Fluoride and Oral Health.

The discovery during the first half of the 20th century of the link between natural fluoride, adjusted fluoride levels in drinking water and reduced dental caries prevalence proved to be a stimulus for worldwide on-going research into the role of fluoride in improving oral health. Epidemiological studies of fluoridation programmes have confirmed their safety and their effectiveness in controlling dental caries. Major advances in our knowledge of how fluoride impacts the caries process have led to the development, assessment of effectiveness and promotion of other fluoride vehicles including salt, milk, tablets, toothpaste, gels and varnishes. In 1993, the World Health Organization convened an Expert Committee to provide authoritative information on the role of fluorides in the promotion of oral health throughout the world (WHO TRS 846, 1994). This present publication is a revision of the original 1994 document, again using the expertise of researchers from the extensive fields of knowledge required to successfully implement complex interventions such as the use of fluorides to improve dental and oral health. Financial support for research into the development of these new fluoride strategies has come from many sources including government health departments as well as international and national grant agencies. In addition, the unique role which industry has played in the development, formulation, assessment of effectiveness and promotion of the various fluoride vehicles and strategies is noteworthy. This updated version of 'Fluoride and Oral Health' has adopted an evidence-based approach to its commentary on the different fluoride vehicles and strategies and also to its recommendations. In this regard, full account is taken of the many recent systematic reviews published in peer reviewed literature.

Validation of fingernail fluoride concentration as a predictor of risk for dental fluorosis.

The aim of this study was to validate the use of fingernail fluoride concentrations at ages 2-7 years as predictors of the risk for developing dental fluorosis in the permanent dentition. Fifty-six children of both genders (10-15 years of age) had their incisors and premolars examined for dental fluorosis using the Thylstrup-Fejerskov index. Fingernail fluoride concentrations were obtained from previous studies when children were 2-7 years of age. Data were analyzed by unpaired t test, ANOVA, and Fisher's exact test when the fingernail fluoride concentrations were dichotomized (≤ 2 or >2 µg/g). Children with dental fluorosis had significantly higher fingernail fluoride concentrations than those without the condition, and the concentrations tended to increase with the severity of fluorosis (r(2) = 0.47, p < 0.0001). Using a fingernail fluoride concentration of 2 µg/g at ages 2-7 years as a threshold, this biomarker had high sensitivity (0.84) and moderate specificity (0.53) as a predictor for dental fluorosis. The high positive predictive value indicates that fingernail fluoride concentrations should be useful in public health research, since it has the potential to identify around 80% of children at risk of developing dental fluorosis.

An assessment of bone fluoride and osteosarcoma.

The association between fluoride and risk for osteosarcoma is controversial. The purpose of this study was to determine if bone fluoride levels are higher in individuals with osteosarcoma. Incident cases of osteosarcoma (N = 137) and tumor controls (N = 51) were identified by orthopedic physicians, and segments of tumor-adjacent bone and iliac crest bone were analyzed for fluoride content. Logistic regression adjusted for age and sex and potential confounders of osteosarcoma was used to estimate odds ratios (OR) and 95% confidence intervals (CI). There was no significant difference in bone fluoride levels between cases and controls. The OR adjusted for age, gender, and a history of broken bones was 1.33 (95% CI: 0.56-3.15). No significant association between bone fluoride levels and osteosarcoma risk was detected in our case-control study, based on controls with other tumor diagnoses.

Assessment of dental fluorosis in Mmp20 +/- mice.

The molecular mechanisms that underlie dental fluorosis are poorly understood. The retention of enamel proteins hallmarking fluorotic enamel may result from impaired hydrolysis and/or removal of enamel proteins. Previous studies have suggested that partial inhibition of Mmp20 expression is involved in the etiology of dental fluorosis. Here we ask if mice expressing only one functional Mmp20 allele are more susceptible to fluorosis. We demonstrate that Mmp20 (+/-) mice express approximately half the amount of MMP20 as do wild-type mice. The Mmp20 heterozygous mice have normal-appearing enamel, with Vickers microhardness values similar to those of wild-type control enamel. Therefore, reduced MMP20 expression is not solely responsible for dental fluorosis. With 50-ppm-fluoride (F(-)) treatment ad libitum, the Mmp20 (+/-) mice had F(-) tissue levels similar to those of Mmp20 (+/+) mice. No significant difference in enamel hardness was observed between the F(-)-treated heterozygous and wild-type mice. Interestingly, we did find a small but significant difference in quantitative fluorescence between these two groups, which may be attributable to slightly higher protein content in the Mmp20 (+/-) mouse enamel. We conclude that MMP20 plays a nominal role in dental enamel fluorosis.

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.

Skeletal fluorosis due to excessive tea and toothpaste consumption.

We describe the case of a 53-year-old woman who presented with a metatarsal fracture and was found to have a bone mineral density (BMD) T-score of +11 in the lumbar spine and +7.6 in the hip. Subsequent investigation revealed very high serum, urine and tissue fluoride levels, associated with excessive tea and toothpaste consumption. The case emphasises the need to exclude fluorosis in individuals with unexpectedly high BMD levels.

Effects of regular and low-fluoride dentifrices on plaque fluoride.

Previous studies have indicated that the use of low-fluoride dentifrices could lead to proportionally higher plaque fluoride levels when compared with conventional dentifrices. This double-blind, randomized, crossover study determined the effects of placebo, low-fluoride, and conventional dentifrices on plaque fluoride concentrations ([F]) in children living in communities with 0.04, 0.72, and 3.36 ppm F in the drinking water. Children used the toothpastes twice daily, for 1 wk. Samples were collected 1 and 12 hrs after the last use of dentifrices and were analyzed for fluoride and calcium. Similar increases were found 1 hr after the children brushed with low-fluoride (ca. 1.9 mmol F/kg) and conventional (ca. 2.4 mmol F/kg) dentifrices in the 0.04- and 0.72-ppm-F communities. Despite the fact that the increases were less pronounced in the 3.36-ppm-F community, our results indicate that the use of a low-fluoride dentifrice promotes a proportionally higher increase in plaque [F] when compared with that achieved with a conventional dentifrice, based on dose-response considerations.

Influence of genetic background on fluoride metabolism in mice.

A/J and 129P3/J mouse strains have different susceptibilities to dental fluorosis, due to their genetic backgrounds. This study tested whether these differences are due to variations in water intake and/or F metabolism. A/J (susceptible to dental fluorosis) and 129P3/J mice (resistant) received drinking water containing 0, 10, or 50 ppm F. Weekly F intake, excretion and retention, and terminal plasma and femur F levels were determined. Dental fluorosis was evaluated clinically and by quantitative fluorescence (QF). Data were tested by two-way ANOVA. Although F intakes by the strains were similar, excretion by A/J mice was significantly higher due to greater urinary F excretion, which resulted in lower plasma and femur F levels. Compared with 129P3/J mice given 50 ppm F, significantly higher QF scores were recorded for A/J mice. In conclusion, these strains differ with respect to several features of F metabolism, and amelogenesis in the 129P3/J strain seems to be unaffected by high F exposure.

Pharmacokinetics of ingested fluoride: lack of effect of chemical compound.

UNLABELLED: Fluoride in drinking water may be present from natural sources or added as sodium fluoride (NaF), sodium silicofluoride (Na(2)SiF(6)) or fluorosilicic acid (H(2)SiF(6)). Results from an early study with rats suggested that, when ingested as Na(2)SiF(6), the absorption and excretion of fluoride were greater than when ingested as NaF. OBJECTIVE: The present single-blind, crossover study with 10 adults was done to determine three key pharmacokinetic parameters: the maximum plasma fluoride concentrations (C(max)), the elapsed time to reach the maximum concentrations (T(max)) and the 6-h areas under the time-plasma concentration curves (AUCs) after ingestion of 500 mL of water containing 0.67 or 5.45 mg F/L present naturally or added as NaF or H(2)SiF(6). DESIGN: Blood was collected prior to and at nine time points during 6h after ingestion of the test solutions. Plasma was analysed by electrode after HMDS-facilitated diffusion and the data were analysed for statistically significant differences using repeated measures ANOVA. RESULTS: The C(max), T(max) and AUC values after ingestion of the solutions containing natural fluoride, NaF or H(2)SiF(6) did not differ significantly at either dose level. Further, the T(max) values associated with the 0.67 and 5.45 mg/L solutions did not differ significantly indicating that the absorption, distribution and elimination rates were not affected by the dose size. CONCLUSIONS: Considered together with published reports, the present findings support the conclusion that the major features of fluoride metabolism are not affected differently by the chemical compounds commonly used to fluoridate water nor are they affected by whether the fluoride is present naturally or added artificially.

Fluoride uptake by plaque from water and from dentifrice.

It has been suggested that fluoride retention in plaque is limited by available binding sites. We determined the effects of fluoridated or placebo dentifrices on plaque and salivary fluoride concentrations [F]s in communities with different water fluoride concentrations (0.04, 0.85, 3.5 ppm). After one week of dentifrice use, samples were collected 1.0 and 12 hrs after the last use of dentifrices. After the use of fluoridated dentifrice, plaque fluoride concentrations were higher at both times, except at 12 hrs in the 3.5-ppm community. Plaque concentrations at 1.0 hr after the use of fluoridated dentifrice increased almost constantly (6.5 mmol/kg), but then decreased approximately 50% at 12 hrs in each community. Unlike previous studies, the present findings suggest that the use of fluoridated dentifrice is likely to increase plaque fluoride concentrations significantly for up to 12 hrs in areas where the water contains fluoride close to 1.0 ppm. As previously reported, plaque fluoride concentrations were directly related to calcium concentrations.

Plaque fluoride concentrations in a community without water fluoridation: effects of calcium and use of a fluoride or placebo dentifrice.

The results of a recent study by Whitford et al. [Caries Res 2002;36:256-265] with subjects whose drinking water was fluoridated led to two major conclusions: (1) Compared to the use of a placebo dentifrice, plaque fluoride concentrations ([F]) throughout much of the day are not significantly increased by the use of an F dentifrice but (2) they are positively related to plaque [Ca] (p = 0.0001). The present double-blind, double-crossover study with 16 subjects used the same protocol and was done to: (1) determine the effects of the use of an F dentifrice on salivary and plaque [F] in a community without water fluoridation and (2) further examine the relationship between plaque [Ca] and [F]. Following the use of an F dentifrice or placebo for one week, whole saliva and plaque were collected 1.0 and 12 h after the last use of the products. The study was repeated to include rinsing with a 20 mmol/l CaCl(2) solution immediately before the use of the dentifrices. The CaCl(2) rinse had only minor effects on salivary [Ca] and [F] and none on the plaque concentrations. Unlike the results found in the fluoridated community, all salivary and plaque [F] associated with the use of the F dentifrice were significantly higher than those associated with the use of the placebo. The results suggest that the cariostatic effectiveness of an F dentifrice should be greater in areas without water fluoridation. As noted previously, plaque [F] were positively related to plaque [Ca] (p = 0.0001).

Relating nickel-induced tissue inflammation to nickel release in vivo.

Nickel has a number of adverse biological effects that have made the use of nickel in biomedical implants controversial. Yet information about the distribution of nickel in tissues around nickel-containing implants is scarce. The purpose of the current study was to use a laser ablation technique, combined with inductively coupled mass spectroscopy, to assess the spatial distribution of nickel around nickel-containing implants in vivo. Polyethylene, pure nickel wire, or a nickel-containing alloy (Ni-Cr) were implanted subcutaneously into rats for 7 days. The tissues were analyzed for Ni content and inflammation at 1-mm intervals up to 5 mm away from the implants. The sham surgery sites and the polyethylene caused mild to moderate inflammation 1-2 mm from the implant site with no detectable nickel in the tissue. The nickel wire caused severe inflammation up to 5 mm away from the implant site with necrosis for 1 mm around the implant. Nickel concentrations reached 48 microg/g near the implants, falling exponentially to undetectable levels at 3-4 mm from the implants. The Ni-Cr wire caused inflammation equivalent to polyethylene, with less than 4 microg/g of nickel present in the tissue for 1-2 mm around the implants. The current study showed that the laser-ablation technique was well suited for the analysis of soft tissues for metal-ion content, and that the nickel distribution in tissues correlated well with overt tissue inflammation.

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.

Fluoride in whole saliva, parotid ductal saliva and plasma in children.

The purpose was to investigate the relation between fluoride concentrations in whole saliva, parotid ductal saliva, and plasma in 5- to 10-year-old children (n = 17). Two stimulated whole-saliva samples were obtained from each child. Before the second sample was obtained, each child rinsed several times with a total of 100 ml of deionized water. Parotid saliva samples were obtained by use of a Lashley cup. Fluoride concentrations were determined by fluoride ion-specific electrode after diffusion with hexamethyldisiloxane. Rinsing with deionized water did not significantly reduce the fluoride concentration in whole saliva. The whole-saliva fluoride concentrations were not significantly related to those in plasma or parotid ductal saliva. Parotid fluoride concentrations, however, were significantly related to plasma fluoride concentrations (p < 0.0001) by a proportionality constant of 0.80. It was concluded that parotid salivary fluoride concentrations can be used to estimate plasma fluoride concentrations in 5- to 10-year-old children.

Effect of resin cure mode and fluoride content on bracket debonding.

Enamel decalcification around brackets is sometimes observed during and after orthodontic treatment. Reports in the literature suggest that the preventive advantage of fluoride-releasing adhesive resins may be compromised by an increased incidence of bond failure. The purpose of this study was to determine the effects on shear debonding of incorporating fluoride into the bracket bonding system. Another purpose was to determine the effect of polymerization mode on debonding. Orthodontic brackets were bonded to bovine enamel using one of three types of adhesive resin--no-mix, chemically cured, or light-cured--each formulated with and without fluoride. The teeth were stored in artificial saliva for 24 hours or 30 days and then debonded in shear. Data analysis was performed using ANOVA followed by post-hoc multiple comparison between group pairs. It was found that: (1) fluoride had either no effect or it increased the bond value; (2) the no-mix adhesive demonstrated the lowest bond value; (3) the duration of storage in artificial saliva had no effect on the bond value of the chemically cured and light-cured adhesives but did affect the no-mix adhesive; and (4) the no-mix adhesive released significantly less fluoride than the two other products. Thus, the presence of fluoride in the bonding adhesive does not reduce the force required to debond in shear, and chemically or light-cured adhesives provide consistently higher bond values over extended immersion times than the no-mix product.

Chronic fluoride ingestion decreases 45Ca uptake by rat kidney membranes.

High exposures to fluoride (F-) may occur in environments rich in F- from natural or industrial sources and from misuse of F--containing dental care products, particularly by children. Both acute and chronic exposures to elevated levels of F- have negative effects on several calcium-dependent processes, including kidney glomerular and tubular function. We examined the effect of chronic F- ingestion on ATP-dependent 45Ca uptake by rat kidney membrane vesicles to characterize the mechanism by which high F- alters Ca++ transport in the kidney. Twenty weanling female Sprague-Dawley rats were raised on low-F- (0.9 mg/L), semi-purified diet with a Ca++ concentration of 400 mg/100g diet. Rats were divided into four groups and were fed ad libitum deionized water containing F- at 0, 10, 50, or 150 mg/L added as NaF for 6 wk. This consumption produced plasma F- levels of <0.4, 2, 7, or 35 micromol/L, respectively. ATP-dependent 45Ca uptake was significantly lower in the 150 mg F-/L exposure group than in the 0 mg F-/L controls (P < 0.05). Studies with thapsigargin, a specific inhibitor of the endoplasmic reticulum Ca++-pump, showed that the lower uptake was associated with significantly lower activities of both the plasma membrane Ca++-pump (P < 0.05, 150 mg F-/L group versus control) and endoplasmic reticulum Ca++-pump (P < 0.05 for both the 50 and 150 mg F-/L groups versus control). Slot blot analysis of kidney homogenates with specific Ca++-pump antibodies showed less (P < 0.05) endoplasmic reticulum Ca++-pump protein and plasma membrane Ca++-pump protein in all treatment groups than controls. Both Ca++-pumps are transport molecules of great importance in the regulation of Ca++ homeostasis. Our study suggests that chronic, high F- ingestion producing high plasma F- levels may occur in humans and may affect Ca++ homeostasis by increasing the turnover or breakdown or decreasing the expression of plasma membrane and endoplasmic reticulum Ca++-pump proteins.

Dental caries and fluorosis among children in a rural Georgia area.

PURPOSE: This IRB-approved study compared the caries experience, fluorosis prevalence, and plaque and salivary fluoride concentrations ([F]) in middle school (MS; N = 51) and elementary school (ES; N = 144) children residing in nonfluoridated and fluoridated communities in rural Georgia. All participants were exposed to fluoridated water at school (0.5-1.2 ppm), some received that level at home, and others received home water with < 0.1 ppm F. METHODS: Subjects' parents completed a questionnaire regarding fluoride exposure. Children were examined at school by two calibrated dentists. RESULTS: No significant differences were seen in DMFS+dfs between children with or without fluoridated home water, nor for those with or without fluorosis. MS children with non-fluoridated home water had lower mean salivary [F] values than MS children with fluoridated home water. No differences were found among MS and ES children in mean plaque [F] for those with or without fluorosis. CONCLUSIONS: Home water fluoridation had little effect on the variables measured. These findings appear to be due to fluoride exposure from fluoridated dentifrices, fluoridated drinking water at school, and the fluoride "halo" effect.

Effects of caffeine on fluoride, calcium and phosphorus metabolism and calcified tissues in the rat.

This 6-week study was designed to determine the effects of graded doses of caffeine intake (3, 25 or 100 mg/kg per day) on the metabolic balance and tissue concentrations of fluoride, calcium and phosphorus in Sprague-Dawley rats. Caffeine intake did not affect the absorption, urinary excretion or balance of fluoride, the plasma, bone or enamel concentrations of fluoride, nor the occurrence of incisor enamel fluorosis. Neither did it affect the metabolism of calcium or phosphorus except that the urinary excretion of calcium was increased. This effect, however, was not sufficient to influence significantly calcium balance. The ash content of the femur epiphysis and bone mineral content of the tibia were significantly reduced only in the group exposed to the highest dose of caffeine. These effects on bone were not significantly related to the balance of calcium or phosphorus. It was concluded that caffeine, even at an extremely high level of intake, has no detectable effect on the balance or tissue concentrations of fluoride, calcium or phosphorus in the rat.

Fluoride metabolism and excretion in children.

This paper compares fluoride pharmacokinetics (plasma, renal, and extrarenal clearances) and metabolic balances in healthy infants or children with those in young or middle-aged adults. Regardless of age, the removal of fluoride from the intra- and extracellular body fluids occurs almost exclusively by uptake in calcified tissues and excretion in the urine. While there can be considerable differences among individuals, the rates at which fluoride is cleared from plasma by calcified tissues and the kidneys in adults are approximately equal. The calcified tissue clearance of fluoride from plasma in children is substantially higher than that by the kidneys. This is due to the greater surface area of the loosely organized crystallites in the developing calcified tissues during growth. Thus, the balance of fluoride (total intake minus total excretion) is typically higher in children than in adults, but it can be positive or negative at any age. Positive balance occurs when chronic fluoride intake is sufficient to prevent plasma concentrations from declining. When positive, the fluoride content of the calcified tissues, which contain more than 99 percent of the body's fluoride, tends to gradually increase. Negative balance, which indicates net mobilization of fluoride from calcified tissues, can occur when plasma concentrations decline due to a reduction in the level of fluoride intake.

pH-dependent fluoride transport in intestinal brush border membrane vesicles.

Fluoride (F) absorption from the rat stomach and urinary bladder, hamster cheek pouch, and the renal tubules of several species are pH gradient-dependent. These observations led to the hypothesis that F crosses these epithelia in the form of the undissociated acid, HF. Several recent reports, however, have provided evidence that F absorption from the rat small intestine is insensitive to the lumenal pH. We report here our evidence that F uptake by rabbit intestinal brush border membrane vesicles (BBMV) occurred rapidly and with an overshoot only in the presence of an inward-directed proton gradient. In the absence of a proton gradient or in the presence of an outward-directed gradient, F uptake was slow and without an overshoot. In the presence of an inward-directed proton gradient, F uptake was partially inhibited by DIDS and DEP but not by diBAC. PCMBS inhibited F uptake by up to 83% in a dose-response manner. DiBAC appeared to reduce intravesicular pH slightly but the other reagents had no effect. When the uptake buffer contained chloride or nitrate, F uptake was partially inhibited compared to the mannitol or gluconate controls. It was concluded that F transport across the rabbit intestinal BBMV occurs via a carrier-mediated process which may involve cotransport of F with H+ or exchange of F with OH-. The inhibitory effects of DIDS, DEP and PCMBS may occur by affecting this carrier-mediated transport.