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1.
Principles of fluoride toxicity and the cellular response: a review.
Johnston, NR, Strobel, SA
Archives of toxicology. 2020;(4):1051-1069
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Abstract
Fluoride is ubiquitously present throughout the world. It is released from minerals, magmatic gas, and industrial processing, and travels in the atmosphere and water. Exposure to low concentrations of fluoride increases overall oral health. Consequently, many countries add fluoride to their public water supply at 0.7-1.5 ppm. Exposure to high concentrations of fluoride, such as in a laboratory setting often exceeding 100 ppm, results in a wide array of toxicity phenotypes. This includes oxidative stress, organelle damage, and apoptosis in single cells, and skeletal and soft tissue damage in multicellular organisms. The mechanism of fluoride toxicity can be broadly attributed to four mechanisms: inhibition of proteins, organelle disruption, altered pH, and electrolyte imbalance. Recently, there has been renewed concern in the public sector as to whether fluoride is safe at the current exposure levels. In this review, we will focus on the impact of fluoride at the chemical, cellular, and multisystem level, as well as how organisms defend against fluoride. We also address public concerns about fluoride toxicity, including whether fluoride has a significant effect on neurodegeneration, diabetes, and the endocrine system.
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Developmental fluoride neurotoxicity: an updated review.
Grandjean, P
Environmental health : a global access science source. 2019;(1):110
Abstract
BACKGROUND After the discovery of fluoride as a caries-preventing agent in the mid-twentieth century, fluoridation of community water has become a widespread intervention, sometimes hailed as a mainstay of modern public health. However, this practice results in elevated fluoride intake and has become controversial for two reasons. First, topical fluoride application in the oral cavity appears to be a more direct and appropriate means of preventing caries. Second, systemic fluoride uptake is suspected of causing adverse effects, in particular neurotoxicity during early development. The latter is supported by experimental neurotoxicity findings and toxicokinetic evidence of fluoride passing into the brain. METHOD An integrated literature review was conducted on fluoride exposure and intellectual disability, with a main focus on studies on children published subsequent to a meta-analysis from 2012. RESULTS Fourteen recent cross-sectional studies from endemic areas with naturally high fluoride concentrations in groundwater supported the previous findings of cognitive deficits in children with elevated fluoride exposures. Three recent prospective studies from Mexico and Canada with individual exposure data showed that early-life exposures were negatively associated with children's performance on cognitive tests. Neurotoxicity appeared to be dose-dependent, and tentative benchmark dose calculations suggest that safe exposures are likely to be below currently accepted or recommended fluoride concentrations in drinking water. CONCLUSION The recent epidemiological results support the notion that elevated fluoride intake during early development can result in IQ deficits that may be considerable. Recognition of neurotoxic risks is necessary when determining the safety of fluoride-contaminated drinking water and fluoride uses for preventive dentistry purposes.
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Efficacy of fluorides and CPP-ACP vs fluorides monotherapy on early caries lesions: A systematic review and meta-analysis.
Tao, S, Zhu, Y, Yuan, H, Tao, S, Cheng, Y, Li, J, He, L
PloS one. 2018;(4):e0196660
Abstract
The study aimed to evaluate the efficacy of the combination of CPP-ACP and fluorides compared with fluorides monotherapy on patients with early caries lesions. The Medline, Embase and Cochrane databases up to August 2017 were scanned, with no restrictions. Studies satisfied the guideline of randomised controlled trials (RCTs), the patients with early caries lesions and data considering the efficacy of fluorides and CPP-ACP versus fluorides alone were selected. There was no language restriction during the literature search process, however, only papers in English or Chinese were included during the selection process. Outcome variables include laser fluorescence, quantitative light-induced fluorescence, lesion area and visual inspection scores. Mean differences were calculated during the data extraction process. Ten studies including 559 patients were selected in the meta-analysis. Fluorides combined with CPP-ACP achieved the same efficacy for early caries lesions on smooth surfaces compared with fluorides monotherapy (mean difference: -13.90, 95% confidence interval: [-39.25, 11.46], P = 0.28), and the combination treatment showed significantly better efficacy than fluorides monotherapy for occlusal early caries lesions (mean difference: -21.02, 95% confidence interval: [-27.94, -14.10], P<0.01). However, further well-designed studies are still needed.
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Fluoride mouthrinses for preventing dental caries in children and adolescents.
Marinho, VC, Chong, LY, Worthington, HV, Walsh, T
The Cochrane database of systematic reviews. 2016;(7):CD002284
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Abstract
BACKGROUND Fluoride mouthrinses have been used extensively as a caries-preventive intervention in school-based programmes and by individuals at home. This is an update of the Cochrane review of fluoride mouthrinses for preventing dental caries in children and adolescents that was first published in 2003. OBJECTIVES The primary objective is to determine the effectiveness and safety of fluoride mouthrinses in preventing dental caries in the child and adolescent population.The secondary objective is to examine whether the effect of fluoride rinses is influenced by:• initial level of caries severity;• background exposure to fluoride in water (or salt), toothpastes or reported fluoride sources other than the study option(s); or• fluoride concentration (ppm F) or frequency of use (times per year). SEARCH METHODS We searched the following electronic databases: Cochrane Oral Health's Trials Register (whole database, to 22 April 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 3), MEDLINE Ovid (1946 to 22 April 2016), Embase Ovid (1980 to 22 April 2016), CINAHL EBSCO (the Cumulative Index to Nursing and Allied Health Literature, 1937 to 22 April 2016), LILACS BIREME (Latin American and Caribbean Health Science Information Database, 1982 to 22 April 2016), BBO BIREME (Bibliografia Brasileira de Odontologia; from 1986 to 22 April 2016), Proquest Dissertations and Theses (1861 to 22 April 2016) and Web of Science Conference Proceedings (1990 to 22 April 2016). We undertook a search for ongoing trials on the US National Institutes of Health Trials Register (http://clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform. We placed no restrictions on language or date of publication when searching electronic databases. We also searched reference lists of articles and contacted selected authors and manufacturers. SELECTION CRITERIA Randomised or quasi-randomised controlled trials where blind outcome assessment was stated or indicated, comparing fluoride mouthrinse with placebo or no treatment in children up to 16 years of age. Study duration had to be at least one year. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces in permanent teeth (D(M)FS). DATA COLLECTION AND ANALYSIS At least two review authors independently performed study selection, data extraction and risk of bias assessment. We contacted study authors for additional information when required. The primary measure of effect was the prevented fraction (PF), that is, the difference in mean caries increments between treatment and control groups expressed as a percentage of the mean increment in the control group. We conducted random-effects meta-analyses where data could be pooled. We examined potential sources of heterogeneity in random-effects metaregression analyses. We collected adverse effects information from the included trials. MAIN RESULTS In this review, we included 37 trials involving 15,813 children and adolescents. All trials tested supervised use of fluoride mouthrinse in schools, with two studies also including home use. Almost all children received a fluoride rinse formulated with sodium fluoride (NaF), mostly on either a daily or weekly/fortnightly basis and at two main strengths, 230 or 900 ppm F, respectively. Most studies (28) were at high risk of bias, and nine were at unclear risk of bias.From the 35 trials (15,305 participants) that contributed data on permanent tooth surface for meta-analysis, the D(M)FS pooled PF was 27% (95% confidence interval (CI), 23% to 30%; I(2) = 42%) (moderate quality evidence). We found no significant association between estimates of D(M)FS prevented fractions and baseline caries severity, background exposure to fluorides, rinsing frequency or fluoride concentration in metaregression analyses. A funnel plot of the 35 studies in the D(M)FS PF meta-analysis indicated no relationship between prevented fraction and study precision (no evidence of reporting bias). The pooled estimate of D(M)FT PF was 23% (95% CI, 18% to 29%; I² = 54%), from the 13 trials that contributed data for the permanent teeth meta-analysis (moderate quality evidence).We found limited information concerning possible adverse effects or acceptability of the treatment regimen in the included trials. Three trials incompletely reported data on tooth staining, and one trial incompletely reported information on mucosal irritation/allergic reaction. None of the trials reported on acute adverse symptoms during treatment. AUTHORS' CONCLUSIONS This review found that supervised regular use of fluoride mouthrinse by children and adolescents is associated with a large reduction in caries increment in permanent teeth. We are moderately certain of the size of the effect. Most of the evidence evaluated use of fluoride mouthrinse supervised in a school setting, but the findings may be applicable to children in other settings with supervised or unsupervised rinsing, although the size of the caries-preventive effect is less clear. Any future research on fluoride mouthrinses should focus on head-to-head comparisons between different fluoride rinse features or fluoride rinses against other preventive strategies, and should evaluate adverse effects and acceptability.
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Fluorescent sensing of fluoride in cellular system.
Jiao, Y, Zhu, B, Chen, J, Duan, X
Theranostics. 2015;(2):173-87
Abstract
Fluoride ions have the important roles in a lot of physiological activities related with biological and medical system, such as water fluoridation, caries treatment, and bone disease treatment. Great efforts have been made to develop new methods and strategies for F(-) detection in the past decades. Traditional methods for the detection of F(-) including ion chromatography, ion-selective electrodes, and spectroscopic techniques have the limitations in the biomedicine research. The fluorescent probes for F(-) are very promising that overcome some drawbacks of traditional fluoride detection methods. These probes exhibit high selectivity, high sensitivity as well as quick response to the detection of fluoride anions. The review commences with a brief description of photophysical mechanisms for fluorescent probes for fluoride, including photo induced electron transfer (PET), intramolecular charge transfer (ICT), fluorescence resonance energy transfer (FRET), and excited-state intramolecular proton transfer (ESIPT). Followed by a discussion about common dyes for fluorescent fluoride probes, such as anthracene, naphalimide, pyrene, BODIPY, fluorescein, rhodamine, resorufin, coumarin, cyanine, and near-infrared (NIR) dyes. We divide the fluorescent probes for fluoride in cellular application systems into nine groups, for example, type of hydrogen bonds, type of cleavage of Si-O bonds, type of Si-O bond cleavage and cylization reactions, etc. We also review the recent reported carriers in the delivery of fluorescent fluoride probes. Seventy-four typical fluorescent fluoride probes are listed and compared in detail, including quantum yield, reaction medium, excitation and emission wavelengths, linear detection range, selectivity for F(-), mechanism, and analytical applications. Finally, we discuss the future challenges of the application of fluorescent fluoride probes in cellular system and in vivo. We wish that more and more excellent fluorescent fluoride probes will be developed and applied in the biomedicine field in the future.
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Fluoride in drinking water and diet: the causative factor of chronic kidney diseases in the North Central Province of Sri Lanka.
Dharmaratne, RW
Environmental health and preventive medicine. 2015;(4):237-42
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Abstract
A significant number of people in the North Central Province of Sri Lanka suffer from chronic kidney diseases (CKD), and the author revisits existing literature related to CKD to find its causative factor. There is a direct connection between high fluoride levels in drinking water and kidney disease, and there are unhealthy levels of fluoride in the groundwater in Sri Lanka's CKD-affected areas. Based on the following observations, the author believes with confidence that excess fluoride in drinking water and in the locally grown food in the affected areas are the culprits of CKD in Sri Lanka. Fluoride excretion rate is considerably lower in children than adults, leading to renal damage of children living in areas with high fluoride. Adults who had renal damage due to fluoride in childhood are vulnerable to CKD with continued consumption of water from the same source. Patients with chronic renal insufficiency are at an increased risk of chronic fluoride toxicity. High content of fluoride in groundwater paves the way to excess fluoride in local food crops, consequently adding more fluoride to the systems of the consumers. People who work outdoors for prolonged periods consume excess water and tea, and are subjected to additional doses of fluoride in their system. In the mid-1980s, the increase in water table levels of the affected areas due to new irrigation projects paved the way to adding more fluorides to their system through drinking water and locally grown foods.
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Exposure to fluoride in drinking water and hip fracture risk: a meta-analysis of observational studies.
Yin, XH, Huang, GL, Lin, DR, Wan, CC, Wang, YD, Song, JK, Xu, P
PloS one. 2015;(5):e0126488
Abstract
BACKGROUND Many observational studies have shown that exposure to fluoride in drinking water is associated with hip fracture risk. However, the findings are varied or even contradictory. In this work, we performed a meta-analysis to assess the relationship between fluoride exposure and hip fracture risk. METHODS PubMed and EMBASE databases were searched to identify relevant observational studies from the time of inception until March 2014 without restrictions. Data from the included studies were extracted and analyzed by two authors. Summary relative risks (RRs) with corresponding 95% confidence intervals (CIs) were pooled using random- or fixed-effects models as appropriate. Sensitivity analyses and meta-regression were conducted to explore possible explanations for heterogeneity. Finally, publication bias was assessed. RESULTS Fourteen observational studies involving thirteen cohort studies and one case-control study were included in the meta-analysis. Exposure to fluoride in drinking water does not significantly increase the incidence of hip fracture (RRs, 1.05; 95% CIs, 0.96-1.15). Sensitivity analyses based on adjustment for covariates, effect measure, country, sex, sample size, quality of Newcastle-Ottawa Scale scores, and follow-up period validated the strength of the results. Meta-regression showed that country, gender, quality of Newcastle-Ottawa Scale scores, adjustment for covariates and sample size were not sources of heterogeneity. Little evidence of publication bias was observed. CONCLUSION The present meta-analysis suggests that chronic fluoride exposure from drinking water does not significantly increase the risk of hip fracture. Given the potential confounding factors and exposure misclassification, further large-scale, high-quality studies are needed to evaluate the association between exposure to fluoride in drinking water and hip fracture risk.
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A new understanding of the relationship between sugars, dental caries and fluoride use: implications for limits on sugars consumption.
Sheiham, A, James, WP
Public health nutrition. 2014;(10):2176-84
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OBJECTIVE To examine the quantitative relationship between sugar intake and the progressive development of dental caries. DESIGN A critical in-depth review of international studies was conducted. Methods included reassessing relevant studies from the most recent systematic review on the relationship between levels of sugars and dental caries. Reanalysis of dose-response relationships between dietary sugars and caries incidence in teeth with different levels of caries susceptibility in children was done using data from Japanese studies conducted by Takeuchi and co-workers. SETTING Global, with emphasis on marked differences in both national sugar intake and fluoride use and preferably where one factor such as sugar intake changed progressively without changes in other factors over a decade or more. SUBJECTS Children aged 6 years or more and adults. RESULTS Caries occurred in both resistant and susceptible teeth of children when sugar intakes were only 2-3 % of energy intake, provided that the teeth had been exposed to sugars for >3 years. Despite increased enamel resistance after tooth eruption, there was a progressive linear increase in caries throughout life, explaining the higher rates of caries in adults than in children. Fluoride affects progression of caries development but there still is a pandemic prevalence of caries in populations worldwide. CONCLUSIONS Previous analyses based on children have misled public health analyses on sugars. The recommendation that sugar intakes should be ≤10 % of energy intake is no longer acceptable. The much greater adult burden of dental caries highlights the need for very low sugar intakes throughout life, e.g. 2-3 % of energy intake, whether or not fluoride intake is optimum.
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The development and validation of a new technology, based upon 1.5% arginine, an insoluble calcium compound and fluoride, for everyday use in the prevention and treatment of dental caries.
Cummins, D
Journal of dentistry. 2013;:S1-11
Abstract
OBJECTIVE This paper briefly discusses caries prevalence, the multi-factorial nature of caries etiology, caries risk and the role and efficacy of fluoride. The paper also highlights research on bacterial metabolism which provided understanding of the mouth's natural defenses against caries and the basis for the development of a new technology for the everyday prevention and treatment of caries. Finally, evidence that the technology complements and enhances the anti-caries efficacy of fluoride toothpaste is summarized. CONCLUSIONS Global data show that dental caries is a prevalent disease, despite the successful introduction of fluoride. Caries experience depends on the balance between consumption of sugars and oral hygiene and the use of fluoride. Three scientific concepts are fundamental to new measures to detect, treat and monitor caries: (1) dental caries is a dynamic process, (2) dental caries is a continuum of stages from reversible, pre-clinical to irreversible, clinically detectable lesions, and (3) the caries process is a balance of pathological and protective factors that can be modulated to manage caries. Fluoride functions as a protective factor by arresting and reversing the caries process, but fluoride does not prevent pathological factors that initiate the process. A novel technology, based upon arginine and an insoluble calcium compound, has been identified which targets dental plaque to prevent initiation of the caries process by reducing pathological factors. As the mechanisms of action of arginine and fluoride are highly complementary, a new dentifrice, which combines arginine with fluoride, has been developed and clinically proven to provide superior caries prevention.
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Dental caries: strategies to control this preventable disease.
Rugg-Gunn, A
Acta medica academica. 2013;(2):117-30
Abstract
OBJECTIVE To provide a brief commentary review of strategies to control dental caries. Dental decay is one of man's most prevalent diseases. In many counties, severity increased in parallel with importation of sugar, reaching its zenith about 1950s and 1960s. Since then, severity has declined in many countries, due to the wide use of fluoride especially in toothpaste, but dental caries remains a disease of medical, social and economic importance. Within the EU in 2011, the cost of dental treatment was estimated to be €79 billion. The pathogenesis is well understood: bacteria in dental plaque (biofilm) metabolise dietary sugars to acids which then dissolve dental enamel and dentine. Possible approaches to control caries development, therefore, involve: removal of plaque, reducing the acidogenic potential of plaque, reduction in sugar consumption, increasing the tooth's resistance to acid attack, and coating the tooth surface to form a barrier between plaque and enamel. At the present time, only three approaches are of practical importance: sugar control, fluoride, and fissure sealing. The evidence that dietary sugars are the main cause of dental caries is extensive, and comes from six types of study. Without sugar, caries would be negligible. Fluoride acts in several ways to aid caries prevention. Ways of delivering fluoride can be classed as: 'automatic', 'home care' and 'professional care': the most important of these are discussed in detail in four articles in this issue of the Acta Medica Academica. CONCLUSION Dental caries is preventable - individuals, communities and countries need strategies to achieve this.