Biomarkers for the Assessment of Exposure to Fluoride in Adults.

To monitor deficient or excessive intakes of biologically available fluoride (F), various biological samples have been tested for use as biomarkers of human exposure to F. Most such studies have concerned children and often have only involved measurement of F in 1 or 2 types of sample. The present study investigated the relationships of F concentrations in biomarkers of F exposure; including plasma, saliva, hair, finger- and toenails, and daily urinary F excretion (UFE) with the total daily F intake (TDFI) of adults. TDFI was assessed in 60 healthy adults, aged ≥20 years; 31 lived in a low-F water area (LFA, 0.04 mg F/L) and 29 in a high-F water area (HFA, 3.05 mg F/L) of Nigeria. All volunteers provided at least 1 biomarker sample from the above list and completed a questionnaire to evaluate F intake from the diet and toothpaste ingestion. TDFI, UFE and F concentrations of biomarkers were statistically significantly higher in the HFA than in the LFA. There were strong statistically significant positive correlations between TDFI and UFE (ρ = 0.730, p < 0.001); plasma F (ρ = 0.729, p < 0.001); fasting whole saliva F (ρ = 0.653, p < 0.001) and hair F (ρ = 0.603, p < 0.001). The statistically significant positive correlations between TDFI and fingernail F (ρ = 0.502, p < 0.001) and between TDFI and toenail F (ρ = 0.556, p < 0.001) were moderate. In conclusion, this study has indicated the usefulness of 24-h UFE as well as F concentration in plasma, fasting whole saliva and hair as biomarkers of contemporary or sub-chronic F exposure in groups of adults. However, they do not appear to have the necessary sensitivity to predict F exposure in individuals.

Biomarkers for the Assessment of Fluoride Exposure in Children.

Due to practical difficulties in quantifying fluoride exposure, the ability of various biomarkers to predict exposure has been investigated previously. However, the results are inadequate for validation of their application and usefulness. This study aimed to investigate the association between contemporary/recent biomarkers of fluoride exposure and total daily fluoride intake (TDFI) of children with large differences in fluoride exposure through drinking water. TDFI was assessed in 61 healthy 4- to 5-year-old children who provided at least 1 biomarker sample; 32 lived in a low-fluoride area (0.04 mg F/L) and 29 lived in a high-fluoride area (3.05 mg F/L). Validated questionnaires were administered to evaluate fluoride intake from diets (including water) and toothpaste ingestion. Daily urinary fluoride excretion (UFE) and fluoride concentrations in plasma, fasting whole saliva, hair, and nails (toenails/fingernails) were evaluated and related to total fluoride exposure. TDFI, UFE, and fluoride concentrations of biomarkers were statistically significantly higher in the high-fluoride area than in the low-fluoride area. There was a strong statistically significant positive correlation between TDFI and UFE (ρ = 0.756, p < 0.001); plasma fluoride concentration (ρ = 0.770, p < 0.001); and toenail fluoride concentration (ρ = 0.604, p < 0.001). The statistically significant positive correlation between TDFI and fingernail fluoride concentration (ρ = 470, p < 0.001) as well as between TDFI and fasting whole saliva fluoride concentration (ρ = 0.453, p = 0.001) was moderate, whereas it was weak between TDFI and hair fluoride concentration (ρ = 0.306, p = 0.027). In conclusion, the current study confirmed the suitability of 24-h urine samples for estimating fluoride exposure in children. The strong correlations between TDFI and fluoride in plasma and toenails also suggest these biomarkers may be considered for health risk assessments of fluoride in children who are susceptible to development of dental fluorosis.

On the relationship between the rate of salivary flow and salivary fluoride clearance.

The amount of fluoride retained in the mouth following the application of dentifrices, mouthwashes, etc. may be important in determining their anticaries efficacy. In this study we investigated the relationship between the salivary flow rate and salivary fluoride clearance. Ten adults tested six mouthrinses, consisting of aqueous sodium fluoride solutions (0.013, 0.026 mol/l) with and without added sodium chloride (1.28 mol/l) or sucrose (0.44 mol/l), in a randomised order. Prior to each test, subjects swallowed, rinsed for 2 min with 2 ml water and then expectorated into a preweighed container to obtain a measure of initial saliva flow rate. Next, the procedure was repeated using one of the test rinses. Finally, samples of unstimulated whole saliva were collected for up to 3 h after each mouthrinse application and analysed for fluoride. Salivary fluoride concentrations were significantly lower after application of mouthrinses that contained either sucrose or NaCl, both of which compounds markedly enhanced salivary flow, than after the use of corresponding mouthrinses without any additive. Area under the salivary fluoride clearance curve (AUC) values were inversely correlated with salivary flow rate on an individual basis (p < 0.01). The observed behaviour could not be completely attributed to treatment dilution by saliva at the time of application.

Fluoridated toothpaste: usage and ingestion of fluoride by 4- to 6-yr-old children in England.

Fluoridated toothpaste is effective for dental caries control, yet may be a risk factor for dental fluorosis. This study aimed to quantify fluoride ingestion from toothpaste by children and to investigate the effects of age, gender, and social class on the amount of fluoride ingested per toothbrushing session. Sixty-one children, 4-6 yr of age, were recruited: 38 were from low socio-economic (LSE) areas of Newcastle, UK, and 23 were from high socio-economic (HSE) areas of Newcastle, UK. All expectorated saliva, rinse water (if used), and residual toothpaste were collected after brushing at home and were analysed for fluoride. Of the children, 74% and 69% from HSE and LSE areas, respectively, claimed that they brushed twice per day. The mean (SD) weight of toothpaste dispensed was 0.67 (0.36) g. The mean (SD) amount of fluoride ingested per toothbrushing session and per day was 17.0 (14.7) and 29.3 (32.8) µg kg(-1) of body weight, respectively. Daily fluoride intake per kilogram of body weight did not differ significantly between children from LSE and HSE areas. Fluoride intake per toothbrushing session was significantly influenced by weight of toothpaste, its fluoride concentration, and the child's age. Whilst the average amount of toothpaste used per toothbrushing session was more than twice the recommended amount (of 0.25 g), only one child had a daily fluoride intake that exceeded the tolerable upper intake level of 0.1 mg kg(-1) of body weight for this age group.

The Relationship between Fluoride Exposure and Cognitive Outcomes from Gestation to Adulthood-A Systematic Review.

Chronic exposure to high levels of fluoride may cause health concerns, including in cognitive function. This study reviewed the evidence on the association between fluoride exposure and cognitive outcomes in children from gestation up to 18 years old. A literature search was conducted for studies on pregnant women and children below 18, exposed to any source of fluoride, and assessed with a validated cognitive tool. The data were analyzed using a systematic narrative synthesis approach and by subgroup: study design, age of participants, levels of fluoride exposure and methodological quality. Our search retrieved 15,072 articles, of which 46 met the inclusion criteria. Only 6 of the studies had a longitudinal design; the remainder were cross-sectional. The levels of fluoride exposure were ≥2 mg/L in 27 studies and <2 mg/L in 13 studies; 6 studies did not report levels of fluoride exposure. Only 1 of 5 studies graded as excellent quality showed a negative association between fluoride exposure and cognitive outcomes, whereas 30 of 34 poor and fair quality studies reported a negative association. The overall evidence from this review suggests that high fluoride exposure might be associated with negative cognitive outcomes in children. However, more longitudinal studies with high methodological quality are needed on this topic.

A Scopus-Based Bibliometric Analysis of Global Research Contributions on Milk Fluoridation.

Fluoridated-milk schemes have been developed and implemented in many countries to prevent dental caries. This study aimed to evaluate the impact/influence of scientific publications, researchers, and institutions conducting research on milk fluoridation; to explore the international and inter-institutional collaboration and illustrate scientific output trends; and to pinpoint research hotspots in milk fluoridation research. This bibliometric analysis of original research articles on milk fluoridation includes all of the original articles published in peer-reviewed journals systematically extracted from the SCOPUS database. In total, 108 articles were included in this study, with a total of 11,789 citations. A majority (67.6%) of these articles were in the subject area of 'dentistry', 22.2% externally funded, 14.8% published in the journal, Caries Research, 7.4% authored/co-authored by Twetman S, 6.5% by authors from Universidad de Chile, and the UK had the highest output (24.1%). The network visualizations showed that those countries with current/past histories of implemented milk fluoridation programs were interconnected on the network visualization map, and they were predominantly the hotspots for original research on milk fluoridation. This study also identified inequalities in research outputs on the topic. With the current enormous global burden of dental caries in children, particularly in low- and middle-income countries, there is an urgent need for greater and more equitable funding of milk fluoridation research globally.

Chapter 5: Microelements: Part II: F, Al, Mo and Co.

Ultratrace element is a relatively new term, and is defined as those elements with an established, estimated, or suspected dietary requirement of minute amount, generally of the order of µg/day. This chapter focuses on fluorine (F), aluminium (Al), molybdenum (Mo), and cobalt (Co). Whilst diet is the principal source of Al, Mo, and Co found in the body, inadvertent ingestion of dental hygiene products accounts for a significant proportion of F intake. Apart from F, the influence of other ultratrace elements on oral health, and in particular dental caries, has not been fully established. The calcified tissues contain 99% of body F. During tooth development, ingested (systemic) F is incorporated into the apatite crystals of the developing tooth which helps in improving resistance to acid demineralisation. However, the presence of low but constant levels of topical F in the fluid phase at the tooth enamel surface are more important in controlling tooth decay in people of all ages. An adequate intake, from all dietary and non-dietary sources, is estimated as 0.05 mg/kg body weight/day for children older than 6 months and adults, based on estimated intakes that have been shown to reduce the incidence of dental caries while minimising adverse health effects such as dental fluorosis. An inverse relationship between incidence of dental caries and levels of Al in drinking water, food, and soils has been indicated by some epidemiological studies. Co and Mo, whilst occasionally showing potential beneficial oral health effects in laboratory experiments, do so at concentrations much higher than found in vivo.

Chapter 4: Microelements: Part I: Zn, Sn, Cu, Fe and I.

Microelements are essential components of the diet. This chapter describes the effect of several such elements: zinc, copper, iron, tin, and iodine, on oral health. As part of normal diets, these elements have limited associations with specific oral conditions. This is partly because of their presence at relatively low concentrations and partly because they are most often present as mixtures where the effect of any one element is confounded by others. Deficiencies in microelements can cause health problems. Hence supplements, often containing one or more microelements, are prescribed to combat such conditions. All these ions exhibit antibacterial properties. Such effects are invariably small at the concentrations found in conventional foods and drinks. However, at higher concentrations, these ions can inhibit acid production by plaque bacteria involved in dental caries. Of more importance, zinc and tin have potentially significant effects on the de- and remineralisation processes involved in dental caries. Indeed, both elements have been included in oral hygiene products such as toothpastes for many years. Zinc, in particular, has demonstrated not only the ability to reduce dissolution rates of enamel and hydroxyapatite but also to inhibit calculus formation. Tin can also markedly reduce the dissolution rates. Both Cu and Fe have demonstrated anti-caries effects in animal models, whilst Fe-containing drinks have been shown to reduce enamel erosion in situ. The broad spectrum antibacterial properties of iodine have been promoted for its potential use against both early childhood caries and chronic periodontitis. However, more convincing clinical research is required to validate efficacy.

Evidence for putting the calculus: caries inverse relationship to work.

OBJECTIVES: To report previously unpublished data from three different types of clinical study to show the strength of the evidence purporting to demonstrate the existence of an inverse relationship between subjects' calculus and caries experience. METHODS: Data have been analysed from: a 3-year caries clinical trial of six toothpastes conducted in Lanarkshire, Scotland that involved 3000 children, Study 1; a caries epidemiological study in the Isle of Lewis that involved 228 children, Study 2; a calculus formation study carried out at Port Sunlight using a wide age range of adults, Study 3. RESULTS: Baseline data taken from Study 1 show that caries prevalence is highly significantly lower in calculus-prone than in calculus-free subjects (P < 0.0001). The inverse relationship is also demonstrated by the 3-year caries increment data for subjects who had used non-zinc toothpastes. Results from Study 2 show that a similar association arose for 8-year olds over a 6-year period, based on their erupting teeth alone. Finally, data from Study 3 show that whilst the extent of caries and calculus experience are both positively linked to age, within specific age groups the relationship between the two dental conditions on an individual subject basis is clearly of an inverse nature. CONCLUSIONS: The present work confirms that calculus status has a direct bearing on both current and future caries experience. Baseline calculus status could be, and has subsequently been demonstrated to be, a useful stratifying factor for caries clinical trials.

Fluoride ingestion from toothpaste: fluoride recovered from the toothbrush, the expectorate and the after-brush rinses.

OBJECTIVES: The aim of this study was to determine the effects of rinsing and spitting on fluoride ingestion from toothpaste during normal oral-hygiene procedures of younger children, and hence to make recommendations on rinsing during toothbrushing. METHODS: The brushing habits of 166 Dutch and 185 Irish children between 1.5 and 3.5 years were observed during home visits. The weight of the toothpaste tube was determined before and after use. After brushing, the toothbrush and any associated expectorate and rinses, combined with any toothpaste spilled during the brushing procedures, were collected. The amounts of fluoride retained on the toothbrush and in the associated expectorate and rinses were measured. RESULTS: Over 90% of the Dutch children used a special toddlers' toothpaste with < or =500 ppm F. Eleven per cent of the younger (<2.5 years) Dutch children and 22% of the older children rinsed after brushing. Of the Irish children approximately 52% used a children's toothpaste containing around 500 ppm F. Of the younger Irish children 31% spat without rinsing, while another 31% rinsed during or after brushing. For the older Irish children, these percentages were 14 and 70%, respectively. On average, 22% of the fluoride dispensed on the toothbrush was retained on the brush after brushing irrespective of the rinsing and spitting behaviour of the children. The maximum ingestible amount of fluoride from toothpaste assuming no rinsing or spitting was calculated. CONCLUSIONS: Fluoride ingestion from toothpaste is significantly reduced by rinsing and/or spitting during toothbrushing. Recommendations that younger children use small amounts of toothpaste (< 0.5 g) and that children using toothpaste with > or = 1000 ppm F rinse their mouths after brushing continue to be valid.

Development of a standardized method for comparing fluoride ingested from toothpaste by 1.5-3.5-year-old children in seven European countries. Part 1: Field work.

OBJECTIVES: To develop a standardized method for measuring the variables affecting fluoride ingestion from toothpaste in young children between the ages of 1.5 and 3.5 years, and to use the method at seven European sites. METHODS: Random samples of children were invited to take part in the study. Parents who gave consent were visited at home. The children brushed their teeth using the toothpaste brand and toothbrush type currently in use. Variables measured were: type of toothpaste used, fluoride concentration of toothpaste used, weight of toothpaste used, frequency of brushing and body weight of the child. RESULTS: It was not possible to follow the agreed protocol in all seven countries and in three countries appropriate alternative methods were employed. There was considerable variation between countries in the variables investigated. Use of children's toothpaste ranged from 69% in Ireland to 98% in Portugal. In the Netherlands up to 60% of the children were using toothpaste containing <400 ppm F and in Finland up to 27% of children were using toothpaste containing >1200 ppm F. Over half of the children used <0.25 g of toothpaste per brushing and the majority of children brushed once or twice per day. CONCLUSION: Although adherence to the agreed protocol was not possible at all study sites there was a clear picture of considerable variation in the oral hygiene practices of young children throughout Europe.

Development of a standardized method for comparing fluoride ingested from toothpaste by 1.5-3.5-year-old children in seven European countries. Part 2: Ingestion results.

OBJECTIVES: To develop a standardized method for measuring the variables affecting fluoride ingestion from toothpaste in young children between the ages of 1.5 and 3.5 years, and to use the method at seven European sites. METHODS: Random samples of children were invited to take part in the study. Parents who gave consent were visited at home. The children brushed their teeth using the toothpaste brand and toothbrush type currently in use. The difference between the fluoride dispensed onto the toothbrush and the fluoride recovered after accounting for losses was deemed to be the fluoride ingested. Details of other oral health-care habits were collected by questionnaire. For each child, the fluoride concentration of the toothpaste used was measured in the laboratory, from which an estimate of total daily fluoride ingestion was made. RESULTS: There was considerable variation between countries in the types of toothpaste used and in the amounts of toothpaste applied and ingested. The amount of fluoride ingested ranged from 0.01 to 0.04 mg fluoride per kg of body weight per day. CONCLUSION: The amount of fluoride ingested that is likely to be a risk factor for the development of dental fluorosis during tooth formation is equivocal and was found to vary widely between European countries. There appears to be a need for clearer health messages regarding the use of fluoridated toothpaste by young children.

Pharmacokinetics in the oral cavity: fluoride and other active ingredients.

Modern commercial toothpastes contain therapeutic ingredients to combat various oral conditions, for example, caries, gingivitis, calculus and tooth stain. The efficient delivery and retention of such ingredients in the mouth is essential for good performance. The aim of this chapter is to review the literature on the oral pharmacokinetics of, primarily, fluoride but also other active ingredients, mainly anti-plaque agents. Elevated levels of fluoride have been found in saliva, plaque and the oral soft tissues after use of fluoridated toothpaste, which persist at potentially active concentrations for hours. Both experiment and mathematical modelling suggest that the soft tissues are the main oral reservoir for fluoride. Qualitatively similar observations have been made for anti-plaque agents such as triclosan and metal cations, though their oral substantivity is generally greater. Scope for improved retention and subsequent efficacy exists.

Anti-calculus and whitening toothpastes.

In terms of novel formulations, there seems to have been a shift in emphasis from anti-caries/anti-gingivitis to anti-calculus/whitening toothpastes in recent years. The anti-calculus and whitening effects of toothpastes are to some extent based on the same active ingredients: compounds of high affinity for tooth mineral. Due to this affinity, crystal growth may be hindered (anti-calculus) and chromophores be displaced (whitening). Besides these common ingredients, both types of toothpaste may contain agents specifically aimed at each condition. Clinical studies have shown that these active ingredients can be successfully formulated in fluoride toothpastes to give significant reductions in supragingival calculus and stain formation and facilitate their removal. Some of the ingredients are formulated in toothpastes that additionally contain anti-plaque and anti-gingivitis ingredients, making these toothpastes (together with the fluoride) truly multi-functional. The development of these products is not straightforward because of interaction between formulation components and because the active ingredients must maintain their beneficial characteristics during the shelf life of the paste. Neither a therapeutic benefit (in terms of less gingivitis or less caries) nor a societal benefit (in terms of less treatment demand) has been demonstrated as a result of the anti-calculus and whitening effects of toothpastes.