Aberrant gut microbiota and fecal metabolites in patients with coal-burning endemic fluorosis in Guizhou, China.

Chronic exposure to excessive environmental fluoride has caused fluorosis to become a major public health problem worldwide. Although studies on stress pathways, signaling pathways, and apoptosis induced by fluoride have provided an in-depth understanding of the mechanism of this disease, its exact pathogenesis remains unclear. We hypothesized that the human gut microbiota and metabolome are associated with the pathogenesis of this disease. To get further insight into the profiles of intestinal microbiota and metabolome in coal-burning-induced endemic fluorosis patients, we conducted 16S rRNA sequencing of the intestinal microbial DNA and carried out non-targeted metabolomics of fecal samples from 32 patients with skeletal fluorosis and 33 matched healthy controls in Guizhou, China. We found that the gut microbiota of coal-burning endemic fluorosis patients displayed significant differences in composition, diversity, and abundance compared with healthy controls. This was characterized by an increase in the relative abundance of Verrucomicrobiota, Desulfobacterota, Nitrospirota, Crenarchaeota, Chloroflexi, Myxococcota, Acidobacteriota, Proteobacteria, and unidentified_Bacteria, and a significant decrease in the relative abundance of Firmicutes and Bacteroidetes at the phylum level. Additionally, at the genus level, the relative abundance of some beneficial bacteria, such as Bacteroides, Megamonas, Bifidobacterium, and Faecalibacterium, was significantly reduced. We also demonstrated that, at the genus level, some gut microbial markers, including Anaeromyxobacter, MND1, oc32, Haliangium, and Adurb.Bin063_1, showed potential for identifying coal-burning endemic fluorosis. Moreover, non-targeted metabolomics and correlation analysis revealed the changes in the metabolome, particularly the gut microbiota-derived tryptophan metabolites such as tryptamine, 5-hydroxyindoleacetic acid, and indoleacetaldehyde. Our results indicated that excessive fluoride might cause xenobiotic-mediated dysbiosis of human gut microbiota and metabolic disorders. These findings suggest that the alterations in gut microbiota and metabolome play vital roles in regulating disease susceptibility and multi-organ damage after excessive fluoride exposure.

Association of Dietary Calcium Intake with Dental, Skeletal and Non-Skeletal Fluorosis among Women in the Ethiopian Rift Valley.

Fluorosis is a major public health problem in the Rift Valley of Ethiopia. Low calcium (Ca) intake may worsen fluorosis symptoms. We assessed the occurrence of fluorosis symptoms among women living in high-fluoride (F) communities in South Ethiopia and their associations with dietary Ca intake. Women (n = 270) from two villages provided clinical and questionnaire data. Dental fluorosis examination was done using Dean's Index, and skeletal and non-skeletal fluorosis assessment was carried out using physical tests and clinical symptoms. Daily Ca intake was estimated by a food frequency questionnaire. Food, drinking water and beverage samples were analyzed for F level. Many subjects (56.3%) exhibited dental fluorosis. One-third of the women were unable to perform the physical exercises indicative of skeletal fluorosis; about half had ≥2 symptoms of skeletal/non-skeletal fluorosis. The average F level in drinking water sources was ~5 mg/L. The F content in staple food samples varied from 0.8-13.6 mg/kg. Average Ca intake was 406 ± 97 mg/day. Women having ≤400 mg/day Ca intake had ~3 times greater odds of developing skeletal rigidity with joint pains [AOR = 2.8, 95%CI: 1.6, 5.0] and muscular weakness [AOR = 2.9, 95%CI: 1.3, 6.3] compared to those with higher intakes. No association of calcium intake was seen with dental fluorosis. As low dietary Ca intake was associated with symptoms related to skeletal and non-skeletal fluorosis, this warrants nutritional intervention on calcium intakes in this setting.

Neuro-medical manifestations of fluorosis in populations living in the Main Ethiopian Rift Valley.

Prolonged exposure to higher concentrations of fluoride (> 1.5 mg/L) is associated with dental and skeletal fluorosis. The effects of fluoride on dental and skeletal system have been studied extensively; however, the neurological consequences of fluoride in population-based studies are limited. The study aims to assess the epidemiology of neurological and other manifestations of fluorosis among rural populations living in the Main Ethiopian Rift valley. In this cross-sectional study, we enrolled 316 individuals from 23 rural communities in the Main Ethiopian Rift valley. Fluoride concentration was measured in drinking water samples collected from 23 community wells. Association between fluoride concentrations and clinical features of fluorosis was assessed using student t test, chi square, multivariable regression using adjusted odds ratio (OR). The mean fluoride concentration in the drinking water was 6.8 ± 4.3 mg/L (range: 0.3-15.5 mg/L). At least one clinical sign of skeletal fluorosis was observed in 54.4% (n = 175) of the study participants. Headache and joint pain reported by 67.1% and 56.3% of the participants as the most common neurological manifestation, and skeletal fluorosis symptom, respectively. The mean fluoride level was higher for those individuals who reported paresthesia compared to those with no-paresthesia. Loss of appetite, constipation, and fatigue were reported by 48.0%, 45.6%, and 56.6% of the participants, respectively. Signs of crippling fluorosis were observed in small proportion (1.6%) of the participants. Individuals who reported headache are most likely exposed to higher fluoride concentrations in drinking water compared to those reported no-headache (p < 0.001). The study demonstrates high prevalence of neuro-medical manifestations of fluorosis in population living in the Main Ethiopian Rift valley. Fluoride concentration in drinking water and joint pain were independent predictors of fluorosis.

Elemental Status and Lipid Peroxidation in the Blood of Children with Endemic Fluorosis.

The study aimed to assess the levels of trace elements, minerals, and toxic elements as well as lipid peroxidation biomarkers (lipid acyl hydroperoxides, 2-thiobarbituric acid reactive substances (TBARS)) in the blood of children with chronic fluorosis from endemic fluorosis areas (Sosnivka village, Lviv region, western Ukraine). The results were compared with healthy children from Staryi Sambir (Lviv region, western Ukraine), whose drinking water contained permissible levels (< 1 ppm) of fluoride. Thirty-one children from the Sosnivka village in the Lviv region, including 16 females and 15 males aged 7-10 years, with clinically diagnosed fluorosis, were recruited for the study. The children had been exposed to fluoride (> 1.5 ppm) through drinking water for more than 5 years. In the blood, eight macro- and microelements (calcium, zinc, potassium, iron, copper, selenium, manganese, chromium), five additional elements (sulfur, bromine, chlorine, nickel, strontium), and four toxic elements (lead, mercury, cadmium, mercury) were assessed with the X-ray fluorescence method. The results of our study demonstrated a 14-fold decrease in the copper level, a 2.5-fold decrease in the calcium and zinc levels, and a 2-fold decrease in the selenium level in the blood of children with chronic fluorosis compared with the healthy children from the non-fluorosis area. In turn, a 1.7- and 1.4-fold increase in the strontium and lead content, respectively, was noted. The sulfur, chlorine, potassium, calcium, copper, zinc, and selenium levels in the blood samples of children with chronic fluorosis were lower than the reference value. The children had higher blood TBARS levels, while the acyl hydroperoxide levels were non-significantly increased in comparison with healthy children living in the non-fluorosis area. Additionally, the bromine level was correlated positively with the selenium level and acyl hydroperoxides. However, more studies are needed to clarify the relationship between blood mineral status, oxidative stress biomarkers, and chronic fluorosis.

Skeletal fluorosis: don't miss the diagnosis!

Skeletal fluorosis is a rare toxic osteopathy characterized by massive bone fixation of fluoride. The disease occurs as an endemic problem in some parts of the world and is the result of prolonged ingestion or rarely by inhalation of high amounts of fluoride. Radiographic presentation is mainly characterized by bone changes with osteocondensation and later ossification of many ligaments and interosseous membranes. Skeletal fluorosis is not clinically obvious and can be confused with other rheumatologic disorders. Its severity lies in the development of skeletal deformities and neurological complications. Management of fluorosis generally focuses on symptom treatment.

A review of global outlook on fluoride contamination in groundwater with prominence on the Pakistan current situation.

Several million people are exposed to fluoride (F-) via drinking water in the world. Current review emphasized the elevated level of fluoride concentrations in the groundwater and associated potential health risk globally with a special focus on Pakistan. Millions of people are deeply dependent on groundwater from different countries of the world encompassing with an elevated level of fluoride. The latest estimates suggest that around 200 million people, from among 25 nations the world over, are under the dreadful fate of fluorosis. India and China, the two most populous countries of the world, are the worst affected. In Pakistan, fluoride data of 29 major cities are reviewed and 34% of the cities show fluoride levels with a mean value greater than 1.5 mg/L where Lahore, Quetta and Tehsil Mailsi are having the maximum values of 23.60, 24.48, > 5.5 mg/L, respectively. In recent years, however, other countries have minimized, even eliminated its use due to health issues. High concentration of fluoride for extended time period causes adverse effects of health such as skin lesions, discoloration, cardiovascular disorders, dental fluorosis and crippling skeletal fluorosis. This review deliberates comprehensive strategy of drinking water quality in the global scenario of fluoride contamination, especially in Pakistan with prominence on major pollutants, mitigation technologies, sources of pollution and ensuing health problems. Considering these verities, health authorities urgently need to establish alternative means of water decontamination in order to prevent associated health problems.

Evaluation of acidity in late Permian outcrop coals and its association with endemic fluorosis in the border area of Yunnan, Guizhou, and Sichuan in China.

The junction area of Yunnan, Guizhou, and Sichuan provinces is the heaviest coal-burning endemic fluorosis zones in China. To better understand the pathogenicity of endemic fluorosis in this area, 87 coal samples from the late Permian outcrop or semi-outcrop coal seams were collected in eight counties of the junction area of Yunnan, Guizhou, and Sichuan provinces. The total fluorine and sulfate content, etc. in the coal was determined using combustion-hydrolysis/fluoride-ion-selective electrode method and ion chromatography, respectively. The results show that the total fluorine concentrations in the samples ranged from 44 to 382 µg g-1, with an average of 127 µg g-1. The average pH of the coals is 5.03 (1.86-8.62), and the sulfate content varied from 249 to 64,706 µg g-1 (average 7127 µg g-1). In addition, the coals were medium- and high-sulfur coals, with sulfur mass fraction ranging from 0.08 to 13.41%. By heating the outcrop coals, HF release from the coal was verified quantitatively without exception, while simulated combustion directly confirmed the release of sulfuric acid (H2SO4). The acid in coal may be in the form of acidic sulfate ([Formula: see text]/H2SO4) because of a positive relationship between pH and [Formula: see text] in the acidic coal. The possible reaction mechanism would be that a chemical reaction between the acid (H2SO4 or [Formula: see text]) and fluorine in the coal occurred, thereby producing hydrogen fluoride (HF), which would be the chemical form of fluorine released from coal under relatively mild conditions. The unique chemical and physical property of HF may bring new insight into the pathogenic mechanism of coal-burning endemic fluorosis. The phenomenon of coal-burning fluorosis is not limited to the study area, but is common in southwest China and elsewhere. Further investigation is needed to determine whether other endemic fluorosis areas are affected by this phenomenon.

A brief and critical review on hydrofluorosis in diverse species of domestic animals in India.

India is one of the fluoride-endemic countries where the maximum numbers of ground or drinking water sources are naturally fluoridated. In India, a total of 23, out of 36 states and union territories have drinking water contaminated with fluoride in varying concentration. In the present scenario, especially in rural India, besides the surface waters (perennial ponds, dams, rivers, etc.), bore wells and hand pumps are the principal drinking water sources for domestic animals such as cattle (Bos taurus), water buffaloes (Bubalus bubalis), sheep (Ovis aries), goats (Capra hircus), horses (Equus caballus), donkeys (Equus asinus) and dromedary camels (Camelus dromedarius). Out of 23 states, 17 states, namely Andhra Pradesh, Assam, Bihar, Chhattisgarh, Gujarat, Haryana, Jharkhand, Karnataka, Kerala, Madhya Pradesh, Maharashtra, Odisha (Orissa), Punjab, Rajasthan, Telangana, Uttar Pradesh and West Bengal, have fluoride beyond the maximum permissible limit of 1.0 or 1.5 ppm in drinking water. This situation is a great concern for the animal health because fluoride is a slow toxicant and causes chronic diverse serious health hazards or toxic effects. Despite the fact that domestic animals are the basic income sources in rural areas and possess a significant contributory role not only in the agriculture sector but also in the strengthening of economy as well as in sustainable development of the country, research work on chronic fluoride intoxication (hydrofluorosis) due to drinking of fluoridated water in domestic animals rearing in various fluoride-endemic states is not enough as compared to work done in humans. However, some interesting and excellent research works conducted on different aspects of hydrofluorosis in domesticated animals rearing in different states are briefly and critically reviewed in the present communication. Author believes that this review paper not only will be more useful for researchers to do some more advance research work on fluoride-induced toxicosis in different species of animals but will also be helpful in the making of health policy for domestic animals at state and national level for the mitigation of hydrofluorosis in India.

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.

Fluoride: A review of pre-clinical and clinical studies.

Fluoride is ubiquitous in environment and profound in bones, teeth and calcified tissues of human body. Fluoride has been the topic of regular discussion and investigations. Besides its toxicity, fluoride has also been examined for its beneficial effects like prevention and treatment of tooth decay, microbial infection, inflammation, cancer, occurrence of renal stone and many more. Since last many decades, several efforts have been made at pre-clinical and clinical level to understand role of fluoride in biological system. The present review gives a brief account of prevalence, sources of fluoride toxicity and pre-clinical and clinical studies carried out on effects of fluoride in last six decades.

Endemic fluorosis in Henan province, China: ERα gene polymorphisms and reproductive hormones among women.

BACKGROUND AND OBJECTIVES: The aim of this study was to explore the influence of fluoride exposure and ERα gene polymorphisms on reproductive hormone concentrations of women in accordance with endemic fluorosis residence. METHODS AND STUDY DESIGN: A cross sectional study was conducted in Tongxu county, Henan Province, China. A total of 679 women were recruited using cluster sampling and each subject provided fasting blood and an associated urine sample. We measured the concentrations of serum gonadotropin releasing hormone (GnRH), follicle-stimulating hormone, luteinizing hormone, and estradiol and urinary fluoride. RESULTS: In the defluoridation project group (DFPG), serum GnRH was lower in women carrying C/C genotype compared to in those carrying C/T and T/T genotypes of ERα gene rs3798577 (p<0.05). In the endemic fluorosis group (EFG), serum GnRH was lower in women carrying Pp genotype compared to in those carrying PP and pp genotypes of ERα PvuII (p<0.05). Serum GnRH in women from EFG who carried Pp, pp, Xx and xx genotypes in ERα gene PvuII and XbaI was lower than in those in the control group (CG) who carried same genotypes (p<0.05). Furthermore, serum GnRH in women from EFG was significantly lower than in those in CG, regardless of whether the women were carrying C/C, C/T or T/T genotypes of ERα rs3798577 (p<0.05). Serum estradiol concentrations in EFG were significantly lower than in CG when the women were carrying the Pp, Xx and T/T genotypes in ERα gene (p<0.05). CONCLUSION: Interaction of ERα gene and fluoride exposure may influence women's serum reproductive hormone concentrations.

Dietary Fluoride Intake and Associated Skeletal and Dental Fluorosis in School Age Children in Rural Ethiopian Rift Valley.

An observational study was conducted to determine dietary fluoride intake, diet, and prevalence of dental and skeletal fluorosis of school age children in three fluorosis endemic districts of the Ethiopian Rift Valley having similar concentrations of fluoride (F) in drinking water (~5 mg F/L). The duplicate plate method was used to collect foods consumed by children over 24 h from 20 households in each community (n = 60) and the foods, along with water and beverages, were analyzed for fluoride (F) content. Prevalence of dental and skeletal fluorosis was determined using presence of clinical symptoms in children (n = 220). Daily dietary fluoride intake was at or above tolerable upper intake level (UL) of 10 mg F/day and the dietary sources (water, prepared food and beverages) all contributed to the daily fluoride burden. Urinary fluoride in children from Fentale and Adamitulu was almost twice (>5 mg/L) the concentration found in urine from children from Alaba, where rain water harvesting was most common. Severe and moderate dental fluorosis was found in Alaba and Adamitulu, the highest severity and prevalence being in the latter district where staple foods were lowest in calcium. Children in all three areas showed evidence of both skeletal and non-skeletal fluorosis. Our data support the hypothesis that intake of calcium rich foods in addition to using rain water for household consumption and preparation of food, may help in reducing risk of fluorosis in Ethiopia, but prospective studies are needed.

Analysis of Phone Calls Regarding Fluoride Exposure made to New Jersey Poison Control Center from 2010 to 2012.

PURPOSE: The American Association of Poison Control Center's annual reports demonstrate that acute fluoride exposure is not an uncommon occurrence. Despite its prevalence, there has been little published research on the topic in the last 10 years. The purpose of this study was to calculate the incidence of acute fluoride toxicity and lethality as it occurs in New Jersey and provide a descriptive epidemiology of acute fluoride exposures. METHODS: The study design was retrospective in nature. Records of phone calls made by individuals reporting excessive fluoride exposure (in an amount greater than directed/prescribed) to New Jersey's poison control center, known as Poison Information and Education System from the years 2010 through 2012, were extracted from Toxicall® (Computer Automatic Systems, Inc.) database. A total of 2,476 human-only exposure records met the inclusion criteria and were analyzed. Incidence rates were calculated, and population characteristics, circumstances and medical outcomes of acute fluoride exposure cases were assessed and categorized. RESULTS: A total of 2,476 phone call records met the inclusion criteria. The fluoride exposures reported were from toothpaste with fluoride (49%, n=1,214), mouth rinse with fluoride (21.6%, n=536), multivitamin with fluoride (21.4%, n=530) and pure fluoride (0.08%, n=199). Medically speaking, 94.75% of calls were asymptomatic cases (n=2,346), 4.24% were symptomatic (n=105) and 1.01% were informational inquiries (n=25). Adverse symptoms reported were mostly minor (83.9% of symptomatic cases, n=88) and moderate (16.1% of symptomatic cases, n=17). The age group 18 months to 3 years of age showed the highest incidence of acute fluoride exposure (53.2%, n=1,317). There was a slightly higher incidence of acute fluoride exposures among males (n=1,317) vs. females (n=1,159). Most incidences occurred in the home (93.1% of records, n=2,305) and occurred unintentionally (96.7%, n=2,394). Calls were mainly made by the subject's mother (67.5%, n=1,671). CONCLUSION: Based on the data, there were no reports of lethality or toxicity due to acute fluoride exposure in New Jersey from 2010 through 2012. Symptomatic reports and informational inquiries were few. All adverse outcomes due to excessive fluoride intake were remedied with calcium as the antidote. Dental hygienists should educate patients on safety measures of fluoride-containing products and evaluate overall fluoride exposure prior to making recommendations. However, findings in this study suggest that levels of fluoride in available commercial products will not produce life-threatening events, even if taken in doses higher than recommended.

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.

[CHRONIC FLUORIDE INTOXICATION AS A RISK FACTOR FOR THE DEVELOPMENT OF ATHEROSCLEROSIS].

In workers employed in the aluminum industry, the main harmful production factor is exposure to fluoride salts, which can cause chronic fluoride intoxication. For the assessment of the impact of chronic fluoride intoxication on the development of atherosclerosis, we conducted a comprehensive survey of 87 aluminum-metal makers with chronic fluoride intoxication and 43 aluminum-metal makers without occupational diseases, mean age--52.1 ± 0.4 years. There were considered the presence and severity of atherosclerosis of brachiocephalic arteries, and the arteries of the lower extremities in the studied group, there was evaluated the effect of other risk factors for atherosclerosis (smoking, presence of hypertension, diabetes, dyslipidemia). With the use of Doppler ultrasound of the arteries it was revealed that in metallurgists with chronic fluoride intoxication atherosclerosis was detected in 73.6% versus 55.8% in persons of the comparison group. The performed analysis of the prevalence of main risk factors for atherosclerosis showed that in metal makers with chronic fluoride intoxication in combination with atherosclerosis hypertension is more common (in 54.7%) than in metallurgists with chronic fluoride intoxication without atherosclerosis--only 26.1%. According to the frequency of occurrence of smoking, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia, there were no significant differences between the metallurgists with chronic fluoride intoxication, with and without atherosclerosis, and the control group, the increase in LDL cholesterol occurs significantly more often in metal-makers with chronic fluoride intoxication in combination with atherosclerosis if compared to workers without occupational diseases. Thus, chronic fluoride intoxication acts as a risk factor in the development of atherosclerosis: atherosclerosis in metal-makers with chronic fluoride intoxication occurs more frequently than in workers who do not have professional pathology. Hypertension and elevated levels of LDL cholesterol were established to increase the relative risk of developing atherosclerosis in metallurgists with chronic fluoride intoxication. At that there are no significant differences in the prevalence of common risk factors for atherosclerosis (smoking, diabetes, hypercholesterolemia, hypertriglyceridemia).

[THE RISK OF THE DEVELOPMENT OF OCCUPATIONAL CHRONIC FLUORIDE POISONING].

On the basis of individual occupational fluoride loads (IOFN) it was established that under current levels of air pollution of the working area by fluorine compounds, occupational fluorosis can occur in mostly sensitive workers with 66 or more years of accumulated period of work, while the most vulnerable are workers with of 9.4 or more years of accumulated period of work. The results obtained in comparison of clinical data with individual fluoride load, testify that in the high-risk group for the development of occupational fluoride intoxication include workers with an average accumulated period of work of 10.5 years or more and Individual Occupational Fluoride Load (IOFL) as 67,7 or more grams. In the high-risk group there are included workers with an average accumulated period ofwork of 13.7 years and IOFL as 89.8 grams or more. With the use of ultrasound densitometry there was revealed a clear cut dynamics of the increase of the speed of ultrasonic wave with the rise in the accumulated period of work at the plant, which indicates to a gradual increase in bone tissue density.

Association of lifetime exposure to fluoride and cognitive functions in Chinese children: a pilot study.

BACKGROUND: A systematic review and meta-analysis of published studies on developmental fluoride neurotoxicity support the hypothesis that exposure to elevated concentrations of fluoride in water is neurotoxic during development. METHODS: We carried out a pilot study of 51 first-grade children in southern Sichuan, China, using the fluoride concentration in morning urine after an exposure-free night; fluoride in well-water source; and dental fluorosis status as indices of past fluoride exposure. We administered a battery of age-appropriate, relatively culture-independent tests that reflect different functional domains: the Wide Range Assessment of Memory and Learning (WRAML), Wechsler Intelligence Scale for Children-Revised (WISC-IV) digit span and block design; finger tapping and grooved pegboard. Confounder-adjusted associations between exposure indicators and test scores were assessed using multiple regression models. RESULTS: Dental fluorosis score was the exposure indicator that had the strongest association with the outcome deficits, and the WISC-IV digit span subtest appeared to be the most sensitive outcome, where moderate and severe fluorosis was associated with a digit span total score difference of -4.28 (95% CI -8.22, -0.33) and backward score with -2.13 (95% CI -4.24, -0.02). CONCLUSIONS: This pilot study in a community with stable lifetime fluoride exposures supports the notion that fluoride in drinking water may produce developmental neurotoxicity, and that the dose-dependence underlying this relationship needs to be characterized in detail.

Evaluation of total oxidative status and total antioxidant capacity in patients with endemic fluorosis.

The objective of the present study was to determine the plasma total oxidative status (TOS) and total antioxidant capacity (TAC) in patients with endemic fluorosis. A total of 79 (35 males and 44 females; mean age 44.0 ± 11.9 years) patients with endemic fluorosis and 55 (23 males and 32 females; mean age 48.3 ± 8.5 years) age-, sex- and body mass index-matched healthy controls were included in this study. The urine fluoride levels and plasma TOS and TAC levels were measured. The urine fluoride levels of fluorosis patients were significantly higher than control subjects as expected (1.91 ± 0.15 vs. 0.49 ± 0.13 mg/L, respectively; p < 0.001). TOS was significantly higher in fluorosis group than in control group (17.55 ± 3.82 vs. 15.06 ± 4.31 µmol H(2)O(2) Eq/L, respectively; p = 0.001). TAC was significantly lower in fluorosis group than in control group (1.60 ± 0.36 vs. 1.82 ± 0.51 mmol Trolox Eq/L, respectively; p = 0.004). Oxidative stress index (OSI) was significantly higher in fluorosis group than in control group (11.5 ± 3.8 vs. 8.8 ± 3.7, respectively; p < 0.001). Correlation analysis in all the groups indicated that TAC was negatively correlated with urine fluoride (r = -0.25, p = 0.003), TOS was positively correlated with urine fluoride (r = 0.34, p < 0.001) and OSI was positively correlated with urine fluoride (r = 0.36, p < 0.001). The results of our study demonstrate that oxidative stress plays an important role in the pathogenesis of the endemic fluorosis.