Skeletal fluorosis: an uncommon cause, yet a rescue treatment?

PURPOSE: Skeletal fluorosis (SF) results from chronic exposure to fluoride (F-) causing excessive aberrantly mineralized brittle bone tissue, fractures, and exostoses. There is no established treatment other than avoiding the source of F-. Still, excess F- can persist in bone for decades after exposure ceases. CASE PRESENTATION: A 50-year-old woman presented with multiple, recurrent, low AQ2 trauma fractures yet high radiologic bone mineral density. Serum F- was elevated, and osteomalacia was documented by non-decalcified transiliac biopsy. She reported intermittently "huffing" a keyboard cleaner containing F- (difluoroethane) for years. Following cessation of her F- exposure, we evaluated the administration of the parathyroid hormone analog, abaloparatide, hoping to increase bone remodeling and diminish her skeletal F- burden. CONCLUSION: Due to the prolonged half-life of F- in bone, SF can cause fracturing long after F- exposure stops. Anabolic therapy approved for osteoporosis, such as abaloparatide, may induce mineralized bone turnover to replace the poorly mineralized osteomalacic bone characteristic of SF and thereby diminish fracture risk. Following abaloparatide treatment for our patient, there was a decrease in bone density as well as a reduction in F- levels.

Sulfuryl Fluoride Poisonings in Structural Fumigation, a Highly Regulated Industry-Potential Causes and Solutions.

Structural fumigations using sulfuryl fluoride for the extermination of dry-wood termites are conducted by the thousands in California and other warm-weather states. Sulfuryl fluoride is an odorless gas that targets the nervous system and can cause respiratory irritation, pulmonary edema, nausea, vomiting, seizures, and death. Structural voids or compartments such as wall sockets, crawl spaces, cabinets, or cells in air mattresses may create ongoing exposure after a structure has been certified as safe. The authors describe a case of potential sulfuryl fluoride exposure to a family following home fumigation. Despite regulation, sulfuryl fluoride poisonings from structural fumigations continue to occur. This article examines the physical characteristics of sulfuryl fluoride and the regulatory oversight of its application, in an effort to understand how and why these poisonings happen. Increasing aeration times of fumigated structures, overseeing monitoring efficacy, and using technology to capture clearance data could reduce sulfuryl fluoride exposure and illness.

Prevention & control of fluorosis & linked disorders: Developments in the 21st Century - Reaching out to patients in the community & hospital settings for recovery.

The review on fluorosis addresses the genesis of the disease, diagnostic protocols developed, mitigation and recovery through nutritional interventions. It reveals the structural and functional damages caused to skeletal muscle and erythrocytes, leading to clinical manifestations in fluorosis. Hormonal derangements resulting in serious abnormalities in the health of children and adults are discussed. Fluoride toxicity destroys the probiotics in the gut, resulting in vitamin B12depletion, an essential ingredient in haemoglobin (Hb) biosynthesis. The article provides an overview of National Technology Mission on Safe Drinking Water and its contributions to fluorosis control. National Programme for Prevention and Control of Fluorosis is presently in operation in India and its focus cited. Major emphasis has been laid on a variety of disorders surfacing in India due to fluoride toxicity/fluorosis as 'fluorosis-linked disorders', viz. anaemia in pregnancy, schoolchildren, thyroid hormone abnormalities, hypertension, iodine deficiency disorders/goitre, renal failure and calcium+vitamin D-resistant rickets in children. The major action taken by the Indian Council of Medical Research (ICMR), Government of India in establishing a Centre of Excellence for Fluorosis Research in India and its contributions are highlighted.

Musculoskeletal problems and fluoride exposure: A cross-sectional study among metal smelting workers.

Frequent and repetitive activities in job and awkward postures are shown as major contributors of musculoskeletal problems in most of the occupational health studies; however, efforts to explore newer risk factor are important to plan interventional measures. In this backdrop, this study examined contribution of fluoride exposure to musculoskeletal complaints. A cross-sectional interviewer-administered questionnaire survey was conducted involving 180 randomly selected subjects from a metal smelting industry. Clinical examination of the subjects was also performed to assess their health status and morbidity details. Assessment of personal exposure to particulate and gaseous fluoride at workplace was conducted. Urinary fluoride level was also examined in post-shift samples collected from study subjects. The mean age of the study subjects was 39.1 (±6.7) years. Majority of the workers (42.5%) were engaged in pot room. About 54% workers were suffering from backache and 66% subjects had joint pain. Exposure of workers to both particulate and gaseous fluoride and post-working shift urinary fluoride level was significantly higher in pot-room workers in comparison with all other workers. It was observed that age (odds ratio (OR): 1.62; 95% confidence interval (CI): 1.18-2.34), drinking untreated water (OR: 1.51; 95% CI: 1.03-2.76), working in pot room (OR: 1.44; 95% CI: 1.13-1.91) and urinary fluoride level (OR: 2.71; 95% CI: 1.81-3.75) had significant effects on musculoskeletal complaints. This study concludes that along with other predictors such as nature of work, posture at work and age of worker, exposure to fluoride also has significant role in the occurrence of musculoskeletal morbidity.

Single oral acute fluoride exposure causes changes in cardiac expression of oxidant and antioxidant enzymes, apoptotic and necrotic markers in male rats.

Several studies have shown that acute fluoride (F(-)) exposure impairs cardiac function, but the molecular mechanism is not clear. In order to study this, male Wistar rats were treated with single oral doses of 45 and 90 mg/kg F(-) for 24 h. A significant accumulation of F(-) was found in the serum and myocardium of experimental rats. F(-) treatment causes myocardial necrosis as evident from increased levels of myocardial troponin I, creatine kinase, lactate dehydrogenase and aspartate transaminase. In addition, F(-) induces myocardial oxidative stress via increased reactive oxygen species, lipid peroxidation, protein carbonyl content and nitrate levels along with decreased in the levels of enzymatic (superoxide dismutase 2, catalase, glutathione peroxidase and glutathione s transferase pi class) and non-enzymatic (reduced glutathione) antioxidants. Notably, F(-) triggers myocardial apoptosis through altered Bax/Bcl2 ratio and increased cytochrome c, caspase 3p20 and terminal deoxynucleotidyl transferase dUTP nick end labeled positive cells. An increased cardiac expression of Nox4 and p38α MAPK in F(-) treated rats indicates the oxidative and apoptotic damage. Moreover, ultra-structural changes, histopathological and luxol fast blue staining demonstrates the degree of myocardial damage at subcellular level. Taken together, these findings reveal that acute F(-) exposure causes cardiac impairment by altering the expression of oxidative stress, apoptosis and necrotic markers.

[Damage of blood brain barrier of spinal cord in rats with chronic fluorosis].

OBJECTIVE: To explore the impairment mechanisms of blood brain barrier in spinal cord and observe the changes of matrix metalloproteinase-9 (MMP-9) and functional improvement in rats with chronic fluorosis. METHODS: A total of 120 Wistar rats were divided randomly into 4 groups, high fluoride (fed by water with a high concentration of sodium fluoride at 200 mg/L), high fluoride control (fed by distilled water), defluorination (fed by water with a high concentration of sodium fluoride at 200 mg/L for 12 weeks and then distilled water for 12 weeks) and defluorination control (n = 30 each). The urinary contents of fluoride were detect for 4 groups at Weeks 4, 8 and 12. The high fluoride and control groups were sacrificed at Week 12 while the defluorination and defluorination control groups at Week 24. Their cervical spinal cords were collected for electron microscope examinations. The expression of MMP-9 protein in thoracic cord was detected by immunohistochemistry and Western blot. Quantitative analysis of function of blood brain cord barrier was performed by the technique of Evans blue. The comparison of measurement data was performed with F test and correlation analysis. The cytological changes of neurons in thoracic spinal cord were detected after chronic fluorosis. RESULTS: Under electron microscope, the pathological manifestations of chronic damage in blood brain barrier could be found. As compared with the high fluoride control group, the content of Evans blue increased markedly in spinal cord of the high fluoride group (29.2 ± 0.1 vs 0.7 ± 0.1 mg/L, P < 0.01). It was higher in the defluorination group than that in the defluorination control group. But there was no significant difference with the high fluoride group (29.2 ± 0.1 vs 28.9 ± 0.2 mg/L, P > 0.01). And the expression of MMP-9 increased in spinal cord of the fluorosis and defluorination groups in comparison with those in the control group. But no difference existed among them. CONCLUSION: The damage of blood brain barrier of spinal cord occurs probably as a result of a higher expression of MMP-9 in rats with chronic fluorosis. Defluorination for a short time may not recover.

Effect of fluoride on insulin level of rats and insulin receptor expression in the MC3T3-E1 cells.

Studies on the role of insulin and insulin receptor (InsR) in the process of skeletal fluorosis, especially in osteogenic function, are rare. We evaluated the effect of increasing F⁻ doses on the marker of bone formation, serum insulin level and pancreatic secretion changes in vivo and mRNA expression of InsR and osteocalcin (OCN) in vitro. Wistar rats (n = 50) were divided into two groups, i.e. a control group and fluoride group. The fluoride groups were treated with fluoride by drinking tap water containing 100 mg F⁻/L. The fluoride ion-selective electrode measured the fluoride concentrations of femurs. The alkaline phosphatase (ALP), OCN, insulin and glucagon of serum were tested to observe the effect of fluoride action on them. Meantime, the pancreas pathological morphometry analysis via ß cells stained by aldehyde fuchsin showed the action of fluoride on pancreas secretion. MC3T3-E1 cells (derived from newborn mouse calvaria) were exposed to varying concentrations and periods of fluoride. The mRNA expression of InsR and OCN was quantified with real-time PCR. Results showed that 1-year fluoride treatment obviously stimulated ALP activity and OCN level along with increase of bone fluoride concentration of rats, which indicated that fluoride obviously stimulated osteogenic action of rats. In vitro study, the dual effect of fluoride on osteoblast function is shown. On the other hand, there was a significant increase of serum insulin level and a general decrease of glucagon level, and the histomorphometry analysis indicated an elevated insulin-positive area and increase in islet size in rats treated with fluoride for 1 year. In addition, fluoride obviously facilitated the mRNA expression of InsR in vitro. To sum up, there existed a close relationship between insulin secretion and fluoride treatment. The insulin signal pathway might be involved in the underlying occurrence or development of skeletal fluorosis.

Combined impact of exercise and temperature in learning and memory performance of fluoride toxicated rats.

In previous studies, we investigated a link between high fluoride exposure and functional IQ deficits in rats. This study is an extension conducted to explore the combined influence of physical exercise and temperature stress on the learning ability and memory in rats and to assess whether any positive modulation could be attenuated due to exercise regimen subjected to F-toxicated animals at different temperatures. Accumulation of ingested fluoride resulted significant inhibition in acetylcholinesterase activity (P < 0.05), plasma cortisol levels (P < 0.05), and impaired the acquisition, performance, latency time, and retention in fluoride-exposed animals. Fluoride-toxicated rats took more number of sessions during the learning phase [F (5, 35) = 19.065; P < 0.05] and post hoc analysis on the number of correct choices revealed that there was a significant effect of treatments [F (5, 30) = 15.763; P < 0.05]; sessions [F (8, 240) = 58.698; P < 0.05]; and also significant difference in the interactions [F (40, 240) = 1.583; P < 0.05]. The latency data also revealed a significant difference between groups [F (5, 30) = 28.085; P < 0.05]; time = [F (8, 240) = 136.314; P < 0.05]; and there was a significant difference in the interactions [F (40, 240) = 2.090; P < 0.05]. In order to ascertain if interdependence between fluoride concentrations and the foregoing free radical parameters, respective correlation coefficients were calculated and results clearly emphasize the positive role of exercise in the promotion of cognitive functions by decreasing fluoride levels in rat hippocampus. A significant recovery in cognitive function was noticed in all the exercised animals due to reduced burden of brain oxidative stress. In comparison to exercise regimens performed at different temperatures, high (35 °C) and low temperatures (20 °C) led to a slower acquisition and poor retention of the task when compared to thermo neutral temperatures (25 and 30 °C). Thus exercise up-regulate antioxidant defenses and promote learning abilities in fluorotic population.

[The experimental search of immunological criteria for identifying stages of development of chronic fluoride intoxication].

The experiment has shown the staging of the development of immune response to the chronic fluoride intoxication. Diagnostic criteria of the initial compensation stage are: leukocytosis against the background of reduced number of lymphocytes and increased one of monocytes; high levels of ceruloplasmin in blood plasma, a progressive increase in TNFalpha and cytokine IL-10. At the decompensation stage there are: leukocytosis with increased number of neutrophils; low levels of ceruloplasmin and the cytokines IL-1beta, IL-4 and the high level of TNFalpha, IL-6, IL-10. At the stage of exhaustion there are: leukopenia against the background of lymphocytosis, a high level of Hp, the low values of the level of IgM, IgG.

[Clinical and pathogenetic aspects of the chronic occupational intoxication with fluorine compounds in modern reality].

Multi-year follow-up of 358 workers of aluminum pot rooms, including 165 individuals suffering from fluorosis, has shown significant changes in the clinical picture of the chronic occupational fluorine intoxication, developed under modern conditions of production, at lower concentrations of fluorine compounds in the air of working area. In this connection, the pathology of the musculoskeletal system plays the dominating role in this clinical picture and has the large variability of combinations of the individual sections destructions of the bone tissue. The main criterion to establish the phase of the disease is still the number and severity of the signs of this destruction. The visceral pathology in contemporary production circumstances is registered with less frequency and loses a number of the previously described clinical manifestations, however, is still of some importance to identify the early signs of the disease and to prevent the dental fluorosis on time.

Effects of fluorosis on QT dispersion, heart rate variability and echocardiographic parameters in children.

OBJECTIVE: Chronic fluoride poisoning is called fluorosis. The aim of the study was to investigate effects of fluorosis on cardiovascular system in children by measuring QT dispersion (QTd), corrected QT dispersion (QTcd), heart rate variability (HRV) and echocardiography findings. METHODS: Thirty-five children with dental fluorosis and 26 children as control group were included in this cross-sectional study. Dean index was used for the clinical diagnosis. The fluoride levels of subjects measured by ion electrode method in spot urine higher than 0.6 ppm were included in the study. Serum electrolytes and thyroid function tests were analyzed. Electrocardiography (ECG), echocardiography and 24-hour ambulatory Holter monitorizations were applied, and all the data were analyzed for measuring HRV, and calculation of QTd and QTcd intervals. Corrected QT (QTc) intervals were determined with the Bazzett formula. Difference between the longest and shortest intervals was considered as dispersion. Statistical analysis was performed Kruskal-Wallis test and Pearson correlation test. RESULTS: Low free thyroxine hormone (FT4) (Control Group, Group 2 1.11 (0.85-1.64) ng/dL, 0.96 (0.85-1.11) ng/dL, p<0.05), calcium (Control Group, Group 1, 2, 9.80 (9.30-10.70) mg/dL, 9.60 (8.90-10.70) mg/dL, 9.50 (8.90-10.10) mg/dL, p<0.05) and high serum sodium levels (Control Group, Group 2 139 (136-142) mEq/L, 141 (138-148) mEq/L, p<0.01), increased QT (Control Group, Group 2 329.8 (300.0-363.5) msec, 351.8 (318.0-372.0) msec, p<0.05) and QTc intervals (Control Group, Group I2 390.6 (309.0-418.5) msec, 366.8 (318.2-468.5) msec, p<0.05) were found in subjects with fluorosis. No significant difference was found with respect to echocardiography and HRV variables. CONCLUSION: Endemic fluorosis is a risk factor for decrease in calcium and FT4 levels, increase in sodium levels and QT prolongation. These findings might be related with some cardiovascular system dysfunctions such as arrhythmias or syncope. Subjects with fluorosis should be monitored in terms of long QT and QTc intervals.

[Changes of certain oxidative, anti-oxidative and vascular function indexes of New Zealand rabbit exposed by high-fluoride].

OBJECTIVE: To observe certain changes of oxidation, anti-oxidation and vascular function indexes of Application of New Zealand rabbit exposed by high-fluoride. METHODS: 20 male New Zealand rabbits were randomly divided into control group, drunk deionized water and feed basic diet. High-fat group, drunk deionized water and feed basic diet plus 0.5% cholesterol and 7% egg yolk powder high fat diet. High-fluorine group, drunk high-fluoride water (ion-100 mg/L) and feed basic diet. High-fluoride and high-fat group, drunk high-fluoride water (ion-100 mg/L) and feed basic diet plus 0.5% cholesterol and 7% egg yolk powder high fat diet. The experimental periods were 6 months. Blood samples were collected to determine the fluorine concentration in plasma, in the third and sixth month before experiment. In the sixth month of the experiment, blood, heart and liver samples were gathered to make homogenate, and detect superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) contents by biochemical method. The 6-keto-prostate F1alpha (6-keto-PGF1alpha), thromboxane B2 (TXB2) and endothelin-1(ET-1) contents were detected by radioimmunoassay. Nitric oxide synthase (NOS), inducible NOS (iNOS), and endothelial NOS (eNOS) were detected by biochemical method. Leukocyte iNOS-mRNA and eNOS-mRNA contents were detected by situ hybridization. RESULTS: In the third and sixth month of experiment, serum fluorides were elevated in rabbits who drunk high-fluorine water, activities of SOD and GSH-Px in blood, liver and heart were decreased (P < 0.01, P < 0.05), while the myocardial MDA contents increased (P < 0.05), 6-keto-PGF1alpha contents in plasma decreased (P < 0.01), TXB2 and ET-1 levels increased (P < 0.01, P < 0.05), total NOS activities in serum decreased (P < 0.05), total NOS activities in liver and iNOS activities in heart and liver increased (P < 0.05). Expression of iNOS-mRNA in leukocyte increased, expression of eNOS-mRNA decreased (P < 0.05) in rabbits who drunk high-fluorine in the sixth month. Factorial analysis of variance, serum, liver and myocardial SOD activities and serum MDA contents, plasma ET-1 contents and serum iNOS activities, liver total NOS activities showed that high-fluorine and high-fat enhanced interactive (P < 0.01 P < 0.05) . CONCLUSION: High-fluoride could inhibit antioxidant enzymes, impair vascular endothelial function, body NO metabolism disorder. High fluoride and high-fat could have a certain synergy in this process.

Use of the Rey-Osterrieth Complex Figure Test for neurotoxicity evaluation of mixtures in children.

The aim of this study was to assess the value of the children's version of the Rey-Osterrieth Complex Figure Test as a screening test in a population exposed to different mixtures of neurotoxicants. Copy and Immediate Recall scores were evaluated through the test. Children were recruited from three sites; an area with natural contamination by fluoride and arsenic (F-As), a mining-metallurgical area with lead and arsenic contamination (Pb-As) and a malaria zone with the evidence of fish contaminated with dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs). Children aged 6-11 years old, living in one of the three polluted sites since birth were recruited (n=166). The exposure was evaluated as follows: fluoride and arsenic in urine, lead in blood and DDT, dichlorodiphenyldichloroethylene (DDE) and PCBs in serum. To evaluate the test performance, z-scores for Copy and Immediate Recall were calculated. The proportion of children by residence area with performance lower than expected by age (below -1 SD) for Copy and Immediate Recall was in the F-As area (88.7% and 59%) and in the DDT-PCBs area (73% and 43.8%), respectively. In the Pb-As area, the proportion was 62% for both tests. After adjustment, Copy correlated inversely with fluoride in urine (r=-0.29; p<0.001) and Immediate Recall correlated inversely with fluoride in urine (r=-0.27; p<0.05), lead in blood (r=-0.72; p<0.01), arsenic in urine (r=-0.63; p<0.05) and DDE (r=-0.25; p<0.05). This study provided evidence that children included in this research are living in high risk areas and were exposed to neurotoxicants. Poor performance in the test could be explained in some way by F, Pb, As or DDE exposure, however social factors or the low quality of school education prevalent in the areas could be playing an important role.

Health effects of groundwater fluoride contamination.

INTRODUCTION: The people in Berhait block, Sahibganj district, Jharkhand state, India, have been exposed chronically to fluoridecontaminated groundwater. Hereby, we report the clinical effects of chronic exposure to fluoride. METHODS: The study population was a convenience sample of 342 adults and 258 children living in the affected area. All volunteers filled out questionnaires and were examined. Well water from the six affected villages and urine samples were analyzed for fluoride using an ion-sensitive electrode. RESULTS: Twenty nine percent of 89 well water samples had fluoride concentrations above the Indian permissible limit of fluoride in drinking water. Eighty-five children and 72 adults had clinical fluorosis. Urine fluoride concentrations in children were 0.758-2.88 mg/L whereas in adults they were 0.331-10.36 mg/L. DISCUSSION: Clinical effects of fluoride included abnormal tooth enamel in children; adults had joint pain and deformity of the limbs and spine, along with ligamentous calcifications and exostosis formations in seven patients. Elevated urine fluoride concentrations supported the clinical diagnosis of fluorosis. Owing to insufficient fluoride-safe wells and lack of awareness of the danger of fluoride toxicity, villagers often drink fluoride-contaminated water. CONCLUSION: Villagers of Berhait block, including children, are at risk from chronic fluoride toxicity. To combat the situation, villagers need fluoride-safe water, education, and awareness of the danger about fluoride toxicity.

Skeletal fluorosis causing high cervical myelopathy.

Skeletal fluorosis is endemic in some parts of the world and is the result of life-long ingestion of high amounts of fluoride in drinking water. Its clinical presentation is characterized mostly by bone and dental changes with later ossification of many ligaments and interosseous membranes. We present a rare case of high cervical myelopathy caused by ossification of the posterior longitudinal ligament and ligamentum flavum in a patient from an area endemic for skeletal fluorosis. The clinical presentation of skeletal fluorosis and treatment options are discussed.

[Current trends in fluorine research]. / Aktualne kierunki badaan nad fluorem.

PURPOSE: Current topics in fluorine research are presented with emphasis on findings by researchers in Szczecin and Poland, as well as in the world. Reports are cited on the distribution of fluorine compounds in the environment, routes of penetration into living organisms, and analytical methods for the quantitative determinations of fluorine content in air, water, soil, and foods. Important contributions have been made by Polish researchers on the role and patterns of fluorides in body fluids, soft and hard tissues, which remain in direct relationship to accumulation and elimination of fluorine. So far, comprehensive studies on mutagenic effects of fluorine and its potential role in bone neoplasms, Down syndrome, and other genetic disorders have not been carried out in Poland. Worthy of mention are reports on mechanisms of action of fluorine compounds on the cellular and subcellular level. CONCLUSIONS: Finally, two achievements of recent years in the field of fluorine research are discussed briefly. The first is concerned with the use in dentistry of chemical analysis for studying mineral reconstruction of teeth throughout the lifetime of an individual. The second is in the field of medicine where molecular modeling has been applied to explain the mechanism of action of aluminofluoride complexes (AlFx) as a messenger of false information during protein biosynthesis and their apparent role in the etiology of Alzheimer's disease.

Fluoride poisoning: a puzzle with hidden pieces.

Key industry data regarding harm from chronically inhaled fluoride have been unavailable publicly for decades. Recent unveiling of unpublished reports reveals three examples of data mishandling that disguised the need for more stringent occupational standards for particulate and gaseous fluorides and fluorine. Injury reports from workers handling chemicals show that unjustifiable reductions of injury and disability numbers in the process of publication shifted concern from respiratory to mineralized tissue damage. Selective editing and data omissions allowed bias that fluoride reduces caries without detrimental effects. Finally, industry's failure to publish an important industry-funded laboratory study buried knowledge of low thresholds for fluoride-induced lung disease. Data from that study are presented to clarify the dose- and duration-dependent changes caused by chronic inhalation of calcium fluoride.