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The aim of this study was to examine the association between fluoride exposure and bone mineral density (BMD) in children and adolescents. We used data from the National Health and Nutrition Examination Survey (NHANES) 2015-2016. The fluoride concentrations in the water samples, plasma samples, and urine samples were measured electrometrically using an ion-specific electrode. Total body less head BMD (TBLH BMD) was measured using dual-energy X-ray absorptiometry (DXA). Weighted generalized linear regression models and restricted cubic splines (RCS) regression models were used to analyze the relationships between the three types of fluoride exposure and TBLH BMD. We performed subgroup analyses stratified by sex. A total of 1413 US children and adolescents were included in our study. In our linear regression models, we found inverse associations between fluoride concentrations in water and plasma and TBLH BMD. Additionally, we discovered a non-linear association between fluoride concentrations in water and plasma and TBLH BMD. No significant association or non-linear relationship was found between urine fluoride levels and TBLH BMD. This nationally representative sample study provides valuable insight into the intricate connection between fluoride exposure and skeletal health in children and adolescents.

Background: Fluoride exposure during pregnancy has been associated with various effects on offspring, including changes in behavior and IQ. To provide clues to possible mechanisms by which fluoride may affect human fetal development, we completed proteomic analyses of cord blood serum collected from second-trimester pregnant women residing in northern California, USA., Objective: To identify changes in cord blood proteins associated with maternal serum fluoride concentration in pregnant women., Methods: The proteomes of 19 archived second-trimester cord blood samples from women living in northern California, USA, and having varied serum fluoride concentrations, were analyzed by quantitative mass spectrometry. The 327 proteins that were quantified were characterized by their abundance relative to maternal serum fluoride concentration, and subjected to pathway analyses using PANTHER and Ingenuity Pathway Analysis processes., Results: Pathway analyses showed significant increases in process related to reactive oxygen species and cellular oxidant detoxification, associated with increasing maternal serum fluoride concentrations. Pathways showing significant decreases included complement cascade, suggesting alterations in alterations in process associated with inflammation., Conclusion: Maternal fluoride exposure, as measured by serum fluoride concentrations in a small, but representative sample of women from northern California, USA, showed significant changes in the second trimester cord blood proteome relative to maternal serum fluoride concentration., (© 2024. The Author(s).)

Increased exposure to fluoride, which notably affects bone metabolism, is a global concern. However, the correlations and sensitivity of bone metabolism to fluoride remain controversial. In this cross-sectional study, 549 children (aged 7-12 years) and 504 adults (≥ 18 years old) were recruited in the high-fluoride areas of the Henan Province. Urinary fluoride (UF) level was determined using a fluoride electrode. Fasting venous blood serum was collected to measure bone metabolism biomarkers. The selected bone metabolism biomarkers for children included bone alkaline phosphatase (BALP), serum alkaline phosphatase (ALP), osteocalcin (OCN), calcitonin (CT), parathyroid hormone (PTH), phosphorus (P 5+ ), and calcium (Ca 2+ ). For adults, the biomarkers included ALP, CT, PTH, β-CrossLaps (β-CTX), P 5+ , and Ca 2+ . The correlations between UF and bone metabolism biomarkers were analyzed using binary logistic regression, a trend test, a generalized additive model, and threshold effect analysis. Regression analysis indicated a significant correlation between serum OCN, PTH, and UF levels in children aged 7-9 years. Serum OCN, PTH, and BALP contents were significantly correlated with UF in boys (P < 0.05). Furthermore, the interaction between age and UF affected serum P 5+ and PTH (P < 0.05). The generalized additive model revealed nonlinear dose-response relationships between P 5+ , BALP, and UF contents in children (P < 0.05). Serum OCN level was linearly correlated with the UF concentration (P < 0.05). Similarly, a significant correlation was observed between β-CTX and UF levels in adults. In addition, significant correlations were observed between UF-age and serum Ca 2+ , β-CTX, and PTH contents. There was a non-linear correlation between serum Ca 2+ , P 5+ , and β- CTX and UF levels (P < 0.05). Overall, serum OCN, BALP, and P 5+ levels can serve as sensitive bone metabolism biomarkers in children, while β-CTX, P 5+ , and Ca 2+ can be considered fluoride-sensitive bone metabolism biomarkers in adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

MK-8507 is an investigational HIV-1 nonnucleoside reverse transcriptase inhibitor being developed for the treatment of HIV-1 infection. MK-8507 contains 2 trifluoromethyl groups that may result in fluoride release through metabolism, but the extent of MK-8507-related fluoride release in humans has yet to be determined. This double-blind, placebo-controlled, 2-period, parallel-group, multiple-dose trial in healthy participants without HIV-1 who were administered a fluoride-restricted diet and once-weekly doses of MK-8507 aimed to estimate the relationship between MK-8507 dose and fluoride exposure. A total of 15 adult male and 3 adult female (of non-childbearing potential) participants were randomized to receive MK-8507 200 mg (n = 6), MK-8507 800 mg (n = 6), or placebo (n = 6). Change from baseline in mean daily fluoride excretion averaged over 7 days following the administration of MK-8507 200 mg resulted in a net mean increase of 19.8 μmol (90% confidence interval, 12.2-27.4) relative to placebo and did not exceed 57 μmol, a threshold related to the mean difference between the daily reference dose set by the US Environmental Protection Agency and the average dietary fluoride intake in the United States. However, daily urinary fluoride excretion exceeded the threshold following administration of 800 mg MK-8507 (75.1 μmol [90% confidence interval, 67.5-82.7]). Assuming a linear relationship between MK-8507 dose and estimated mean daily fluoride released at steady-state, data interpolation suggests that the US Environmental Protection Agency reference dose for fluoride would not be exceeded in most patients when administering MK-8507 at doses currently under clinical investigation (≤400 mg once weekly)., (© 2021 Merck Sharp & Dohme Corp. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objectives: The present study aimed to evaluate the effects of waste anaesthetic gases on cytokines and oxidative stress of hospital health team members following exposure to waste anaesthetic gases (WAGs)., Subjects and Methods: In total, 180 participants took part in this study; 60 of these were healthy male controls and the 120 participants in the intervention group were staff who work in the operating room. This latter group comprises six occupational subgroups (1) surgeons, (2) surgical assistants, (3) anaesthesiologists (4) anaesthesiology assistants, (5) nurses and (6) janitors. The following parameters were assessed: catalase (CAT), glutathione peroxidase (GSHpx) and superoxide dismutase (SOD) activities, plasma fluoride, serum interferon gamma (IFN-γ), serum interleukin 2 (IL2), serum interleukin 4 (IL4) and plasma thiobarbituric acid reactive substances (TBARS)., Results: Anaesthesiologists and their assistants exhibited the highest levels of plasma fluoride, serum IFN-γ and IL 2, exceeding the levels in detected in all the other occupational subgroups. Furthermore, the serum levels of IL4 were significantly raised in anaesthesiologists and the difference between this group and other groups was statistically significant. However, compared with the other subgroups, surgeons exhibited elevated plasma TBARS and reduced CAT, GSHpx and SOD; these variances were also statistically significant., Conclusion and Recommendations: The findings of this study indicate that operating room staff exposed to WAGs are vulnerable to experiencing immunotoxicity as the WAGs are considered to initiate oxidative stress and increase the levels of cytokines in serum. Thus, an education programme is warranted to inform staff working in environments where they may be subjected to WAGs on the effects that the gases can have upon their health and how to minimise their exposure to WAGs. An ongoing effort is also needed to ensure anaesthesia safety standards are maintained at all times. The findings of this study may provide a springboard for future research into occupational exposure to WAGs and their wider effect upon health., (© 2021. The Author(s).)

Objective: Increased fluoride levels can lead to numerous complications, including skeletal effects, cardiotoxicity, endocrine dysfunction, neurotoxicity, hepatotoxicity and nephrotoxicity. The aim of this study was to analyze the relationship between serum fluoride levels and MetS or its individual components, and to assess the diagnostic usefulness of fluoride as a factor contributing to MetS., Patients and Methods: The study included a group of 475 women (mean age of 52.9 years), living in the West Pomeranian Voivodeship in Poland. The study involved data collection and biochemical analysis., Results: Analysis of the relationship between the levels of fluoride and the presence of MetS or its components showed that the mean fluoride level was statistically significantly higher in patients with hypertriglyceridemia (dCohen = 0.39; 95% CI; confidence limits: 0.13, 0.63) and hypertension (dCohen = 0.25; 95% CI; confidence limits: 0.07, 0.44). Moreover, the mean fluoride level was significantly higher in women who met the diagnostic criteria for MetS than in the remaining subjects (dCohen = 0.40; 95% CI; confidence limits: 0.17, 0.64)., Conclusions: Elevated serum fluoride levels may be associated with an increased incidence of MetS among perimenopasal women, although its diagnostic value as a marker of MetS is limited.

Despite increasing concerns about neurotoxicity of fluoride in children, sources of fluoride exposure apart from municipal water fluoridation are poorly understood. We aimed to describe the associations of demographics, drinking water characteristics, diet, and oral health behaviors with plasma fluoride concentrations in U.S. children. We used data from 3928 6-19-year-olds from the 2013-2016 National Health and Nutrition Examination Survey. We used a 24-h dietary recall to estimate recent consumption of fluoridated tap water and select foods. We estimated the associations of fluoridated tap water, time of last dental visit, use of toothpaste, and frequency of daily tooth brushing with plasma fluoride concentrations. The participants who consumed fluoridated (≥0.7 mg/L) tap water (n = 560, 16%) versus those who did not had 36% (95% CI: 22, 51) higher plasma fluoride. Children who drank black or green tea (n = 503, 13%) had 42% higher plasma fluoride concentrations (95% CI: 27, 58) than non-tea drinkers. The intake of other foods and oral health behaviors were not associated with plasma fluoride concentrations. The consumption of fluoridated tap water and tea substantially increases plasma fluoride concentrations in children. Quantifying the contribution of diet and other sources of fluoride is critical to establishing safe target levels for municipal water fluoridation.

A significant health risk exists within a section of health workers that are exposed to anaesthetic gas and vapours, found in the atmosphere of treatment or operating rooms. These compounds are classified as waste anaesthetic gases (WAG). The present study aimed at identifying alterations in hepatic and haematological parameters occurring as a result of chronic exposure to WAG potentially affecting the health of team members working in hospitals. Therefore, operating room operatives, vulnerable to long-standing WAG exposure, were recruited for this study. Sevoflurane anaesthesia metabolites (inorganic fluoride and hexafluoroisopropanol (HFIP)), haematological indices and liver toxicity markers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase and osteopontin) were measured. The collected results showed increased plasma inorganic fluoride, HFIP and liver toxicity markers, as well as disturbances in haematological parameters. In conclusion, exposure to halogenated inhalational anaesthetics, in general, and Sevoflurane, in particular, induces alterations in hepatic markers and haematological indices.

Fluorosis is a common disease characterized by disruptions in bone metabolism and enamel development. The production of reactive oxygen species is thought to play an important role in fluorosis. Gastrodin (4-hydroxybenzylalcohol4-O-beta-D-glucopyranoside) has been reported to have antioxidative activity, and so here we examined whether gastrodin has protective effects against oxidative stress and bone tissue toxicity in rats with fluorosis. Wistar rats were given different doses of gastrodin 1 month after fluoride administration, and samples of blood, bone and teeth were collected after 2, 3 and 4 months; glutathione peroxidase glu, CAT and SOD levels in the fluorosis group were lower than those in the control group. Gastrodin treatment in rats ameliorated oxidative stress and fluoride accumulation that were induced by fluoride; treatment with 400 mg·kg -1 gastrodin protected trabecular bone structure and reduced femur and alveolar bone injury in rats with fluorosis. Enhanced expression of cysteinyl aspartate-specific proteinase (caspase) 3, caspase-9 and Bax and decreased expression of Bcl-2 induced by fluoride were also reversed by gastrodin. In summary, the present data suggest that gastrodin, and in particular a dose of 400 mg·kg -1 , can improve the antioxidative capacity of rats, reduce concentration of fluoride in tissues, alleviate bone damage and modulate expression of Bcl-2, Bax, caspase-3 and caspase-9., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Chronic kidney disease of uncertain etiology (CKDu) is a common health issue among farming communities in the dry zone of Sri Lanka where groundwater fluoride is known to be higher than recommended levels. Excessive environmental ingestion of fluoride is widely considered as a possible factor for the onset of CKDu. This study was carried out to evaluate the serum and urine fluoride levels in biopsy-proven, non-dialysis CKDu patients. Control subjects were selected from the same area without any deteriorated kidney functions. Serum and urine fluoride levels were determined by ion-selective electrode method. Higher content of serum and urine fluoride levels were observed in patients with chronic renal failures. In CKDu cases, the serum fluoride concentrations ranged between 0.47 and 9.58 mg/L (mean 1.39 ± 1.1 mg/L), while urine levels were varied between 0.45 and 6.92 mg/L (mean 1.53 ± 0.8 mg/L). In patients, urine fluoride levels showed a significant difference with the CKDu stage; however, no difference was obtained between genders and age. In endemic controls, serum and urine fluoride levels ranged between 0.51 and 1.92 mg/L (mean = 1.07 ± 0.3 mg/L) and 0.36 and 3.80 mg/L (mean = 1.26 ± 0.6 mg/L), respectively. Significantly higher fluoride in serum and urine was noted in CKDu patients compared to endemic control groups. Higher fluoride exposure via drinking water is possibly the reason for higher fluoride in serum, while excessive urinary excretion would be due to deterioration of the kidney, suggesting a possible nephrotoxic role of environmental fluoride exposure.

Background: Previous studies have shown a correlation between fluoride concentrations in urine and community water fluoride concentrations. However, there are no studies of the relationship between community water fluoridation, urine, serum, and amniotic fluid fluoride concentrations in pregnant women in the US. The aim of this study was to determine the relationship between maternal urine fluoride (MUF), maternal urine fluoride adjusted for specific gravity (MUF SG ), maternal serum fluoride (MSF), amniotic fluid fluoride (AFF) concentrations during pregnancy, and community water fluoridation in Northern California., Methods: Archived samples of urine, serum and amniotic fluid collected from second trimester pregnant women in Northern California from 47 different communities in Northern California and one from Montana (n = 48), were analyzed for fluoride using an ion specific electrode following acid microdiffusion. Women's addresses were matched to publicly reported water fluoride concentrations. We examined whether fluoride concentrations in biospecimens differed by fluoridation status of the community water, and determined the association between water fluoride concentrations and biospecimen fluoride concentrations using linear regression models adjusted for maternal age, smoking, Body Mass Index (BMI), race/ethnicity, and gestational age at sample collection., Results: Fluoride concentrations in the community water supplies ranged from 0.02 to 1.00 mg/L. MUF, MSF , and AFF concentrations were significantly higher in pregnant women living in communities adhering to the U.S. recommended water fluoride concentration (0.7 mg/L), as compared with communities with less than 0.7 mg/L fluoride in drinking water. When adjusted for maternal age, smoking status, BMI, race/ethnicity, and gestational age at sample collection, a 0.1 mg/L increase in community water fluoride concentration was positively associated with higher concentrations of MUF (B = 0.052, 95% CI:0.019,0.085), MUF SG (B = 0.028, 95% CI: -0.006, 0.062), MSF (B = 0.001, 95% CI: 0.000, 0.003) and AFF (B = 0.001, 95% CI: 0.000, 0.002)., Conclusions: We found universal exposure to fluoride in pregnant women and to the fetus via the amniotic fluid. Fluoride concentrations in urine, serum, and amniotic fluid from women were positively correlated to public records of community water fluoridation. Community water fluoridation remains a major source of fluoride exposure for pregnant women living in Northern California.

Background: Several animal studies have suggested that fluoride exposure may increase the levels of cardiometabolic risk factors, but little is known about whether fluoride exposure is associated with such risk in humans., Objectives: We examined the cross-sectional association between peripubertal exposure to fluoride and markers of cardiometabolic risk in 280 girls and 256 boys at age 10-18 years living in Mexico City., Methods: We measured plasma fluoride concentration using a microdiffusion method. We collected data on anthropometry including BMI, waist circumference (WC) and trunk fat percentage. We measured serum markers of cardiometabolic risk, including fasting glucose, insulin and lipids. All the indicators of outcome were converted to age- and sex-specific z-scores. We also calculated a summary cardiometabolic risk score for each participant. Multivariable linear regression models were used to examine these associations., Results: The geometric mean (95% confidence interval (CI)) of plasma fluoride was 0.21 μmol/L (0.20, 0.23 μmol/L) in the total sample. In girls, plasma fluoride concentrations were associated with higher z-scores for all the individual markers (except for lipids) and for the combined cardiometabolic risk score (risk score: β = 1.28, 95% CI: 0.57-2.00, p-sex interaction = 0.02)), adjusting for covariates. No associations were found in boys., Conclusions: We found that higher peripubertal fluoride exposure at the levels observed in this study population was significantly associated with increased levels of cardiometabolic risk factors in Mexican girls but not boys. Future studies with a longitudinal design are needed to confirm our findings and further elucidate the role of fluoride in cardiometabolic risk., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The current effective delivered dose is a quality indicator for continuous renal replacement therapy. Its periodic assessment might enable physicians to deliver personalised treatments. Yet, its quantification as by extracorporeal urea clearance (Cl) is cumbersome and thus often neglected in routine practice. The aim of this in vitro study is to demonstrate the non-inferior effectiveness of assessing the current effective delivered dose using a simpler, cheaper and faster approach based on measurement of fluoride rather than urea extracorporeal Cl., Methods: We compared urea and fluoride removal in 3 post-dilution continuous veno-venous haemofiltration (CVVH) and 3 continuous veno-venous haemodialysis (CVVHD) in vitro experimental models. Experiments ran for 180 min, using 3 L of human blood, heparin anticoagulation and a machine dose of 30 mL/kg/h. Urea and fluoride were measured in the inflow, outflow and effluent lines to compare sieving coefficients (SC), saturation coefficients (SA) and transmembrane Cls., Results: In CVVH, the median SC values were 1.06 (1.02-1.07) and 1.02 (1.01-1.04) for fluoride and urea, respectively (discrepancy of 4.3%), while transmembrane convective Cls were 31.28 (30.01-31.31) mL/kg/h and 30.30 (29-31.85) mL/kg/h (discrepancy of 3.13%), respectively. In CVVHD, the median SA values were 1.01 (0.96-1.02) and 1 (0.95-1.01) for fluoride and urea, respectively (discrepancy of 1.6%), while transmembrane dialytic Cls were 30.26 (29.52-31.32) mL/kg/h and 31.16 (30-31.75) mL/kg/h (discrepancy of -2.97%), respectively., Conclusion: Fluoride transmembrane removal was close to that observed with urea, in terms of SC, SA and transmembrane Cl. Fluoride seems as much accurate as urea in assessing the current effective delivered dose during both CVVH and CVVHD and might therefore be adopted for dose measurement. Besides accuracy, fluoride bedside assessment could present many advantages over urea, particularly in terms of availability, costs, time requirement and rapidity of assessment., (© 2020 S. Karger AG, Basel.)

Introduction: A greater prevalence of dental fluorosis has been reported in higher- versus lower-altitude communities. This study, for the first time, examined several aspects of fluoride metabolism in children, aged 4-5 years, and their parent, living at lower altitude (<78 m) and higher altitude (>1487) areas in Nepal., Methods: The study assessed total daily fluoride intake (TDFI), 24 h urinary fluoride excretion (UFE), and fluoride concentrations of toe- and finger-nail (FC toenail , FC fingernail ) in children and parents as well as fluoride concentration of plasma (FC plasma ) in parents. Fractional urinary fluoride excretion (FUFE) was calculated as the ratio between UFE and TDFI. FC toenail , FC fingernail and FC plasma were normalised for TDFI by dividing the variables by TDFI and the ratio was reported as the percentage., Results: In total, 89 children and 80 parents took part in the study: 42 children and 41 parents from the lower altitude area; 47 children and 39 parents from the higher altitude area. Fluoride concentration of drinking water was significantly (P < 0.001) higher at lower altitude (0.395 mg F/l) than at higher altitude (0.104 mg F/l). TDFI was significantly (p < 0.001) higher in both children and parents living in lower altitude than those living at higher altitude. There was a statistically significant (p = 0.044) difference in the mean FUFE of children living at lower altitude (53%) and higher altitude (46%). However, no significant difference in FUFE was found between parents living at lower altitude (47%) compared with higher altitude (41%). In both children and parents, no statistically significant differences in normalised FC toenail , FC fingernail were found between the two altitude areas. However, normalised FC plasma was statistically significantly (P = 0.005) higher in parents living at higher altitude (0.15%) compared with those living at lower altitude (0.11%)., Conclusion: The results suggest that higher altitude living results in decreased urinary fluoride excretion, and consequently increased fluoride retention in children for a given dose (amount) of fluoride., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Background: Fluoride from environmental sources accumulates preferentially in the pineal gland which produces melatonin, the hormone that regulates the sleep-wake cycle. However, the effects of fluoride on sleep regulation remain unknown. This population-based study examined whether chronic low-level fluoride exposure is associated with sleep patterns and daytime sleepiness among older adolescents in the United States (US)., Method: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (2015-2016). We analyzed data from adolescents who had plasma fluoride (n = 473) and water fluoride (n = 419) measures and were not prescribed medication for sleep disorders. Relationships between fluoride exposure and self-reported sleep patterns or daytime sleepiness were examined using survey-weighted linear, binomial logistic or multinomial logistic regression after covariate adjustment. A Holm-Bonferroni correction accounted for multiple comparisons., Results: The average age of adolescents was 17 years (range = 16-19). Median (IQR) water and plasma fluoride concentrations were 0.27 (0.52) mg/L and 0.29 (0.19) μmol/L respectively. An IQR increase in water fluoride was associated with 1.97 times higher odds of reporting symptoms suggestive of sleep apnea (95% CI: 1.27, 3.05; p = 0.02), a 24 min later bedtime (B = 0.40, 95% CI: 0.10, 0.70; p = 0.05), a 26 min later morning wake time (B = 0.43, 95% CI: 0.13, 0.73; p = 0.04), and among males, a 38% reduction in the odds of reporting snoring (95% CI: 0.45, 0.87, p = 0.03)., Conclusions: Fluoride exposure may contribute to changes in sleep cycle regulation and sleep behaviors among older adolescents in the US. Additional prospective studies are warranted to examine the effects of fluoride on sleep patterns and determine critical windows of vulnerability for potential effects.

In Togo, the phosphate ore mill discharges waste containing xenobiotics like cadmium, lead and fluoride. If the role of heavy metals in the appearance of pathologies is known, the role of fluoride remains to be studied alongside xenobiotics. This study tested the hypothesis that the toxicity of fluoride contributes, along with heavy metals, to physiological dysfunction. In this process, we have studied the variation in the parameters of cardiovascular functioning, depending on the level of human contamination by fluoride and xenobiotics. The concentration of Cd and Pb in blood samples were determined by AAS and fluoride by titanium-chloride method. Lipid peroxidation, the total antioxidant potential of collected blood samples and the parameters of cardiovascular dysfunction were also measured. Cd, Pb and F contents and lipid peroxidation were found to be significantly elevated in polluted areas than control zone as well as total cholesterol, LDL and triglyceride. HDL and antioxidant potential of blood decreased in the polluted areas. Correlation tests showed that fluoride levels are related to variations in the bio-indicators of high blood pressure and oxidative stress (R varied from 0.354 to 0.907). Togo phosphate treatment leads to human contamination with fluoride, along with Cd and Pb, increasing the risk of cardiovascular dysfunction and oxidative stress., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

A simple fluorescence turn on sensor for the detection of fluoride ion in totally aqueous medium has been developed by integrating boronic acid functionalized carbon quantum dot (BNSCQD) and dopamine. The intense emission of BNSCQD is quenched due to photoelectron transfer (PET) from BNSCQD to dopamine. A remarkable enhancement of emission intensity in presence of F - is achieved due to high reactivity of F - towards boron centre of the BNSCQD-dopamine complex and hence restricting PET between BNSCQD and dopamine. The LOD of our sensor is 0.7 pM. The sensor is not cytotoxic and could be utilised to trace fluoride level changes in human serum as well as in living cells., (Copyright © 2019. Published by Elsevier B.V.)

Water fluoridation is the most widespread measure to prevent dental caries but its relationship with the development of type-1 diabetes (T1D), which has been increasing by 2-5% worldwide, is not quite well understood., Aim: This study evaluated if fluoride (F) administered in the drinking water can prevent or reduce the development of T1D in non-obese diabetic (NOD) mice, as well as to explore the underlying mechanisms., Materials and Methods: Twenty-four weaning NOD mice received water containing 0, 10 or 50 ppm F for 21 days. Plasma glucose and insulin were analyzed. Quantitative proteomic analysis was conducted in the liver and gastrocnemius muscle., Results: Animals treated with 10 ppm F had significantly lower glucose levels than the control group, but there was no significant difference among the groups in relation to insulin. The % of β-cell function was significantly higher in the 10 ppm F group. Changes in the proteomic profile of muscle and liver were seen among the groups. In the muscle, the 10 ppm F group presented, when compared with control, increased expression of proteins involved in energy metabolism. The 50 ppm F group, compared with control, presented increased expression of proteins related to muscle contraction, differentiation of brown adipose tissue and apoptosis. For the liver, the 10 ppm F group had increase in proteins involved in energy metabolism and protein synthesis, in respect to control. There was also an increase in isoforms of Glutathione S transferase, which was confirmed by Western blotting. In the group treated with 50 ppm F, proteins related to ROS metabolism and energetic metabolism were altered., Conclusion: Increased expression of antioxidant proteins by treatment with low F concentration may possibly help to explain protection against the development of T1D, which should be better explored in future mechanistic studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Long-term occupational exposure to low level of fluoride can induce oxidative stress and apoptosis in many cells, including lymphocyte. However, the underlying mechanism remains unclear. Hence, this study was designed to explore the potential oxidative stress and apoptosis of long-term occupational exposure to low level of fluoride in aluminum smelter workers. A total of 120 aluminum smelter workers were recruited in control, low-, middle-, and high-fluoride exposure groups with 30 workers for each group. The peripheral blood samples were collected, centrifuged, and isolated to obtain serum and lymphocyte suspensions. The air and serum fluoride concentrations were detected by fluoride ion-selective electrode method. The lymphocytic apoptosis rate, DNA damage, oxidative stress, and mRNA levels of p53, Bcl-2, and Bax were assessed by Annexin V/PI staining, comet assay, attenuated total reflectance Fourier transform infrared spectroscopy and real-time polymerase chain reaction, respectively. Results showed that the air and serum fluoride concentrations of fluoride-exposed groups were higher than those of the control group (p < 0.05). Fluoride exposure might induce apoptosis, DNA damage and oxidative stress in a dose-dependent manner in lymphocytes (p < 0.05). The expression levels of p53 and Bax were increased with fluoride exposure in lymphocytes (p < 0.05), whereas the Bcl-2 expression was decreased but not significantly. Taken together, these observations indicate that long-term occupational exposure to low level of fluoride may lead to oxidative stress and induce apoptosis through the p53-dependent pathway in peripheral blood lymphocytes of aluminum smelter workers. Serum fluoride level may be the potential biomarker of fluoride exposure.

The aim was to compare potential methods for fluoride analysis in microlitre-volume plasma samples containing nano-gram amounts of fluoride. Methods: A group of 4 laboratories analysed a set of standardised biological samples as well as plasma to determine fluoride concentration using 3 methods. In Phase-1, fluoride analysis was carried out using the established hexamethyldisiloxane (HMDS)-diffusion method (1 mL-aliquot/analysis) to obtain preliminary measurement of agreement between the laboratories. In Phase-2, the laboratories analysed the same samples using a micro-diffusion method and known-addition technique with 200 µL-aliquot/analysis. Coefficients of Variation (CVs) and intra-class correlation coefficients (ICCs) were estimated using analysis of variance to evaluate the amount of variation within- and between-laboratories. Based on the results of the Phase-2 analysis, 20 human plasma samples were analysed and compared using the HMDS-diffusion method and known-addition technique in Phase-3. Results: Comparison of Phase-1 results showed no statistically significant difference among the laboratories for the overall data set. The mean between- and within-laboratory CVs and ICCs were < 0.13 and ≥0.99, respectively, indicating very low variability and excellent reliability. In Phase-2, the overall results for between-laboratory variability showed a poor CV (1.16) and ICC (0.44) for the micro-diffusion method, whereas with the known-addition technique the corresponding values were 0.49 and 0.83. Phase-3 results showed no statistically significant difference in fluoride concentrations of the plasma samples measured with HMDS-diffusion method and known- addition technique, with a mean (SE) difference of 0.002 (0.003) µg/mL. In conclusion, the known-addition technique could be a suitable alternative for the measurement of fluoride in plasma with microlitre-volume samples., (© 2018 S. Karger AG, Basel.)

Routine administration of trace elements is recognised as a standard of care in children requiring parenteral nutrition. However, there is a lack of global consensus regarding trace elements provision and dosing in pediatric parenteral nutrition. This review provides an overview of available evidence regarding trace elements supply and posology in parenteral nutrition in neonates and children. Trace elements provision in children should be tailored to the weight and clinical condition of the child with emphasis on those at risk of toxicity or deficiency. Based on current evidence, there is a need to review the formulation of commercial solutions that contain multiple-trace elements and to enable individual trace elements additives to be available for specific indications. Literature supports the removal of chromium provision whereas manganese and molybdenum supplementation are debated. Preterm neonates may have higher parenteral requirements in iodine, selenium and copper than previously recommended. There is growing support for the routine provision of iron in long-term parenteral nutrition. Further studies on trace elements contamination of parenteral nutrition solutions are needed for a range of trace elements.

Fluoride (F) can induce changes in the expression of several liver proteins. It is suggested that these changes are dose- and time-dependent. The objective of this study was to analyze the effect of different F concentrations and exposure times to this ion on the pattern of protein expression in the liver of rats. Thirt-six 21-day-old male Wistar rats were divided into 2 groups (n = 18) according to the treatment duration (20 or 60 days). Each of these groups was then divided into 3 subgroups (n = 6) according to the concentration of F administered in drinking water, as follows: 0 mg/L (control), 15 mg/L or 50 mg/L. After the experiment periods, the animals were anesthetized and the liver and blood were collected. F was analyzed in plasma and liver. Part of the liver was fixed for histological analysis. Liver proteins were extracted and prepared for quantitative label-free mass spectrometry analysis. F concentrations in plasma and liver were significantly higher in the group treated with 50 mg /L in comparison with control, regardless the time of exposure. Histological alterations in the liver were more evident in the subgroups treated for 20 days. The proteomic analysis revealed changes in proteins related to endoplasmic reticulum and mitochondrial oxidative stress, mitochondrial alteration, apoptosis and cellular respiration upon exposure to F. The results reinforce previous findings showing that the effects of F in the liver are dose- and time-dependent and provide the molecular basis for understanding the evolution of these effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The susceptibility of the kidneys to fluoride toxicity can largely be attributed to its anatomy and function. As the filtrate moves along the complex tubular structure of each nephron, it is concentrated in the proximal and distal tubules and collecting duct. It has been frequently observed that the children suffering from renal impairments also have some symptoms of dental and skeletal fluorosis. The findings suggest that fluoride somehow interferes with renal anatomy and physiology, which may lead to renal pathogenesis. The aim of this study was to evaluate the fluoride-associated nephrotoxicity. A total of 156 patients with childhood nephrotic syndrome were screened and it was observed that 32 of them had significantly high levels ( p ≤ 0.05) of fluoride in urine (4.01 ± 1.83 ppm) and serum (0.1 ± 0.013 ppm). On the basis of urinary fluoride concentration, patients were divided into two groups, namely group 1 (G-1) ( n = 32) containing normal urine fluoride (0.61 ± 0.17 ppm) and group 2 (G-2) ( n = 32) having high urine fluoride concentration (4.01 ± 1.83 ppm). Age-matched healthy subjects ( n = 33) having normal levels of urinary fluoride (0.56 ± 0.15 ppm) were included in the study as control (group 0 (G-0)). Kidney biopsies were taken from G-1 and G-2 only, who were subjected to ultrastructural (transmission electron microscopy) and apoptotic (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling) analysis. Various subcellular ultrastructural changes including nuclear disintegration, chromosome condensation, cytoplasmic ground substance lysis, and endoplasmic reticulum blebbing were observed. Increased levels of apoptosis were observed in high fluoride group (G-2) compared to normal fluoride group (G-1). Various degrees of fluoride-associated damages to the architecture of tubular epithelia, such as cell swelling and lysis, cytoplasmic vacuolation, nuclear condensation, apoptosis, and necrosis, were observed.

Ammonium bifluoride is an inorganic, fluoride-containing compound found in glass and metal etching products, as well as wheel cleaners. Fluoride toxicity is a common cause of preventable poisoning and has been reported to cause life-threatening ventricular dysrhythmias. Here, we report a case of recurrent ventricular fibrillation secondary to ingestion of ammonium bifluoride. The patient presented with vomiting and coma. She was intubated for altered mental status and respiratory failure and subsequently had 5 episodes of ventricular fibrillation, each resolving with a single defibrillation. She developed metabolic acidosis and hypocalcemia, which were treated with sodium bicarbonate and calcium gluconate, respectively. During transfer to a tertiary care children's hospital, ventricular fibrillation recurred despite electrolyte correction. Hemodialysis (HD) was initiated emergently. No further dysrhythmia occurred after initiation of HD. The result of a basic urine drug screen was negative, and a comprehensive drug screen (gas chromatography and mass spectroscopy) revealed only a nonsignificant peak for diphenhydramine. Subsequent laboratory evaluation revealed an elevated serum fluoride level. Diagnostic laryngoscopy and upper endoscopy did not reveal evidence of caustic injury. She was successfully extubated on hospital day 2 and discharged from the hospital on day 4 with no neurologic sequelae. With this example, we demonstrate a potential therapeutic approach to this potentially lethal poisoning. Fluoride toxicity is typically treated with calcium. However, dysrhythmia may result from calcium-independent direct myocardial toxicity. The kinetics of fluoride are amenable to HD, and renal clearance is slow. The potential use of HD in cases of fluoride poisoning refractory to other therapies warrants further study., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background: Bone union after spinal fusion surgery with instrumentation has been determined only with imaging studies. We evaluated the usefulness of the serum ionic fluoride (SIF) concentration as a biomarker of the bone union status., Methods: We enrolled 25 patients who underwent spinal surgery in our institution, and we divided patients into three groups with and without instrumentation (G1, G2, and G3). We collected the fasting serum level preoperatively and on day 1 (D1), week 1 (D7), week 2 (D14), month 1 (D30), month 3 (D90), and month 6 (D180) postoperatively, and measured SIF concentrations using the flow injection method with an ion-selective electrode., Results: Although preoperative SIF concentrations were similar among the 3 groups, postoperative SIF concentrations were different among the groups. SIF concentrations in groups with instrumentation (G2 and G3) increased between D14 and D90 postoperatively and decreased at D180 postoperatively. SIF concentrations in the group without instrumentation (G1) decreased between D30 and D180 postoperatively., Conclusions: An SIF concentration that is higher postoperatively than preoperatively may indicate unstable bone union, whereas a lower SIF concentration postoperatively than preoperatively may indicate stable bone union. We concluded that the SIF concentration may be useful for diagnosing bone union., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To investigate the clinical characteristics of patients with hydrofluoric acid (HF) burns. Methods: Clinical data of 316 patients with HF burns admitted to Zhejiang Quhua Hospital from January 2004 to December 2016 were retrospectively analyzed. Patients were divided into non and mild poisoning group (NMP, n =157), moderate poisoning group (MP, n =120), and severe and fatal poisoning group (SFP, n =39) based on the severity of poisoning. Occurrences of hypocalcemia, hypomagnesemia, hypokalemia, and hyperkalemia of patients within 24 hours after admission were recorded. Values of emergency urinary fluoride of patients on admission were recorded. Values of urinary fluoride of patients admitted to hospital in 4 hours post injury in groups MP and SFP at post injury hour 4, 12, and 24 and on post injury day 2, 3, 4, 5, 6, and 7 were also recorded. Electrocardiographic abnormalities of patients within 24 hours after admission were recorded. Data were processed with chi-square test, Kruskal-Wallis H test, and Mann-Whitney U test. Results: (1) Hypocalcemia, hypomagnesemia, and hypokalemia occurred in some patients in each of the three groups, but no patient had hyperkalemia. Taking serum calcium namely total serum calcium as reference, the incidence rate of hypocalcemia of patients in group NMP was close to that in group MP ( χ (2)=0.05, P >0.05). The incidence rate of hypocalcemia of patients in group SFP was significantly higher than that in group NMP or group MP ( χ (2)=10.53, 7.92, P <0.01). The incidence rates of hypokalemia in the three groups were close ( χ (2)=0.63, P >0.05). Taking serum ionized calcium as reference, the incidence ratio of hypocalcemia of patients in group NMP was close to that in group MP ( χ (2)=0.01, P >0.05), while there were statistically significant differences in incidence ratio of hypocalcemia of patients between group SFP and each of group NMP and group MP ( χ (2)=4.66, 4.47, P <0.05). Taking serum calcium as reference, the incidence rate of hypocalcemia of patients was 7.3% (23/316). Taking serum ionized calcium as reference, the incidence rate of hypocalcemia of patients was 60.0% (42/70), which was significantly higher than that of taking serum calcium as reference ( χ (2)=113.74, P <0.01). The incidence rates of hypomagnesemia of patients in groups MP and NMP were close ( χ (2)=0.02, P >0.05). The incidence rate of hypomagnesemia of patients in group SFP was significantly higher than that in group NMP or group MP ( χ (2)=14.69, 9.94, P <0.01). (2) The urinary fluoride levels were tested in 288 patients, with the value of emergency urinary fluoride of patients on admission 0.2-590.0 mg/L. The values of urinary fluoride of 202 patients were above the normal value. The values of emergency urinary fluoride of patients in groups NMP, MP, and SFP were 2.15 (1.11, 4.30), 5.89 (1.72, 14.25), and 36.0 (13.2, 103.2) mg/L, respectively. The values of emergency urinary fluoride of patients in groups MP and SFP were significantly higher than the value in group NMP ( χ (2)=23.28, 66.03, P <0.01). The value of emergency urinary fluoride of patients in group SFP was significantly higher than that in group MP ( χ (2)=39.23, P <0.01). The value of urinary fluoride of 33 patients admitted to hospital within 4 hours post injury in groups MP and SFP reached the top at 4 hours post injury and then gradually declined, which returned to normal on about 5 days post injury. The values of urinary fluoride of patients in group SFP at 4, 12, and 24 hours post injury and on 2, 3, 4, 5, 6, and 7 days post injury were significantly higher than those in group MP ( Z =-4.28, -4.15, -3.81, -4.21, -2.48, -2.06, -2.31, -2.68, -3.03, P <0.05 or P <0.01). (3) Twenty-seven patients had electrocardiographic abnormality. There were 12 patients with T wave changes (the most common), 8 patients with ST-T changes, 6 patients with ventricular arrhythmias, 6 patients with conduction block, and 1 patient with broadened QRS waveform. There was no patient with prolonged Q-T interval. The ratios of patients with the above electrocardiographic abnormalities in group SFP were higher than those in group NMP and group MP. Conclusions: Clinical manifestations of patients with HF burn are hypocalcemia, hypomagnesemia, hypokalemia, and electrocardiographic abnormality. In addition to routine serum electrolyte and electrocardiogram monitoring, the levels of serum ionized calcium and urinary fluoride can be helpful to evaluate the severity of illness of the patients.

The present study investigated the effect of chronic exercise on fluoride (F) metabolism in fluorosis-susceptible mice exposed to high-F and explored the relationship between F concentrations in bone and plasma. Thirty male mice were randomised into three groups: Group I (No-F, No-Exercise), Group II (50 ppmF, No-Exercise), Group III (50 ppmF, Exercise). Body weight and physical performance of all mice were measured at baseline and end of experiment. F concentrations of plasma and bone were measured at the end of experiment. Mean plasma F concentration was significantly higher (p < 0.001) in Groups II and III compared with Group I. Mean bone F concentration was also significantly higher (p < 0.01) in Groups II and III compared with Group I. There was a significant correlation (p = 0.01, r = 0.54) between F concentration of plasma and bone. Mean body weight of Group I mice was significantly higher than Group II (p < 0.001) and Group III (p = 0.001) mice at the end of the experiment. This study, which provides the first data on the effect of chronic exercise on F metabolism in fluorosis-susceptible mice, suggests no effect of chronic exercise on F in plasma and bone. However, exposure to high-F resulted in lower body weight and exercise capacity in mice.

The contamination of ground water by fluoride has been reported worldwide. Most fluoride (approximately 70%) is filtered by the kidneys; humans or experimental animals with renal damage therefore may be more affected by fluoride exposure than those with normal kidney function. Tubulointerstitial fibrosis, which involves macrophage-promoted extracellular matrix production and myofibroblast migration, can be induced in rats by unilateral ureteral obstruction (UUO). We examined the effects of fluoride exposure on tubulointerstitial fibrosis in the obstructed kidney of UUO rats. The left ureters of 6-week-old male rats were ligated using silk sutures. Fluoride was then administered for 2 weeks at doses of 0, 75, and 150ppm in the drinking water. Real-time polymerase chain reaction was performed to analyze transforming growth factor beta 1 (TGF-β 1 ) transcription; histological and immunohistochemical staining were used to identify positive areas within the renal cortex and staining-positive cells by image analysis. Significant increases were observed in the obstructed kidneys of UUO rats exposed to 150ppm fluoride (compared to 0ppm) for areas or number of cells that stained with Masson trichrome or with antibodies against collagen type I, alpha-smooth muscle actin (α-SMA, a myofibroblast marker), ED1, ED2, and ED3 (macrophage markers), and TGF-β 1 . Taken together, these observations suggested that fluoride exacerbates tuburointerstitial nephropathy resulting from UUO, and that this effect occurs via activation of the M2 macrophage-TGF-β1-fibroblast/myofibroblast-collagen synthesis pathway., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study was conducted to investigate the effects of excess dietary fluoride (F) on serum biochemical indices, egg quality, and concentrations of F in soft tissues, eggs, and serum of laying hens. Commercial laying hens (n = 576, 51 weeks of age) were randomly allotted to 6 treatments with 6 replicates of 16 birds. The basal diets contained fluorine inclusions at a level of 16 mg/kg, and graded sodium fluoride was added to the basal diet to achieve fluorine inclusions, respectively, at a level of 200, 400, 600, 800, and 1000 mg/kg in the experimental diets. Dietary F levels at 600, 800, and 1000 mg/kg decreased (P < 0.05) albumin height and yolk color, while eggshell strength and eggshell thickness significantly decreased at 800 and 1000 mg/kg, respectively, compared with the control group. Fluoride concentrations in eggshell, albumin, yolk, liver, kidney, ovary, and oviduct responded to dietary F levels positively, and F concentrations in eggshell were the highest. Fluorine concentrations in albumin and yolk increased with the feeding time at the same dietary F levels (P < 0.05). Dietary F level at 400 mg/kg increased serum calcium level and activity of glutamic oxalacetic transaminase (P < 0.05). In conclusion, dietary F levels at 600 mg/kg decreased albumin height and yolk color, while eggshell strength and eggshell thickness significantly decreased at 800 and 1000 mg/kg, respectively. F concentrations in soft tissues, albumin, yolk, and eggshell of layers had a positive correlation with dietary F levels. By disturbing Ca and phosphorus metabolism, dietary F levels affected the formation of eggshell, reducing eggshell strength and eggshell thickness.

Background: Toxicity due to excess fluoride concentration in drinking water is of great concern in people who rely only on the ground water as their water source in many region of the world., Methods: We collected samples and examined the toxicity of fluoride in a population residing at Salem, Dharmapuri and Krishnagiri districts of Tamil Nadu, India and measured HDL bound enzyme (PON1), erythrocyte membrane bound enzymes (acetylcholinesterase, AChE) and adenosine 5' triphosphatase (ATPases), plasma enzyme (butyrylcholinesterase, BChE) and rate limiting enzyme in heme biosynthesis (delta aminolevulinic acid dehydratase, δ-ALAD) activities., Results: In fluorosis patients, formation of lipid peroxidation product was more in erythrocytes than in plasma. The observation further revealed that there was 50% reduction in the activity of HDL bound anti atherogenic enzyme-paraoxonase (PON1). The activities of membrane bound and signaling enzymes (acetylcholinesterase - AChE and adenosine 5' triphosphatase - ATPase) of erythrocyte were also diminished. These results suggested that there was defectiveness in the signaling and energy metabolism in fluorosis patients. Altered isoenzyme pattern of lactate dehydrogenase (LDH) in fluorosis samples was observed. Furthermore, the result suggested that both the heart (LDH 1) and liver (LDH 5) were most affected by fluoride toxicity. The study also provided reference values for tests which are used to predict the severity of fluoride toxicity., Conclusion: The toxic effect of fluoride was due to the collective effects on vital protective system rather than single factor., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Excessive fluoride consumption leads to accelerated red blood cell death and anaemia. Whether that increases the haematological alteration in subjects with haematological disorders (iron deficiency, thalassaemia, and G-6-PD deficiency) is still unclear. The fluoride in serum and urine and haematological parameters of students at Mae Tuen School (fluoride endemic area) were analysed and compared to those of students at Baan Yang Poa and Baan Mai Schools (control areas). Iron deficiency, thalassaemia, and G-6-PD deficiency were also diagnosed in these students. The students at Mae Tuen School had significantly (P < 0.001) higher levels of mean fluoride in the serum and urine than those in control areas. In both control and fluoride endemic areas, students with haematological disorders had significantly lower levels of Hb, Hct, MCV, MCH, and MCHC than those without haematological disorders. Moreover, the lowest levels of Hb, MCH, and MCHC were observed in the students with haematological disorders who live in the fluoride endemic area. Thus, the excessive fluoride consumption increased haematological alteration in subjects with iron deficiency, thalassaemia, and G-6-PD deficiency and that may increase the risk of anaemia in these subjects.

An online membrane-based distillation (MBD) coupled with ion chromatography (IC) method was proposed for automatic detection of trace fluoride (F - ) in serum and urine samples. The system consisted of a sample vessel, a lab-made membrane module and an ion chromatograph. Hydrophobic polytetrafluoroethylene (PTFE) hollow fiber membrane was used in MBD which was directly performed in serum and urine samples to eliminate the matrix interferences and enrich fluoride, while enabling automation. The determination of fluoride in biological samples was carried out by IC with suppressed conductometric detection. The proposed method feasibly determined trace fluoride in serum and urine matrices with the optimized parameters, such as acid concentration, distillation temperature, and distillation time, etc. Fluoride exhibited satisfactory linearity in the range of 0.01-5.0mg/L with a correlation coefficient of 0.9992. The limit of detection (LOD, S/N=3) and limit of quantification (LOQ, S/N=10) were 0.78μg/L and 2.61μg/L, respectively. The relative standard deviations of peak area and peak height were all less than 5.15%. The developed method was validated for the determination of fluoride in serum and urine with good spiked recoveries ranging between 97.1-101.9%. This method also can be proposed as a suitable alternative for the analysis of fluoride in other complex biological samples., (Copyright © 2017. Published by Elsevier B.V.)

The present study was designed to investigate the role of postnatal fluoride intake on [3H]glucose uptake and transport in rat brain and peripheral tissues. Sodium fluoride (NaF) in a concentration of 10 or 50 ppm was added to the drinking water of adult Wistar rats. The control group received distilled water. After 4 weeks, respective plasma fluoride levels were 0.0541 ± 0.0135 μg/ml (control), 0.0596 ± 0.0202 μg/ml (10 ppm), and 0.0823 ± 0.0199 μg/ml (50 ppm). Although plasma glucose levels were not altered in any group, the plasma insulin level in the fluoride (50 ppm) group was elevated (0.72 ± 0.13 μg/ml) versus the control group (0.48 ± 0.24 μg/ml) and fluoride (10 ppm) group. In rats receiving fluoride for 4 weeks at 10 ppm in drinking water, [3H]glucose uptake was unaltered in all tested parts of the brain. However, in rats receiving fluoride at 50 ppm, [3H]glucose uptake in cerebral cortex, hippocampus, and thalamus with hypothalamus was elevated, versus the saline group. Fluoride intake had a negligible effect on [3H]glucose uptake by peripheral tissues (liver, pancreas, stomach, small intestine, atrium, aorta, kidney, visceral tissue, lung, skin, oral mucosa, tongue, salivary gland, incisor, molars, and jawbone). In neither fluoride group was glucose transporter proteins 1 (GLUT 1) or 3 (GLUT 3) altered in frontal cortex and striatum versus control. On the assumption that increased glucose uptake (by neural tissue) reasonably reflects neuronal activity, it appears that fluoride damage to the brain results in a compensatory increase in glucose uptake and utilization without changes in GLUT 1 and GLUT 3 expression.

For the first time, for 2013-2014, as part of ongoing National Health and Nutrition Examination Survey, data for fluoride concentrations in water and plasma for U.S. children and adolescents were released in the public domain. This study was undertaken to investigate how fluoride concentrations vary in water and plasma with age, gender, race/ethnicity, housing ownership, use of prescription fluoride drops and/or tablets, exposure to environmental tobacco smoke, and recent use of tobacco products (among adolescents). Fluoride concentrations in water were found to be lower among those aged 3-5 years than those aged 6-11 years (p=0.02), lower for non-Hispanic Asians than Hispanics (p=0.04) among 3-5 years old, lower for non-Hispanic Asians than non-Hispanic blacks (p=0.04) among 6-11 years old, and lower for those who used prescription fluoride drops and/or tablets than those who did not (p≤0.048) among 12-19 years old. Adjusted fluoride concentrations in plasma were found to be lower for females than males (p<0.01) among those aged 6-11 years, lower for Hispanics than non-Hispanic whites (p<0.01) among those aged 12-19 years, and lower for those who used prescription fluoride drops and/or tablets than those who did not (p=0.03) among 12-15 years old. Recent smokers were found to have higher fluoride concentration (p=0.03) in plasma than non-smoker adolescents. Over 60% of the children aged 6-11 years and adolescents aged 12-19 years were at the risk of developing dental caries/decay. About 30% of the children were at the risk of dental fluorosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Many studies have demonstrated that exposure to excess fluoride was associated with a variety of diseases. Little is known about the variation of testosterone (T) levels caused by fluoride exposure. The aim of this study is to explore the association of fluoride exposure and age with serum T and androgen-binding protein (ABP) levels in male farmers. A cross-sectional study was conducted in a county of Henan Province, China, including high fluoride exposure from drinking water villages and control villages. Male farmers aged 18-55 years old who lived in these villages were recruited by cluster sampling and divided into a higher fluoride exposure group (HFG) and a lower fluoride exposure group (LFG) according to the level of urinary fluoride. Levels of T and ABP in serum were measured using chemiluminescence immunoassay (CLIA) and enzyme-linked immunosorbent assay (ELISA) respectively. Markedly lower T levels were observed in male farmers from the HFG than in those from the LFG (t = 2.496, P < 0.05). Furthermore, younger farmers, 18-29 and 30-39 years old, may be the most likely to have lower T levels when exposed to fluoride (P < 0.05). No significant differences were observed in serum ABP levels in all male farmers between the two groups with different fluoride exposure. These results supported that excess fluoride exposure decreased serum T levels of male farmers with age-specificity.

Environmental hazards from natural or anthropological sources are widespread, especially in the north-central region of Mexico. Children represent a susceptible population due to their unique routes of exposure and special vulnerabilities. In this study we evaluated the association of exposure to environmental kidney toxicants with kidney injury biomarkers in children living in San Luis Potosi (SLP), Mexico. A cross-sectional study was conducted with 83 children (5-12 years of age) residents of Villa de Reyes, SLP. Exposure to arsenic, cadmium, chromium, fluoride and lead was assessed in urine, blood and drinking water samples. Almost all tap and well water samples had levels of arsenic (81.5%) and fluoride (100%) above the permissible levels recommended by the World Health Organization. Mean urine arsenic (45.6ppb) and chromium (61.7ppb) were higher than the biological exposure index, a reference value in occupational settings. Using multivariate adjusted models, we found a dose-dependent association between kidney injury molecule-1 (KIM-1) across chromium exposure tertiles [(T1: reference, T2: 467pg/mL; T3: 615pg/mL) (p-trend=0.001)]. Chromium upper tertile was also associated with higher urinary miR-200c (500 copies/μl) and miR-423 (189 copies/μL). Arsenic upper tertile was also associated with higher urinary KIM-1 (372pg/mL). Other kidney injury/functional biomarkers such as serum creatinine, glomerular filtration rate, albuminuria, neutrophil gelatinase-associated lipocalin and miR-21 did not show any association with arsenic, chromium or any of the other toxicants evaluated. We conclude that KIM-1 might serve as a sensitive biomarker to screen children for kidney damage induced by environmental toxic agents., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: There is need to assess the developmental neurotoxicity of fluoride. Our knowledge of prenatal fluoride exposure is challenged as few population-based studies have been conducted and these generally date back several decades, provide incomplete data on sociodemographic variables, and have methodological limitations., Objective: To measure urinary and plasma fluoride levels across three time points in pregnant mothers who were enrolled in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohort study., Methods: Fluoride levels were characterized in archived urine and plasma from 872 pregnant mothers sampled from the ELEMENT cohort. Various statistical methods were used to analyze the fluoride data with particular consideration for changes across three stages of pregnancy and against sociodemographic variables., Results: All samples had detectable levels of fluoride. The mean urinary and plasma fluoride levels were 0.91 and 0.0221mg/L respectively, and these were not statistically different across three stages of pregnancy. Fluoride levels correlated across the stages of pregnancy studied, with stronger correlations between neighboring stages. Urinary fluoride changed as pregnancy progressed with levels increasing until ~23 weeks and then decreasing until the end of pregnancy. For plasma fluoride, there was a decreasing trend but this was not of statistical significance. Creatinine-adjusted urinary fluoride levels did not associate consistently with any of the sociodemographic variables studied., Conclusions: This study provides the most extensive characterization to date of fluoride exposure throughout pregnancy. These results provide the foundation to explore exposure-related health outcomes in the ELEMENT cohort and other studies., (Copyright © 2016. Published by Elsevier Inc.)

Excessive exposure to fluoride results in structural and functional damages to the central nervous system (CNS), and neurotoxicity of fluoride may be associated with neurodegenerative changes. Chronic microglial activation appears to cause neuronal damage through producing proinflammatory cytokines and is involved in many neurodegenerative disorders. It is not known about effects on microglia of fluoride. In the present study, healthy adult Wistar rats were exposed to 60 and 120 ppm fluoride in drinking water for 10 weeks, and control rats received deionized water. After 10 weeks, rats were sacrificed under anesthesia then apoptosis in neuron and inflammatory factors secreted by microglia were determined. We found that apoptosis of neurons in fluoride-treated rat brain increased and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive immunofluorescence increased with increasing fluoride concentrations. Bax protein expression increased and Bcl-2 protein expression decreased in fluoride-treated rat brain compared with that of the control rat brain. The microglia in the hippocampus and cortex of fluoride-treated rats were activated by immunostaining with OX-42, a marker of activated microglia, and OX-42-positive microglia cells were more abundant in the hippocampus than in the cortex. The levels of IL-1β and IL-6 protein expression in OX-42-labeled microglial cells were significantly increased in the cortex and hippocampus of rats exposed to fluoride, and TNF-α immunoreactivity in microglial cells of the hippocampus was significantly higher in the 120 ppm fluoride-treated group than that in the control group. Our results indicate that fluoride induced neuron apoptosis and expressions of inflammatory factors by activating microglia in rat brain.

Skeletal fluorosis is a metabolic bone disease caused by excessive accumulation of fluoride. Although the cause of this disease is known, the mechanism by which fluoride accumulates on the bone has not been clearly defined, thus there are no markers that can be used for screening skeletal fluorosis in epidemiology. In this study, osteoclasts were formed from bone marrow cells of C57BL/6 mice-treated with macrophage colony stimulating factor and receptor activator of nuclear factor kappa-B ligand. The mRNA expression of tartrate-resistant acid phosphatase 5b (TRAP5b), osteoclast-associated receptor (OSCAR), calcitonin receptor (CTR), matrix metalloproteinase 9 (MMP9) and cathepsin K (CK) were detected using real-time PCR (RT-PCR). Results showed that fluoride between 0.5 and 8mg/l had no effect on osteoclast formation. However fluoride at 0.5mg/l level significantly decreased the activity of osteoclast bone resorption. Fluoride concentration was negatively correlated with the activity of osteoclast bone resorption. On day 5 of osteoclast differentiation maturity, MMP9 and CK mRNA expression were not only negatively correlated with fluoride concentration, but directly correlated with the activity of osteoclast bone resorption. TRAP5b, CTR and OSCAR mRNA expression were positively correlated with the number of osteoclast and they had no correlation with the activity of osteoclast bone resorption. Thus, it can be seen that MMP9 and CK may reflect the change of activity of bone resorption as well the degree of fluoride exposure. TRAP5b, CTR and OSCAR can represent the change of number of osteoclast formed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To probe on the influence by four kinds of total ionic strength regulating buffer (TISAB) in establishing the standard curve and determining the level of fluoride in trace serum sample (rats serum and the calf serum) by fluoride ion selective electrode, and further explore the optimal volume ratio among TISAB and serum samples., Methods: Standard curve equations of four TISAB were established to clarify the influence of TISAB kinds. And the trace serum samples (rats and calf) were diluted to 1 times by TISAB, and then levels of fluoride in the samples that added by the standard sodium fluoride were detected, subsequently the influence of TISAB kinds on recovery rate were analyzed. Finally, the optimal ratio among serum sample and each TISAB in different serum was determined according to the recovery rate of the serum sample with different volume ratio., Results: The standard curve of TISAB III sample exhibited best fitting effect (R2 = 0.9926 ), and it also showed the overwhelming superiority with the scope of recovery rates ranged from 90% to 105% in the rat serum standard addition recovery experiments. As calf serum, TISAB IV (recommended by health industry standard) performed superior than others with the scope of recovery rate ranged from 90% to 110% in standard addition recovery experiment. When the volume ratio changed, every kinds of TISAB had an optimal proportion with good recovery rate, only TISAB III with the proportion as 1: 1, nevertheless, those change little affected on the recovery rate in calf serum., Conclusion: The method recommended by health industry standard is only suitable for detecting the trace amounts of fluoride in the serum sample as calf, but not the serum sample as rats.

Supportive care guidelines recommend antimold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed to have high risk for invasive fungal infection, leading to long-term use of voriconazole after allogeneic HSCT in patients who remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients after solid organ transplantation, HSCT, and leukemia therapy. The aims of this study were to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess among allogeneic HSCT patients taking voriconazole, to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain, and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between January 1, 2009 and July 31, 2012. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 μmol/L (range, 2.4 to 24.7). The median duration of voriconazole was 163 days (range, 2 to 1327). The median time to fluoride measurement was 128 days after voriconazole initiation (range, 28 to 692). At 1 year after the start of voriconazole after HSCT, 15.3% of patients had developed pain associated with voriconazole use and 35.7% developed pain while on voriconazole after 2 years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2, and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase, and voriconazole concentration did not predict for fluoride excess and associated pain. Periostitis due to fluoride excess is a common adverse effect of voriconazole that should be considered in patients presenting with pain and is often reversible after drug discontinuation. Alternative antifungal agents with a lower risk for fluoride excess should be considered in patients receiving voriconazole who develop fluoride excess and pain., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

An understanding of all aspects of fluoride metabolism is critical to identify its biological effects and avoid fluoride toxicity in humans. Fluoride metabolism and subsequently its body retention may be affected by physiological responses to acute exercise. This pilot study investigated the effect of exercise on plasma fluoride concentration, urinary fluoride excretion and fluoride renal clearance following no exercise and three exercise intensity conditions in nine healthy adults after taking a 1-mg Fluoride tablet. After no, light, moderate and vigorous exercise, respectively, the mean (SD) baseline-adjusted i) plasma fluoride concentration was 9.6(6.3), 11.4(6.3), 15.6(7.7) and 14.9(10.0) ng/ml; ii) rate of urinary fluoride excretion over 0-8 h was 46(15), 44(22), 34(17) and 36(17) μg/h; and iii) rate of fluoride renal clearance was 26.5(9.0), 27.2(30.4), 13.1(20.4) and 18.3(34.9) ml/min. The observed trend of a rise in plasma fluoride concentration and decline in rate of fluoride renal clearance with increasing exercise intensity needs to be investigated in a larger trial. This study, which provides the first data on the effect of exercise with different intensities on fluoride metabolism in humans, informs sample size planning for any subsequent definitive trial, by providing a robust estimate of the variability of the effect.

We describe a case of development of painful periostitis deformans in a 39-year-old woman who was receiving long-term voriconazole treatment for Aspergillus infection as a complication of orthotopic liver transplant. Measurement of fluoride levels strongly supports fluorosis to be the mechanism of the voriconazole-induced periostitis deformans and supports the concept that such measurements might be of use in predicting this complication of long-term voriconazole treatment., (© The Author(s) 2015.)

Various fluoride compounds are widely used in industry. The present risk assessment study was conducted using a series of inorganic binary fluorides of the type XFn, where X(n) = Na(+), K(+), Li(+), Mg(2+), Ca(2+), Sr(2+), Ba(2+), Al(3+), Nd(3+), La(3+), Ce(3+), Sm(3+), Gd(3+), Y(3+), Yb(2+), and Zn(2+). The aqueous solutions of these salts were orally administrated to 16 experimental groups (one for each of the salts tested). The levels of fluoride, N-acetyl-β-D-glucosaminidase in cumulative 24-h urine samples and creatinine clearance were measured to assess possible acute renal damages. The levels of fluoride, alanine aminotransferase, and aspartate aminotransferase were also determined in serum samples to assess possible acute hepatic damages. The results reveal that sodium fluoride (NaF), potassium fluoride (KF), and zinc fluoride tetrahydrate (ZnF2 (.)4H2O) can carry the fluoride ion into the bloodstream and that it is excreted via urine more readily than the other compounds tested. These fluorides were assigned the highest risk impact factor. Most of the rare earth fluorides are insoluble in water while those groups 2 and 13 of the periodic table are slightly soluble, so that they do not have a significant negative risk. These findings suggest that the biological impact of fluoride depends on the accompanying counter ion and its solubility. The risk map obtained in the present study shows that the graphical visualization map technique employed is a valuable new tool to assess the toxicological risk of chemical compounds.

A simple and convenient method to detect fluoride in biological samples was developed. This method was based on derivatization with 2-(bromomethyl)naphthalene, headspace solid phase microextraction (HS-SPME) in a vial, and gas chromatography-tandem mass spectrometric detection. The HS-SPME parameters were optimized as follows: selection of CAR/PDMS fiber, 0.5% 2-(bromomethyl)naphthalene, 250 mg/L 15-crown-5-ether as a phase transfer catalyst, extraction and derivatization temperature of 95 °C, heating time of 20 min and pH of 7.0. Under the established conditions, the lowest limits of detection were 9 and 11 μg/L in 1.0 ml of plasma and urine, respectively, and the intra- and inter-day relative standard deviation was less than 7.7% at concentrations of 0.1 and 1.0 mg/L. The calibration curve showed good linearity of plasma and urine with r=0.9990 and r=0.9992, respectively. This method is simple, amenable to automation and environmentally friendly., (Copyright © 2015 Elsevier B.V. All rights reserved.)