Fluoride Absorption Research Articles

Fluoride, calcium and phosphorus metabolism in the rat: Comparison of ‘natural ingredient’ with semipurified diets

Three groups of weanling female rats were fed different, commercially available, ‘natural ingredient’ diets containing 12, 28 or 45 parts/10 6 F, mainly as bone meal, for six weeks. Two other groups were fed a low-fluoride (0.76 parts/10 6) semipurified diet. They received fluoride doses, either in the drinking water or by daily intraperitoneal injection, which were approximately equal to the average dose of the other three groups. Rats on the ‘natural ingredient’ diets ingested more food and water and excreted more faeces arid urine, effects which were attributed to the higher amounts of dietary fibre, Na, K and Cl. Thus, at any given concentration of fluoride in the food or water, the level of fluoride ingestion and the ensuing effects would be influenced by the type of diet used. The values for fractional fluoride absorption (45–49%) and retention (38–47%) were similar among the groups given ‘natural ingredient’ diets. In the groups given semipurified diet, the corresponding values were about twice as high with the exception that fractional absorption was negative (−41%) in the injected group, which indicated net intestinal secretion of fluoride. Fluoride balances and tissue concentrations were highest in the groups fed the semipurified diet, even though the level of intake was not always higher. The fractional values for calcium and phosphorus absorption (41–51%) and retention (33–43%) were also similar among the groups given ‘natural ingredient’ diets. The corresponding values were about twice as high in the groups fed the semipurified diet. In terms of supporting maximum bone calcification, phosphorus absorption was marginal in two of the groups on the ‘natural ingredient’ diets. Because of their variable fluoride concentrations and ill-defined compositions, the use of ‘natural ingredient’ diets in research should be avoided.

Fluoride bioavailability from slow-release sodium fluoride given with calcium citrate

Clinical pharmacology of slow-release sodium fluoride given with calcium citrate was examined in acute and long-term studies. Following a single oral administration of 50 mg slow-release sodium fluoride, a peak serum fluoride concentration (Cmax) of 184 ng/ml was reached in 2 h; thereafter, serum fluoride concentration declined with a T1/2 of 5.9 h. The concurrent administration of calcium citrate (400 mg calcium) gave an equivalent Tmax (time required to attain Cmax) and T1/2, but a lower Cmax of 135 ng/ml. The coadministration of a meal with fluoride also reduced Cmax but increased Tmax. The area under the serum concentration curve of slow-release sodium fluoride was reduced 17-27% by a meal or calcium citrate. Thus, calcium citrate reduced fluoride absorption and peak fluoride concentration in serum of slow-release sodium fluoride but did not affect the time required to reach peak concentration or the rate of subsequent decline. The effect of a meal was similar, except for a longer period required to reach peak serum concentration. During long-term administration of 25 mg slow-release sodium fluoride coadministered with 400 mg calcium as calcium citrate on a twice daily schedule, the trough level of serum fluoride could be kept between 95 and 190 ng/ml, believed to be the therapeutic window.

Mechanism of fluoride absorption from the rat small intestine

Fluoride (F) is readily absorbed from the small intestine. In many epithelia, F transport appears to occur predominantly as the weak acid HF. For the same mechanism to exist in intestinal epithelium, with the high pH of the intestinal lumen (and thus low proportion of HF), the discrimination in favor of HF vs F − would have to exceed 10 4:1. We have investigated the mechanism of intestinal F absorption in vitro, using segments of rat jejunum mounted in a modified Ussing apparatus. F was added to the mucosal buffer (0.1–1.0 mM F), and mucosal to serosal F transfer was measured after 30 minutes. F transfer was proportional to mucosal F concentration, but was found not to be pH dependent within the range pH 6.0–8.0. F transfer was strongly affected by changing the transmural potential difference (by substitution of Cl − and Na +, and by ouabain inhibition). The data indicate that intestinal F passage occurs predominantly as the anion F − rather than the weak acid HF.

Journal of Bone and Mineral Research

The gastrointestinal absorption of enteric-coated (EC) tablets of sodium fluoride (NaF) with respect to different time schedules of administration of calcium supplements in solution was tested. It was found that the simultaneous administration of these two medications under these formulations did not interfere with fluoride absorption. The calcium was also well absorbed as shown by the rise in serum ionized calcium concentration. Other schedules were studied as well, such as EC NaF tablets taken 1 hour after or 3 hours before the administration of calcium supplements. No superiority was shown, on the contrary, compared with the simultaneous administration of both medications. It was concluded that EC tablets of NaF and calcium supplements in solution can be provided simultaneously to enhance compliance.

Journal of Bone and Mineral Research

To assess whether an interval of a few hours would be advisable between an intake of sodium fluoride (NaF) and that of calcium salts when treating osteoporotic patients with vertebral collapse, we carried out three pharmacokinetic studies in 12 healthy fasting volunteer subjects to compare the fluoride bioavailability provided by NaF alone and NaF combined with two calcium salts. The results were as follows: (1) When NaF is accompanied by calcium, the fluoride peak level is lower and delayed. (2) Fluoride absorption varied greatly among individuals in both experiments, but none of the 6 subjects proved to be nonabsorbers. (3) The areas under the curves obtained with each of the three preparations were not significantly different, but 24-h urinary fluoride was significantly lower in volunteers receiving simultaneously NaF and calcium salts than in volunteers receiving only NaF.

The Nature and Mechanisms of Dental Fluorosis in Man

Any use of fluorides, whether systemic or topical, in caries prevention and treatment in children results in ingestion and absorption of fluoride into the blood circulation. The mineralization of teeth under formation may be affected so that dental fluorosis may occur. Dental fluorosis reflects an increasing porosity of the surface and subsurface enamel, causing the enamel to appear opaque. The clinical features represent a continuum of changes ranging from fine white opaque lines running across the tooth on all parts of the enamel to entirely chalky white teeth. In the latter cases, the enamel may be so porous (or hypomineralized) that the outer enamel breaks apart posteruptively and the exposed porous subsurface enamel becomes discolored. These changes can be classified clinically by the TF index to reflect, in an ordinal scale, the histopathological changes associated with dental fluorosis. Compared with Dean's and the TSIF index, we consider the TF index to be more precise. Recent studies on human enamel representing the entire spectrum of dental fluorosis have demonstrated a clear association between increasing TF score and increasing fluoride content of the enamel. So far, no useful data on dose (expressed in mg fluoride/kg b.w.)-response (dental fluorosis) relationships are available. In this paper, we have, therefore, re-evaluated the original data by Dean et al. (1941, 1942), Richards et al. (1967), and Butler et al. (1985) from the USA, by applying the equation of Galagan and Vermillion (1957) which permits the calculation of water intake as a function of temperature.(ABSTRACT TRUNCATED AT 250 WORDS)

Computer simulation of oral fluoride clearance

The presence of fluoride in saliva and dental plaque is important for prevention of dental caries. The elimination of fluoride from the oral cavity after introduction of a fluoride containing agent is a complicated physiological process. This process was simulated with a Pascal program running under MS-DOS on IBM-compatible microcomputers. The program calculated the fluoride concentration in saliva as a function of time from several input parameters, the most important being the amount of fluoride, salivary stimulation due to the fluoride vehicle, resting salivary flow rate and volume factors. Furthermore, factors such as excretion of fluoride in the saliva following fluoride absorption in the intestinal tract were modeled. The fluoride concentration in dental plaque due to diffusion was also calculated. Output was directed to files which could be processed by a graphics interface. The results of the computations were very similar to findings in vivo.

Estimation of Fluoride Absorption from Swallowed Fluoride Toothpastes

Eight adults ingested five different toothpastes with and without 1,000 ppm (1 microgram/g) fluoride added as NaF or Na2PO3F. The systemic fluoride absorption was estimated by by comparing the areas under salivary fluoride concentration curves produced after the toothpaste ingestion. Of the toothpastes investigated--chalk, dicalcium phosphate dihydrate, silica or alumina with sodium monofluorophosphate, and silica with sodium fluoride--the fluoride absorption was found to be statistically significantly lower only from the dicalcium phosphate dihydrate toothpaste. Measuring changing fluoride levels in saliva appears to be an acceptable non-invasive technique for following systemic fluoride absorption.

Acute Fluoride Toxicity

Acute intoxication with inorganic fluoride disrupts numerous physiological systems. As a potent acid it acts corrosively on the skin and mucous membranes, producing severe burns. As the most electronegative element it tightly binds many cations essential to homeostasis, producing, for example, profound hypocalcaemia and resultant inhibition of normal blood coagulation. As a metabolic poison it stimulates some enzymes, such as adenylate cyclase, and severely inhibits others, such as Na(+)-K(+)-ATPase and the enzymes of carbohydrate metabolism. Death can result from these processes and also from a delayed, explosive hyperkalaemia. Therapy of acute poisoning is aimed first, at preventing the absorption of fluoride by incorporating it into insoluble fluoride compounds; secondly, at enhancing fluoride tolerance by maintaining normal blood pH and electrolytes, and aggressive general support of the toxic patient; and thirdly, at manipulating renal excretion or removing fluoride with dialysis and haemoperfusion. If the poisoned patient can be supported for 24 hours, the prognosis improves markedly, although delayed toxicity can occur.

Fluoride in workplace air and in urine of workers concentrating fluorspar

The urinary fluoride concentrations of workers exposed to calcium fluoride (CaF2) during fluorspar processing were measured. Personal dust measurement showed that the mean occupational exposure to fluoride for 12 workers in the most dusty environment was 24.3 mg/m3, which is 9.7 times the threshold limit value (TLV) of 2.5 mg/m3. Exposure was below the TLV for the remaining 23 workers. Urinary fluoride concentrations were measured pre- and postshift. The heavily exposed workers had a mean preshift concentration of 3.3 mg/liter (range 1.4-8.5 mg/liter), only slightly higher than the mean of 2.8 mg/liter (range 1.3-4.2 mg/liter) in the workers with fluoride exposure below the TLV. Four of the preshift concentrations exceeded the recommended upper limit of 4 mg/liter. The mean postshift concentration for workers exposed above the TLV was 4.4 mg/liter (range 2.4-7.1 mg/liter) and the difference between pre- and postshift concentrations was significant (p less than 0.05). Only one urinary concentration exceeded the recommended upper limit of 7 mg/liter. There was poor correlation between intensity of environmental exposure to fluorspar and postshift fluoride concentration in the urine. Eighteen workers provided a urine sample 7-14 hr after the end of a shift. The mean fluoride concentration was 4.7 mg/liter (range 2.4-11.7 mg/liter), which exceeded their postshift concentration by 0.2 mg/liter. These results indicate that the low aqueous solubility of fluorspar reduced the biologic availability of the fluoride ion but that this did not prevent excessive fluoride absorption in some workers.

Genotoxic evaluation of chronic fluoride exposure: micronucleus and sperm morphology studies.

The purpose of this study was to investigate the genotoxic effects of chronic fluoride exposure on mammalian cells in vivo by use of the mouse bone-marrow micronucleus test and the sperm morphology methodology. Mice of genotype B6C3F1 were obtained at weaning and maintained on a low-fluoride diet (less than 0.2 ppm F) ad libitum throughout the experiment. The animals were randomly assigned to seven groups and given fluoride (as sodium fluoride) in concentrations ranging from 1.0 to 75 ppm in the drinking water. Negative (distilled water) and positive (cyclophosphamide) controls were included. After a 21-week treatment period, the animals were killed by cervical dislocation, and blood was obtained by cardiac puncture. Slides of femur marrow cells were prepared and blindly examined for the frequency of micronucleated polychromatic erythrocytes (MN-PCE). Slides of sperm from the cauda epididymides of the male mice were also prepared and similarly examined for morphological abnormalities. Weight of the testes was recorded, and the plasma, humeri, testes, and carcasses were saved for fluoride analyses. Analyses of bone and plasma fluoride confirmed the effective absorption of fluoride following ingestion. The frequency of MN-PCE, the count of abnormal sperm, and the weight of the testes for mice chronically exposed to fluoride, in doses ranging from approximately 0.3 to 23 mg/kg/day, were not significantly different from those of the negative control animals. The results of this study support the view that fluoride has no genotoxic effects.

Fluoride Absorption from the Gastrointestinal Tract of Rats

The contribution of the stomach and the small intestine to absorption of fluoride from the gastrointestinal tract was examined in rats. Fasted adult male rats weighing approximately 350 g were given 50 micrograms of fluoride in 1 ml of water by stomach intubation, with 14C-labeled polyethylene glycol as a marker of water movement through the gastrointestinal tract. Rats were killed at intervals up to 120 min, and the stomach, duodenum, jejunum, ileum, distal ileum and cecum were rapidly clamped and removed for fluoride analysis and 14C counting. Approximately 90% of the fluoride dose was absorbed in 120 min. Peak plasma fluoride concentration occurred 10 min after intubation and began to decline after 40 min as the rate of fluoride absorption slowed. Absorption from the stomach was derived from rates of gastric emptying and remaining fluoride. Even at 10 min after intubation, when the bulk of the fluoride remained in the stomach, only approximately 25% of fluoride absorption had occurred from the stomach and 75% from the small intestine. After 120 min, 19.8% of total fluoride absorption had occurred from the stomach. Although the stomach is unquestionably a significant site for fluoride absorption, its contribution is much smaller than that of the small intestine.

The effect of fluoride on bone histology in postmenopausal osteoporosis depends on adequate fluoride absorption and retention.

Forty-one women with idiopathic postmenopausal osteoporosis have been followed for 2 years after initiation of sodium fluoride at 40-50 mg/day, given together with a daily calcium supplement of 1 gram and vitamin D2, at 50,000 IU weekly. Histological and histomorphometric analyses were done on bone biopsies taken prior to and after 1 year of treatment (mean 1.25 +/- 0.35 years). Thirty patients (74%) developed the histological fluoride effect of hyperosteoidosis, while the remaining 11 patients (26%) had no change from pretreatment biopsies. Hyperosteoidosis was based on increased values for osteoid volume and/or thickened osteoid with greater than 3 lamellar bands. Based on previously reported findings, this histological evidence of hypersoteoidosis within 12-18 months of initiation of therapy provides a useful predictor of ultimate satisfactory fluoride response in terms of bone mineral accretion. No increases in bone mass (measured by neutron activation analysis) were observed at the time of the posttreatment biopsy but, according to this previous work, increases are anticipated over a further 2-3 years of treatment. Factors affecting the development of hyperosteoidosis were analyzed. Hyperosteoidosis was associated with a significantly higher dose of sodium fluoride and a significantly higher level of bone fluoride retention but without significant increase in fasting serum fluoride. Results suggest that fluoride retention depends not only on fluoride dose but also on body size, renal function, and intestinal absorptions of calcium and fluoride. There were no differences in the initial investigations between patients with and without hyperosteoidosis, with respect to age, years of postmenopause, estrogen use, initial biochemistry, or initial bone histology.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluoride effects on the mulberry-silkworm system.

Absorption and accumulation of fluoride (F) from ambient air by mulberry leaves, and its transfer and effects on silkworm development, were examined. When the concentration of F in air exceeded 1.5 microg dm(-2). day (-1), using lime filter papers as static monitors, the F content of mulbery leaves was more than 30 ppm, the threshold for injury to silkworm larvae. Fluoride-polluted mulberry leaves inhibited growth and development of silkworms. Leaves containing more than 80 ppm F severely inhibited cocoon production. Fluoride was absorbed from the atmosphere by the mulberry leaf and was transferred to the silkworm, soil, water, and back to the atmosphere, forming a cycle.

Influence of type and level of dietary calcium on fluoride bioavailability in the rat

Two experiments were conducted with weanling rats fed a purified diet to determine the influence of dietary calcium (0.1, 0.2, 0.5, 1.0%) on fluoride bioavailability (2 or 10 ppm as sodium fluoride). The chemical form of calcium was the carbonate in experiment 1 and the gluconate in experiment 2. During each 6-week period the highest level of dietary calcium significantly reduced apparent fluoride absorption relative to controls (0.5% Ca), which was reflected in fluoride content of femur and most clearly in molar teeth, regardless of the solubility of calcium. When all levels of dietary calcium were considered, fecal fluoride excretion was found to be directly related to dietary calcium whereas urinary fluoride excretion was inversely related to calcium regardless of the solubility of calcium or the level of dietary fluoride. These effects, however, were markedly influenced by the fact that the amount of absorbed fluoride that was actually retained for incorporation into bones and teeth was directly related to dietary calcium level. Although high dietary calcium significantly depressed fluoride bioavailability during growth, it is equally clear that predictions about the magnitude of this relationship originating from gastric intubation studies have been greatly overstated.

Influence of dietary lead on fluoride bioavailability in the rat

A factorial experiment was conducted with weanling rats fed a purified diet to determine the influence of dietary lead (0 or 100 ppm) as either lead acetate or lead carbonate on fluoride bioavailability (2 or 10 ppm as sodium fluoride). During the 6-wk study, both forms of lead depressed weight gain, regardless of the fluoride level, despite the fact that food intake was similar for all treatment groups. Both forms of lead produced a small, but significant, reduction in femur and second molar fluoride. This effect, however, could only be demonstrated in rats fed diets containing 10 ppm fluoride, indicating a significant interaction between lead and fluoride for these indices of fluoride bioavailability. This interactive effect between fluoride and lead was also demonstrated for apparent fluoride absorption. Both forms of dietary lead significantly increased the lead concentration of plasma, femur, liver, and kidney, and both forms of lead significantly increased the urinary excretion of delta-aminolevulinic acid. The level of dietary fluoride failed to influence these measurements. We therefore conclude that, although small amounts of dietary lead reduce fluoride bioavailability, small amounts of dietary fluoride do not appear to significantly influence the utilization of dietary lead.

Effects of fluoride on the mouse sperm morphology test.

There has been little information and much confusion regarding the genotoxic effects of fluoride. The purpose of this study was to examine the spermatogenic influence of sodium fluoride (NaF) on the germ cells by means of the mouse sperm morphology test. Male mice of genotype B6C3F1 were obtained at about eight weeks of age and maintained on a low-fluoride diet (less than 0.2 ppm F) and distilled water ad libitum throughout the experiment. At approximately 13 weeks of age, the animals were randomly assigned to eight groups. Group I was intubated with the Maximum Tolerable Dosage (MTD) of NaF (70 mg/kg). Groups II through VI received NaF by stomach intubation at doses of 35, 20, 10, 1, and 0.1 mg/kg, respectively. Group VII served as a negative control and was intubated with distilled water. The positive control, Group VIII, was exposed to a known mutagen, cyclophosphamide (20 mg/kg, i.p.). The animals were treated daily for five days, and killed by cervical dislocation 35 days after the first exposure to chemicals. Slides of sperm from the cauda epididymides were prepared and blindly scored for morphological abnormalities. Weight of the testes was recorded, and the femurs were saved for fluoride (F) analysis. Analysis of bone F demonstrated the effective absorption of fluoride following intubation. The counts of abnormal sperm and the weights of the testes for mice exposed to NaF doses up to the MTD were not significantly different from those of the negative control. The results of this study showed that NaF did not have adverse effects on mouse sperm morphology.

Pharmacokinetic aspects of topical fluorides.

Pharmacokinetic studies have revealed quantitative information about the bioavailability, rate of absorption, distribution, and clearance of fluoride following the use of fluoride-containing dentifrices, gels, varnishes, and solutions. It is concluded that following the use of topical fluoride products, variable amounts of fluoride are swallowed and absorbed into the systemic circulation--amounts which may be sufficient to produce acute or chronic side-effects. Pharmacokinetic data should, therefore, form part of the basis for the optimal and safe use of fluoride products. In addition, there is a need for future research to determine the kinetics of fluoride in the oral fluids after the application of topical fluoride agents and to determine the associated changes in the composition of the mineral components of the oral fluids.

Influence of Dietary Magnesium on Fluoride Bioavailability in the Rat

A factorial experiment was conducted with weanling rats fed a purified diet to determine the influence of dietary magnesium (200, 500 or 2500 ppm) as the carbonate on fluoride bioavailability (2 or 10 ppm as sodium fluoride). After 6 wk, rats fed the lowest magnesium-containing diets had significant reductions of plasma and femur magnesium. Higher dietary fluoride prevented accumulation of calcium in the kidneys of magnesium-deficient rats. Rats fed the lowest magnesium-containing diets had significantly more fluoride in their femurs and molar teeth than other groups at both levels of fluoride, whereas rats fed diets containing 5 times normal magnesium had less fluoride in their femurs and molars. The magnitude of the magnesium effect was considerably greater in rats fed diets containing 10 ppm fluoride compared to 2 ppm, indicating a highly significant, level-dependent interaction between magnesium and fluoride. Five-day metabolic studies conducted during wk 3 and 6 showed that low dietary magnesium significantly enhanced fluoride absorption, whereas high dietary magnesium significantly reduced fluoride absorption. Fluoride retention values simply reflected absorptive changes, which indicates that the site of the interaction between magnesium and fluoride is at the intestinal level, most likely involving insoluble complex formation.

Influence of Dietary Chloride on Fluoride Bioavailability in the Rat

A factorial experiment was conducted with weanling rats fed a purified diet to determine the influence of dietary chloride (0.02, 0.10 and 0.50%) as sodium chloride on fluoride bioavailability (2 or 10 ppm as sodium fluoride). After 6 wk, rats fed the lowest chloride-containing diets had significant reductions of plasma chloride, urinary chloride excretion and growth rate compared to other chloride groups. Depressed growth occurred in rats fed chloride-deficient diets despite the fact that food intake was similar for all treatments. Fluoride retention was greatest in chloride-deficient rats, which was reflected in enhanced skeletal uptake of fluoride. Fluoride absorption was not inhibited by high chloride intake. We therefore conclude that emphasis on the effect of chloride on fluoride bioavailability should be directed towards an enhancement of fluoride retention by low salt (sodium chloride) diets rather than in terms of a possible negative effect of a high salt diet on fluoride absorption.