Amalgamation of Sodium Fluoride studies - Conclusions

1. As a metaphor, the Majesty of the human body is akin to a warzone, but with a difference. The beneficent intelligence of the body oversees that the ‘realm’ is always in peace, or at least, is always seeking equilibrium within by quelling potential quarrels with neighbours (dysfunctions) and out-right invasion by pathogenic tribes (toxins), attempting to capture a city, an organ in this analogy, change functions, alter processes whereby it can grow outwardly by slowly building parts within the city (the cell) to allow slow migration into other cities (angiogenesis) where it can bridge and connect, using the GLUT-1 transporter to funnel in ‘money/fuel’ - in the form of glucose to use pyruvate to generate ATP; to continue ‘funding’ for producing material (building blocks) within the cytoplasm to enable further annexing town-by-town, city-by-city - until it becomes a “Cancer Stronghold”, now able to signal changes outside of its microenvironment and manipulate metabolism and DNA to its advantage, bypassing normal functioning cells or re-purpose cell functions The body attempts to ‘’police’’ this peaceful warzone, picking up offenders, arresting them, holding them, or keeping them suspended until the crime scene has been cleared, the cleaners have been called, the logs and reports are updated (immune memory) and the offenders may have a second purpose (being repurposed and transformed, almost as if redeemed), to serve another function within the kingdom of potential peace

2. 1Chronic Exposure to Sodium Fluoride Triggers Oxidative Biochemistry Misbalance in Mice: Effects on Peripheral Blood Circulation Small fluoride concentrations have therapeutical action against dental caries. However, exposure to high doses from water ingestion and the use of fluoride toothpastes or fluoride-rich diets increases the body burden of this ion In the present study, fluoride exposure significantly increased plasma fluoride concentrations. Moreover, chronic fluoride exposure induced biochemical alterations in the peripheral blood of mice, such as increased lipid peroxidation levels and decrease of the CAT (Catalase) activity and NO (Nitric Oxide) levels. 1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129794/

3. 1Chronic Exposure to Sodium Fluoride Triggers Oxidative Biochemistry Misbalance in Mice: Effects on Peripheral Blood Circulation In addition, high doses of ingested fluoride might damage several biological systems, including the central nervous system [9], reduction of splenic and humoral cell immunity [10], dysfunction of the male reproductive system [11], and liver damage [12, 13]. Evidence in animal models suggests that fluoride concentrations above 5 mg/L in drinking water can modify cellular processes such as respiration and metabolism, thus leading to oxidative stress [7]. The fluoride can act as an enzyme inhibitor, due to its strong electronegativity. Thus, it forms ions in solution and the main toxic effect of fluoride derives from its interaction with enzymes [7] 1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129794/

4. 1Chronic Exposure to Sodium Fluoride Triggers Oxidative Biochemistry Misbalance in Mice: Effects on Peripheral Blood Circulation  In addition, fluoride can also inhibit the protein secretion and/or synthesis involved in signalling pathways (mitogen-activated protein kinase (MAPK), p53, activator protein-1 (AP-1), and nuclear factor kappa B (NF-κB) [37–39] and antioxidant enzymes (SOD, glutathione levels, and CAT) [40]. Thus, the inhibition of antioxidant enzymes results in the excessive production of ROS at the mitochondrial level, leading to cell damage. The CAT activity was significantly decreased upon treatment with fluoride, regardless of the dose. However, only the highest fluoride dose significantly decreased GSH levels compared to control, denoting that fluoride can act as inhibitor of enzymatic antioxidants (CAT) or nonenzymatic antioxidants (GSH – Glutathione). Other studies show that fluoride (F)reducesCAT activity and GSH levels, but not the activity of SOD activity in human erythrocytes [49]  1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129794/

5. 1Chronic Exposure to Sodium Fluoride Triggers Oxidative Biochemistry Misbalance in Mice: Effects on Peripheral Blood Circulation Studies show that treatment with antioxidants, such as ascorbic acid, tamarind seed coat extract, blackberry, and quercetin, prevented fluoride-induced changessuch as increase of oxidant (reactive oxygen species generation, lipid peroxidation, protein carbonyl content, and NO) and inhibition of antioxidant superoxide dismutase, catalase, glutathione peroxidase, and glutathione) parameters, suggesting that the major mode of action of fluoride is dependent of oxidative/nitrosative mechanism [53–55]. In our study, we observed that MDA (MalonDiAldehyde)levels increased after fluoride exposure in a dose-dependent manner. In this way, we strongly believe that as the fluoride concentration increases, more antioxidant enzymes are impaired and, consequently, the MDA increases. Changes in TBARS, NO, and TEAC, as well as CAT activity and GSH levels, especially in the group exposed to the highest dose of fluoride, indicate that this ion is a toxicant, inducing metabolic alterations in the blood and interacting with the antioxidant system in mice chronically exposed. Thus, exposure to excessive fluoride doses in the long term must be avoided. 1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129794/

6. [9] The Influence of Fluorine on the Disturbances of Homeostasis in the Central Nervous System - Biological Trace Element Research Volume 177, Issue 2, 1 June 2017, Pages 224-234 Additionally, fluorine changes the concentration of non-enzymatic advanced glycation end products (AGEs), the metabolism of neurotransmitters(influencing mainly glutamatergic neurotransmission) and theenergy metabolism of neurons by the impaired glucose transporter—GLUT1. It can also change activity and lead to dysfunction of important proteins which are part of the respiratory chain. Excessive exposure to this element can cause harmful effects such as permanent damage of all brain structures, impaired learning ability, memory dysfunction and behavioural problems. This paper provides an overview of the fluoride neurotoxicityin juveniles and adults. Other changes include CD3* T-Lymphocyte Cell significantly decreased as were CD19* B Lymphocytes The protein expression levels of TGF-β (Transforming Growth Factor Beta), TNF-α (Tumour Necrosis Factor Alpha), and Cytokine IL-2 (Interleukin-2) were significantly decreased, IL-10 protein expression levels were significantly higher IgA (Immunoglobulin secreted by B-Cells) contents were significantly decreased - IgGcontents were significantly lower - IgM contents were significantly decreased, as were Interferon Gamma (IFN-y) IL-10 and TGF-β are inhibitory cytokines and are synthesized by T cells and B cells. Glutathione (GSH) protected the cells from loss of mitochondrial membrane potential and there was no cytochrome c exit or Bcl-2 down-regulation, and we suggest that these antioxidants prevent apoptosis induced by NaF

7. Abstract Sodium fluoride (NaF) administered orally to adult male rats at a dose level of 4.5 ppm and 9.0 ppm for 75 days caused significant decrease in the body weight, brain index and testicular index. A significant decrease in sperm count, sperm motility, sperm viability and sperm function (HOS positive) with increased sperm abnormalities was also observed in NaF-exposed male rats. The activity levels of testicular steroidogenic marker enzymes 3beta-hydroxysteroid dehydrogenase (3 beta-HSD) and 17 beta-hydroxysteroiddehydrogenase (17 beta-HSD) were significantly decreased in NaF-treated rats indicating decreased steroidogenesis and in turn spermatogenesis in ratsexposed to NaF. Exposure to high fluoride concentration in drinking water will affect spermatogenesis and steroidogenesisin male albino rats. (Research Ginseng Extract [GE] and Banaba Leaf Extract [BLE]) to off-set Sodium Fluoride toxicity as does Vitamin E which promotes antioxidant enzymes (Alpha-Tocapherol found in hazelnuts, dry roasted peanuts, sunflower seeds/oil, curcumin/tumeric )

8. [7] 1 The effects of fluoride on cell migration, cell proliferation, and cell metabolism in GH4C1 pituitary tumour cells - Toxicology Letters Volume 190, Issue 2, 28 October 2009, Pages 179-186 Our results show that biologically relevant concentrations of fluoride are capable of increasing cell migration in tumour cells, suggesting that exposureto fluoride could stimulate tumour invasion. 1https://doi.org/10.1016/j.toxlet.2009.07.014

9. [49] 1In Vitro Effect of Sodium Fluoride on Malondialdehyde Concentration and on Superoxide Dismutase (SOD), Catalase (CAT), and Glutathione Peroxidase ( GSHPx) in Human Erythrocytes - The Scientific World Journal, vol. 2013 Oxidative stress is characterized by an excess of reactive oxygen species(ROS) that react with the main cellular macromolecules, causing alterations in cellular homeostasis [16, 17]. The main damage caused by ROS is lipid peroxidation of the polyunsaturated fatty acids of cellular membranes, from which malondialdehyde(MDA) is produced as a product. Moreover, the activity of the main antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GlPx), is also affected [16, 17] NaF(Sodium Fluoride) increases ROS, which in turnincreasesMDA, as well as decreasing the activity of the major antioxidant enzymessuch as SOD, CAT, and GlPx

10.  In this regard, in addition to vitamin E, other well-known natural products (e.g., curcumin, N-acetylcysteine(NAC), and Ginkgo biloba), with antioxidant properties, have been used in vivo and in vitro experiments to prevent or counteract the damage caused by free radicals generated by the intoxication with NaF and other toxic compounds that frequently contaminate the environment, mainly aquifers [41–45]. Our results show that the presence of Vit-E partially prevented the inhibition of the activity of antioxidant enzymes caused by NaF. Nonetheless, the mechanism by which Vit-Eprevents the inhibition of SOD, CAT, and GlPxantioxidant enzymes induced by NaFmust be investigated in more detail. 1 https://www.hindawi.com/journals/tswj/2013/864718/

11. [17] Effects of chronic fluoride intake on the antioxidant systems of the liver and kidney in rats - Journal of Fluorine Chemistry, vol. 168, no. 0, pp. 212–217, 2014. In the kidneys, the SOD, GPx, GSH and antioxidants levels significantly decreased, while the fluoride and LH levels significantly increased. In the liver, the CAT and TBARS levels significantly decreased, while the fluoride, SOD, LH and antioxidants levels significantly increased. In summary, these results show that chronic fluoride administration alters the antioxidant systemof rats.

12. Connecting terms to investigate causality p53 (TP53)  Oxidative Stress and Oocytes  Gametes and Sperm FusionJUNO and IZOMITOL  Acetylcholine Receptors, Muscaritic Acid, Serotonin, Melatonin, Norepinephrine, Dopamine Receptors D1-5 Sodium Fluoride  Affects Antioxidant DefenceEnzymes ReducesGlutathione levels, SOD, Catalase, IgA, IgG, IgM, Apoptosis and Cell-mediated Death Promotes Pro-inflammatory Responses (Cytokines) Helicobactor Pylori  Lowers Glutathione  Adrenal Glands  TP53/p53 GLUT-1 and GLUT-4 transporter used by Ascorbic Acid  Aspartame Sodium Fluoride Helicobacter pylori induces somatic mutations inTP53via overexpression of CHAC1 in infected gastric epithelial cells 7 February 2018 - doi:10.1002/2211-5463.12402 Infection with Helicobacter pylori is known to decrease the level of glutathione (GSH) in gastric epithelial cells and increase the production of reactive oxygen species (ROS), which can lead to DNA damage and the development of gastric carcinoma (cancer)

13. Inhibiting the system xC−/ glutathione axis selectively targets cancers with mutant-p53 accumulation 2017 Mar 28. doi: 10.1038/ncomms14844 We show that accumulated mutant-p53 protein suppresses the expression ofSLC7A11, a component of the cystine/glutamate antiporter, system xC−, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage We demonstrate that high levels of mutant-p53, through binding to NRF2and impairingits canonical antioxidant activities, directly promote ROS accumulation in cancer cells… normal cells can mount an optimal NRF2-mediated response to oxidative stress  Seminal studies have shown that the master antioxidant transcription factor, NRF2, intimately regulates SLC7A11transcription14,15 and cells that are p53 null or wild-type have relatively higher levels of SLC7A11 expression, It may be prudent to seek supply or elements for cystineto enable GSH synthesis This protein (SLC7A11) has been identified as the predominant mediator of Kaposi sarcoma-associated herpes virus fusion and entry permissiveness into cells

14. Dual pharmacological inhibition of glutathione and thioredoxin systems synergizes to kill colorectal carcinoma stem cells 2016 Aug 3. doi: 10.1002/cam4.844 A continual cystine supply is crucial for de novo synthesis of glutathione and thioredoxin antioxidant peptides, highlighting CD44v9's role in redox regulation(4, 5). The transcription factor NRF2(encoded by theNFE2L2 gene), a master regulatoragainst oxidative stress NRF2, as a redox sensor and feedback regulator, integrates three groups of enzymes (those associated with the glutathione and thioredoxin systems and NADPH production) to reduce reactive oxygen species (ROS) (9). Hence, NRF2 stabilizes intracellular redox potential and ensures robust cellular systems against potential harmful effects of ROS. For example, once the glutathione system is disrupted (e.g., by pharmacological inhibition), increased ROS activates NRF2, and subsequently, the other thioredoxin system is augmented for compensation NRF2up‐regulatesGCLC and GCLM genes, components of glutathione system. NRF2up‐regulatesPRDX1, TXN, and TXNRD1 genes, components of thioredoxin system.

15. Effects of smoking and tumor process on the contents of key proteins of apoptosis and activity of antioxidant enzymes in blood. [2012 Jan-Feb;(1):19-26 - Article in Russian] Abstract The effects of smoking on the contents of the apoptosis markers Bcl-2 and p53 proteinsin blood plasma; the activity of the antioxidant (AO) enzymesCu, Zn-superoxide dismutase (SOD), glutathione peroxidase (GP), glutathione reductase (GR), glutathione S-transferase(GST), and catalase; and the content of malondialdehyde (MDA) in erythrocytes from healthy donors and cancer patients were studied. Two groups of donors were revealed among healthy smokers: one with high SOD and GP activities and high Bcl-2 protein levels and the other with lower Bcl-2 levels compared with those found in non-smokers. In the group of cancer patients (both smokers and non-smokers), significantly increased p53 protein levels and increased activity of GST were found. A negative correlation between MDAand GST in the group of smoking healthy donors and a positive correlation between MDA and p53 in cancer patients were found. The results suggest a relationship between the components of enzymatic defence and lipid peroxidation and the content of apoptosis regulator proteins in healthy smokers and cancer patients.

16. *Sodium Fluoride, Aspartameand Organophosphates– A common denominator of Inflammatory, Oxidative Stress (ROS) responses and pain pathways 1Main toxic effect is *Sodium Fluoride and interaction with Enzymes Modifies cellular processes which lead to oxidative stress (or ROS generation) Dysfunction of the male reproductive system, CNS, reductionof humoral cell immunity Interferes with signalling pathways MAPK, p53, antioxidant enzymes SOD, Glutathione (GSH) levels Reductionof Catalase, Activator Protein-1 (AP-1) Nuclear Factor Kappa causing ROSelevation by inhibiting enzymatic antioxidants but not always SuperOxide Dismutase (SOD) and can modify cellular processes such as respiration and metabolism Causes lipid peroxidation, protein carbonyls and Nitric Oxide (NO) reduction As more antioxidant enzyme are impaired, increase of Malondialdehyde (MDA) observed AltersTBARS, Nitric Oxide (NO) Catalase Activity and Glutathione levels indicating the ion is a toxicant, inducting metabolic alterationsto the antioxidant system 1Chronic Exposure to Sodium Fluoride Triggers Oxidative Biochemistry Misbalance in Mice: Effects on Peripheral Blood Circulation [9] Permanent damage of all brain structures, impaired learning ability,memorydysfunction and behavioural problems Changes the concentration of non-enzymatic advanced glycation end products (AGEs), Metabolism of neurotransmitters (influencing mainly glutamatergic neurotransmission) and the energy metabolismof neuronsby the impairedglucose transporter—GLUT1

17. Other changes include : CD3* T- Lymphocyte Cell significantly decreased as were CD19* B Lymphocytes The protein expression levels of TGF-β(Transforming Growth Factor Beta), TNF-α(Tumour Necrosis Factor Alpha), and Cytokine IL-2 (Interleukin-2) were significantly decreased Interleukin-10(IL-10) protein expression levels were significantly higher IgA(Immunoglobulin secreted by B-Cells) contents were significantly decreased IgGcontents were significantly lower IgMcontents were significantly decreased, as were Interferon Gamma (IFN-y) IL-10 and TGF-β are inhibitory cytokinesand are synthesized by T cells and B cells. Glutathione(GSH) protected the cells from loss of mitochondrial membrane potential and there was no cytochrome c exit or Bcl-2 down-regulation, and we suggest that these antioxidants prevent apoptosisinduced by NaF (fluoride) [9] The Influence of Fluorine on the Disturbances of Homeostasis in the Central Nervous System - Biological Trace Element Research Volume 177, Issue 2, 1 June 2017, Pages 224-234 Sodium fluoride (NaF) administered orally to adult male rats at a dose level of 4.5 ppm and 9.0 ppm for 75 days caused significant decrease in the body weight(Cachexia) brain index and testicular index (see Cachexia/ Anorexia Nervosa in Cancer patients)

18. A significant decrease in sperm count, sperm motility, sperm viability and sperm function (HOS positive) with increased sperm abnormalities was also observed in NaF-exposed male rats. 1https://doi.org/10.1016/j.toxlet.2009.07.014 The activity levels of testicular steroidogenic marker enzymes 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) were significantly decreased in NaF-treated rats indicating decreased steroidogenesis and in turn spermatogenesisin rats exposed to NaF [7] 1 The effects of fluoride on cell migration, cell proliferation, and cell metabolism in GH4C1 pituitary tumour cells - Toxicology Letters, Volume 190, Issue 2, 28 October 2009, Pages 179-186 [7] that biologically relevant concentrations of fluorideare capable of increasing cell migration in tumour cells, suggesting that exposure to fluoride could stimulate tumour invasion. [49] 1In Vitro Effect of Sodium Fluoride on MalondialdehydeConcentration and on Superoxide Dismutase (SOD), Catalase (CAT), and Glutathione Peroxidase ( GSHPx) in Human Erythrocytes - The Scientific World Journal, vol. 2013 [49] Oxidative stress is characterized by an excess of reactive oxygen species(ROS) that react with the main cellular macromolecules, causing alterations in cellular homeostasis

19. The main damage caused by ROS is lipid peroxidation of the polyunsaturated fatty acids of cellular membranes, from which malondialdehyde(MDA) is produced as a product Moreover, the activity of the main antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GlPx), is also affected [16, 17] NaF(Sodium Fluoride) increases ROS, which in turn increases MDA, as well as decreasing the activityof the major antioxidant enzymes such as SOD, CAT(Catalase), and GlPx (Glutathione Peroxidase) [49] 1In Vitro Effect of Sodium Fluoride on MalondialdehydeConcentrationand on Superoxide Dismutase (SOD), Catalase (CAT), and Glutathione Peroxidase ( GSHPx) in Human Erythrocytes - The Scientific World Journal, vol. 2013 Sodium Fluoride  Affects Antioxidant Defence Enzymes  ReducesGlutothione levels, SOD, Catalase, IgA, IgG, IgM, Apoptosis and Cell-mediated Death Promotes Pro-inflammatory Responses (Cytokines) [16] B. Halliwell and J. M. C. Gutteridge, “Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts,” Archives of Biochemistry and Biophysics, vol. 246, no. 2, pp. 501–514, 1986.- Not publicly accessible. Unavailable to read [17] No search results to view

20. Potential remedies and natural adjuvants 1 Research GinsengExtract[GE] and Banaba Leaf Extract [BLE]) to off-set Sodium Fluoride toxicity Vitamin E which promotes antioxidant enzymes (Alpha-Tocapherolfound in hazelnuts, dry roasted peanuts, sunflower seeds/oil, curcumin/tumeric ) 1 the presence of Vit-E partially prevented the inhibition of the activity of antioxidant enzymes caused by NaF(fluoride) The mechanism by which Vit-Eprevents the inhibition of SOD, CAT, andGlPxantioxidant enzymes induced by NaF must be investigated in more detail. [17] Effects of chronic fluoride intake on the antioxidant systems of the liver and kidney in rats- Journal of Fluorine Chemistry, vol. 168, no. 0, pp. 212–217, 2014. In the kidneys, the SOD, GPx, GSHand antioxidants levels significantly decreased, while the fluoride and LH levels significantly increased. In the liver, the CATand TBARSlevels significantly decreased, while the fluoride, SOD, LH and antioxidants levels significantly increased. In summary, these results show that chronic fluoride administration altersthe antioxidant system of rats. 1 https://www.hindawi.com/journals/tswj/2013/864718/

21. [49] Reports from in vitro and in vivo experiments, as well as data obtained from patients with fluorosis, indicate that NaF is an oxidative stress-causing agent. NaF increases ROS, which in turn increases MDA, as well as decreasing the activity of the major antioxidant enzymes such as SOD,CAT, andGlPx[11–15, 38].. caused by an alteration in the antioxidant enzymatic (e.g., SOD, CAT, and GlPx) and nonenzymatic (e.g., glutathione, urea, and Vit-E) defense systems [1–3, 11–15, 38]. The observed damage in the erythrocyte membrane was partially prevented by the presence of Vit-E (a well-known antioxidantcommonly used in in-vitro and In-vivo experiments), which can act as a “trap” (scavenger) for ROS, reducing the damage they cause [24, 35, 39, 40]…The in vitro damage caused by NaF is partially reversed by vitamin E, which is a well-known natural antioxidant. [1] (Rall and Sutherland, 1958). In these studies,10 mMsodium fluoride (NaF), in itself, was found to stimulate cyclic AMP production, as well as to potentiate hormonal effects. Fluoridewas thus identified as a stimulator of adenylatecyclase [49] 1In Vitro Effect of Sodium Fluoride on Malondialdehyde Concentration and on Superoxide Dismutase(SOD), Catalase (CAT), and Glutathione Peroxidase (GSHPx) in Human Erythrocytes - The Scientific World Journal, vol. 2013 [1] The Biochemistry and Physiology of Metallic Fluoride : Action, Mechanism, and Implications

22. [1] Brudevold and colleagues (1972) studied the fluoride complexes in the tap water from 26 communities in three states in the United States. The total fluoride concentration in these sources of water ranged from 0.2-5 ppm. They found that Al (Aluminum) was the principal complexing element for F (Fluorine) in the drinking water. Higher Al concentration and marked complexing with F were found to be associated with treatment of water with alum. Boiling of the drinking water(1 ppm F) in an aluminum pot increased the water Al content from 0.03 ppm to 0.20 ppm In the stomach, where most of the fluoride is absorbed, pH is around 1.2. When fluoride level is between 1 and 5 ppm,a significant portion of Al-F complexes in the stomach is AlF3 (see Fig. 5). AlF3 is an electrically neutral species. It is much more likely to be absorbed in the GI tract than other charged complexes of Al and F. There are two recognized sources of Al in drinking water (for a review, see Flaten, 2001). First, acid rain enhances the leaching of Al from minerals into natural water. Second, Al is widely used as a coagulant in water treatment to improve the water colour. This often results in an increased Al concentration in drinking water(Flaten, 2001). Another potential source of Al is related to water fluoridation. Sodium fluoride, used in water fluoridation, usually comes as a by-product from Na3AlF6 in the aluminum smelting industry. Certain medications, such as Al-containing antacids and buffered aspirin, as well as baking powder also contain very high levels of Al. [1] The Biochemistry and Physiology of Metallic Fluoride : Action, Mechanism, and Implications

23. [1] Aluminum is generally considered a neurotoxin. Al is strongly associated with Alzheimer's disease (AD). Many epidemiological studies seem to suggest a correlation between Alzheimer's disease and Al in drinking water One research group (Isaacson et al., 1997; Varner et al., 1998) tested the neurotoxicityof Al-F complexes in rats. They administered either plain double-distilled water (ddw), or ddw containing 0.5 ppm, 5.0 ppm, 50 ppm AlFx , or 2.1 ppm NaF(containing an amount of Fequivalent to that in 0.5 ppm AlF3 ) to a group of rats for 52 weeks.Both the NaF and the AlFx groups showed increased brain Al levelsas compared with controls (2 times more Al in the NaF group, and 2.5 times more in the 0.5 ppm AlFx group). This indicates that the physiological level of fluoride(2.1 ppm) can increase Al absorption and depositionin the brain In summary, this study seems to show that chronic administration of a fairly low level of AlFx(0.5 ppm) in drinking water results in distinct morphological changes in the brain Clinical studies have shown that fluoride treatment resulted in increased bone mass and bone density in spinal bone. However, a high concentration of fluoride can accumulate in bone. This can have an inhibitory effect on bone mineralization and may reduce the mechanical quality of bone crystals (Caverzasio et al., 1998). Due to the above facts, the therapeutic use of fluoride in osteoporosis is highly controversial. [1] The Biochemistry and Physiology of Metallic Fluoride : Action, Mechanism, and Implications

24. Fluorosis is an occupational disease among workers in the aluminum smelting industry In the presence of 5 mMAl, fluoride (50-750 mM) stimulated tyrosine phosphorylation and cell proliferation (Caverzasio et al., 1996). A study with rabbits showed that Al levels in tibia were significantly increased by the addition of F to the drinking water, even in animals receiving no additional Al in their drinking water (Ahn et al., 1995). Bone crystals are actively resorbed by resorbing osteocytes and osteoclasts. It seems that both F and Al tend to be concentrated in a surface layer of mineral, where active bone growth and remodeling occur (Smith, 1985; Priest, 1993). It is reasonable to suspect that high concentrations of labile F and Al and their complexes may exist in the extracellular fluid surrounding these cells. This unique microenvironment is the likely site where Al-F complexes exert their effects on bone cells.

25. Dentistry and Fluorosis Fluoride is incorporated into enamelduring the tooth forming stage, when ameloblastsare functionally active(Bawden et al., 1995). Enamel is first secreted as a protein matrix by ameloblasts(secretory stage). These same cells subsequently secrete proteinases that degrade matrix proteins almost completely(maturational stage) Ameloblasts can be affected by an increased level of fluoride during bothsecretory and maturational stages. A study by Matsuo et al. (1996) clearly showed the influence of fluoride on the secretory pathway of ameloblasts in enamel fluorosis. Apparently, acute exposure to a high concentration of fluoride disturbs the synthetic and secretory pathways in ameloblasts. Ameloblastssynthesize and secrete large amounts of proteinases during the post-secretory stage. Thus, some of the effects of fluoride on secretory ameloblastsmay also hold true in the maturational stage. It does not seem likely that fluoridewould directly affect the proteolytic activity of enamel matrix proteinases (Gerlach et al., 2000). Fluoride may influence the maturational stage ofameloblastsby two means. It may reduce the quantity of the proteinasesby interfering with the synthetic or the secretory pathway of ameloblasts, or it may reduce the quality of the proteinasesby affecting gene expression or the protein synthesis process (DenBesten and Heffernan, 1989)

26. This study found that teeth in the high-water-F region (5 ppm) contain six- to seven-fold higher levels of Al than teeth in the low water-F regions. This suggests that Al and F may interact chemically during the mineralization process. It is long known that dental plaque can accumulate F (Dawes et al., 1965). A steady F concentration in the whole plaque from people who use NaF containing toothpaste (1000-1500 ppm F) was found to be around 4 ppm(Duckworth et al., 1994). Another potential source of Al-F complexes is toothpaste. Over 95% of the population in developed countries use fluoride-containing toothpaste, which contains, on average, 1000 ppmF (Warren and Levy, 1999). A 1000-ppm quantity of F in an aqueous solution would generate 53 mM F. In contrast, many toothpastes use Al compounds as the abrasive base, such as aluminaand ordinary alum. Fluoridehas been found to inhibitavariety of enzymes for more than half a century. Of all metal ions, F- binds to Al3+ most strongly. Only a trace amount of Al is needed to formiologically active fluoride complexes. At acidic pH (e.g., pH 1-4), the concentration requirement forF to formeffective Al-F complexes is greatly reduced. At pH 4, a significant amount of AlF3 is formed in the presence of 50-100 mMF. Regular fluoridated drinking water (1 ppm F) contains 53 mM F, and gastric juice usually falls between pH 1 and 2.