The Pharmacology of Fluoride

By Gustav Wm. Rapp, PhD

Summary: A fourteen-page paper on fluorine and its effects in the human body. “All cells are affected by fluoride to a greater or lesser degree,” writes Dr. Rapp. “While most of the interest in fluoride as a drug has centered upon its activity on oral structures, there are many other parts of the human body that feel [its] effects [including] the bones…skin, hair, viscera, circulatory system, and genitourinary system.” Scientifically sound, the author’s discussion raises many troubling questions. From The Bur magazine, 1950. Lee Foundation for Nutritional Research reprint 53.

[The following is a transcription of the original Archives document. To view or download the original document, click here.]

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The Pharmacology of Fluoride[spacer height=”20px”]

The dental profession and the public at large have been made conscious of the potentially important role of fluoride in the control of dental caries.

While the reports coming from such sources as the United States Public Health Service are encouraging, the lay press has unfortunately printed a picture that would at times seem to be much too optimistic. At this time there are two distinct methods for the use of fluoride as a prophylaxis against dental caries. The topical application of soluble fluoride to tooth surfaces has had a moderate amount of practical success; however, not content with the recommendations of the originators of this method, many commercial firms have modified and adjusted the simple procedure of applying 2 percent sodium fluoride to the teeth so that now the dentist, if he wishes, may practice a therapeutic ritual that, while impressive to the patient, cannot be any more effective—optimistic advertising notwithstanding.

The second method of fluoride treatment, which consists of adding the drug to communal waters, is based on the premise that adding sodium fluoride to ordinary domestic water produces the same aqueous environment for teeth as is found in the endemic fluoride areas in the country. The validity for this premise is still highly questionable and is to be touched on later in the paper.

While most of the interest in fluoride as a drug has centered on its activity on oral structures, there are many other parts of the human body that feel the effects of the presence of fluoride. This paper has as its object a review and evaluation of data concerning the pharmacology of fluoride, with special emphasis on those aspects that might be of practical interest to the dental profession.

Sources of Fluorides

We are so used to thinking of the water supply as the source of fluoride we consume that we are apt to forget the numerous other sources in our daily life. A review of the literature indicates that many of the common foods in the American diet contain fluoride concentrations in the same order of magnitude as the soil or water in the environment in which they grow. Table I gives examples of some of these foods.

Table I. The Concentration of Fluoride in Some Common Foods

Food	Fluoride (parts per million)
Milk	0.05–0.23
Eggs	0.04–2.0
Butter	1.5
Cheese	1.6
Liver	1.5–1.6
Chicken	1.4
Pork	0.2
Oysters	1.5
Whole wheat	1.3
White bread	1.0
Gelatin	0.0
Dextrose	0.5
Honey	1.0
Tea (dry)	30.0–60.0
Tomatoes	0.6–0.9
Apples	0.8

[spacer height=”20px”]It will be noted that even if an individual were to drink fluoride-free water, he could virtually not escape ingesting some fluoride in the course of a normal meal. In addition to these, which might be considered natural sources of fluoride, there are others with which we are apt to come in contact and that, as an inspection of Table II will indicate, are potentially great sources of fluoride intake.[spacer height=”20px”]

Table II. Fluoride Sources of Industrial Origin

Use	Fluoride Compound(s)
Binder for emery wheels	CaF2
Laundry bleach	Na2SiF6
Coagulating rubber	Na2SiF6, MgSiF6
Disinfection of hides and skins	H2SiF6
Fixer in dye works	SbF3
Flux	Na3AlF6, CaF2
Glass etching	HF, NH4F
Insect powders	NaF
Optical paste	CaF2
Wood stain	CrF3

[spacer height=”20px”]The chief observation that should be made at this point of the discussion is that the daily intake of fluoride must be considered from several sources and not from water alone. This becomes important to areas that are now adding or contemplating adding soluble fluoride to their water supply.[spacer height=”20px”]

Absorption and Retention of Fluoride

The absorption of fluoride into the body can be brought about in a number of ways. It has been noted, for instance, that workers in cryolite plants achieve a rather high body fluoride content because of its absorption from inhaled cryolite dust. To be sure, this pathway of absorption is unusual, but it points to the fact that we must take many sources of fluoride into consideration when we discuss the matter of fluorosis. By far the most important pathway for the absorption of fluoride is the alimentary tract.

Let us first discuss some factors that influence the rate and the amount of fluoride absorption. The solubility of the fluoride source is one of the most important. This can be seen in Table III. Since the solubility of fluoride sources is related to the acidity
 or alkalinity of the medium in which they exist, and since in general a low pH 
is conducive to solubilizing fluoride sources, the mere fact that a salt, such as calcium fluoride, is insoluble in water does not necessarily mean that it is not a good source of available fluoride. This is so because the high acidity of the stomach can dissolve a good portion of the ingested calcium fluoride, which might then be absorbed by the gastrointestinal tract. There is a secondary mitigating influence in the human gastrointestinal tract, and that is the high alkalinity of the intestinal juices in the small intestine. In contradistinction to the solubilizing effect of the gastric juice, the intestinal juices change many soluble fluorides into insoluble ones.

Table III. Solubility of Some Fluoride Salts

Compound	Solubility (grams per 100 cc)
NaF	4.0
Na2SiF6	0.65
AgF	182.0
CaF2	0.0016
PbF2	0.064
LiF	0.27
MgF2	0.0087
MgSiF6	65.0

[spacer height=”20px”]A second factor influencing absorption is concentration of fluoride in the source. The absorption of fluoride is a strictly physical phenomenon. As such it depends entirely on the relative concentration of the drug on either side of a membrane. The laws of physical absorption state that the higher the concentration, the greater will be the rate and amount of material absorbed.[spacer height=”20px”]

A third factor influencing absorption is the amount of substance available. This is such an obvious limitation that no further discussion is necessary.

A fourth factor, and indeed an important one, is the pH of the medium from which absorption is to take place. While at first glance this may seem to be a duplicate of the first criterion discussed, the implications are far different. Studies have indicated that the absorption of fluoride takes place largely from the undissociated hydrogen fluoride molecule. From any source the amount of undissociated hydrogen fluoride is a direct function of the pH. Table IV indicates data obtained when the absorption of fluoride from an intact intestinal loop of a dog is measured. These experiments illustrate quite clearly that there is a very close relationship between the acidity of the medium and the absorption of fluoride from it.

Table IV. Fluoride Absorption from a 0.01 Percent Sodium Fluoride Solution Placed into an Intact Dog’s Intestinal Loop

pH	Percent Absorbed
8.0	18
7.0	22
6.0	39
5.0	46
4.0	52
3.0	67

[spacer height=”20px”]The fifth factor influencing the absorption of fluoride is the presence or absence of fluoride-insolubilizing substances. It is obvious from a consideration of the first factor discussed above that under conditions whereby the available fluoride is rendered insoluble by the presence of, say, excess calcium ions, the amount absorbed materially diminishes. This statement is borne out by the experiments that are summarized in Table V. In this experiment rats were fed fluoride in food or in water at a 20 ppm level. Control groups received only the fluoridated food or water, whereas the experimental groups received calcium hydroxide in addition to the fluoridated food or water. The amounts of fluoride ingested and excreted were measured from the food consumption and the fluoride concentration in the excreta, respectively. From these data we can calculate the amount of fluoride retained by the animal. Since the retention in the body is a mirror of the amount absorbed—as will be explained in a subsequent section—we can assume that a high fluoride excretion under the conditions of this experiment indicates a low absorption.[spacer height=”20px”]

Table V.
 Effect of an Insolubilizer on Fluoride Absorption

Group	Average Amount of Fluorine Ingested (mg)	Average Amount of Fluorine Excreted (mg)
Fluoride in Water	17.5	8.4
Fluoride in Food	23.2	12.7
Fluoride in Water plus Ca(OH)2	18.7	17.5
Fluoride in Food plus Ca(OH)2	21.5	19.7

[spacer height=”20px”]In addition to the factors that influence absorption, we must also consider the factors that influence fluoride retention. One of these factors is the amount of fluoride being ingested. In general the greater the amount ingested, the greater 
the amount that will be retained. This follows from the law of mass action. It is important to remember in this connection that more fluoride will be retained if it is given in multiple small doses than when a similar quantity is given in a fewer number of larger doses.[spacer height=”20px”]

A second factor that influences fluoride retention is the activity of the calcifying tissues. Since in general the only so-called storage depot for calcium in the body is a calcified structure [i.e., a bone or tooth], and since the method of storage is to build the fluoride ion into the crystalline structure of the bones and teeth, [we know] that those animals in an act of calcification will retain more fluoride in their body than those in whom the calcification process is virtually finished. This phenomenon can be recognized by inspecting Table VI. It will be seen that as these animals grew older, they retained less of their ingested fluoride than when they were young.

Table VI. Relationship Between Amount of Fluoride Retained and Age of Animal from Time of Weaning

Days on Experiment	Percent Fluoride Intake Excreted
1	52
40	58
80	63
120	68
160	72
200	79
220	83

[spacer height=”20px”]Distribution of Fluoride in the Body

We normally think of fluorides as being accumulated in the hard structures of the body, such as the bones and the teeth. However, since the fluoride ion is so small and so diffusible, it may be found distributed throughout the entire body. It is true of course that we find a high concentration in the hard tissues, which, as has been indicated, is due to the fixing of fluoride as an integral part of those structures. Table VII illustrates the distribution of fluoride throughout the body tissue of normal adult humans.

Table VII. Distribution of Fluoride in Normal Body Tissues

Tissue	Fluoride (parts per million)
Blood	3.5
Brain	0.6
Liver	2.1
Kidney	4.5
Heart	1.6
Spleen	2.7
Muscles	1.6
Femur	2.9

[spacer height=”20px”]If we compare these values with those illustrated in Table VIII, it is little short of astonishing to find only small differences—for the values found in Table VIII were obtained from individuals who had died of fluoride poison, and figures have been interpreted as being the lethal fluoride concentrations for those internal organs. From a comparison of these two tables, it would appear that while the concentration of fluoride in the normal and fluorosed individual is small, the activity of fluoride may be vastly different and possibly accounts for the physiologic differences between these two groups.[spacer height=”20px”]

Table VIII. Lethal Fluoride Concentration in Body Tissues

Tissue	Fluoride (parts per million)
Blood	3.6
Brain	1.6
Liver	4.0
Kidney	4.6
Heart	2.1
Spleen	3.9
Muscles	2.6

[spacer height=”20px”]This problem of fluoride activity rather than fluoride concentration appears to be an important one and will be referred to again in a later potion of the paper.[spacer height=”20px”]

Table IX indicates a rather interesting distribution of fluoride in male and female rats. There can be no doubt that female rats retain a greater portion of fluoride than do males. This difference possibly has as its basis the higher metabolic rate in the females. This contention is strengthened somewhat by a report of an investigation in which the metabolic rate of male rats was artificially increased. Under these circumstances the male rats had a fluoride retention more comparable to that found in the females.

Table IX. Total Amount of Fluoride in Rat Carcass After Feeding 4 ppm Fluoride

	Rat	Weight (grams)	Fluorine (ppm)
Male	1	230.2	13.0
	2	271.2	10.9
	3	346.2	11.6
	4	271.2	11.3
Average		279.7	11.7
Female	5	172.7	13.7
	6	187.9	14.1
	7	177.3	13.9
	8	175.4	14.7
	9	173.3	13.9
Average		177.3	14.1

[spacer height=”20px”]Table X illustrates the high specific distribution of fluoride in teeth. Again, the most physiologically active portions seem to contain the greater amount of fluoride. This highly selective concentration of fluoride in teeth is of course the basis of systemic therapy for caries prevention.[spacer height=”20px”]

Table X. The Accumulation of Fluoride in Human Teeth

Treatment	Incisors		Molars
	Enamel	Dentin	Enamel	Dentin
Distilled water	36 ppm	46 ppm	34 ppm	89 ppm
10 ppm fluoride in water	160 pm	495 ppm	130 ppm	415 ppm

[spacer height=”20px”]It is interesting to note that the fluoride ion passes the placental barrier. The importance of this is that the fetus has already accumulated fluoride during its development. This also accounts for the fact that the deciduous teeth of youngsters living in endemic fluoride areas show a greater resistance to caries than those living in nonfluoride areas.[spacer height=”20px”]

The Excretion of Fluorides

Because of its water solubility, the fluoride ion is excreted through all pathways that have water as the vehicle. We find fluoride in urine, feces, sweat, saliva, and tears. The fluoride concentration of urine in subjects living on fluoride-free water ranges from 0.3 to 1 ppm. If the fluoride content of the ingested water rises to as little as 0.5 to 1 ppm, the urinary fluoride concentration may rise to as high as 3 ppm.

Workers in a magnesium foundry where fluoride-bearing dust is inhaled have been found with a urinary fluoride as high as 10 ppm.

From a practical point of view, the dentist should be interested in fluoride excretion through the saliva. Since saliva bathes the teeth more or less constantly, it would seem that the salivary fluoride should act as additional protection against tooth decay. Unfortunately, the data that relate salivary fluoride to blood fluoride indicate that only about one-tenth the blood fluoride concentration is found in the saliva. This points to a selective retention of fluoride in the blood or perhaps a barrier to fluoride excretion through the saliva, since a similar study on blood and salivary chloride indicates that there is a saliva-to-plasma chloride ratio of approximately 0.4 to 1.

The sweat serves as a surprisingly good pathway of fluoride excretion. Subjects living in a fluoride water area excrete sweat containing from 0.3 to 2.0 ppm of fluoride. When these same individuals are placed on nonfluoride water, their excretion in the sweat drops to approximately 0.2 to 0.3 ppm after two weeks.

When an experimental animal is first placed on a fluoride-containing diet, he retains virtually one-half of the absorbed fluoride. As the concentration in the diet is increased, there is a progressively greater output through the excretory organs, and above a given level virtually all of the additional fluoride in the food is apparently excreted. These data point toward a saturation phenomenon. In humans it has been found that a total daily fluoride intake of from 4 to 5 milligrams produces saturation. Below this figure some of the ingested fluoride is retained, but above this figure there is no further retention.

Pharmacologic Effects of Fluorides

In the human body, the physiologic systems that are affected by fluorides are the bones, teeth, skin, hair, viscera, circulatory system, and genitourinary system. The manner in which each of these systems is affected varies with the concentration of the drug, the length of time it is allowed to remain in contact, and the individual susceptibility of the system to fluorides.

This problem of fluoride susceptibility seems at first glance to be a rather unpredictable one. However, when one considers the basic mode of action of fluorides, most of the symptomatic phenomena can be understood.

In general, fluorides seem to exert their effects on enzymes, cells, and calcifying tissues. In the case of the effect on enzymes, there is a selective activity demonstrated in its effect. Since enzymes can be considered to be complexes consisting of proteins, vitamins, and a metallic component, and since the metal portion of each enzyme is not identical with that in another enzyme, it follows that only those enzymes that have metallic components capable of being rendered insoluble, or nonavailable, will be affected by the presence of fluorides.

Some of the most important systems of enzymes that are susceptible to fluorides are those involved with phosphate transport. The effect on phosphates and phosphorylases becomes important from several points of view.

In this first place, phosphate-transporting enzymes are important in the absorption of carbohydrates from the small intestine. When these enzymes are absent or poisoned in any manner, sugar absorption takes place only slowly. Secondly, these enzymes are also important in the utilization of carbohydrates in the body. Indirectly, they are also concerned with the metabolism of fats and proteins. In the presence of an adequate amount of fluorides, these enzymes are poisoned, and, as will be seen from Table XI, the normal sugar metabolism is disturbed.

Table XI. An Effect of Fluoride on Carbohydrate Metabolism

Group	Blood Glucose	Blood Lactic Acid	Liver Glycogen	Muscle Glycogen
Control	118 mg%*	17 mg%	3.6%	0.78%
20 ppm fluoride in water	223 mg%	198 mg%	0.64%	0.17%

*[mg% = mg/100 ml]

Compare the blood sugar, muscle and liver glycogen, and blood lactic acid concentrations under the influence of fluorides. A more than casual glance a this table will indicate that the effects are very similar to those obtained in a diabetic animal. This does not mean at all that fluorides cause diabetes! It merely means that the presence of fluorides seems to interfere with metabolic systems similar to those affected by an insufficiency of insulin.

A recent study has pointed to the importance of these same phosphate-transporting enzymes for renal reabsorption of glucose. In the presence of an adequate amount of fluorides, a normal animal, such as a [healthy] dog or rabbit, can be made to have glycosuria. This glycosuria can be produced even in the animal with normal blood sugar levels, indicating quite clearly that the fault lies with a deficiency of renal reabsorption.

Much speculation has been raised about the effect of fluorides on the blood-clotting mechanism, since this depends in part on the availability of calcium ions. Calcium ions have a high affinity for fluorides and can conceivably remove these from solution. As a corollary, fluoride ions can remove essential calcium ions from solution. In the test tube, we can demonstrate an interference with the blood-clotting mechanisms by adding fluorides. In the intact animal, no such interference has ever been demonstrated unless impractically high concentrations were used. This difference between the in vitro and in vivo behavior of the drug towards the clotting mechanisms is not easily explained.

The effect of fluorides on cells is of importance. All cells are affected by fluoride to a greater or lesser degree. The extent of effect on a cell seems to be directly related to the cell’s dependence on carbohydrate metabolism. While tissue cells are affected to some degree, of more importance is the fact that fluorides in the proper concentrations can affect bacterial cells. It can be shown that microorganisms inhabiting the oral cavity can be materially inhibited by fluorides. It is interesting, however, that the concentrations must be many times those required to inhibit enzymes. For example, the concentration that inhibits acid production is 1 ppm, while lactobacilli are not inhibited until a concentration of 250 ppm is used.

The effects of fluorides on the calcified structures of the body are striking. Fluorosed tooth enamel, for example, is denser, harder, and more resistant to acid decalcification than is a corresponding normal enamel. These effects have been ascribed to the fact that fluoride becomes part of the crystal lattice of the calcified structures. It differs physically from the hydroxyl-containing crystal only in its denseness of packing.

Sometimes the effect of fluoride fixation by the calcified structures results in a visible change in the normal structure. The dental profession is very familiar with the mottled enamel of fluorosed teeth. While the exact nature of this malformed tooth substance is not known, it seems likely that the presence of a certain critical amount of fluoride during the formative stage of the enamel so affects some enzymes concerned with the formation of this material that an abnormal structure results.

The well known practical effects of fluoride affecting the tooth enamel are on the one hand desirable and on the other hand lamentable. When fluorides are present in the environment of calcifying tooth enamel below a certain critical level, the fluoride is simply built into the crystal lattice, and hard, dense, resistant enamel is formed, which clinically has the ability to resist the carious process. Such a building of fluoride into the enamel, at least on its surface, seems also to be achieved by topical application of a concentrated solution of soluble fluoride (2 percent sodium fluoride). The exact manner in which this method of fluorosing the enamel exerts its beneficial effect is not yet determined. However, the practical result seems to be a reduction in the caries experience of individuals thus treated. Recent evidence indicates that adults as well as children can benefit from such a treatment when it is carried out correctly.

On the other side of the picture is the fact that when the critical level of fluoride in the environment from which the tooth is calcifying is overstepped, unsightly mottling can result. It appears to be simply a matter of concentration control in order to achieve either of the two results mentioned. Unfortunately, the line between mottling and no mottling is an elusive one, and the degree of control to be exercised seems to be very fine.

The experimental addition of soluble fluorides to domestic water supplies in concentrations resembling those found in natural fluoride waters is interesting and bears very close watching. While there seems to be no doubt that it is, in fact, the fluoride content of the natural water that is responsible for the beneficial effects from such waters, there are still some very important questions that need answering. What is the response of the body to fluoride that is not accompanied by the other mineral substances invariably found in natural fluoride waters? Do these substances augment or limit the effective activity of fluoride even though they do not affect its concentration? What relation exists between the concentration of fluoride and its activity in media of various mineral compositions? What is the relation between the intake of fluoride from food and/or water and its activity with respect to its concentration associated with calcifying tissues?

When these questions have been answered, together with those other questions that continued research on fluoride and its effect on living systems will propose, then only can we say that fluoride therapy is out of the experimental stage. Until that time we must be wary not to draw hasty, unwarranted, and perhaps regrettable conclusions.

By
 Gustav W.M. Rapp, PhD. From the Departments of Chemistry and Physiology of the School of Dentistry of Loyola University, Chicago, College of Dental Surgery. Reprinted from the The Bur, April 1950, by the Lee Foundation for Nutritional Research.

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