterol, ↑K+, and ↑Na+ ,↓SGPT, ↓SGOT, ↓ALP,
↑Plasma Na+, ↑ALP, and ↑cholesterol 		[159]
04. Adult female Wistar rats 100 μg/kg bw/day; i.p. 28 days 150 mg/L administered perorally ↓Brain MDA,↑SOD,
↑GPx, ↑GR, ↑GSH, ↑CAT 		[101]
05. Adult female
Wistar rats		 100 μg/kg bw/day; i.p. 14 days 150 ppm, administered perorally ↑AChE activity in plasma, RBCs, heart, and brain. [164]
06. Adult female
Wistar rats		 50, 100, and
200 μg/kg bw/day; i.p. 		21 days 150 ppm, administered perorally ↓ Plasma F, lipid peroxidation (LPO), ↓alkaline
phosphatase (ALP), ↑plasma and RBCs acetyl cholinesterase (AChE) activity. ↓Plasma and RBCs LPO Red blood cells (RBCs). ↑RBCs
GSH, CAT, GR, and GPx level. 		[165]
Quercetin
01. Male Wistar rats NaF at a dose of 600 ppm; administered perorally 14 days Quercetin 10 to 20 mg/kg; i.p. ↓Kidney Glutathione (GSH), ↓LPO, ↓ Superoxide dismutase (SOD), ↓ catalase activity [4]
Lycopene
01. Adult male albino rats NaF 10.3 mg/kg body weight/day, administered perorally 35 days Lycopene (10 mg/kg body weight/day), administered perorally ↑Glutathione level, total anti-oxidant capacity and superoxide
dismutase activity 		[166]

Conclusions

Through this review, it is summarized that having the electronegativity, fluoride is ubiquitously present in the environments. In some countries it is within the range, whereas most of the countries which have been reviewed showed more than the permissible level as per guideline recommended by WHO. Among different sources, water is the important source of fluoride exposure. Hence, water purification techniques should be developed for safe and economic method for portable water. High fluoride exposure affects human beings and animals health through oxidative stress, immune suppression, apoptosis, and affecting nutrient utilization. Hence, ameliorative measures are important to prevent their endemicity and disease progress. Meanwhile, plant bioactive molecules, several synthetic molecules, and pineal gland secretions have shown protective effect against fluoride toxicity. However, more extensive studies are required for wide application of these molecules as therapeutics agents.

  1. Jentsch TJ, Stein V, Weinreich F, Zdebik AA (2002) Molecular structure and physiological function of chloride channels. Physiol Rev 82: 503–568. Link: https://goo.gl/28dJtp
  2. Edwards JC, Kahl CR (2010) Chloride channels of intracellular membranes. FEBS Lett 584: 2102–2111. Link: https://goo.gl/CGDqTs
  3. Zimmermann MB (2011) The role of iodine in human growth and development. Semin Cell Dev Biol 22: 645–652. Link: https://goo.gl/F5pIa0
  4. Nabavi SM, Nabavi SF, Eslami S, Moghaddam AH (2012) In vivo protective effects of quercetin against sodium fluoride-induced oxidative stress in the hepatic tissue. Food Chem 132: 931–935. Link: https://goo.gl/IHEO8G
  5. Jagtap S, Yenkie MK, Labhsetwar N, Rayalu S (2012) Fluoride in drinking water and defluoridation of water. Chem Rev 112: 2454–2466. Link: https://goo.gl/9fdnB3
  6. Weinstein LH, Davison A (2004) Fluorides in the environment: effects on plants and animals. CABI Publishing, Cambridge. Link: https://goo.gl/bPwLXC
  7. WHO (2006). World Health Organization, Fluoride in Drinking water, Fawell J, Bailey K, Chilton J, Dahi E, Fewtrell L, and Magara Y, Eds., IWA Publishing, Alliance House, 12 Caxton Street, London SW1H 0QS, UK, 41–75. Link: https://goo.gl/aIhF6h
  8. WHO (2003). Background Document for Preparation of WHO Guidelines for Drinkingwater Quality. Fluoride in Drinking-water. Geneva: WHO. Link: https://goo.gl/4YSqwa
  9. U.S. Environmental Protection Agency. (2003) Ground Water and Drinking Water. Drinking Water Contaminants (Online 2003). Link: https://goo.gl/8qPCS2
  10. European Commission. (2011) “Critical review of any new evidence on the hazard profile, health effects, and human exposure to fluoride and the fluoridating agents of drinking water,” Scientific Committee onHealth and Environmental Risks (SCHER). Link: https://goo.gl/fn283a
  11. Planning Commission, India. (2007) Eleventh five-year plan approach paper. Rural watersupplyandsanitation. Link: https://goo.gl/VgUWJk
  12. Franzaring J, Klumpp A, Fangmeier A (2007) Active Biomonitoring of Airborne Fluoride near an HF Producing Factory Using Standardized Grass Cultures. Atmos Environ 41: 4828- 4840. Link: https://goo.gl/GWku0c
  13. Alves ES, Moura BB, Domingos M (2008) Structural Analysis of Tillandsia usneoides L. Exposed to Air Pollutants in São Paulo City-Brazil. Water Air Soil Pollu, 189: 61-68. Link: https://goo.gl/tZOEpo
  14. Reddy MP, Kaur M (2008) Sodium fluoride induced growth and metabolic changes in Salicornia brachiata Roxb. Water Air Soil Pollut 188: 171-179. Link: https://goo.gl/TUhXeP
  15. Lovelace CJ, Miller GW (1967) In vitro effects of fluoride on tricarboxylic acid cycle dehydrogenases and oxidative phosphorylation: Part I. J Histochem Cytochem 15: 195-201. Link: https://goo.gl/4pAqBe
  16. Melchior NC, Melchior JB (1956) Inhibition of yeast hexokinase by fluoride ion. Sci 124: 402-403.
  17. Lee C, Miller GW, Welkie GW (1965) The effects of hydrogen fluoride and wounding on respiratory enzymes in soybean leaves. Air Water Pollut Int J 10: 169-181.
  18. Miller JE, Miller GW (1974) Effects of fluoride on mitochondrial activity in higher plants. Physiol Plant 32: 115–121. Link: https://goo.gl/sguKvD
  19. Khandare AL, Kumar PU, Shankar HN. (2007) Effect of calcium deficiency induced by fluoride intoxication on lipid metabolism in rabbits. Fluoride 40: 184–189. Link: https://goo.gl/UWS01J
  20. Coetzee PP, Coetzee LL, Puka R, Mubenga1 S (2003) Characterization of selected South African clays for defluoridation of natural waters. Water SA 29: 331–338. Link: https://goo.gl/GniZ6V
  21. Dunipace AJ, Edward JB, Wilson ME (1998) Chronic fluoride exposure does not cause detrimental, extra skeletal effects in nutritionally deficient rats. J Nutr 128: 1392–1400. Link: https://goo.gl/N8G15g
  22. Lohakare J, Pattanaik A, Khan SA (2010) Effect of long-term fluoride exposure on growth, nutrient utilization and fluoride kinetics of calves fed graded levels of dietary protein. Biol Trace Elem Res 138: 148–162. Link: https://goo.gl/lzBFk5
  23. Heber D (2010) Pomegranate. Chapter 30. In Nutrition and Health: Bioactive Compounds and Cancer. Edited by J.A. Milner and D.F. Romagnolo. Humana Press, c/o Springer Science and Business Media LLC, New York 725-734. Link: https://goo.gl/QoGK92
  24. Nabavi SF, Eslami SH, Moghaddam AH, Nabavi SM (2011) Protective effects of curcumin against fluoride-induced oxidative stress in the rat brain. Neurophysiol 43: 287-291. Link: https://goo.gl/VRqZVv
  25. Nabavi SM, Nabavi SF, Eslami S, Moghaddam AH (2012a) In vivo protective effects of quercetin against sodium fluoride-induced oxidative stress in the hepatic tissue. Food Chem 132: 931-935. Link: https://goo.gl/eQA1JV
  26. Nabavi SF, Nabavi SM, Abolhasani F, Moghaddam AH, Eslami S (2012b) Cytoprotective effects of curcumin on sodium fluoride induced intoxication in rat erythrocytes. Bull Environ Contam Toxicol 88: 486-490. Link: https://goo.gl/xxeyxK
  27. Finger GC (1961) Fluorine Resources and Fluorine Utilization. Adv Fluorine Chem 2: 35-54.
  28. Giri A, Bharti VK, Angmo K, Kalia S, Kumar B (2016) Fluoride versus Oxidative stress, Immune System and Apoptosis in Animals: a Review. Int J Bioass 5: 5163-5173. Link: https://goo.gl/1QiNES
  29. Department of Health and Human Services. (1991) Report of the subcommittee on fluoride of the Committee to Coordinate Environmental Health and Related Programs, USPHS. Review of fluoride: benefits and risks. Public Health Service. Link: https://goo.gl/SF4MCG
  30. Cengeloglu Y, Esengul K, Ersoz M (2002) Removal of Fluoride from aqueous Solution by Using red mud. Sep Pur Tech 28: 81-86. Link: https://goo.gl/Dn1unl
  31. Susheela AK (1999) Fluorosis management programme in India. Curr Sci India 77: 1050–1256. Link: https://goo.gl/V4VjHH
  32. Bombik E, Bombik A, Gorski K, Saba L, Bombik T, et al. (2011) Effect of Environmental Contamination by Fluoride compounds on selected horse tissues. Polish J Environ Stud 20: 37-43. Link: https://goo.gl/Ev5Ob6
  33. Begum A (2012) Soil Profiles and Fluoride Adsorption in Intensely Cultivated Areas of Mysore District, Karnataka, India. Chem Sci Trans 1: 410-414. Link: https://goo.gl/d1YElI
  34. Blagojevic S, Jakovljevic M, Radulovic M (2002) Content of Fluorine in Soils In The Vicinity of Aluminium Plant in Podgorica. J Agricul Sci 47: 1‑8. Link: https://goo.gl/pzHtdc
  35. Ericson B, Hanrahan D, Kong V (2014) The world’s worst pollution problems; the top ten of the toxic twenty. Link: https://goo.gl/4saMAJ
  36. Li C, Gao X, Wang Y (2014) Hydrogeochemistry of high-fluoride groundwater at Yuncheng Basin, northern China. Sci Total Environ 508C: 155–165. Link: https://goo.gl/FA4STx
  37. NRC (1960) The Fluorosis problem in livestock production. A report of the NRC committee on animal nutrition. Publication 824, National Research Council, Washington. Link: https://goo.gl/EFXplv
  38. Radostits OM, Gay CC, Blood DC, Hinchcliff KW (2000) Veterinary Medicine, a textbook of the diseases of cattle, sheep, pigs, goats and horses, 9th edn. WB Saunders Company Ltd, London. Link: https://goo.gl/ixXkHL
  39. Mascola JJ, Barth KM, McLaren JB (1974) Fluoride intake of cattle grazing fluoride-contaminated forage, as determined by esophageal-fistulated steers. J Anim Sci 38: 1298–1303. Link: https://goo.gl/xdgvvv
  40. Araya O, Wittwer F, Villa A (1993) Evolution of fluoride concentration in cattle and grass following a volcanic eruption. Vet Hum Toxicol 35: 437–440. Link: https://goo.gl/IDlfgN
  41. Bellomo S, Aiuppa A, D’Alessandro W, Parello F (2007) Environmental impact of magmatic fluorine emission in the Mt. Etna area. J Volcanol Geoth Res 165: 87–101. Link: https://goo.gl/vi0hp9
  42. Thorarinsson S (1979) On the damage caused by volcanic eruptions with special reference to tephra and gases. In: Sheets PD, Grayson DK (eds) Volcanic activity and human ecology. Academic Press, New York, 125–159.
  43. SEAN (1989) Lonquimay, continued tephra emission: cattle sickened by ash. Scientific Event Alert Network Bull, Smithsonian Institution 14: 2–3.
  44. Armienta MA, de La Cruz-Reyna S, Cruz O, Ceniceros N, Aguayo A, et al. (2011) Fluoride in ash leachates: environmental implications at popocatepetl volcano, central Mexico. Nat Hazards Earth Syst Sci 11: 1949–1956. Link: https://goo.gl/Y2qCZr
  45. Flueck WT, Smith-Flueck JA (2013) Severe dental fluorosis in juvenile deer linked to a recent volcanic eruption in Patagonia. J Wildlife Dis 49: 355–366. Link: https://goo.gl/oQO8DP
  46. WHO (2002) World Health Organization, Geneva, Fluorides, Environmental Health Criteria, 227.
  47. Paul ED, Gimba CE, Kagbu JA, Ndukwe GI, Okibe FG (2011) Spectrometric Determination of Fluoride in Water, Soil and Vegetables from the Precinct of River Basawa, Zaria, Nigeria. J Basic Appl Chem 1: 33-38. Link: https://goo.gl/c95FyM
  48. WHO (2000) Fluorides. In: Chapter 6.5 Air quality guidelines, 2nd edn. WHO regional office for Europe, World Health Organization, Copenhagen.
  49. Guijian L, Liugen Z, Duzgoren-Aydin NS, Lianfen G, Junhua L et al. (2007) Health effects of arsenic, fluorine, and selenium from indoor burning of Chinese coal. Rev Environ Contam Toxicol 189: 89–106. Link: https://goo.gl/Sf7JAD
  50. Swarup D, Dwivedi SK (2002) Environmental pollution and effects of lead and fluoride on animal health. Indian Council of Agricultural Research, Pusa, New Delhi. Link: https://goo.gl/3d5B5B
  51. Swarup D, Dey S, Patra RC, Dwivedi SK, Ali SL (2001) Clinico-epidemiological observation of industrial bovine fluorosis in India. Indian J Anim Sci 71: 1111–1115. Link: https://goo.gl/rPNGGc
  52. Patra RC, Dwivedi SK, Bhardwaj B, Swarup D (2000) Industrial fluorosis in cattle and buffalo around Udaipur, India. Sci Total Environ 253: 145–150. Link: https://goo.gl/is32K0
  53. Sahoo N, Singh PK, Ray SK, Bisoi PC, Mahapatra HK (2003) Fluorosis in sheep around an aluminium factory. Indian Vet J 80: 617–621. Link: https://goo.gl/zSW3gJ
  54. Sahoo N, Ray SK (2004) Fluorosis in goats near an aluminium smelter plant in Orissa. Indian J Anim Sci 74: 48–50. Link: https://goo.gl/WPKkDk
  55. Karram MH, Ibrahim TA (1992) Effect of industrial fluorosis on haemogram of camels. Fluoride 25: 23–36. Link: https://goo.gl/dh5oDh
  56. Singh JL, Swarup D (1995) Clinical observations and diagnosis of fluorosis in dairy cows and buffaloes: case report. Agri Practice 16: 25–30.
  57. Chinoy JN (1991) Effects of fluoride on physiology of animals and human beings. Indian J Environ Toxicol 1: 17-32.
  58. Grobler SR, Dreyer AG, Blignaut RJ (2001) Drinking water in South Africa: Implications for fluoride supplementation. J South Afr Dent Assoc 56: 557–559. Link: https://goo.gl/7xnSHG
  59. Mothusi B (1998) Psychological effects of dental fluorosis, Fluoride and Fluorosis, The Status of South African Research, Pilanesberg National Park, North West Province, 7, (1995): as cited in Muller WJ, Heath RGM, Villet MH, Finding the optimum: Fluoridation of potable water in South Africa. Water SA, 24: 1–27.
  60. WHO (2005) World Health Organization, Geneva, Switzerland. Link: https://goo.gl/woF1q5
  61. Apambire WB, Boyle DR, Michel FA (1997) Geochemistry, genesis, and health implications of fluoriferous ground waters in the upper regions of Ghana. Environ Geol 33: 13–24. Link: https://goo.gl/CeENsA
  62. Kaimenyi TJ (2004) Oral health in Kenya. Int Dent J 54: 378–382. Link: https://goo.gl/VKAjUS
  63. Nair KR, Manji F (1982) Endemic fluorosis in deciduous dentition—A study of 1276 children in typically high fluoride area (Kiambu) in Kenya. Odonto-Stomatologie Tropicale 4: 177–184. Link: https://goo.gl/GXKvU4
  64. Nair KR, Manji F, Gitonga JN (1984) The occurrence and distribution of fluoride in groundwaters in Kenya. East Afr J Med 61: 503–512. Link: https://goo.gl/rhgcUL
  65. Wongdem JG, Aderinokun GA, Sridhar MK, Selkur S (2000) Prevalence and distribution pattern of enamel fluorosis in Langtang town, Nigeria. Afr J Med Medical Sci 29: 243–246. Link: https://goo.gl/rWqVEw
  66. Brouwer ID, Dirks OB, De-Bruin A, Hautvast JGAJ (1988) Unsuitability of World Health Organization guidelines for fluoride concentrations in drinking water in Senegal. Lancet 30: 223–225. Link: https://goo.gl/282Cqj
  67. Mjengera H, Mkongo G (2003) Appropriate deflouridation technology for use in flourotic areas in Tanzania. Physics Chem Earth 28: 1097–1104. Link: https://goo.gl/sWTTM7
  68. Rwenyonyi CM, Birkeland JM, Haugejorden O, Bjorvatn K (2000) Age as a determinant of severity of dental fluorosis in children residing in areas with 0.5 and 2.5 mg fluoride per liter in drinking water. Clin Oral Invest 4: 157–161. Link: https://goo.gl/fNLxny
  69. Ibrahim YE, Affan AA, Bjorvatn K (1995) Prevalence of dental fluorosis in Sudanese children from two villages with respectively 0.25 mg/L and 2.56 mg/L F in the drinking water. Int J Paediatr Dent 5: 223–229. Link: https://goo.gl/3K3OQL
  70. Smith DA, Harris HA, Kirk R (1953) Fluorosis in the Butana, Sudan. J Tropic Med Hyg 56: 57–58. Link: https://goo.gl/wd3zrZ
  71. Al-Khateeb TL, Al-Marasafi AI, O’Mullane DM (1991) Caries prevalence and treatment need amongst children in an Arabian community. Commun. Dentistry Oral Epidemiol 19: 277–280. Link: https://goo.gl/lJVBxY
  72. Akpata ES, Fakiha Z, Khan N (1997) Dental fluorosis in 12–15-year-old rural children exposed to fluorides from well drinking water in the Hail region of Saudi Arabia. Comm Dentistry Oral Epidemiol 25: 324–327. Link: https://goo.gl/OAmBxw
  73. Health Canada (1993) Priority Substances List Assessment Report on Inorganic Fluorides, Canadian Environmental Protection Act, Minister of Supply and Services Canada, Canada Communication Group-Publishing, Ottawa, Canada K1A 0S9, 12–19. Link: https://goo.gl/llzi4a
  74. Ismail AI, Messer JG (1996) The risk of fluorosis in students exposed to a higher than optimal concentration of fluoride in well water. J Public Health Dent 56: 22–27. Link: https://goo.gl/usvYm7
  75. Paoloni JD, Fiorentino CE, Sequeira ME (2003) Fluoride contamination of aquifers in the southeast subhumid pampa, Argentina. Environ Toxicol 18: 317–320. Link: https://goo.gl/iIZosO
  76. Cortes DF, Ellwood RP, O’Mullane DM, de Magalhaes Bastos JR (1996) Drinking water fluoride levels, dental fluorosis and caries experience in Brazil. J Public Health Dentistry 56: 226–228. Link: https://goo.gl/RqfSlb
  77. Haimanot RT, Fekadu A, Bushra B (1987) Endemic fluorosis in the Ethiopian Rift Valley. Tropic Geogr Med 39: 209–217. Link: https://goo.gl/6NkJq2
  78. Kloos H, Tekle-Haimanot R, Kloos H, Zein AH (1993) The Ecology of Health and Disease in Ethiopia, Westview Press, Boulder, CO, 445–541.
  79. Diaz-Barriga F, Navarro-Quezada A, Grijalva MI, Grimaldo M, Loyola-Rodriguez JP et al. (1997) Endemic fluorosis in Mexico. Fluoride 30: 233–239.
  80. Cohen D, Conrad MH (1998) 65,000 GPD fluoride removal membrane system in Lakeland, California, USA. Desalination 117: 19–35. Link: https://goo.gl/hOkasl
  81. Reardon JE, Wang Y (2000) A limestone reactor for fluoride removal from wastewaters. Environ Sci Technol 34: 3247–3253. Link: https://goo.gl/fKCdDk
  82. Heikens A, Sumart S, vanBergen M, Widianarko B, Fokkert L et al. (2005) The impact of the hyperacid Ijen Crater Lake: Risks of excess fluoride to human health. Sci Tot Environ 346: 56–69. Link: https://goo.gl/GJhB3H
  83. Queste A, Lacombe M, Hellmeier W, Hillermann F, Bortulussi B et al. (2001) High concentrations of fluoride and boron in drinking water wells in the Muenster region—Results of a preliminary investigation. Int J Environ Health 203: 221– 224. Link: https://goo.gl/iZknCh
  84. Kim K, Jeong YG (2005) Factors influencing natural occurrence of fluoride-rich groundwaters: A case study in the southeastern part of the Korean Peninsula. Chemosphere 58: 1399–1408. Link: https://goo.gl/K2y2CJ
  85. Bardsen A, Klock KS, Bjorvatn K (1999) Dental fluorosis among persons exposed to high- and low-fluoride drinking water in western Norway. Commun Dentistry Oral Epidemiol 27: 259–267. Link: https://goo.gl/21NdXZ
  86. Czarnowski W, Wrzesniowska K, Krechniak J (1996) Fluoride in drinking water and human urine in Northern and Central Poland. Sci Total Environ 191: 177–184. Link: https://goo.gl/UyUi99
  87. Hardisson A, Rodriguez MI, Burgos A, Flores LD, Gutierrez R et al. (2001) Fluoride levels in publically supplied and bottled drinking waters in the island of Tenerife. Spain. Bull Environ Contamin Toxicol 67: 163–170. Link: https://goo.gl/rF0qtH
  88. Wang GQ, Huang YZ, Xiao BY, Qian XC, Yao H et al. (1997) Toxicity from water containing arsenic and fluoride in Xinjiang. Fluoride 30: 81–84. Link: https://goo.gl/dvIRx4
  89. Azbar N, Turkman A (2000) Defluoridation in drinking waters. Water Science and Technology. 42: 403–407. Link: https://goo.gl/XQE0vb
  90. Tsutsui A, Yagi M, Horowitz AM (2000) The prevalence of dental caries and fluorosis in Japanese communities with up to 1.4 ppm of naturally occurring fluoride. J Public Health Dentistry 60: 147–153. Link: https://goo.gl/KEdrCB
  91. McGrady MG, Ellwood RP, Srisilapanan P, Korwanich N, Worthington HV et al. (2012) Dental fluorosis in populations from Chiang Mai, Thailand with different fluoride exposures – Paper1: assessing fluorosis risk, predictors of fluorosis and the potential role of food preparation. BMC Oral Health 12: 16. Link: https://goo.gl/rFfy3Q
  92. Dissanayake CB (1996) Water quality and dental health in the Dry Zone of Sri Lanka. Environ Geochem Health 113: 131–140. Link: https://goo.gl/jOsSYw
  93. Ayoob S, Gupta AK (2006) Fluoride in drinking water: a review on the status and stress effects. Crit Rev Environ Sci Technol 36: 433–487. Link: https://goo.gl/Wkh1Q6
  94. Susheela AK (2003) A treatise on fluorosis, revised second edition, Fluorosis Research and Rural Development Foundation, New Delhi, India, 13–14. Link: https://goo.gl/OIDxVj
  95. Jha SK, Nayak AK, Sharma YK (2010) Potential fluoride contamination in the drinking water of Marks Nagar, Unnao district, Uttar Pradesh, India. Environ Geochem Health 32: 217-226. Link: https://goo.gl/YKtBuC
  96. Shah MT, Danishwar S (2003) Potential fluoride contamination in the drinking water of Naranji area, Northwest Frontier Province, Pakistan. Environ Geochem Health 25: 475–481. Link: https://goo.gl/AOX0v8
  97. Choubisa SL (2012) Fluoride in drinking water and its toxicosis in tribals, Rajasthan, India. Proc Nat Acad Sci India Sect B Biol Sci 82: 325-330. Link: https://goo.gl/BTXpaO
  98. Choubisa SL (2015) Industrial fluorosis in domestic goats (Capra hircus), Rajasthan, India. Fluoride 48: 105-112. Link: https://goo.gl/lhOKN6
  99. Patel PD, Chinoy NJ (1998) Influence of fluoride on biological free radical reactions in ovary of mice and its reversal. Fluoride 31: S27.
  100. Eraslan G, Kanbur M, Silici S (2007) Evaluation of propolis effects on some biochemical parameters in rats treated with sodium fluoride. Pest Biochem Physiol 88: 273–283. Link: https://goo.gl/SXqLRo
  101. Bharti VK, Srivastava RS (2009) Fluoride-induced oxidative stress in rat’s brain and its amelioration by buffalo (Bubalus bubalis) pineal proteins and melatonin. Biol Trace Elem Res 130: 131–140. Link: https://goo.gl/BvH6mX
  102. Garcia-Montalvo EA, Reyes-Perez H, del Razo LM (2009) Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress. Toxicol 263: 75–83. Link: https://goo.gl/J3vzdx
  103. Zhang M, Wang AG, He WH (2007) Effects of fluoride on the expression of NCAM, oxidative stress, and apoptosis in primary cultured hippocampal neurons. Toxicol 236: 208–216. Link: https://goo.gl/VmfRKA
  104. Ghosh J, Das J, Manna P (2008) Cytoprotective effect of arjunolic acid in response to sodium fluoride mediated oxidative stress and cell death via necrotic pathway. Toxicol in vitro 22: 1918–1926. Link: https://goo.gl/rnURqR
  105. Morgan KT, Ni H, Brown HR (2002) Application of cDNA microarray technology to in vitro toxicology and the selection of genes for a real-time RT-PCR-based screen for oxidative stress in Hep-G2 cells. Toxicol Pathol 30: 435-451. Link: https://goo.gl/371SMA
  106. Gao Q, Liu YJ, Guan ZZ (2008) Oxidative stress might be a mechanism connected with the decreased alpha 7 nicotinic receptor influenced by high-concentration of fluoride in SHSY5Y neuroblastoma cells. Toxicol In Vitro 22: 837-843. Link: https://goo.gl/qNC3zB
  107. Sireli M, Bulbul A (2004) The effect of acute fluoride poisoning on nitric oxide and methemoglobin formation in the Guinea pig. Turk J Vet Anim Sci 28: 591–595. Link: https://goo.gl/JOeKTE
  108. Izquierdo-Vega JA, Sanchez-Gutierrez M, del Razo LM (2008) Decreased in vitro fertility in male rats exposed to fluoride-induced oxidative stress damage and mitochondrial transmembrane potential loss. Toxicol Appl Pharmacol 230: 352–357. Link: https://goo.gl/vOX7PY
  109. Flora SJ, Mittal M, Mishra D (2009) Co-exposure to arsenic and fluoride on oxidative stress, glutathione linked enzymes, biogenic amines and DNA damage in mouse brain. J Neurol Sci 285: 198–205. Link: https://goo.gl/V9DhQj
  110. Shanthakumari D, Srinivasalu S, Subramanian S (2004) Effects of fluoride intoxication on lipidperoxidation and antioxidant status in experimental rats. Toxicol 204: 219–228. Link: https://goo.gl/nChBcL
  111. Chouhan S, Lomash V, Flora SJS (2010) Fluoride-induced changes in haem biosynthesis pathway, neurological variables and tissue histopathology of rats. J Appl Toxicol 30: 63–73. Link: https://goo.gl/f94rRP
  112. Aydin G, Cic E, Akdogan M, Gokalp O (2003) Histopathological and biochemical changes in lung tissues of rats following administration of fluoride over several generations. J Appl Toxicol 23: 437–446. Link: https://goo.gl/rtCTt3
  113. Liu G, Chai C, Cui L (2003) Fluoride causing abnormally elevated serum nitric oxide levels in chicks. Environ Toxicol Pharmacol 13: 199–204. Link: https://goo.gl/9U8h3r
  114. Hassan HA, Yousef MI (2009) Mitigating effects of antioxidant properties of black berry juice on sodium fluoride induced hepatotoxicity and oxidative stress in rats. Food Chem Toxicol 47: 2332–2337. Link: https://goo.gl/IibpcW
  115. Zhan XA, Wang M, Xu ZR (2006) Effects of fluoride on hepatic antioxidant system and transcription of Cu/Zn SOD gene in young pigs. J Trace Elem Med Biol 20: 83–87. Link: https://goo.gl/0tquA8
  116. Ghosh D, Das S, Maiti R, Jana D, Das U (2002) Testicular toxicity in sodium fluoride treated rats: association with oxidative stress. Reprod Toxicol 16: 385–390. Link: https://goo.gl/U0aMrL
  117. Guo XY, Sun GF, Sun YC (2003) Oxidative stress from fluoride induced hepatotoxicity in rats. Fluoride 36: 25–29. Link: https://goo.gl/yVLwIU
  118. Zhan XA, Xu ZR, Li JX (2005) Effects of fluorosis on lipid peroxidation and antioxidant systems in young pigs. Fluoride 38: 157–161. Link: https://goo.gl/rjuwIF
  119. Mc-Cord JM, Keele BB, Fridovich I (1984) An enzyme based theory of obligate anaerobiosis, the physiological functions of superoxide dismutase. Proc Natl Acad Sci 68: 1024–1027. Link: https://goo.gl/PyLXOU
  120. Guney M, Oral B, Demirin H (2007) Protective effects of vitamins C and E against endometrial damage and oxidative stress in fluoride intoxication. Clin Exp Pharmacol Physiol 34: 467–474. Link: https://goo.gl/sjbWZr
  121. Mittal M, Flora SJS (2007) Vitamin E protects oxidative stress and essential metal imbalance during concomitant exposure to arsenic and fluoride in male mice. Drug Chem Toxicol 30: 263–281. Link: https://goo.gl/VSqhiW
  122. Chouhan S, Flora SJS (2008) Effects of fluoride on the tissue oxidative stress and apoptosis in rats: biochemical assays supported by IR spectroscopy data. Toxicol 254: 61–67. Link: https://goo.gl/8AXH7T
  123. Jhala DD, Chinoy NJ, Rao MV (2008) Mitigating effects of some antidotes on fluoride and arsenic induced free radical toxicity in mice ovary. Food Chem Toxicol 46: 1138–1142. https://goo.gl/wXhFT8
  124. Kanbur M, Eraslan G, Silici S (2009) Effects of sodium fluoride exposure on some biochemical parameters in mice: evaluation of the ameliorative effect of royal jelly applications on these parameters. Food Chem Toxicol 47: 1184–1189. Link: https://goo.gl/kp99Fl
  125. Basha PM, Madhusudhan N (2010) Pre and post natal exposure of fluoride induced oxidative macromolecular alterations in developing central nervous system of rat and amelioration by antioxidants. Neurochem Res 35: 1017–1028. Link: https://goo.gl/r7ApN0
  126. Chen T, Cui Y, Gong T (2009) Inhibition of splenocyte proliferation and spleen growth in young chickens fed high fluoride diets. Fluoride 4: 203-209. Link: https://goo.gl/1ntzY3
  127. Shivarajashankara YM, Shivashankara AR, Gopalakrishna BP (2001) Oxidative stress in children with endemic skeletal fluorosis. Fluoride 34: 103–107. Link: https://goo.gl/3zlHEg
  128. Xu B, Xu Z, Xia T (2011) Effects of the Fas/Fas-L pathway on fluoride-induced apoptosis in SH-SY5Y cells. Environ Toxicol 26: 86-92. Link: https://goo.gl/EWa7SM
  129. Salgado-Bustamante M, Ortiz-Perez MD, Calderon-Aranda E (2010) Pattern of expression of apoptosis and inflammatory genes in humans exposed to arsenic and/or fluoride. Sci Total Environ 408: 760–767. Link: https://goo.gl/X9m6K5
  130. Qiao J, Cui Z, Sun Y, Hu Q, Guan X (2014) Simultaneous removal of arsenate and fluoride from water by Al-Fe (hydr)oxides. Frontiers Environ Sci Eng 8: 169-179. Link: https://goo.gl/MnQCgQ
  131. Chai L, Wang Y, Zhao N, Yang W, You X (2013) Sulfate-doped Fe3O4/Al2O3 nanoparticles as a novel adsorbent for fluoride removal from drinking water. Water Res 47: 4040-4049. Link: https://goo.gl/Zd3CKL
  132. Mondal NK, Bhaumik R, Baur T, Das B, Roy P et al. (2012) Studies on Defluoridation of Water by Tea Ash: An Unconventional Biosorbent. Chem Sci Trans 1: 239-256. Link: https://goo.gl/36J8xV
  133. Chakrabarty S, Patra PK (2013) Effect of sodium fluoride on seed germination, seedling growth and biochemistry of paddy (Oryza sativa L.). Asian J Exp Biol Sci 4: 540-544.
  134. Thole B, Mtalo F, Masamba W, (2012) Effect of particle size on loading capacity and water quality in water defluoridation with 200°C calcined bauxite, gypsum, magnesite and their composite filter. Afri J Pure Appl Chem 6: 26-34. Link: https://goo.gl/9aJIPJ
  135. Ghorai S, Pant KK (2005) Equilibrium, kinetics and breakthrough studies for adsorption of fluoride on activated alumina. Sep Purification Technol 42: 265– 271. Link: https://goo.gl/xTfLIc
  136. Tripathy SS, Bersillon JL, Gopal K (2006) Removal of fluoride from drinking water by adsorption onto alum-impregnated activated alumina. Sep Purific Technol 50: 310–317. Link: https://goo.gl/a523Fm
  137. Chauhan VS, Dwivedi PK, Iyengar L (2007) Investigations on activated alumina based domestic defluoridation units. J Hazardous Materials 139: 103–107. Link: https://goo.gl/ZRriyI
  138. Hernandez-Montoya V, Elizalde-Gonzalez MP, Trejo-Vazquez R (2007) Screening of commercial sorbents for removal of fluoride in synthetic and groundwater. Environ Technol 28: 595–607. Link: https://goo.gl/HfqhqK
  139. Daifullah AAM, Yakout SM, Elreefy SA (2007) Adsorption of fluoride in aqueous solutions using KMnO4-modified activated carbon derived from steam pyrolysis of rice straw. J Hazardous Materials 147: 633–643. Link: https://goo.gl/yDCcbH
  140. Kumar S, Gupta A, Yadav JP (2007) Fluoride removal by mixtures of activated carbon prepared from Neem (Azadirachta indica) and Kikar (Acacia arabica) leaves. Indian J Chem Technol 14: 355–361. Link: https://goo.gl/A7dkPD
  141. Bashir MT, Salmiaton A, Nourouzi MM, Azni I, Harun R (2015) Fluoride removal by chemical modification of palm kernel shell-based adsorbent: a novel agricultural waste utilization approach. Asian J Microbiol Biotech Env Sci 17: 533-542. Link: https://goo.gl/w1I91L
  142. Vardhan C, Karthikeyan J (2011) Removal of fluoride from water using low-cost materials. In: Fifteenth International Water Technology Conference. [Online] Alexandria, Egypt. Link: https://goo.gl/1ghK4y
  143. Wartelle L, Marshall W (2006) Quaternized agricultural by-products as anion exchange resins. J Environ Manage 78: 157-162. Link: https://goo.gl/2s3mco
  144. Shen F, Chen X, Ping G, Chen G (2003) Electrochemical removal of fluoride ions from industrial wastewater. Chem Eng Sci 58: 987– 993. Link: https://goo.gl/pV6s1u
  145. Pinon-Miramontes M, Bautista-Margulis RG, Perez-Hernandez A (2003) Removal of arsenic and fluoride from drinking water with cake alum and a polymeric anionic flocculent. Fluoride 36: 122–128. Link: https://goo.gl/rjlp1o
  146. Tahaikt M, Achary I, Menkouchi SMA, Amor Z, Taky M et al. (2006) Defluoridation of Moroccan groundwater by electrodialysis: continuous operation. Desalination 189: 215– 220. Link: https://goo.gl/Bc77Ae
  147. Arora M, Maheshwari RC, Jain SK, Gupta A (2004) Use of membrane technology for potable water production. Desalination. 170: 105–112. Link: https://goo.gl/Azw8Qj
  148. Hu K, Dickson JM (2006) Nanofiltration membrane performance on fluoride removal from water. Membrane Sci 279: 529–538. Link: https://goo.gl/t2QzrH
  149. Qianhai Zuo, Xueming Chen, Wei Li, Guohua Chen (2008) Combined electrocoagulation and electroflotation for removal of fluoride from drinking water. J Hazardous Materials 159: 452–457. Link: https://goo.gl/BBSf7i
  150. Hassan HA, Abdel-Aziz AF (2010) Evaluation of free radical-scavenging and anti-oxidant properties of blackberry against fluoride toxicity in rats. Food Chem Toxicol 48: 1999–2004. Link: https://goo.gl/pXybJx
  151. Basha PM, Saumya SM (2013) Suppression of Mitochondrial Oxidative Phosphorylation and TCA Enzymes in Discrete Brain Regions of Mice Exposed to High Fluoride: Amelioration by Panax ginseng (Ginseng) and Lagerstroemia speciosa (Banaba) Extracts. Cell Mol Neurobiol 33: 453–464. Link: https://goo.gl/J7vuxH
  152. Nabavi SF, Habtemariam S, Sureda A, Akbar HM, Daglia M, et al. (2013) In vivo protective effects of gallic acid isolated from peltiphyllum peltatum against sodium fluoride-induced oxidative stress in rat erythrocytes. Arh Hig Rada Toksikol 64: 553-559. Link: https://goo.gl/xBd4BC
  153. Sinha M, Manna P, Sil PC (2008) Terminalia arjuna Protects Mouse Hearts Against Sodium Fluoride-Induced Oxidative Stress. J Med Food 11: 733–740. Link: https://goo.gl/8aU6DN
  154. Vasant RA, Narasimhacharya AVRL (2012) Ameliorative effect of tamarind leaf on fluoride-induced metabolic alterations. Environ Health Prev Med 17: 484–493. Link: https://goo.gl/6koPxk
  155. Chawla SL, Yadav R, Shah D, Rao MV (2008) Protective action of melatonin against fluoride induced hepatotoxicity in adult female mice. Fluoride 41: 44-51. Link: https://goo.gl/QqxdDn
  156. Jain A, Mehta VK, Chittora R, Mahdi AA, Bhatnagar M (2015) Melatonin ameliorates fluoride induced neurotoxicity in young rats: an in vivo evidence. Asian J Pharm Clin Res 8: 164-167. Link: https://goo.gl/HJElEk
  157. Bharti VK, Srivastava RS, Kumar H, Bag S, Majumdar AC, et al. (2014) Effects of melatonin and epiphyseal proteins on fluoride-induced adverse changes in antioxidant status of heart, liver, and kidney of rats. Adv Pharmacol Sci 2014:532969. Link: https://goo.gl/IESXbF
  158. Bharti VK, Srivastava RS (2011a) Effects of epiphyseal proteins and melatonin on the blood biochemical parameters of fluoride-intoxicated rats. Neurophysiol 42: 258-264. Link: https://goo.gl/5pgiO3
  159. Rao MV, Chawla SL, Patel N (2009) Melatonin reduction of fluoride-induced nephrotoxicity in mice. Fluoride 42: 110–116. Link: https://goo.gl/BtLwwO
  160. Bharti VK, Srivastava RS (2011b) Effect of pineal proteins and melatonin on certain biochemical parameters of rats exposed to high-fluoride drinking water. Fluoride 44: 30–36. Link: https://goo.gl/kwE7ZU
  161. Chawla SL, Rao MV (2012) Protective effect of melatonin against fluoride induced oxidative stress in the mouse ovary. Fluoride 45: 125–132. Link: https://goo.gl/7nWbhZ
  162. Rao MV, Bhatt RN (2012) Melatonin protection against F-induced oxidative stress and testicular dysfunction in rats. Fluoride 45: 116-124. Link: https://goo.gl/NICNbv
  163. Rao MV, Vyas DD, Meda RB, Chawla SL (2011) In vitro protective role of melatonin against hemolysis induced by sodium fluoride in human red blood cells. Fluoride 44: 77–82. Link: https://goo.gl/b5WUTb
  164. Bharti VK, Srivastava RS, Anand AK, Kusum K (2012) Buffalo (Bubalus bubalis) epiphyseal proteins give protection from arsenic and fluoride-induced adverse changes in acetylcholinesterase activity in rats. J Biochem Mol Toxicol 26: 10-15. Link: https://goo.gl/Ofll3W
  165. Bharti VK, Srivastava RS (2011c) Effect of pineal proteins at different dose level on fluoride-induced changes in plasma biochemicals and blood antioxidants enzymes in rats. Biol Trace Elem Res141: 275-282. Link: https://goo.gl/8eDjlV
  166. Mansour HH, Tawfik SS (2012) Efficacy of lycopene against fluoride toxicity in rats. Pharm Biol 50: 707–711. Link: https://goo.gl/z2hgHD
© 2017 Bharti VK, et al. This is an open-pjestcess article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 

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