RESEARCH: FLUORIDE AS AN ESSENTIAL ELEMENT IN DISEASE PREVENTION

Published in the Journal Medical Hypotheses
Vol 62/5 pp 710-717

FLUORIDE AS AN ESSENTIAL ELEMENT IN DISEASE PREVENTION

 

ABSTRACT

The concentration of fluoride in drinking water has been shown to be inversely correlated with the incidence of dental caries and cancer. It is proposed that dental caries, cancer and possibly other diseases are the result of a nutritional deficiency in fluoride.

Cancer incidence rates are positively correlated with latitude.1 Around the globe, the cancer incidence rate increases as the latitude increases. It is unlikely that an organic compound is responsible for the reduction in the cancer incidence rate due to the wide variety of food consumed around the world. Exposure to the sun and the associated increase in vitamin D production has been proposed as a factor in decreasing the cancer incidence rate.2 However, epidemiologic research has not supported this theory.3 To date, no theory has explained why cancer incidence rates increase as latitude increases.

There is a stronger correlation between temperature and the cancer incidence rate (r = -0.87) than latitude and the cancer incidence rate (r = 0.71).4 The warmer the average high ambient temperature, the lower the cancer incidence rate.3 It is, therefore, likely that the cancer incidence rate is affected by ambient temperature and not latitude.

It is unlikely that a warmer climate directly affects the cancer incidence rate because humans are warm blooded and maintain a stable body temperature. In order to maintain a stable body temperature a warm-blooded animal must consume greater quantities of water in higher temperatures. While it is unlikely an increase in water consumption could directly affect the cancer incidence rate, it is likely that something in the water could affect the cancer incidence rate. Upon review of the inorganic compounds found in the water supply throughout the world it has been found that there is an inverse correlation between the concentration of fluoride in the drinking water and the cancer incidence rate (r = -0.75).4

The discovery that fluoride reduces the incidence of caries was made in the early 1900’s.5 By the 1950’s municipal water departments were beginning to add fluoride to the water supply.5 As water was being fluoridated concerns that fluoride is carcinogenic were being voiced. The concern that fluoride might increase the incidence of cancer has prompted studies to determine if fluoride in the drinking water was related to cancer incidence rates.

In 1974 Nixon and Carpenter published a paper comparing standardized mortality ratios in relation to the amount of fluoride in the drinking water.6 They reported finding a statistically significant negative correlation between the standardized mortality rate and the fluoride content of the water. They concluded that all indications were that naturally occurring fluoride was likely to reduce cancer incidence. Hoover et al studied fluoride concentration in drinking water as it applies to standard mortality rates in Texas counties.7 Consistent trends were found for cancers of the buccal cavity, pharynx (males only) esophagus (males and females) and skin cancer (females). All trends indicated a reduction in cancer incidence with increased fluoride concentration. Multiple regression analysis revealed a statistically significant inverse correlation with the fluoride variable in 4 out of 64 tests of significance. Doll and Kinlen studied cancer incidence between 1950 and 1970 in cities with fluoridated water and in cities without fluoridation. When account was taken for age, sex, and ethnic group the ratio between observed cancer mortality and expected cancer mortality in cities with fluoridated water fell slightly, and did not change in non-fluoridated cities.8

Mcguire et al in a case-control study of osteosarcoma patients found an inverse correlation between fluoride concentration and the incidence of osteosarcoma.9 In 1995 Gelberg et al published a case-control study comparing fluoride exposure and childhood osteosarcoma.10 They found a statistically significant correlation between increased fluoride intake and a decrease in the incidence of osteosarcoma for males. They proposed that fluoride might have a protective effect for males.

In the 1970’s a series of studies were carried out on normal cells treated with various agents known to initiate mutations by inducing chromosomal damage. Vogel reported a strong antimutagenic effect of fluoride on mutation induced by Trenimon and 1-phenyl-3,3-dimethyltriazene in Drosophila.11 In 1973 Obe and Slacik-Erben reported findings similar to Vogel, and proposed that sodium fluoride exerts its antimutagenic action by suppressing events leading to chromosomal breakage.12 In 1976 Slacik-Erben et al reported that chromosomal aberrations induced by Trenimon revealed that pre, simultaneous and post-treatments of sodium fluoride significantly enhanced the frequency of undamaged mitosis.13 They interpreted their findings as an indication that sodium fluoride had significant antimutagenic activity.

Hirano et al studied the in vitro effects of fluoride on cultures of the osteosarcoma cell line UMR 106. The addition of 0.5 mM fluoride resulted in the induction of apoptosis and a decrease in cell proliferation.14 Anuradha et al reports that fluoride causes cell death in human leukemia (HL-60) cells by the activation of caspase-3, which in turn cleaves poly(ADP-ribose) polymerase leading to apoptosis.15

All valid scientific investigations lead to the conclusion that an increase in fluoride intake is associated with a decrease in the cancer incidence rate.

Steiner compared worldwide cancer incidence rates with the fluoride concentration in the drinking water and found an inverse relationship between the cancer incidence rate and the amount of fluoride in the drinking water.4 The cancer reporting areas with the lowest cancer incidence rate were found in areas with very high fluoride concentrations in the drinking water (Table 1). The cancer reporting areas with the highest cancer incidence rate were found in areas with very low fluoride concentrations in the drinking water (Table 2).

Cancer is the loss of control of the cell cycle. Throughout the cell cycle both internal and external factors determine if the cell will remain at rest, begin to divide and multiply or enter into programmed cell death (apoptosis). A tumor develops when the cell looses the ability to regulate its cell cycle and continues to divide and increase in numbers. Cancer develops when the dividing cells begin to invade surrounding tissues and spread throughout the body.

The factors that regulate the cell cycle have only recently begun to be understood. Cells respond to the needs of the organism by reacting to the presence of molecules that come into contact with the cell’s membrane. If the cell has a receptor for a molecule that contacts its membrane a cell membrane receptor will initiate a reaction that is transmitted into the cell. G proteins are responsible for signal transduction from the cell membrane to other parts of the cell and are essential for proper regulation of the cell cycle.39,40

G proteins (GTP-dependent signal transducers) are GTPases and cycle between their active GTP-bound form and their inactive GDP-bound form.41,42 In other words, G proteins have the intrinsic ability to convert GTP to GDP thereby automatically converting itself from the active GTP form into inactive GDP.43 However, since GTP is much more abundant than GDP there is a predilection for G proteins to bind GTP and remain in its active state.

Inactive G proteins are located inside the cell membrane and are bound to GDP. When external signals such as growth factors, neurotransmitters or hormones react with a receptor on the cell membrane G proteins transfer this external signal into the cell and activate target/effector molecules such as adenylate cyclase.43 The stimulation of receptors on the cell membrane causes the release of GDP from the G protein which is replaced with GTP thereby activating the G protein.
If an external signal is a growth hormone which activates G proteins to signal for cell division the intrinsic GTPase activity of the G proteins provides a degree of self regulation. However, hydrolysis of GTP to GDP is very slow and inadequate to limit cell division.

Several different proteins bind to and stimulate or inhibit the hydrolysis of GTP to GDP. The proteins that regulate activity of G proteins are identified by various names but the group that has received attention in relation to cancer are the GTPase activating proteins(GAPs). GAPs are produced by tumor suppresser genes that regulate G proteins by facilitating the hydrolysis of GTP to GDP.44 GAPs combine with the active G protein (GTP-bound) and speed up the hydrolysis of GTP to GDP. 44 Therefore, GAPs are powerful inhibitors of G protein signal transduction. If an external molecule stimulates cell division by converting GDP-bound G protein(inactive) to GTP-bound G protein(active) the signal to proceed with cell division is limited in the presence of GAPs.

In the 1990’s the structure of Ras G protein and its GAP was elucidated.45 There is no binding when Ras and its GAP were mixed, therefore, RasGTP was not hydrolized to RasGDP. However when aluminum fluoride, magnesium fluoride or berylliumn fluoride is added the Ras/RasGAP complex readily forms.46,47 It was also found that for this reaction to occur it was necessary that free fluoride be available in solution. The complex of Ras and its GAP is shown in Figure 1. A schematic of the complex is drawn in Figure 2. Ras and its GAP fit together structurally and aluminum fluoride is located between Ras and its GAP. Fluoride is located at a critical location in the Ras/RasGAP complex. The ability of the GAP molecule to react with Ras has been shown to be critical for the proper control of the cell cycle.

Genes produce G proteins and their GAPs to closely regulate the cell cycle. However, if a mutation occurs these proteins can loose the ability to regulate the cell cycle and can contribute to the development of cancer.

Molecular oncologists have studied G proteins called Ras and Rho because they are highly oncogenic. It is estimated that mutations in Ras G proteins are associated with 30% of all human cancers. Ras mutations are found in 90% of pancreatic cancers and 50% of colon cancers.48 The Ras G proteins are responsible for signaling cell growth. When a mutation occurs at a critical place on a ras gene the Ras protein produced by this gene is left in the switched “on” mode and continually stimulates the cell to divide.49

It has been found that a mutation in one oncogene is insufficient to produce cancer. However, if a mutation also occurs in a gene that is involved in the regulation of the mutated gene, uncontrolled cell growth and cancer can occur.50

Mutant RhoGAP effectively forms the transition state complex RhoGDP-AlF-RhoGAP.51 The mutation of arginine to alanine is overcome in the presence of aluminum fluoride. In the presence of aluminum fluoride mutant RhoGAP is as effective as normal RhoGAP in binding to create the RhoRhoGap complex.51 For cancer to develop multiple mutations must occur in the regulator genes. A mutation in a signaling G protein and a mutation in the corresponding GAP would likely result in cancer. However, if aluminum fluoride is present, mutated GAP molecules may overcome the mutation.

The Rho family of G proteins is downregulated by an intrinsic GTPase, which is further downregulated by GTPase-activating proteins (GAPs). RhoGAPs contain an arginine residue that is involved in the catalysis of GTP to GDP. When the RhoGAP is normal, this protein will produce hydrolysis of RhoGTP to RhoGDP 38,000 fold.51 When RhoGAP is mutated with a substitution of the arginine residue to an alanine residue, the RhoGAP will only hydrolyze RhoGTP to RhoGDP 160 fold.51 This mutation significantly reduces the ability of RhoGAP to convert the active RhoGTP G protein to the inactive RhoGDP G protein.

RhoGAPs and RasGAPs form Aluminum fluoride complexes with the RhoGDP and RasGDP which represent analogues of the transition state of Rho and Ras hydrolysis.45,46,52,53 Fluoride has been found to be intimately associated with two areas of the RasRasGAP complex involved with the hydrolysis of GTP to GDP. Fluoride ligands contact the positively charged guanidinum group of Arg789 which is a critical part of the catalytic mechanism.45 Fluoride has also been found to be involved in the stabilization of the switch II region of RasGAP complex. In the RasGAP complex Gln61 contacts one of the fluoride ions contributing to the stability of the transition state.45

The Rho GTP-binding protein Cdc42 has a low intrinsic GTPase activity that is enhanced by its GTPase activating protein Cdc42GAP. Cdc42GAP stabilizes both the switch I and switch II domains of Cdc42 and contributes arginine305 to the active site. Arg305 represents the catalytic arginine and mutation of this arginine lead to a 40 fold loss in catalytic activity.54 However with Aluminum fluoride in the active site of the Cdc42-Cdc42GAP(R305) complex it has been found that the mutant is still able to stabilize the transition state of the GTP-hydrolytic reaction. The stabilization of the switch domains explains how dc42GAP(305) mutant is able to stimulate GTP hydrolysis.54

In addition to fluoride’s association with G proteins, fluoride is also known to increase the bioreactivity of organic compounds. When fluoride is present in sufficient quantities the highly reactive fluoride anion will replace a hydroxyl radical and thereby increase the compounds bioreactivity. If fluoride is not present the molecule will substitute the fluoride anion with a hydroxyl radical which will allow the molecule to perform its intended function, but at a lower level of activity.
It is proposed that fluoride plays an essential role in the normal control of the cell cycle and also allows the cell to adapt to mutations that might otherwise lead to loss of control of the cell cycle and the development of cancer.

The worldwide concentration of fluoride in the drinking water varies from 0.0mg/l to 35 mg/l. With this variation it is difficult to see how such a critical roll for fluoride could develop. In an effort to understand the development of fluoride in tumor suppression it is necessary to look at how fluoride is handled in the body and how fluoride tumor suppression capabilities might have evolved.

Consumed fluoride will circulate through the body and be either retained by the bones or excreted by the kidneys. Fluoride is taken rapidly into bone by replacing hydroxyl ions in bone apatite. The process by which fluoride enters the apatite crystals occurs by the formation of new bone or by a three stage ion exchange process. The amount of fluoride in bone is dependent on fluoride intake, age and bone type. Approximately 20% of fluoride consumed by children is retained by the bones.55

Fluoride is released from bone as evidenced by its continuous appearance in the urine after the intake of fluoride has stopped. The release of fluoride from bone when fluoride is not being consumed is by both the rapid process of ion exchange and the slower process of osteoclastic resorption.

Fluoride is primarily excreted in the urine.56 Fluoride is also found in the saliva and crosses the placenta. Renal fluoride is excreted by way of glomerular filtration followed by pH dependent tubular resorption. The amount of fluoride excreted is influenced by current intake, previous intake, age, urinary flow and urine pH.

It is proposed that the body has developed this intricate system of fluoride intake, storage, release and excretion in order to maintain a steady level of fluoride in the blood and tissues.

Archeology has traced human evolution back to the Rift Valley area of Eastern Africa. It is believed that Homo sapiens and their ancient ancestors spent millions of years evolving in this part of Africa. The Rift Valley is in the fluoride belt that stretches across northern and eastern Africa into the Middle East, across Pakistan and India, into Southeast Asia and the south of China. Due to high concentrations of fluoride in the soil the amount of fluoride in the drinking water commonly ranges between 2.5 and 35 mg/l.

While it is significant that human evolution occurred in an area of high fluoride concentration, another evolutionary event occurred that would greatly increase man’s consumption of fluoride. Early man was covered with hair much like his closely related primates. However, as man evolved, he began to loose his hair and develop a more efficient method of maintaining body temperature. One of man’s most significant evolutionary developments was the loss of hair combined with a significant increase in sweat glands. Animals covered with hair have sebaceous sweat glands, which provide effective cooling until the hair is saturated. When hair is saturated cooling efficiency is lost and the animal overheats. As man evolved, he gradually lost his hair, which allowed him to cool his body through profuse sweating without overheating. Early man could now pursue his prey until they overheated and overtake an otherwise stronger more powerful animal.

Man’s ability to cool himself during the heat of the day gave him a significant advantage over his prey, but this also required a much greater water intake. As early man’s water intake increased, so too did his fluoride intake. It is likely that as man began to consume larger amounts of fluoride, he began to use this fluoride in essential biologic reactions, which differentiates him from other members of the animal kingdom.

In the 1930’s it was found that people living in high fluoride areas did not develop dental caries.57 The fluoride stored in the body is deposited in the teeth during development. Fluoride excreted in the saliva is deposited on the tooth’s surface. Fluoride reduces the pH necessary to dissolve the crystalline structure of enamel and dentin. If an individual has an adequate supply of fluoride stored in the body, dental caries is prevented. It is proposed that through evolution Homo Sapiens, developed this mechanism of fluoride intake, storage, release and excretion in order to provide the body with a stable supply of fluoride for vital metabolic processes involved in the prevention of disease.

The fluoride belt stretches across northern and eastern Africa into the Middle East, across Pakistan and India, into Southeast Asia and the south of China.58 In a publication of worldwide mortality rates, the International Agency for Research on Cancer identifies the areas in the world with low cancer incidence rates as “Only south-central and western Asia (Indian Subcontinent, central Asia and the middle-eastern countries) and Northern Africa are well below the world average of 90 deaths per 100,000 population annually.59

It has been shown that fluoride is involved in the regulation of signal transduction through G proteins in vitro. It has been shown that a supply of free fluoride ion is needed for binding of the G protein Ras and its GAP in vitro. It has been found that the presence of aluminum fluoride can restore a mutated RhoGAPs binding ability in vitro. It is proposed that the mechanism of fluoride intake, storage, retention and excretion plays a vital role in supplying fluoride in proper concentrations in order to properly regulate the cell cycle and prevent cancer.

The great Diaspora of human migration occurred approximately 100,000 years ago when early man left eastern Africa and migrated throughout the world. After spending his entire evolutionary history consuming large amounts of fluoride man now migrated to lands deficient in fluoride. This lack of adequate of fluoride intake has resulted in the development of dental caries and likely other diseases.

TABLE 1

VERY LOW CANCER INCIDENCE RATE (PER 100,000) WITH LATITUDE, TEMPERATURE AND FLUORIDE CONCENTRATION IN THE DRINKING WATER

Location Total CI16 Lat.16 Temp17 Fluoride Fluorosis Fluoridation
The Gambia 98** 13 80 10 mg/l 18 +18 –19
Barshi, Paranda, Bhum 104 18 91 10 mg/l 20 +20 –19
Senegal, Dakar 151*** 13 80 10 mg/l 18 +18 –19
Algeria, Setif 174 35 72 4.0 mg/l 21 +21 –19
India, Karunagappally 188 9 86 5.1 mg/l 22,23 +23 –19
India, Trivandrum 194 8 87 5.1 mg/l 22,23 +23 –19
Mali, Bamako 215 13 92 10 mg/l 18 +18 –19
India, Bangalore 216 13 83 9.1 mg/l 22,23 +23 –19
Israel, Non-Jews 222 32 69 5.0 mg/l 24 +24 –19
Singapore, Indian 229 1 87 0.7 mg/l 25 +25 +25
Kuwait, Kuwaitis 230 29 90 0.4 mg/l 26 +27 –19
Viet Nam, Hanoi 232 21 80 unknown unknown unknown
India, Madras 247 13 90 3.3 mg/l 28 +28 –19
India, Bombay 256 19 88 .32 mg/l 28 +28 –19
Singapore, Malay 278 1 87 0.7 mg/l 25 +25 +25
Lima, Peru 275 12 73 unknown unknown unknown
Thailand, Chiang Mai 297 16 89 5.0 mg/l 29 +30 –19
New Mexico, Am Indian 299 35 70 4.1 mg/l 31 +31 –19
Uganda, Kyadondo 301 0 79 1.5 mg/l 32 +32 –19

* Total cancer incidence is a combination of the male and female cancer incidence
** Data from an earlier edition of Cancer incidence in five continents Vol VI 1992
*** Data from an earlier edition of Cancer incidence in five continents Vol IV 1982

 

TABLE 2
VERY HIGH CANCER INCIDENCE RATE ( PER 100, 000 ) WITH LATITUDE, TEMPERATURE AND FLUORIDE IN THE DRINKING WATER

Location Total CI*16 Lat16 Temp17 Fluoride Fluorosis** Fluoridation***
San Francisco, Black 751 38 63 <.4 mg/l +19
Detroit, Black 742 42 58 <.4 mg/l +19
San Francisco, White 713 38 63 <.4 mg/l +19
Atlanta, Black 703 34 72 <.4 mg/l +19
New Zealand, Maori 700 40 59 <.4 mg/l +19
Connecticut, Black 698 41 60 <.4 mg/l +19
Detroit, White 695 42 58 <.4 mg/l +19
Hawaii, White 693 22 84 <.4 mg/l –33
New Orleans, Black 689 30 78 <.4 mg/l +19
Los Angeles, Black 687 34 73 <.4 mg/l –34
Seattle 685 47 59 <.4 mg/l +19
Los Angeles, White 677 34 73 <.4 mg/l –34
Italy, Trieste 670 45 63 <.4 mg/l –35
New Orleans, White 662 30 78 <.4 mg/l +19
Atlanta, White 657 34 72 <.4 mg/l +19
Uruguay, Montevideo 626 35 70 <.4 mg/l +19
Central Calif., White 622 36 76 <.4 mg/l +19
Canada, Yukon 621 63 40 <.4 mg/l +19
Iowa 619 42 60 <.4 mg/l +19
New Mexico, White 615 35 70 <.4 mg/l +19
Canada, Nova Scotia 606 49 48 <.4 mg/l +19
Canada, Ontario 587 45 54 <.4 mg/l +36 +19
Canada, Manatoba 586 49 47 <.4 mg/l +19
Canada, Prince Edward Is 582 47 49 <.4 mg/l +19
Australia, South 575 35 70 <.4 mg/l +19
Scotland, West 573 57 52 <.4 mg/l –37
Austria, Tyrol 565 46 57 <.4 mg/l –38
Australia, West 564 32 75 <.4 mg/l +19
Scotland 563 56 53 <.4 mg/l -37
Canada, British Columbia 561 49 56 <.4 mg/l +19

*Total cancer incidence is a combination of the male and female cancer incidence
** Fluorosis is determined by a citation of fluorosis in the literature
*** All fluoridated cities have low natural fluoride concentration in the drinking water supply

 

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