Gary M. Whitford

The Physiological and Toxicological Characteristics of Fluoride

The metabolism and toxicity of fluoride are discussed with emphasis on new scientific findings. The gastric absorption, tissue distribution, and renal excretion of the ion are all influenced by the magnitude and direction of the pH gradient between adjacent body fluid compartments. This mechanism explains the asymmetric distribution of fluoride across cell membranes, and the manipulation of transmembrane pH gradients has proven efficacious in acute fluoride toxicity. The comparative metabolism and relative toxicities of ionic fluoride and monofluorophosphate are discussed. It is no longer certain that there is a difference between the acute toxic potentials of sodium fluoride and those of MFP. It is concluded that the “probably toxic dose” or PTD of fluoride—the dose which should trigger therapeutic intervention and hospitalization—is 5 mg/kg of body weight. As currently packaged, many dental products contain sufficient fluoride to exceed the PTD for young children. There is a need for additional research into the sources, effects, and fate of strongly bound or organic fluoride compounds. Attention is drawn to the fact that, while the metabolic characteristics and effects of fluoride in young and middle-aged adults have received considerable research attention, there is a paucity of such information for young children and the elderly. The increasing prevalence of dental fluorosis is addressed. It is concluded that non-dietary sources of fluoride, mainly fluoride-containing dental products, are a major source of ingested fluoride. The article concludes with 12 recommendations for future research.

Fluoride absorption: The influence of gastric acidity

SummaryThe influence of gastric acidity on the absorption of intragastrically administered fluoride was investigated in rats. Intact animals were pretreated with atropine or cimetidine to reduce gastric acid secretion or were given fluoride in NaHCO3 to reduce the acidity of the gastric contents. Compared with pentagastrin-treated animals or animals that received fluoride in 0.1 N HCl, their rate of fluoride absorption was markedly reduced as judged by lower plasma fluoride concentrations and areas under the time-plasma concentration curves, especially during the first hour after dosing. In crossover studies with the stomachs isolatedin situ, fluoride absorption was at least 50% faster from a pH 2.1 buffer compared with its absorption from a pH 7.1 buffer. The findings are consistent with the hypothesis that fluoride is absorbed from the gastric lumen principally as the undissociated molecule, HF. The results may contribute to a more complete understanding of acute fluoride toxicity, the development of dental fluorosis and, perhaps, the use of fluoride in the treatment of osteoporosis.

Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy.

BACKGROUND We describe a heart transplant patient with painful periostitis and exostoses who was receiving long-term therapy with voriconazole, which is a fluoride-containing medication. Elevated plasma and bone fluoride levels were identified. Discontinuation of voriconazole therapy led to improvement in pain and reduced fluoride and alkaline phosphatase levels. METHODS To determine whether voriconazole is a cause of fluoride excess, we measured plasma fluoride levels in 10 adult post-transplant patients who had received voriconazole for at least 6 months and 10 post-transplant patients who did not receive voriconazole. To assess the effect of renal insufficiency on fluoride levels in subjects receiving voriconazole, half were recruited on the basis of a serum creatinine level of ≥1.4 mg/dL on their most recent measurement, whereas the other 5 subjects receiving voriconazole had serum creatinine levels <1.4 mg/dL. All control subjects had serum creatinine levels of ≥1.4 mg/dL. Patients were excluded from the study if they received a fluorinated pharmaceutical other than voriconazole. RESULTS All subjects who received voriconazole had elevated plasma fluoride levels, and no subjects in the control group had elevated levels (14.32 μmol/L ± 6.41 vs 2.54 ± 0.67 μmol/L; P<.001). Renal function was not predictive of fluoride levels. Plasma fluoride levels remained significantly higher in the voriconazole group after adjusting for calcineurin inhibitor levels and doses. Half of the voriconazole group subjects had evidence of periostitis, including exostoses in 2 patients. Discontinuation of voriconazole therapy in patients with periostitis resulted in improvement of pain and a reduction in alkaline phosphatase and fluoride levels. CONCLUSIONS Voriconazole is associated with painful periostitis, exostoses, and fluoride excess in post-transplant patients with long-term voriconazole use.

Plaque fluoride concentrations are dependent on plaque calcium concentrations

Despite the 1,000-fold difference between the fluoride concentrations ([F]) in dentifrices and fluoridated drinking water, clinical and epidemiological studies have shown that they have similar cariostatic effects. This double-blind, crossover study was done to determine whether the [F] in dental plaque is related more to the [F] of the dentifrice used or to the plaque concentrations of calcium and magnesium. The subjects (n = 13) were adults and residents of a city served with fluoridated drinking water. After 1 week of using a fluoridated dentifrice (940 ppm) or a placebo dentifrice, whole saliva and plaque were collected 1.0 h and approximately 12 h after the last use of the dentifrices. The average salivary [F] after brushing with the F dentifrice was higher than after using the placebo. The average plaque [F] 1.0 h after brushing with the F dentifrice was higher than after using the placebo (p < 0.01), but the difference at 12 h was not significant. Plaque [Ca] and [F] were directly related under all experimental conditions (p = 0.0001). The relationships between plaque [Mg] and [F] were weaker and inconsistent. Based on these findings and reports in the literature it is concluded that, for persons whose drinking water is fluoridated, plaque [F] throughout much of the day is not significantly increased by the use of a fluoridated dentifrice. Instead they are directly related to plaque [Ca]. These findings offer at least a partial explanation for why fluoridated dentifrices and drinking water have similar cariostatic effects.

Dentin Permeability: A Comparison of Functional Versus Anatomical Tubular Radii

Two independent techniques (filtration and surface tension) were developed to measure the functional tubular radii of 11 dentin and 2 glass discs. Anatomic radii were determined using SEM for comparative purposes. The functional radii of the dentin discs ranged from 5 to 40% of the anatomic radii. This difference was due to the fact that SEM visualizes only the surface while the functional techniques measure the radii within dentin tubules. It is concluded that the functional methods are preferred whenever the dynamics of fluid flow through dentin are under consideration.

Plasma and Developing Enamel Fluoride Concentrations During Chronic Acid-base Disturbances

Mild acid-base disturbances were induced in rats for 30 days. These disturbances did not affect % ash of maxillary incisors or % P of the developing enamel from mandibular incisors. Total fluoride intake (food and water) among groups drinking fluoride-free water was constant. Nevertheless, average plasma and developing enamel fluoride concentrations were highest in the acidotic group and lowest in the alkalotic group. Among groups drinking water containing 50 ppm fluoride, total fluoride intake was highest by the alkalotic group and lowest by the acidotic group. Plasma and enamel fluoride concentrations, however, were highest in the acidotic group. It is concluded that plasma and developing enamel fluoride levels can be independent of, or inversely related to, fluoride intake.

Plasma Fluoride Levels and Enamel Fluorosis in the Rat

This study examined the relationship between transient peak plasma fluoride levels (subcutaneous injections) as well as lower but relatively constant levels (subcutaneous constant infusion) and the occurrence of disturbances in the enamel mineralization of the rat incisor as determined microradiographically. The fluoride doses were administered for 1 week, and the animals were killed 2 weeks later. Once daily peak plasma fluoride levels of 10 μM were uniformly associated with disturbances in the mineralization of the enamel, but once daily peak levels of 5 μM were not. Neither were twice daily 5-μM peaks. Relatively constant plasma fluoride levels, which averaged 3.3 μM, were associated with an increased incidence of changes in enamel formation and levels of 4.7 μM consistently associated with disturbances in enamel mineralization. These findings suggest that (1) the rat is a better model for the study of human enamel fluorosis than previously believed, and (2) slightly elevated but relatively constant plasma fluoride levels are more likely to be associated with the occurrence of fluorotic disturbances in the mineralization of enamel than are the more rare high and transient peak levels.

Development of Gold Standard Ion-Selective Electrode-Based Methods for Fluoride Analysis

Background/Aims: Currently available techniques for fluoride analysis are not standardized. Therefore, this study was designed to develop standardized methods for analyzing fluoride in biological and nonbiological samples used for dental research. Methods: A group of nine laboratories analyzed a set of standardized samples for fluoride concentration using their own methods. The group then reviewed existing analytical techniques for fluoride analysis, identified inconsistencies in the use of these techniques and conducted testing to resolve differences. Based on the results of the testing undertaken to define the best approaches for the analysis, the group developed recommendations for direct and microdiffusion methods using the fluoride ion-selective electrode. Results: Initial results demonstrated that there was no consensus regarding the choice of analytical techniques for different types of samples. Although for several types of samples, the results of the fluoride analyses were similar among some laboratories, greater differences were observed for saliva, food and beverage samples. In spite of these initial differences, precise and true values of fluoride concentration, as well as smaller differences between laboratories, were obtained once the standardized methodologies were used. Intraclass correlation coefficients ranged from 0.90 to 0.93, for the analysis of a certified reference material, using the standardized methodologies. Conclusion: The results of this study demonstrate that the development and use of standardized protocols for F analysis significantly decreased differences among laboratories and resulted in more precise and true values.

Fingernail Fluoride: A Method for Monitoring Fluoride Exposure

This work was based on the hypothesis that fingernail clippings can be used as a biomarker for the subchronic exposure to fluoride. The results provide data on factors that may affect the concentration of fluoride in fingernail clippings as determined with the electrode following HMDS–facilitated diffusion. The following variables had only minor or no effects on the concentrations: (1) the surface area of the clippings (intact, minced or filed into powder) that were placed into the diffusion dishes; (2) soaking in deionized water for up to 6 h; (3) soaking in fluoridated water (1.0 ppm) for 2 h, and (4) removal of the organic material of nails by dry ashing. Fingernail fluoride concentrations were approximately 50% higher than those in toenails. A 1–month period of increased fluoride intake by one of the authors resulted in significant increases in fingernail fluoride concentrations after a lag time of approximately 3.5 months. The fluoride concentrations in fingernail clippings obtained from three groups of Brazilian children were directly related to the concentrations in the drinking water (0.1, 1.6 or 2.3 ppm). The results indicate that: (1) HMDS–facilitated diffusion completely separates fluoride from intact nail clippings, so the need for ashing or other preparative methods is obviated; (2) fingernail fluoride is derived mainly from the systemic circulation, and (3) fluoride intake is reflected by the concentrations in fingernails.

Environmental and Physiological Factors Affecting Dental Fluorosis

In addition to differences in fluoride intake and possibly to calcium deficiency or malnutrition, there are several factors which may account for individual differences in the occurrence of dental fluorosis. Disorders in acid-base balance affect the renal handling of fluoride such that, in acidosis, the excretion rate is diminished and, in alkalosis, the excretion rate is enhanced. Thus, any factor that can decrease urinary pH would be expected to increase the likelihood of dental fluorosis and vice versa. Results from studies with both rats and dogs have shown that acid-base disturbances per se, especially acidosis, adversely affect the mineralization of enamel in a manner that resembles fluorosis. It has been found that the retention and tissue levels of fluoride are increased by residence at high altitude. It has also been found that, in the absence of fluoride exposure, residence at high altitude per se can have a profound disruptive effect on ame-logenesis which could be confused with fluorosis. The effects of diseases which lead to increases in urinary flow rate and water intake on the likelihood of the occurrence of dental fluorosis are also discussed.