INTAKE AND METABOLISM OF FLUORIDE

G.M. WHITFORD

Department of Oral BiologySchool of DentistryMedical College of GeorgiaAugusta, Georgia 30912-1129

Adv Dent Res 8(1):5-14, June, 1994

Abstract—The purpose of this paper is to discuss the majorfactors that determine the body burden of inorganic fluoride.Fluoride intake 25 or more years ago was determined mainlyby measurement of the concentration of the ion in thedrinking water supply. This is not necessarily true todaybecause of ingestion from fluoride-containing dentalproducts, the "halo effect", the consumption of bottled water,and the use of water purification systems in the home.Therefore, the concentration of fluoride in drinking watermay not be a reliable indicator of previous intake. Undermost conditions, fluoride is rapidly and extensively absorbedfrom the gastrointestinal tract. The rate of gastric absorptionis inversely related to the pH of the gastric contents. Overallabsorption is reduced by calcium and certain other cationsand by elevated plasma fluoride levels. Fluoride removalfrom plasma occurs by calcified tissue uptake and urinaryexcretion. About 99% of the body burden of fluoride isassociated with calcified tissues, and most of it is notexchangeable. In general, the clearance of fluoride fromplasma by the skeleton is inversely related to the stage ofskeletal development. Skeletal uptake, however, can bepositive or negative, depending on the level of fluorideintake, hormonal status, and other factors. Dentin fluorideconcentrations tend to increase throughout life and appear tobe similar to those in bone. Research to determine whetherdentin is a reliable biomarker for the body burden of fluorideis recommended. The renal clearance of fluoride is highcompared with other halogens. It is directly related to urinarypH. Factors that acidify the urine increase the retention offluoride and vice versa. The renal clearance of fluoridedecreases and tissue levels increase when the glomerularfiltration rate is depressed on a chronic basis.

This manuscript was presented during a Workshop onMethods for Assessing Fluoride Accumulation and Effects inthe Body, sponsored by the National Institute of DentalResearch (Bethesda, MD), January 13-15, 1993.

This work was supported in part by USPHS ResearchGrants DE-06113 and DE-06429from the National Instituteof Dental Research, National Institutes of Health, Bethesda,MD 20892.

FLUORIDE INTAKEThe major sources of fluoride in the United States are food,drinking water, beverages, and fluoride-containing dentalproducts (Myers, 1978; Burt, 1992). The atmosphere carriessome fluoride, but it supplies only a small fraction of thedaily exposure except in heavily polluted areas (Hodge andSmith, 1977). Most foods have fluoride concentrations lessthan 0.5 ppm (Taves, 1983), the major exception beingmarine fish, which have concentrations that range from about6 to 27 ppm (Muhler, 1970). Most drinking water supplies towhich fluoride is not added in controlled amounts haveconcentrations less than 0.3 ppm, but a few have levels in the4-6-ppm range, particularly in the southwest and northcentral states (Centers for Disease Control, 1985). Therecommended concentration range is 0.7-1.2 ppm, dependingon the average regional temperature. Approximately 55% ofthe US population is served with water containing fluoridewithin this range. The lower levels are recommended forwarmer regions where water intake tends to be higher(Galagan and Vermillion, 1957).

Beverages include soft drinks, fruit juices and drinks, tea,and Gatorade as well as several others consumed lessfrequently. Beverage fluoride concentrations reflect those inthe water used for preparation. In general, they range from0.1 to about 1.4 ppm except for tea, which contains up to 7ppm (Clovis and Hargreaves, 1988; Pang et aL, 1992).

Dental products have fluoride concentrations that rangefrom 230 ppm in over-the-counter mouthrinses to 12,300ppm in APF gels which are applied topically to the teeth bydental professionals. Toothpastes, the most frequently useddental products, contain fluoride at 1000-1500 ppm either assodium fluoride or disodium monofluorophosphate.

The average daily intake of dietary fluoride by youngchildren whose water supply is optimally fluoridated isapproximately 0.5 mg or 0.04-0.07 mg/kg per day (McClure,1943; Ophaug et aL, 1980a,b, 1985; Featherstone andShields, 1988). It was determined in the 1930's and 1940'sthat this intake range was "optimal" in that it provided a highdegree of protection against dental caries and a lowprevalence of dental fluorosis. There is no reason to thinkthat the effect of this level of intake would be any differenttoday than it was 50 years ago.

Table 1 summarizes the results from several studies thatdetermined dietary fluoride intake data for various agegroups. Intake by infants depends mainly on whether they arefed breast milk or a formula. Human breast milk containsonly a trace of fluoride and provides less than 0.01 mg/day.Infants fed breast milk can be in a negative fluoride balancefor some time, which indicates a net loss from bones andprobably teeth (Ekstrand et aL, 1984). Ready-to-feedformulas generally contain fluoride at less than 0.4 ppm(Johnson and Bawden, 1987; McKnight-Hanes et aL, 1988),while formulas reconstituted with optimally fluoridated water

WHITFORD

TABLE 1

AVERAGE INTAKE OF DIETARY FLUORIDE BY AGE

ADV DENT RES JUNE 1994

Age

0-6 moBreast-fedFormula-fed:

Ready-to-feed

Reconstituteda

6 mo

2y

Adult

Mg F/Day

VOL.8(1) INTAKE AND METABOLISM OF FLUORIDE

children who do not have good control of the swallowingreflex (Hellstrom, 1960; Ericsson and Forsman, 1969;Hargreaves et aL, 1972; Parkins, 1972; Barnhart et aL, 1974;Baxter, 1980; Dowell, 1981; Wei and Kanellis, 1983; Bell etaL, 1985; Bruun and Thylstrup, 1988; Simard et aL, 1989,1991; Drummond et aL, 1990; Naccache et aL, 1990; Levyand Zarei-M., 1991; Horowitz, 1992; Pang and Vann, 1992).The average amount of fluoride ingested with toothpaste (ormouthrinse) by children whose water is fluoridated, who havegood control of swallowing, and who brush (or rinse) twice aday is approximately equal to the daily intake of fluoride withthe diet (Whitford et aL, 1987). In the case of youngerchildren or those who, for any other reason, have poor controlof swallowing, the daily intake of fluoride from theseproducts could exceed intake with the diet. For those whosedrinking water has a low fluoride concentration, intake fromthese products could exceed intake with the diet regardless ofwhether swallowing occurs.

Dietary fluoride supplements are provided in the form ofdrops, tablets, or urinse supplements". They are intended foringestion in areas where the fluoride concentration in thedrinking water is less than 0.7 ppm. While the ingestion offluoride supplements has been linked to an increasedprevalence of dental fluorosis (for reviews, see Burt, 1992;Workshop Report, 1992), there is little or no evidence thatthey provide excessive amounts of fluoride when they areprescribed and taken according to the dosage schedulerecommended currently (Table 2). There is convincingevidence, however, that supplements are sometimesprescribed at the wrong dosage as well as in areas where thewater is adequately fluoridated (Margolis et aL, 1980; Levyand Muchow, 1992).

In some areas of the United States, however, especiallythose where most of the urban public water supplies arefluoridated, even properly prescribed fluoride supplementsmay add enough to the total intake to cause dental fluorosis.This is because of fluoride ingestion from other sources,principally toothpastes as discussed earlier, and the "haloeffect". The halo effect occurs when foods and beverages areproduced with fluoridated water and then shipped forconsumption in communities that do not have fluoridatedwater. Of particular importance in this regard are the softdrinks and juices. Several studies have shown that thesebeverages have replaced milk and water to a significantextent as the liquids of choice. Pang et aL (1992) reportedthat about 60% of the total daily liquid intake by 2-to- 10-year-olds was in the form of soft drinks, fruit juices or drinks,tea, coffee, and Gatorade. The fluoride concentrations ofthese fluids ranged from < 0.1 ppm to 6.7 ppm. Theassociated average daily fluoride intake ranged from 0.36 mgin the 2-to-3-year-old group to 0.60 mg in the 7-to-10-year-old group. The average daily intake by 4-to-6-year-oldchildren was 0.54 mg. The maximum intake values in thesegroups were 1.42, 2.39, and 2.00 mg/day, respectively. Thesedata are actually underestimates of fluoride intake withliquids, because all water intake was excluded, and beveragesrequiring reconstitution were prepared with distilled water.Thus, in communities without water fluoridation, the

consumption of these beverages is an important source offluoride that has reduced the difference in fluoride intake thatused to exist between areas with and without waterfluoridation. Prescribers of dietary fluoride supplements needto be aware of this fact and take it into account beforedeciding on the proper dose level for individual patients.Because of the multiple sources of fluoride in the US and thedocumented increase in the prevalence of dental fluorosis,consideration has been and is being given to revising thedosage schedule for fluoride supplementation (WorkshopReport, 1992). In Canada and some European countries, ithas been recommended recently that fluoride supplements berestricted to persons older than three years.

Other factors that complicate the estimation of totalfluoride intake are the use of water purifiers and bottled waterin the home. Most of the purifiers sold do not removefluoride, but some, such as the reverse-osmosis type, do. Thepercentage of US homes with water purifiers is not known.At least ten publications have documented the fluorideconcentrations of bottled water. Most concentrations havebeen below 0.3 ppm, so that, to the extent that they areconsumed in an area with fluoridated water, daily fluorideintake would be reduced, whereas it would not be muchaffected in an area without fluoridated water. Hargreaves andChatha (1986) reported that the fluoride concentrations intheir sample of bottled waters ranged from < 0.1 ppm to 10.0ppm. Dabeka et aL (1992) analyzed domestic and importedbottled waters in Canada and found a range of from 0.05 to5.85 ppm (average, 0.54; median, 0.14). Other studies havereported similarly wide concentration ranges (Nowak andNowak, 1989; Flaitz et aL, 1989; Stannard et aL, 1990).Obviously, products with concentrations higher than that inthe available well or tap water would increase the intake offluoride.

We are left with the following conclusion. Unlike thesituation that existed when the only significant source offluoride was the diet, reasonably accurate estimates of totaldaily fluoride intake are no longer simple and

TABLE 2

DIETARY FLUORIDE SUPPLEMENT DOSAGESCHEDULE

Drinking WaterFluoride Concentration, ppm

Age, years Less than 0.3 0.3-0.7 Greater than 0.7

Birth to 2

2-3

3-13

0.25a

0.50

1.00

0

0.25

0.50

0

0

0

aValues are milligrams of fluoride per day (2.2 mg NaF = 1.0 mg F).This schedule is recommended by the ADA Council onDental Therapeutics.

WHITFORD ADV DENT RES JUNE 1994

5CALCIFIEDTISSUES

HOURS

Fig. 1—A typical plasma concentration curve after theingestion of a small amount of fluoride and the majorfeatures of fluoride metabolism.

straightforward. Investigators seeking to examine possiblerelations between fluoride intake and biological effects orhealth outcomes, such as dental fluorosis or the quality ofbone or its strength, need to be aware of the complexsituation that exists today. It is no longer feasible to estimatewith reasonable accuracy the level of fluoride exposure basedsimply on the concentration of the ion in the drinking water.

FLUORIDE METABOLISMGeneral FeaturesWhen considering this subject, it is helpful to keep in mindthat hydrogen fluoride (HF) is a weak acid with a pKa of 3.4.There is a considerable body of evidence showing thatseveral of the aspects of fluoride metabolism are pH-dependent and that the transmembrane migration of the ionoccurs in the form of HF in response to differences in theacidity of adjacent body fluid compartments (Whitford,1989). Studies with lipid bilayer membranes have shown thatthe permeability coefficient of HF is more than one milliontimes greater than that of ionic fluoride (Gutknecht andWalter, 1981).

Fig. 1 shows the major features of fluoride metabolism(Whitford, 1989). After ingestion, plasma fluoride levelsincrease measurably within the first few minutes and reach apeak concentration within 20-60 minutes. The peakconcentration depends on the amount ingested, rate ofabsorption, volume of distribution, and the rates of fluorideclearance from plasma by the kidneys and skeleton. The rapiddecline in plasma concentrations that occurs as the rate ofabsorption declines is due to the renal and skeletal clearancesof fluoride.

AbsorptionIn the absence of high concentrations of certain cations, such

as calcium and aluminum, that form insoluble compoundswith fluoride, about 80-90% of the ingested amount isabsorbed from the gastrointestinal tract (Cremer and Biittner,1970). The half-time for absorption is about 30 minutes. Theabsorption of fluoride is unusual in that it can occur from thestomach to a considerable extent. The rate of gastricabsorption is directly related to the acidity of the contents sothat, for any given dose, the peak plasma level is higher andoccurs sooner when the contents are more acidic (Whitfordand Pashley, 1984). Most of the fluoride that escapesabsorption from the stomach will be absorbed from theproximal small intestine. These facts are based on studieswith young or middle-aged adult laboratory animals orhumans (Whitford, 1989). They may be quantitativelydifferent in young children and older subjects.

Fecal fluoride is usually considered to be that which wasnot absorbed. In general, this is probably true, but it has beenshown that fecal fluoride excretion by rats can be increasedsignificantly by two means: first, by elevating plasmafluoride concentrations; and second, by increasing thecalcium concentration of the diet (Whitford and Augeri,1993; Whitford, 1994). There were three main groups in thestudy (n = 10/group). One group received fluoride only in thelow-fluoride diet (1.5 ppm), while the others received anadditional 0.25 or 0.50 mg F/day, respectively, delivered bymini-osmotic pumps implanted subcutaneously. Each groupwas subdivided according to the concentration of calcium inthe food (0.4% or 1.4%). Fluoride intake and excretion (24 h)were determined twice each week for one month. Table 3shows some of the results.

The groups did not differ with respect to fluoride intakewith the diet. Fecal fluoride excretion, however, increased inproportion to plasma fluoride concentrations regardless ofthe dietary calcium concentration. In the groups fed theadequate-calcium diet (0.4%), the plasma levels increasedfrom 0.39 to 8.17 |xmol/L, reflecting the level of fluorideexposure. Fecal fluoride excretion increased from 9.5 to 29.1fig/day, and fluoride absorption from the diet declined from73.5% to only 23.7%. These data are consistent with the netmigration of fluoride from the systemic circulation into theintestinal tract. They suggest that the concentrations ofdiffusible fluoride in some portions of the tract—probably inthe distal ileum and colon, because of extensive fluorideabsorption in the more proximal regions and unabsorbedcalcium and other ions that can bind fluoride—were lowerthan those in plasma.

Qualitatively similar results occurred in the groups fed thehigh-calcium diet. Compared with the 0.4% calcium groups,however, fecal fluoride excretion was higher, suggesting thatthe concentration of unabsorbed calcium in the chyme wasbinding fluoride entering the intestinal tract, thus reducing theconcentration of diffusible fluoride and allowing more tomigrate into the tract. It was noteworthy that, in the fluoride-infused, high-calcium groups, the absorbed percentages ofdietary fluoride were negative, i.e., fecal fluoride excretionexceeded intake with the diet. Between the two groups thatreceived fluoride only in the diet, the plasma and femur

VOLS(I) INTAKE AND METABOLISM OF FLUORIDE

TABLE 3

INTAKE, FECAL EXCRETION, PERCENT ABSORPTION OF FLUORIDE, ANDPLASMA AND FEMUR EPIPHYSIS ASH FLUORIDE CONCENTRATIONS IN RATS

AS FUNCTIONS OF FLUORIDE EXPOSURE AND DIET CALCIUM CONCENTRATION

0/0.4 0/1.4 0.25/0.4Groupa

0.25/1.4 0.5/0.4 0.5/1.4

Intake withdiet, |xgk

Fecalexcretion, |ULJ

Percentabsorption

Plasma [F],|xmol/L

Femur [F],mg/kg

36.5±1.5

9.5±0.5

73.5±1.4

0.39±0.02

329±21

40.9±1.3

21.3±0.9

47.1±2.3

0.23±0.02

136±8

40.1±2.1

24.5±1.9

38.7±3.9

4.94±0.28

1262±51

40.7±1.3

64.0±4.5

-58.5±10.9

5.18±0.33

1114±31

38.6±1.5

29.1±2.1

23.7±5.2

8.17±0.79

1724±81

42.9±1.7

107.4±8.0

- 165.6±24.2

8.56±0.33

1596±70

^kjroup designations (x/y) indicate: x, the quantity of fluoride (mg/day) infused into each rat via mini-osmotic pump; y, the calcium concentration(percent) of the food.

^There were two rats per metabolic cage. Units for intake and excretion values are (jug/2 rats per day. All data expressed as mean ± SE.

epiphysis ash fluoride concentrations were significantlylower (p < 0.001) in the high-calcium group. Both of thevariables tested in this study (plasma fluoride concentrationand unabsorbed calcium) may be important in explainingwhy osteoporotic patients differ in their response to fluoridetherapy, especially when the regimen includes supplementalcalcium. The findings from this study also raise doubt aboutthe concept that fecal fluoride is only that which was notabsorbed.

PlasmaFluoride in plasma is not bound by proteins or any otherconstituent of plasma (Taves, 1968). The concentration variesaccording to the level of intake and several physiologicalfactors (Whitford, 1989). In general, however, the numericalvalue of the fasting plasma concentration of healthy adultswhose main source of fluoride is the diet is roughly equal tothat in the drinking water, provided that the plasmaconcentration is expressed as (xmol/L and the waterconcentration as mg/L or ppm (Guy et al., 1976). Thus, thefasting plasma concentration of a person whose watercontains 1.0 ppm would be about 1.0 |xmol/L. If the watercontained 2.0 ppm, then the plasma concentration would beabout 2.0 |xmol/L, and so on. Variations around theseexpected values would be due largely to individualdifferences in the rates of removal of fluoride by the kidneysand skeleton. Nevertheless, the general relation means thatplasma fluoride concentrations are not homeostaticallyregulated, as was once believed. Again, these values are

based largely on results from studies with young or middle-aged healthy adults. They are probably lower in youngchildren and higher in the elderly, but there is a paucity ofdata to support these assumptions.

Soft TissuesBased on results from short-term studies with radioactivefluoride in laboratory animals, it has been shown thatintracellular fluoride concentrations are from 10-50% lowerthan those of plasma, but they change simultaneously and inproportion to those of plasma (Whitford et ah, 1979a). Thetissue-to-plasma ratios of radioactive fluoride are consistentwith the hypothesis that HF is the form in which fluoridemigrates and establishes diffusion equilibrium across cellmembranes. Since the pH gradient across the membranes ofmost cells can be decreased or increased by alteringextracellular pH, it is possible to promote the net flux offluoride into or out of cells. This is the basis for thesuggestion that alkalinization of the body fluids is a usefuladjunct in the treatment of acute fluoride toxicity (WhitfordetaU 1979b).

Specialized Body FluidsEach of these transcellular fluids is separated from what isusually meant by extracellular fluid by an epithelium with itsown peculiar transport properties. Rat and dog cerebrospinalfluid and human, horse, and cow milk have fluorideconcentrations that are 50% or less than that of plasma.Gingival crevicular fluid fluoride levels are slightly higher

10 WHITFORD ADV DENT RES JUNE 1994

(ca. 10%) than those in plasma, whereas the concentrations inparotid and submandibular ductal saliva are slightly lower.The concentrations in these oral fluids, however, changesimultaneously and in proportion to those in plasma(Whitford, 1989).

Fig. 2 shows the ductal salivary-to-plasma fluorideconcentration ratios of five young adult humans afterswallowing 10 mg fluoride as sodium fluoride (Whitford,1989). The average pre-dose plasma concentration was 0.67jxmol/L, the average peak concentration, which occurredwithin the first hour, was 15.2 jimol/L, and the average aftertwo hours was 12.4 |xmol/L. In spite of the rapidly changingplasma concentrations and the fact that there is a brief lag-time when stimulated saliva is moving through the ductalsystem, the ratios fell within a narrow range. The averageratios for the submandibular and parotid secretions were 0.88and 0.79, respectively. These data indicate that plasmafluoride concentrations can be closely estimated based on theanalysis of ductal saliva. Parotid saliva is easily collectedwith the Lashley cup or some similar device. Collection ofsubmandibular saliva (including some sublingual saliva)requires the fabrication of a customized collection device.Whole saliva has variable but higher fluoride concentrationsthan ductal saliva that do not correlate well with plasmaconcentrations which is probably due to exogenouscontamination from food, water, dental products, etc., andfluoride that may migrate from dental plaque. The literatureappears to contain no data concerning the fluorideconcentrations of the oral minor mucous glands.

Renal ExcretionAfter about 50% of an ingested fluoride dose has beenabsorbed, plasma concentrations decline rapidly. This is dueto renal excretion and uptake by calcified tissues. Fluoride is

nîLJO

§o0.

nL LLJ

o

o

0.9-

0.8-

0.7-

0.6-

0 -

T /

I /

"̂

1

0 0.5Hours

/^ T T

1aJL

1

1.0After 10 mg

Submandibular

^J T•>K I

Parotid

i i

1.5 2.CF Dose

Fig. 2—Ductal saliva-to-plasma fluoride concentrationratios for two hours after ingestion of 10 mg of fluoride(Whitford, 1989; reproduced with permission).

freely filtered through the glomerular capillaries and thenundergoes a variable degree of tubular re-absorption. Amongthe halogens, the renal clearance of fluoride is unusuallyhigh. The clearances of chloride, iodide, and bromide inhealthy young or middle-aged adults are generally less than 1or 2 mL/min, whereas that of fluoride is about 35 mL/min.The range of values among individuals within a given study,however, is high. Waterhouse et al. (1980) reported a rangeof from 28 to 52 mL/min, and Schiffl and Binswanger (1982)reported a range from 12 to 71 mL/min.

These investigators did not attempt to determine why theclearances differed so much. Other studies with humans andlaboratory animals, however, have found that fluoride renalclearance is directly related to glomerular filtration rate (Spaket al, 1985), urinary pH (Whitford et al, 1976; Ekstrand et al,1982), and, under some conditions, flow rate (Chen et al,1956). Like the gastric absorption and migration across cellmembranes of fluoride, the mechanism for the tubular re-absorption appears to be the diffusion of HF. Thus, factorssuch as the composition of the diet, certain drugs andmetabolic or respiratory disorders, and the altitude of residencethat affect urinary pH have been shown or can be expected toaffect the metabolic balance and tissue concentrations offluoride (Whitford, 1989). The effect can be profound. In a 30-day study with rats that were acidotic, "normolotic", oralkalotic, the fluoride concentrations in plasma and incisordeveloping enamel were about twice as high in the acidoticgroup as in the alkalotic group, while those of the controlgroup were intermediate (Whitford and Reynolds, 1979).

While there appears to be no information on the renalhandling of fluoride in the elderly, there is some for youngchildren. Spak et al (1985) concluded that their data from 4-to-18-year-old patients "... suggest that children have lowerrenal fluoride clearance rates than adults ..." They thoughtthat their findings were due to a higher extra-renal clearanceby the developing bones of the children, an effect which hasbeen demonstrated clearly in growing rats and dogs(Whitford, 1989). Ekstrand et al (1992) studied the renalclearance and retention of orally administered fluoride ininfants whose ages ranged from 38 to 411 days. Theyreported that the percentage of the dose that was retained, i.e.,not excreted in the urine, increased as the dose (adjusted forbody weight) increased. This suggested a dose-dependentmechanism for fluoride uptake by calcified tissues, aphenomenon not known to occur in adults. Overall, anaverage of 86.8% of the dose was retained by the infants,which is about 50% higher than would be expected for adults.The renal clearance values ranged from 3.8 to 9.3 mL/min.They concluded that "... the pharmacokinetics of fluoride ininfants reveal(s) a completely different pattern compared towhat has been found in adults." There is a clear need formore information about the renal handling and generalmetabolism of fluoride in young children and the elderly.

Fluoride in Calcified TissuesApproximately 99% of the body burden of fluoride isassociated with calcified tissues. The fluoride concentration

VOL8(1) INTAKE AND METABOLISM OF FLUORIDE 11

in bone is not uniform. In long bones, for example, theconcentrations are highest in the periosteal region(Weatherell et al., 1977). They decline sharply within a fewmillimeters of the periosteal surface and increase slightly asthe endosteal region is approached. Cancelous bone hashigher fluoride concentrations than compact bone. Dentin andbone appear to have similar fluoride concentrations whichincrease with age, while that of enamel is markedly lower.Surface enamel fluoride concentrations tend to decrease withage in areas subjected to tooth wear but increase in areas thataccumulate plaque (Weatherell et al., 1972). Dentin fluoridelevels decline progressively from the pulpal surface to thedentin-enamel junction (DEJ). Enamel fluorideconcentrations are highest at the surface and declineprogressively toward the DEJ. Bulk enamel (all the enamelfrom a tooth) fluoride concentrations mainly reflect the levelof fluoride exposure during tooth formation, while dentin andbone fluoride concentrations are generally proportional to thelong-term level of intake (Weatherell, 1969).

The clearance of fluoride from plasma by the skeletonproceeds at a high rate that exceeds even that for calcium(Costeas et al., 1971). Approximately 50% of the fluorideabsorbed each day by healthy young or middle-aged adultsbecomes associated with calcified tissues within 24 hours,while virtually all of the remainder is excreted in the urine.This 50:50 distribution is shifted strongly in favor of greaterretention in infants and young children (Whitford, 1989) andis probably shifted in favor of greater excretion in the elderly,although less is known about this.

Increased retention by the developing skeleton appears tobe due almost entirely to the rich blood supply andcomparatively large surface area of bone crystallites, whichare smaller, more loosely organized, and more numerous thanthose of mature bone. Accordingly, peak plasma fluoridelevels and the areas under the time-plasma concentrationcurves (AUC) are directly related to age during the period ofskeletal development. Fig. 3 illustrates this point (Whitford,1989). In this study, three dogs ranging in age from fourweeks to several years were given 5 mg/kg by continuousinfusion for 20 min, and then the pump was shut off. Thepeak plasma concentration in the weanling puppy was 308jjumol/L, and the pre-infusion concentration was reached inabout 3 h. In the oldest dog, whose age was estimated at morethan 4 years, the peak concentration was 1370 (xmol/L. Evenafter 6 h, the concentration was still 50 times higher than thepre-infusion level. The cumulative AUC values are shown inthe inset. The AUC of the oldest dog was more than 10 timeshigher than that of the 4-week-old puppy. The data for the 6-month-old dog, who was still in a period of rapid growth,were intermediate.

It has been proposed that the uptake of fluoride by boneoccurs in stages (Neuman and Neuman, 1958). The first stageinvolves fluoride migration into the hydration shells of bonecrystallites. These ion-rich aqueous shells are continuouswith, or at least available to, the extracellular fluids.Presumably, fluoride in this pool is rapidly exhangeable sothat it can undergo net migration in either direction,

1400

1 2 3 4 5

Hours After Starting F Infusion (5 mg/kg)

Fig. 3—Plasma fluoride concentrations in three dogs ofdifferent ages during and after the 20-minute IV infusion offluoride (5 mg F/kg body weight). The cumulative areasunder the time-plasma concentration curves are shown in theinset (Whitford, 1989; reproduced with permission).

depending on the relative concentrations in the extracellularfluid and the hydration shells (Whitford, 1989). Later stagesinvolve fluoride association with or incorporation intoprecursors of hydroxyfluorapatite and finally into the apatiticlattice itself. Apatitic fluoride re-enters the circulating bodyfluids as a result of the long-term process of bone resorption.

To clarify the concept of the exchangeable fluoride pool, itis useful to imagine a steady-state distribution of fluoridebetween extracellular fluid and the hydration shell that isstrongly in favor of the latter compartment. The ratio ofexchangeable fluoride ions, for example, might be 1:1000.Any factor that increases the ratio, such as increasing plasmaconcentrations or migration from the hydration shell ontocrystal surfaces, would result in a net flux of fluoride fromextracellular fluid to the hydration shell. Conversely, anyfactor that decreases the ratio, such as falling plasmaconcentrations, would result in a net flux in the oppositedirection, although the quantity probably is less than thatwhich moved into the hydration shells recently, because somewould have become loosely associated with crystallitesurfaces, especially in developing or young bone. In theabsence of such perturbations, as should occur when post-

12 WHITFORD ADV DENT RES JUNE 1994

absorptive extracellular fluoride levels are relatively constantand when mineralization is proceeding slowly or not at all,there would be little net movement in either direction.

MARKERS FOR BONE FLUORIDECONCENTRATIONS

To the extent that this steady-state relationship exists, plasmafluoride concentrations would be influenced by the fluorideconcentrations in the exchangeable pool of bone. Thispossibility is relevant to a subject of current interest, viz., thebody fluids or tissues that may be used to estimate bonefluoride concentrations. A reliable marker for bone fluoridewould be of value in interpreting the results from studies ofthe possible relations among fluoride exposure and thequantity, density and strength of bone, and the occurrence ofbone tumors.

The fluoride concentration in plasma from a fastingsubject is a function of several physiological variables,including the fluoride concentration in the exchangeable poolof bone, the rates of bone accretion and resorption, and therenal clearance of fluoride. Parotid ductal salivary fluorideconcentrations would be influenced by the same variables. Ingeneral, urinary fluoride levels are proportional to plasmaconcentrations, but they are more variable because of theeffects of urinary flow rate and the extent of tubular re-absorption. Re-absorption may be affected by glomerularfiltration rate, tubular fluid flow rate, and pH.

Plasma or salivary fluoride levels do not necessarilyreflect the concentrations in the non-exchangeable pool ofbone, the largest pool by far. Provided that exposure tofluoride has been relatively constant in recent years, however,a direct relationship between the concentrations in theexchangeable and non-exchangeable pools of bone may exist.Glomerular filtration rate and the renal clearance of fluorideare easily determined, and there are markers, such as plasmaosteocalcin concentrations, that could be used to normalizeplasma fluoride levels for bone resorption rates. Aconsiderable amount of research is obviously needed todetermine the relation between the fluoride concentrations infasting plasma or ductal saliva and bone as well as therelative importance of the factors that can affect the relation.

The apparent similarity between the fluorideconcentrations in bone and dentin is intriguing and deservesfurther research attention. In many cases, dentin is anaccessible tissue, and, as discussed above, its fluorideconcentration profile and changes with age appear to besimilar to those of cortical bone (Weatherell et aL, 1977). Itmay, therefore, be a good biomarker for the body burden offluoride in bone. Research subjects that require careful study,however, are: (1) the methods of sampling the tissues; (2) thelocations from which the samples are taken (root or coronaldentin; epiphyseal, metaphyseal or diaphyseal bone); and (3)the geometry of the samples because of the lack of uniformityin fluoride concentration throughout bone and dentin.

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