燃煤污染型氟中毒患者氟暴露、骨相损伤程度与骨形成标志物的关系

慢性氟暴露是世界范围内的公共卫生问题之一.为研究燃煤污染型氟中毒患者中氟暴露、骨相损伤程度与骨形成标志物血清碱性磷酸酶(ALP)、骨钙素(BGP)之间的相关关系,以贵州省织金县荷花村(燃煤污染型地方性氟中毒病区)和安顺市张官村(非氟暴露村)为调查点,采集环境样品,采用氟离子选择电极法测定环境介质及食物中的氟含量.在知情同意的原则下,对295例氟暴露和85例非氟暴露调查对象进行氟斑牙、氟骨症诊断;收集其尿液及外周血,测定尿氟(UF)浓度、ALP活性和BGP含量.结果表明: 病区环境中大米、辣椒、玉米、饮水、黏土、菜土、煤以及室内外空气氟含量均明显高于对照区,但较以往报道数据降低;随着尿氟浓度的升高,ALP活性、BGP含量显著升高,氟骨症病情差异有统计学意义,氟斑牙病情差异无统计学意义;氟骨症病情与ALP活性、BGP含量呈正相关.表明燃煤污染型低氟暴露可引起人群的骨相损害,且ALP、BGP可用于评估氟骨症患者骨转换情况,在氟骨症的辅助诊断、疗效评估中有着一定的应用价值.     

Serum Parathyroid Hormone Levels in Chronic Endemic Fluorosis

Endemic waterborne fluorosis is a public health problem in Isparta, a city located in southern Turkey. Fluoride is a cumulative element that increases metabolic turnover of the bone and also affects the homeostasis of bone mineral metabolism. There are number of similarities between the effects of excess parathyroid hormone (PTH) and fluorosis on bone. So fluoride might show its effect via PTH. We aimed to determine PTH levels in patients with endemic fluorosis to estimate the possible toxic effects of chronic fluoride intake. Fifty-six patients with endemic fluorosis and 28 age-, sex-, and body-mass-index-matched healthy controls were included in this study. Endemic fluorosis was diagnosed according to the clinical diagnosis criteria of Wang. The urine fluoride levels of fluorosis patients were significantly higher than those of control subjects as expected (1.9 ± 0.1 vs. 0.4 ± 0.1 mg/L, respectively; P < 0.001). PTH levels in fluorosis group were significantly higher than control group (65.09 ± 32.91 versus 47.40 ± 20.37, respectively; P = 0.01). The results of our study demonstrate that serum PTH levels are increased in patients with endemic fluorosis. Fluoride, by interfering calcium balance, may be the cause of secondary hyperparathyroidism.     

Renal excretion of fluoride in renal failure and after renal transplantation.

We have compared the renal excretion of fluoride in a variety of patients with chronic renal failure maintained with and without protein restriction before and during regular dialysis treatment and after transplantation. The patients tended to continue to excrete normal dietary loads of fluoride quite well until renal function was seriously reduced. From a regression of function on excretion the mean level of creatinine clearance when a normal dietary load of fluoride 0.0526 plus or minus 0.019 mmol/2 h (1.0 plus or minus 0.36 mg/24h) has a 90% chance of being excreted lies around 16 ml/min, a level when most patients with renal failure will be symptomatic. Acute loading of such patients with additional fluoride in the form of sodium fluoride from 40 mg to 60 mg/day showed a twofold to threefold increase of serum fluoride concentrations, slight increases in urinary fluoride excretion, and heavy tissue absorption, suggesting that prior fluoride loading of the skeleton had not taken place. These effects contrasted with those in one patient with normal renal function and with those in one patient with skeletal saturation due to prolonged loading. After renal transplantation fluoride excretion increased but reached normal levels within three months of satisfactory function, suggesting that fluoride loading in renal failure and during regular dialysis therapy had not been excessive.     

Reversal of fluoride induced cell injury through elimination of fluoride and consumption of diet rich in essential nutrients and antioxidants

The objective of the present communication is to address the issues concerning reversal of fluoride induced cell injury and disease (i.e. fluorosis) through the elimination of fluoride and consumption of a diet containing essential nutrients and antioxidants. Humans afflicted with fluorosis, as a result of consuming fluoride contaminated water or food, have been investigated. Hospital based diagnostic procedure for early detection of fluorosis, through retrieval of history, clinical complaints, testing of blood, urine and drinking water for fluoride using ion selective electrode technology, along with X-ray of the forearm have been carried out. Confirmed cases of fluorosis were introduced to an intervention protocol consisting of (1) provision of safe drinking water with fluoride levels less than 1 mg/L and (2) counselling on nutritional supplementation with focus on adequate intake of calcium, vitamins C, E and antioxidants. The patients were monitored at frequent intervals up to one year and the results are reported. With a standardized early diagnosis, elimination of fluoride intake and supplementation of a diet rich in essential nutrients and antioxidants, we have shown that the fluorosis can be reversed.     

Reversal of fluoride induced cell injury through elimination of fluoride and consumption of diet rich in essential nutrients and antioxidants

The objective of the present communication is to address the issues concerning reversal of fluoride induced cell injury and disease (i.e. fluorosis) through the elimination of fluoride and consumption of a diet containing essential nutrients and antioxidants. Humans afflicted with fluorosis, as a result of consuming fluoride contaminated water or food, have been investigated. Hospital based diagnostic procedure for early detection of fluorosis, through retrieval of history, clinical complaints, testing of blood, urine and drinking water for fluoride using ion selective electrode technology, along with X-ray of the forearm have been carried out. Confirmed cases of fluorosis were introduced to an intervention protocol consisting of (1) provision of safe drinking water with fluoride levels less than 1 mg/L and (2) counselling on nutritional supplementation with focus on adequate intake of calcium, vitamins C, E and antioxidants. The patients were monitored at frequent intervals up to one year and the results are reported. With a standardized early diagnosis, elimination of fluoride intake and supplementation of a diet rich in essential nutrients and antioxidants, we have shown that the fluorosis can be reversed.     

Investigation and mapping of fluoride-endemic areas and associated health risk—A case study of Agra,Uttar Pradesh,India

The present study aimed at identifying the fluoride-endemic areas in five different blocks in Agra district, Uttar Pradesh, India. A total of 365 groundwater samples from 73 villages were analyzed for establishing the concentration range of fluoride in drinking water. The fluoride level in the study area varied from 0.14 to 4.88 mg/L. Out of 73, the fluoride levels in 45 villages did not meet the permissible Word Health Organization standards. The Baroli Ahir block was found the highly fluoride-endemic area followed by Saiyan, Bichpuri, Achnera and Etmadpur. Chronic daily intake of fluoride in adults was 1.25 and 1.5 times higher than those in children and infants, respectively. The probability of dental fluorosis in infants was higher (42%) while adults were more prone to bone and skeletal fluorosis (60%). The hazard quotient analysis revealed that children were found to be at maximum risk followed by infants and adults. Sensitivity analysis revealed that the fluoride concentration is the major influencing parameter responsible for different types of fluorosis in various age groups.     

Treatment of osteoporosis with human parathyroid peptide and observations on effect of sodium fluoride.

OBJECTIVE--To evaluate the need for a randomised study of treatment of spinal osteoporosis with human parathyroid peptide in the secondary prevention of crush fractures; to study the effect of human parathyroid hormone peptide 1-34 plus sex hormones on vertebral body cancellous bone; and, separately, to determine the effect of relatively low doses of sodium fluoride plus calcium on spinal bone mineral density. DESIGN--Open study of patients with primary or postmenopausal osteoporosis. All patients had serial bone densitometry of the spine by quantitative computed tomography and dual photon absorptiometry as well as serial densitometry of the radial midshaft (cortical) and radial distal (trabecular) bone by quantitative computed tomography. Changes in the spinal bone not forming the spongiosa of the vertebral bodies ("cortical" bone) were determined from the difference between the two axial measurements, after correction to the same units of measurement. SETTING--Northwick Park Hospital and Medical Research Council Clinical Research Centre. PATIENTS--24 Patients who fulfilled the conventional criteria for type 1 (vertebral) osteoporosis not secondary to recognised causes other than sex hormone deficiency and with at least one crush or wedge vertebral fracture and a spinal bone density (quantitative computed tomography) less than 80 mg/cm3 or two or more fractures. Twelve patients received human parathyroid peptide and 12 sodium fluoride; they were not randomised. MAIN OUTCOME MEASURES--Trends in axial and peripheral bone mass values determined by linear, time dependent regression analyses. RESULTS--The patients receiving the peptide showed a substantial increase in vertebral spongiosa (mean 25.6 mg/cm2 two years after the start of treatment). No significant changes were seen in spinal cortical or radial bone density. The patients receiving sodium fluoride showed roughly equal increases in cancellous and cortical bone over the same period (mean increase in vertebral spongiosa 16.1 mg/cm3). No significant changes were seen in radial bone. CONCLUSIONS--Treatment of postmenopausal women with human parathyroid peptide selectively increases spinal cancellous bone density by amounts that may prove useful in secondary prevention. Peptide treatment should now be tested in a randomised study in which the important end point is prevention of fractures as the usefulness of sodium fluoride in this context is doubtful.     

Elevation of PTH and PTHrp Induced by Excessive Fluoride in Rats on a Calcium-deficient Diet

Study on the role of parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrp) in the process of skeletal fluorosis, involved especially in calcium deficiency, is rare. We evaluated the level of serum PTH and mRNA expression of PTHrp in femur when rats were exposed to excessive fluoride with low-calcium diet. Wistar rats (n = 60) was divided into four groups, a control group, fluoride group, low-calcium group, and low-calcium fluoride group. The fluoride groups were treated with fluoride by drinking tap water containing 100 mg F-/L. The low-calcium diet contained 0.05% calcium. Serum was collected in the first, fourth, eighth, and 12th of phase for the detemination of PTH and Ca²⁺. RNA extraction from femora was used to analyze the mRNA express of PTHrp, osteopontin (OPN), and osteocalcin (OCN) after 12 weeks of fluoride dosing. Results showed that serum PTH increased gradually with the extension of fluoride exposure, but Ca²⁺ decreased, both of which embodied a time-dependent relationship. Cotreatment of excessive fluoride with low-calcium diet largely stimulated the secretion of PTH. The low dietary calcium markedly increased mRNA expression of PTHrp in animals with fluoride treatment. Expression of OPN and OCN significantly increased in the rats treated with excessive fluoride and low-calcium diet. We demonstrated that fluoride by itself affected the body's calcium metabolism and stimulate the secretion of PTH. PTH may play an important role in anabolic effect of excessive fluoride on bone turnover of skeletal fluorosis and calcium deficiency exacerbated the action of PTH and PTHrp on the characteristic bone lesion of fluorosis.     

Fluoride and environmental health: a review

The relationship between environmental fluoride and human health has been studied for over 100 years by researchers from a wide variety of disciplines. Most scientists believe that small amounts of fluoride in the diet can help prevent dental caries and strengthen bones, but there are a number of adverse affects that chronic ingestion at high doses can have on human health, including dental fluorosis, skeletal fluorosis, increased rates of bone fractures, decreased birth rates, increased rates of urolithiasis (kidney stones), impaired thyroid function, and lower intelligence in children. Chronic occupational exposure to fluoride dust and gas is associated with higher rates of bladder cancer and variety of respiratory ailments. Acute fluoride toxicity and even death from the ingestion of sodium fluoride pesticides and dental products have also been reported. The distribution of fluoride in the natural environment is very uneven, largely a result of the geochemical behavior of this element. Fluorine is preferentially enriched in highly evolved magmas and hydrothermal solutions, which explains why high concentrations are often found in syenites, granitoid plutonic rocks, alkaline volcanic, and hydrothermal deposits. Fluoride can also occur in sedimentary formations that contain fluoride-bearing minerals derived from the parent rock, fluoride-rich clays, or fluorapatite. Dissolved fluoride levels are usually controlled by the solubility of fluorite (CaF₂); thus, high concentrations are often associated with soft, alkaline, and calcium-deficient waters. Although much is known about the occurrence and health effects of fluoride, problems persist in Third World countries, where populations have little choice in the source of their drinking water and food. However, even in developed nations, fluoride ingestion can exceed the recommended dose when sources other than drinking water are ignored.     

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 ?? 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.     

The decreased expression of mitofusin-1 and increased fission-1 together with alterations in mitochondrial morphology in the kidney of rats with chronic fluorosis may involve elevated oxidative stress

This study was designed to characterize changes in the expression of mitofusin-1 (Mfn1) and fission-1 (Fis1), as well as in mitochondrial morphology in the kidney of rats subjected to chronic fluorosis and to elucidate whether any mitochondrial injury observed is associated with increased oxidative stress. Sixty Sprague-Dawley (SD) rats were divided randomly into 3 groups of 20 each, i.e., the untreated control group (natural drinking water containing <0.5 mg fluoride/L), the low-fluoride group (drinking water supplemented with 10 mg fluoride/L, prepared with NaF) and the high-fluoride group (50 mg fluoride/L), and treated for 6 months. Thereafter, renal expression of Mfn1 and Fis1 at both the protein and mRNA levels was determined by immunohistochemistry and real-time PCR, respectively. In addition, the malondiadehyde (MDA) was quantitated by the thiobarbituric acid procedure and the total antioxidative capability (T-AOC) by a colorimetric method. The morphology of renal mitochondria was observed under the transmission electron microscope. In the renal tissues of rats with chronic fluorosis, expression of both Mfn1 protein and mRNA was clearly reduced, whereas that of Fis1 was elevated. The level of MDA was increased and the T-AOC lowered. Swollen or fragmented mitochondria in renal cells were observed under the electronic microscope. These findings indicate that chronic fluorosis can lead to the abnormal mitochondrial dynamics and changed morphology in the rat kidney, which in mechanism might be induced by a high level of oxidative stress in the disease.     

Enduring fluoride health hazard for the Vesuvius area population: the case of AD 79 Herculaneum

Background

The study of ancient skeletal pathologies can be adopted as a key tool in assessing and tracing several diseases from past to present times. Skeletal fluorosis, a chronic metabolic bone and joint disease causing excessive ossification and joint ankylosis, has been only rarely considered in differential diagnoses of palaeopathological lesions. Even today its early stages are misdiagnosed in endemic areas.

Methodology/Principal Findings

Endemic fluorosis induced by high concentrations of fluoride in water and soils is a major health problem in several countries, particularly in volcanic areas. Here we describe for the first time the features of endemic fluorosis in the Herculaneum victims of the 79 AD eruption, resulting from long-term exposure to high levels of environmental fluoride which still occur today.

Conclusions/Significance

Our observations on morphological, radiological, histological and chemical skeletal and dental features of this ancient population now suggest that in this area fluorosis was already endemic in Roman times. This evidence merged with currently available epidemiologic data reveal for the Vesuvius area population a permanent fluoride health hazard, whose public health and socio-economic impact is currently underestimated. The present guidelines for fluoridated tap water might be reconsidered accordingly, particularly around Mt Vesuvius and in other fluoride hazard areas with high natural fluoride levels.     

Impaired Heart Rate Recovery in Patients with Endemic Fluorosis

The objective of the present study was to determine the heart rate recovery index (HRRI), a marker of autonomic nervous system function in patients with endemic fluorosis. Forty patients with endemic fluorosis (16 men/24 women) and 40 age-, sex-, and body mass index-matched healthy controls (16 men/24 women) with normal fluoride intake were enrolled in this study. HRRI was calculated by subtracting the heart rate values at the first, second, and third minutes of the recovery phase from the peak heart rate (HRRI 1, HRRI 2, HRRI 3). Urine fluoride levels of fluorosis patients were significantly (P?<?0.001) higher than control subjects as expected. HRRI 2 was significantly lower in fluorosis patients than in the controls. The incidence of abnormal HRRI 1 was significantly higher in fluorosis patients than in the controls (P?<?0.05). We observed that HRRI, a marker of autonomic nervous system function, is impaired in patients with chronic fluorosis.     

Sodium fluoride induces apoptosis in the kidney of rats through caspase-mediated pathways and DNA damage

Long-term excessive sodium fluoride (NaF) intake can cause many bone diseases and nonskeletal fluorosis. The kidneys are the primary organs involved in the excretion and retention of NaF. The objective of the present study was to determine the effects of NaF treatment on renal cell apoptosis, DNA damage, and the protein expression levels of cytosolic cytochrome C (Cyt C) and cleaved caspases 9, 8, and 3 in vivo. Male Sprague-Dawley rats were divided randomly into four groups (control, low fluoride, medium fluoride, and high fluoride) and administered 0, 50, 100, and 200 mg/L of NaF, respectively, via drinking water for 120 days. Histopathological changes in the kidneys were visualized using hematoxylin and eosin staining. Renal cell apoptosis was examined using flow cytometry, and renal cell DNA damage was detected using the comet assay. Cytosolic Cyt C and cleaved caspases 9, 8, and 3 protein expression levels were visualized using immunohistochemistry and Western blotting. The results showed that NaF treatment increased apoptosis and DNA damage. In addition, NaF treatment increased the protein expression levels of cytosolic Cyt C and cleaved caspases 9, 8, and 3. These results indicated that NaF induces apoptosis in the kidney of rats through caspase-mediated pathway, and DNA damage may be involved in this process.     

Simultaneous bilateral posteromedial tibial epiphysis stress fractures in a healthy young man: A case report

We present a compelling case of simultaneous, bilateral tibial stress fractures occurring in a unique epiphyseal and posterior location, with unclear aetiology. An overweight, Caucasian male in his late 20s developed synchronous bilateral medial knee pain following an intense 10-day training regimen. His radiographies were normal, but MRI revealed almost identical bilateral stress fracture lines in the posteromedial tibial epiphyses. Bone mineral densitometry and a full metabolic and hormonal panel were performed to further investigate potential underlying metabolic bone disease. He was found to have normal bone mineral densitometry and low Vitamin D serum values. Symptomatology greatly improved with activity modification. There were no further complaints and complications at 12 months’ follow-up. Diagnosis can be challenging and the treating physician should be acquainted with the basic science of stress fractures and main discriminating clinical, biochemical and radiological characteristics from insufficiency fractures, to avoid pitfalls in treatment decision.     

The Influence of Fluoride on the Expression of Inhibitors of Wnt/β-Catenin Signaling Pathway in Rat Skin Fibroblast Cells

The effective therapy of fluoride-induced bone diseases requires an understanding of the mechanism of the disorders. Changes in the inhibitors of the Wnt/β-catenin pathway, Dickkopf-1 (Dkk-1) and Sclerostin (SOST),were studied in supernatants harvested from rat skin fibroblasts cultured with varied doses of fluoride. The contents of SOST and Dkk-1 in fibroblast supernatants were assessed at four exposure time-points and investigated by using the method of ELISA. Compared to the relevant controls(0 mg F(?)/L), a significant decrease of the concentrations of SOST and Dkk-1 was observed as the fluoride concentration increased. Compared to the relevant time controls (24 h), a significant decrease of the concentrations of SOST and Dkk-1 was observed with the extension of time. Our results suggest that the Wnt/β-catenin pathway inhibitors Dkk-1 and SOST play an important role in skeletal fluorosis. They can be used as important indications for diagnosing bone metabolism changes caused by fluoride exposure and therapeutic targets in diseases resulting from fluoride exposure.     

Effect of Endemic Fluorosis on Hematological Parameters

Although so many studies exist on effect of fluoride on hematological parameters in experimental animals, a few studies have been conducted to investigate the effects of chronic fluorosis on hematological parameters in humans’ subjects with endemic fluorosis. So we aimed to determine the hematological parameters in patients with endemic fluorosis. The study group consisted of 60 patients with endemic fluorosis (27 females, 33 males, and mean age 33.4?±?9.6 years). An age-, gender-, and body mass index-matched control group was composed of 34 healthy volunteers (11 females, 23 males with a mean age 32.6?±?5.6 years). Urine fluoride levels of fluorosis patients were significantly higher than control subjects as expected (0.42?±?0.09 vs 1.92?±?0.14 mg/l, respectively; P?<?0.001). There were no statistically significant differences between the fluorosis group and control group with respect to hematological parameters (complete blood count and ferritin). We concluded that chronic fluorosis has no effect on hematological parameters in patients with endemic fluorosis.     

Effects of fluoride emissions from a modern primary aluminum smelter on a local population of white-tailed deer (Odocoileus virginianus)

The influence of fluoride emissions from a modern aluminum smelter on concentrations of skeletal fluoride and dental fluorosis in a resident population of white-tailed deer was studied. The smelter was located on Mount Holly Plantation in South Carolina, and concentrations of skeletal fluoride in the deer collected at Mount Holly increased approximately five-fold 3 yr after the operation began. Increases in skeletal fluoride of less than two-fold were observed in deer obtained from Medway Plantation which has its nearest boundary 1.6 km from the smelter site. No dental fluorosis was observed in deer collected at Medway Plantation, but mild dental fluorosis was observed in a significant number of deer collected at Mount Holly Plantation. The dental fluorosis that was observed was not associated with incisor wear or with fluoride-induced molar wear. Osteofluorosis of mandibles or metacarpals was not observed in any of the deer obtained from either plantation. The data obtained from this study indicated that the presence of a modern aluminum smelter caused a detectable increase in concentration of skeletal fluoride in the resident population of white-tailed deer, but that no adverse health effects were seen.     

Paleopathology of skeletal fluorosis

Skeletal fluorosis is one of a range of conditions causing excessive ossification and joint ankylosis in skeletons. It is rarely considered, however, in differential diagnoses of palaeopathological lesions. This paper considers the identification of skeletal fluorosis in a skeletal sample from the island of Bahrain, Arabian Gulf, dating to ca. 250 BC–AD 250. Approximately 4% of 255 adult skeletons in the sample have hyperostosic lesions resulting in joint ankylosis primarily of the lumbar vertebrae, as well as the major joints. These lesions most frequently occur among males in the 50+ age group. Chemical analysis on a small series of bone and dental samples confirmed the presence of high levels of fluoride, while staining of the teeth is evidence of dental fluorosis. The level of dental fluorosis is comparable with a naturally occurring fluoride level in water of between 1–2 ppm. The prevalence of hyperostosic lesions, however, appears higher than expected, and two possible reasons are suggested: confusion between a diagnosis of diffuse idiopathic skeletal hyperostosis and skeletal fluorosis on partial or less severely affected skeletons; and the presence of predisposing factors for skeletal fluorosis on the island in the past. Am J Phys Anthropol 109:465–483, 1999. © 1999 Wiley-Liss, Inc.     

Secondary Hyperparathyroidism in Patients with Endemic Skeletal Fluorosis

Investigation of 20 patients with skeletal fluorosis showed that five had clear evidence of secondary hyperparathyroidism. The hyperactivity of the parathyroid glands in skeletal fluorosis in the presence of decreased solubility of the bone mineral (fluoroapatite) strongly suggests that it is a compensatory attempt to maintain a normal extracellular ionized calcium equilibrium. Further study of the parathyroid glands and of bone lesions in skeletal fluorosis is in progress.