by Paul Connett
Fluorine is the most reactive element, but the fluorides it forms with metals (such as sodium, calcium, magnesium, aluminum) are not very chemically reactive. On the other hand, soluble metal fluorides are very active biologically, as we shall see in the section on biochemistry below.
The Free Fluoride Ion (F-)
When metal fluorides dissolve in water, their constituents separate as ions. For all intents and purposes, a solution of sodium fluoride can be treated as two separate substances—sodium ions (Na+) and fluoride ions (F-). You will notice that when concentrations are reported on bottled water in Canada and Europe, the concentrations of the positive ions (e. g. , Na+, Mg2+, etc. ) and the negative ions (e. g. , Cl-, F-, carbonate, etc. ) are reported separately.
Thus, most of the discussion on toxicology focuses on the free fluoride ion (F-). Organofluorine compounds (certain plastics, pesticides, and pharmaceuticals) enter our fluoridation picture only if, in the human body, they are metabolized to release free fluoride ions.
This is about as much chemistry as most of us need to know to explore the issue of fluoridation’s dangers.
Biochemistry
Enzymes are very large protein molecules (thousands of times larger than the simple water molecule, H2O) that catalyze (facilitate) most of the ten thousand or so chemical reactions that occur in our bodies and other living things. Fluoride is a well-known inhibitor of enzymes in vitro (in test tube experiments). In this respect, it is interesting to note that some of the earliest opponents of fluoridation in the 1950s were biochemists who used fluoride to poison enzymes in their experiments. One of these was Dr. James Sumner, who was the director of enzyme chemistry in the department of biochemistry and nutrition at Cornell University. Sumner won the Nobel Prize for his work in enzyme chemistry. He is quoted as saying, “We ought to go slowly. Everybody knows fluorine and fluorides are very poisonous substances and we use them in enzyme chemistry to poison enzymes, those vital agents in the body. That is the reason things are poisoned, because the enzymes are poisoned and that is why animals and plants die. ”1
Even though enzyme molecules are very large, the chemical reaction they help steer is usually facilitated by a small section on the enzyme molecule called the “active center. ” Frequently, metal ions like Mg2+, Zn2+, and Cu2+ are located at these active sites.
Fluoride can interfere with enzyme function in two ways: either by attaching itself to a metal ion located at an enzyme’s active site or by forming a competing hydrogen bond (see the next section) at this same active site. Either way, these interactions can block or interfere with the enzyme’s function.
Hydrogen Bonds
The fluoride ion interferes with hydrogen bonding. 2 Hydrogen bonding occurs when a hydrogen atom in a molecule finds itself located between two atoms of either oxygen or nitrogen or one of each. These bonds (or attractions) can form within the same molecule if it is very large (e. g. , a protein) or between different molecules (e. g. , between water molecules). Hydrogen bonds are weaker than the covalent chemical bonds that link atoms together, and they can be more easily disrupted. Hydrogen bonds are of critical importance to both the structure and function of some of the most important molecules in the body. In the big polymer molecules (particularly proteins and nucleic acids), there are literally hundreds, even thousands, of these hydrogen bonds giving a stable shape to the molecules. In small molecules the shape is rigidly determined by the covalent bonds. In the larger molecules in living things the shape is much more flexible, and it is largely the hydrogen bonds that provide the final and operative shape. In biochemistry shape and function are intimately connected. Some of these hydrogen bonds can easily be pulled apart without a full chemical reaction (i. e. , without breaking the covalent bonds); they are the Velcro strips of biology.
Formation of Complex Ions
Because the fluoride ion is negatively charged, it is attracted to positive ions (usually metal ions) and forms clusters with them of a fixed formula and shape called complex ions. (For our purposes, the only thing we need to know about the charges on ions is that opposites attract and like charges repel. ) Fluoride forms these complexes with every metal ion except the alkali metals (lithium, sodium, and potassium). Two complex ions we are going to meet in these pages are silicon hexafluoride (SiF62- ) and aluminum tetrafluoride (AlF4- ).
The fluoride ion forms complexes with metal ions that are needed in the body (e. g. , calcium and magnesium) as well as with metals that are toxic to the body (e. g. , lead and beryllium). This can cause a variety of problems, including the following examples:
1. Fluoride interferes with enzymes where metal ions are located at the active sites or where, as with magnesium ions, they act as an important co-factor. (A co-factor is not actually part of an enzyme’s structure but expedites its action by aligning the molecules in the right position. )
2. Fluoride can form complexes with metal ions like Al3+ and Pb2+ and may facilitate their uptake into tissues where those metals might not otherwise go. 3–6
Aluminum Fluoride Complexes
With the aluminum ion (Al3+ ) the fluoride ion can form the ion AlF4-, an ion that has about the same size and shape as the phosphate ion (PO43- ), an ion of huge biological significance. Both RNA and DNA (polymers of nucleic acids) are synthesized using the triphosphates of their corresponding bases: adenosine, cytosine, guanosine, and thymine (or uracil for RNA). Phosphate is also involved in the storage and use of energy in the body; energy is stored by converting adenosine diphosphate (two phosphates on the molecule) to adenosine triphosphate (three phosphates on the molecule), and energy is released by reversing the process and converting adenosine triphosphate back to adenosine diphosphate. Some biological switching devices (e. g. , see the discussion of G proteins in the next section) are controlled by substituting guanosine triphosphate for guanosine diphosphate. Any basic textbook on biochemistry goes into these processes in great detail. It is not unreasonable to think that AlF4- might do damage to biological systems, and much more attention needs to be paid to this possibility.
Interference with G Proteins
One of the things that the AlF4- ion can do, which we know most about, is to switch on G proteins in vitro and thereby disrupt the transmission of important messages across cell membranes. 7, 8
The G protein system is located in the outer membranes of the cells in every tissue that requires external regulation. The system is needed to enable water-soluble messengers like hormones and growth factors, which cannot cross the cell membranes (membranes are made largely of fat and repel water-soluble compounds), to get their message inside the cells of the tissues they are meant to excite. The G protein system performs this function.
This is how the G protein switch works: In the off position guanosine diphosphate (two phosphates on the molecule) sits in a pocket in the G protein, but in the on position guanosine triphosphate (three phosphates on the molecule) occupies the pocket. The switch from “on” to “off” is normally triggered by a hormone or other water-soluble messenger arriving at a receptor on the cell’s surface.
However, AlF4- has the ability to “trick” the G protein to act as if it has been switched on when it hasn’t (i. e. , no normal messenger has arrived). This is how that works: The AlF4- ion can enter the G protein in the off position and form a combination with guanosine diphosphate, which makes it look like guanosine triphosphate, thus switching the G protein to the “on” position. The result is that AlF4- is able to mimic the transmission of critical messages across cell membranes when no actual messenger has arrived at the receptor on the membrane surface.
Given a sufficiently high concentration (20–200 ppm F-), which certainly occurs in bones and teeth and possibly at the interface between calcified deposits and the soluble part of the cell in bone and other calcifying tissues, such interactions give aluminum-fluoride complexes the potential to interfere with many hormonal, some growth-factor, and some neurochemical signals. 9, 10 There are approximately three thousand reports in the scien
tific literature of scientists using aluminum fluoride to switch on G proteins. Researchers have suggested mechanisms involving G proteins to explain fluoride’s ability to damage the growing tooth enamel (see chapter 11), as well as stimulating bone turnover. The bone, like every other tissue in the body, is continually being broken down (resorbed) and rebuilt (ossified) from its constituent materials; see chapter 17. TSH, the thyroid-stimulating hormone, is one of the hormones whose signals aluminum fluoride can mimic, at least in test tubes (see chapter 16).
An excellent summary of the biochemistry of fluoride can be found in the book by Kenneth L. Kirk titled Biochemistry of the Elemental Halogens and Inorganic Halides. 11
Calcium-Fluoride Interactions
There was an old adage in the long history of lead toxicity: Lead follows calcium. The same adage also applies to fluoride: Fluoride follows calcium. In the sixty years of water fluoridation most of the attention has been focused on fluoride’s interaction with the calcium in the hard tissues (the teeth and bone); however, it may well turn out that fluoride’s more worrying impacts on the body will turn on its interaction with calcium ions in the soft tissues.
It is well established that fluoride interacts with the key structural material of both the tooth enamel and the bone: calcium hydroxyapatite. In this process the fluoride ion replaces a hydroxyl ion, making the enamel harder and more resistant to acid attack (which is the first step in dental decay) and also making the bone harder but possibly more brittle (see chapter 17). A great deal of research has been done on these interactions between fluoride and calcium. However, surprisingly, much less work has been done investigating fluoride’s possible interaction with calcium’s other functions.
Two important functions of calcium are (1) the transmission of messages across the junction between two nerve cells (the synaptic cleft) and (2) the communication between the nerve cell and muscles at the neuromuscular junction. Both of these calcium actions hinge on the remarkable fact that in our tissues the concentration of calcium ions outside the cell is about ten thousand times greater than the concentration inside. This huge difference has been exploited by nature to allow the influx of calcium ions into the cell to become a very important messenger and regulator. Equally important is to get the calcium ions out of the cell once its regulatory job has been done. This involves proteins that straddle the cellular membrane and use chemical energy to pump the calcium out of the cell (or at least away from the key action area).
So the key question to ask is whether fluoride ions can cause some kind of interference with these calcium ion movements and thereby disrupt their delicate regulatory role. The simple answer is that we don’t really know because few researchers in the West have pursued the matter very closely. However, there has been a great deal of research on fluoride’s impact on the brain in China, and gradually more people are hearing about these studies. For example, there are now over eighty experiments that show that fluoride interferes with animal brain, twenty-three studies that have found an association between moderate to high fluoride exposure and lowered IQ in children, three studies that have found fluoride damage to fetal brain, and one study showing altered behavior in children in areas endemic for natural fluoride exposure. All of these studies are identified, and some discussed, in chapter 15. However, there are many different ways that a toxic substance can interfere with the brain in addition to calcium-regulating mechanisms.
A very recent study (Zhang et al. 2010)12 has found a relationship between fluoride and calcium that may explain fluoride’s role in causing brain damage. However, it is not a direct interaction between fluoride and calcium ions per se; rather it appears that fluoride might be interfering with the process responsible for the production of the proteins that comprise the channels through which calcium flows or the pumps that clear it from the scene of action.
It can only be hoped that researchers will pursue this matter further and find out just what fluoride may be doing to the developing brain and determine the mechanisms involved. Hopefully, solid answers will be achieved in this before too many more children are unnecessarily exposed to excessive fluoride.
Oxidative Stress
Meanwhile, as this book goes to press, a review article by E. Gazzano et al. , “Fluoride Effects: The Two Faces of Janus, ” has been published and summarizes much of what is known about fluoride’s mechanisms of toxicity. Of particular interest is the ability of fluoride to cause oxidative stress by interfering with the body’s defense mechanisms against reactive oxidative species (ROS), which can otherwise attack membranes (lipid peroxidation) and presage inflammation and a whole range of degenerative disesases. 13
Physiology
An important starting point for a discussion of fluoride’s physiology is the level of fluoride naturally present in mother’s milk. This has been measured in several studies. Reported concentrations generally lie in the range of 0. 004– 0. 04 ppm. 14–20 These concentrations are very much lower than the average level used in fluoridation programs (0. 6–1. 2 ppm). As discussed in chapter 1, there is little or no evidence that fluoride is an essential nutrient.
Possibly the low levels in mother’s milk may tell us that there were reasons for keeping the fluoride ion away from the infant’s developing tissues. Having had a glimpse of fluoride’s biochemistry above, that would seem to be a fortunate result.
While there is no evidence that any mechanism has evolved for concentrating fluoride in the milk—which would be necessary if a baby were to receive anything approaching the amount of fluoride he gets from formula made with fluoridated water—there is some evidence that fluoride may be partially excluded from human milk.
Increasing daily fluoride intake does not necessarily increase the concentration of fluoride in human milk. Some studies suggest that the concentration of fluoride in milk is influenced by the amount ingested;21, 22 others find no significant correlation. 23, 24 Overall, any correlation appears weak. One problem in interpreting these results is that they usually do not take into account the total fluoride intake from all sources. Such an accounting was, however, attempted by G. N. Opinya and colleagues, who calculated total fluoride ingestion by individual mothers living in an area with a naturally high fluoride concentration in water (9 ppm). Total daily intakes ranged between 9. 5 mg and 37. 2 mg, yet, despite the wide variation, there was no significant correlation with human milk fluoride, which averaged only 0. 033 ppm. 25 When a single large dose of fluoride is ingested, the concentration rises sharply in the blood plasma. However, Ekstrand et al. 26, 27 found that despite the rise, the concentration in milk showed little or no change.
We can conclude from the above only that human babies are adapted to develop with very little or no fluoride in their diet. It seems reckless to imagine that we know better what is good for them. In particular, infancy is not the time when one would want exposure to a substance that can affect the brain (see chapter 15), especially at levels that are 25–250 times the concentration found naturally in mother’s milk.
One of the reasons that Dr. Arvid Carlsson, a neuropharmacologist, gave in 1978 for opposing fluoridation in Sweden was the far greater exposure bottle-fed babies would get to fluoride than breast-fed babies. He wondered what this “may mean for the development of the brain and the other organs. ”28 Thirty-two years later we may be beginning to find out (see chapter 15).
Circulation of Fluoride
Fluoride enters the bloodstream via the gums, the stomach, the intestinal lining, the lung (in the case of airborne fluoride), and possibly the skin during baths or showers (there seems to have been little formal study of this route of exposure). Once in the bloodstream, it circulates throughout the body and can then enter every other tissue. However, only in the calcifying tissues (which include the pineal gland; see chapter 16) will the concentration rise substantially higher than the concentration in the blood.
On average, only 50 percent of the fluoride we ingest each day is excreted through the kidneys, the remainder largel
y accumulating in our bones, teeth, pineal gland, and other calcifying tissues. People with poor kidney function excrete less fluoride. This affects the elderly, as kidney function decreases with age. Because the total mass of our bones is so large, 99 percent of the total fluoride accumulates there, although that does not mean concentrations reached in other tissues are not significant. This may be particularly true of the pineal gland (see chapter 16).
Inkielewicz and Krechniak showed that fluoride accumulated in rat testis in a dose- and time-dependent manner. 29 Others have shown that fluoride can cross the blood-brain barrier and accumulate in rat brain (see chapter 15). However, when considering the extent of accumulation in the brain, it is important to distinguish between accumulation in the brain itself and the demonstrated accumulation in the pineal gland30, 31 (see chapter 16). The pineal gland is outside the blood-brain barrier but may have been included in some of the analyses of the whole brain.
If the kidney is damaged, more fluoride will accumulate, especially in the bone. To a certain extent, the accumulation of fluoride in the bone could be viewed as having a protective effect by keeping fluoride away from more sensitive tissues. However, it may produce two problems: First, as the fluoride accumulates in the bone over time, it may reach levels where it affects the bone itself (and connective tissue; see chapter 17), including the bone marrow, which is responsible for generating key cells and molecules involved in the immune system. Second, fluoride accumulated in the bone may cause problems for other tissues by passing into the circulation during bone turnover. Bone turnover—the dynamic process of resorption and ossification—may accelerate during fasting, ill health, and pregnancy, either by slowing down desorption or accelerating resorption, or a combination of both.
Fluoride’s Slow Turnover in Bone
The time it takes a substance to go from a given concentration to half that concentration in the absence of continued input is called the substance’s half-life. The half-life of fluoride in bone is thought to be about twenty years, 32 with complete turnover occurring three or four times in a lifetime. Thus, turnover under normal circumstances is slow; however, in times of stress, disease, or prolonged reduced diet, the turnover can increase. According to the 2006 NRC panel, twenty years may not be the true half-life. The report states, “A study of Swiss aluminum workers found that fluoride bone concentrations decreased by 50 percent after 20 years. . . Twenty years might not represent a true half-life. Recent pharmacokinetic models. . . are nonlinear, suggesting that elimination rates might be concentration dependent. ”33
