Chronic Fluoride Toxicity Research Articles

Kronik Flor Toksikasyonu Oluşturulan Farelerde Testis Dokusundaki Oksidatif Hasar Üzerine Panax ginseng’in Koruyucu Etkilerinin Araştırılması

Kronik Flor Toksikasyonu Oluşturulan Farelerde Testis Dokusundaki Oksidatif Hasar Üzerine Panax ginseng’in Koruyucu Etkilerinin Araştırılması

Level of Certain Micro and Macro Minerals in Blood of Cattle from Fluoride Polluted Localities of Udaipur, India

Analysis of soil, fodder and water samples collected from some localities of Udaipur district, Rajasthan, India revealed high fluoride concentrations indicating the areas endemic for fluoride pollution. Concentration of micro and macro minerals was estimated in blood samples collected from cattle reared in these localities, and with clinical lesions suggestive of chronic fluoride toxicity. In comparison to healthy controls, zinc, copper and manganese levels were significantly (p < 0.05) lower, while cobalt and magnesium concentrations were significantly (p < 0.05) higher in fluoride-intoxicated cattle. Results of the present study suggested that interaction of fluoride with other minerals possibly played a role in pathogenesis of chronic fluoride intoxication.

Fluoridation of drinking water and chronic kidney disease: absence of evidence is not evidence of absence

There are two areas of concern regarding the nephrotoxic potential of fluoride. A small and inclusive amount of research suggests that fluoridation of community water actually causes kidney disease. Kidney damage to tubular function and structure, and reduction in glomerular filtration rate occurred in residents of endemic fluoride areas [2] and anecdotal cases of fluoride intoxication [3] suggested a causal relationship between fluoride intake and renal failure. Ludlow et al. are correct that no evidence of an increased frequency of kidney disease or tubular dysfunction has been observed in early US epidemiological studies, comparing non-fluoridated areas (0.3mg/dl)toupto8mg/l fluoride in drinking water. None of these studies described renalfunctionoftheparticipantsorserialchangesinsimple urinalysis.Ofinterest,thedataofarecentlypublishedstudy suggested that drinking water contains fluoride levels over 2.0 mg/l—half of the fluoride concentration deemed safe by the US Environmental Protection Agency (EPA)—could cause damage to renal tubular structures in children. This conclusion is based on an investigation of 210 children living in areas of China with varying levels of fluoride in the community water (0.6–5.7 ppm). Children drinking water withmorethan2ppmfluoridewerefoundtohaveincreased levels of NAG and yGT in their urine—both markers of renal tubular damage [4]. It may be stated that there are no known adverse effects associated with the ingestion of relatively low levels of fluoride (1–2 ppm in drinking water) on a chronic basis. However, the actual levels of intake have to include fluoride not only in water, but also in the diet and in other fluoride containing products. Moreover, a fairly substantial body of research indicates that patients with chronic renal insufficiency are at an increased risk of chronic fluoride toxicity. Patients with reduced glomerular filtration rates have a decreased ability to excrete fluoride in the urine. These patients may develop skeletal fluorosis even at 1 ppm fluoride in the drinking water [5]. Whether or not the body burden of fluoride may further damage the diseased kidneys is unknown. The National Kidney Foundation in its ‘Position Paper on Fluoride—1980’ as well as the Kidney Health Australia express concern about fluoride retention in kidney patients. They caution physicians to monitor the fluoride intake of patients with advanced stages of kidney diseases. However, a number of reasons will account for the failure to monitor fluoride intake in patients with stages 4 and 5 of chronic kidney diseases and to detect early effects of fluoride retention on kidneys and bone. The safety margin for exposure to fluoride by renal patients is unknown, measurements of fluoride levels are not routine, the onset of skeletal fluorosis is slow and insidious, clinical symptoms of this skeletal disorder are vague, progression of renal functional decline is multifactorial and physicians are unaware of side effects of fluoride on kidneys or bone.

Antioxidant defense system and lipid peroxidation in patients with skeletal fluorosis and in fluoride-intoxicated rabbits.

Fluorosis is a serious public health problem in many parts of the world where drinking water contains more than 1 ppm of fluoride. The main manifestations of skeletal fluorosis are crippling bone deformities, spinal compressions, and restricted movements of joints. Although fluorosis is irreversible, it could be prevented by appropriate and timely intervention through understanding the process at biochemical and molecular levels. As in the case of many chronic degenerative diseases, increased production of reactive oxygen species (ROS) and lipid peroxidation has been considered to play an important role, even in the pathogenesis of chronic fluoride toxicity. However, there is inconclusive proof for an altered oxidative stress and antioxidant balance in fluorosis, and the existing data are not only conflicting but also contradictory. In the present communication we have evaluated the antioxidant defense system (both enzymatic and nonenzymatic) and lipid peroxidation in both humans from an endemic fluorosis area (5 ppm fluoride in the drinking water) and in rabbits receiving water with 150 ppm of fluoride for six months. There was no significant difference in lipid peroxidation, glutathione, and vitamin C in the blood of human fluorotic patients and fluoride-intoxicated rabbits as compared to respective controls. Neither were there any changes in the activities of catalase, superoxide dismutase, glutathione peroxidase, or glutathione S-transferase in the blood due to fluoride intoxication (of rabbits) or fluorosis in humans. The results together do not subscribe to oxidative stress theory in fluorosis. Thus, in the absence of clear proof of oxidative damage and to counter toxic effects of fluoride through supplementation of antioxidants, extensive investigations are needed to conclusively prove the role of oxidative stress in skeletal fluorosis.

Chronic fluoride toxicity decreases the number of nicotinic acetylcholine receptors in rat brain

In order to investigate the molecular mechanism(s) underlying brain dysfunction caused by chronic fluorosis, neuronal nicotinic acetylcholine receptors (nAChRs) in the brain of rats receiving either 30 or 100 ppm fluoride in their drinking water for 7 months were analyzed in the present study employing ligand binding and Western blotting. There was a significant reduction in the number of [ 3H]epibatidine binding sites in the brain of rats exposed 100 ppm of fluoride, but no alteration after exposed to 30 ppm. On the other hand, the number of [ 125I]α-BTX binding sites was significantly decreased in the brains of rats exposed to both levels of fluoride. Western blotting revealed that the level of the nAChR α4 subunit protein in the brains of rats was significantly lowered by exposure to 100 ppm, but not 30 ppm fluoride; whereas the expression of the α7 subunit protein was significantly decreased by both levels of exposure. In contrast, there was no significant change in the level of the β2 subunit protein in the brains of rats administered fluoride. Since nAChRs play major roles in cognitive processes such as learning and memory, the decrease in the number of nAChRs caused by fluoride toxicity may be an important factor in the mechanism of brain dysfunction in the disorder.

Lipid peroxidation and antioxidant defense systems in liver of rats in chronic fluoride toxicity.

Lipid peroxidation and antioxidant defense systems in liver of rats in chronic fluoride toxicity.

Some observations on endemic fluorosis in domestic animals in Southern Rajasthan (India).

Chronic fluoride toxicity in the form of osteo-dental fluorosis was observed in cattle, buffaloes, sheep and goats from 21 villages of Banswara, Dungarpur and Udaipur districts of Southern Rajasthan where the mean fluoride concentration in drinking water varied from 1.5 to 4.0 ppm. The prevalence of dental fluorosis in calves (< 1 year age) was greater than that in adult cattle and buffaloes. At a fluoride concentration in the water of 4.0 ppm, 100% of calves, 65.6% of buffaloes and 61.0% of cattle were found to be affected with dental fluorosis to varying degrees. In the older group of buffaloes, their teeth were brownish black instead of creamy yellow as found in calves and cattle. Out of 780 goats and 564 sheep, none revealed evidence of osteo-dental fluorosis. The overall prevalence of skeletal fluorosis was 8.5%, with the highest prevalence of 29.0% in cattle and 37.5% in buffaloes at a fluoride concentration of 3.2 ppm. None of the calves were affected with skeletal fluorosis. Intermittent lameness was observed in the older group of animals (> 7 years age) at 2.8 ppm fluoride or more in the water. None of the fluorotic animals exhibited any apparent evidence of hypothyroidism, stunted growth or low milk production. There was no correlation between gender and the prevalence of fluorosis, but the prevalence and severity of skeletal fluorosis increased with increasing fluoride concentration and age. Possible factors causing variation in fluorosis in the cattle and buffaloes in villages with identical fluoride concentrations are discussed.

Endemic chronic fluoride toxicity and dietary calcium deficiency interaction syndromes of metabolic bone disease and deformities in India: year 2000.

Epidemiological studies during 1963-1997 were conducted in 45,725 children exposed to high intake of endemic fluoride in the drinking water since their birth. Children with adequate (dietary calcium > 800 mg/d) and inadequate (dietary calcium < 300 mg/d) calcium nutrition and with comparable intakes of fluoride (mean 9.5 +/- 1.9 mg/d) were compared. The toxic-effects of fluoride were severe and more complex and the incidence of metabolic bone disease (rickets, osteoporosis. PTH bone disease) and bony leg deformities (genu valgum, genu varum, bowing, rotational and wind-swept) was greater (> 90%) in children with calcium deficiency as compared to < 25% in children with adequate calcium who largely had osteosclerotic form of skeletal fluorosis with minimal secondary hyperparathyroidism. The syndrome of skeletal fluorosis and associated metabolic bone disease and deformity is a unique clinical entity classified as a variant of osteosclerotic form of skeletal fluorosis. This syndrome chiefly results from the biological impact of excess fluoride, low calcium, high PTH and 1,25 (OH)2D3 separately and through their interactions on bone structure and metabolism as studied by radiology, bone scanning, bone histomorphometry and relevant metabolic and endocrine laboratory investigations. Metabolically active and vascular bones of children accumulate fluoride at faster and greater rate than adults (at the sites of active growth). In calcium deficient children the toxic effects of fluoride manifest even at marginally high (> 2.5 mg/d) exposures to fluoride. Fluoride toxicity also exaggerates the metabolic effects of calcium deficiency on bone. The findings strongly suggest that children with calcium deficiency rickets reported in the literature should be re-investigated for possible fluoride interactions. Deep bore drinking water supply with fluoride < 0.5 ppm and improvement of calcium nutrition provide 100% protection against the toxic effects of fluoride and are recommended as the cost effective and practical public health measures for the prevention and control of endemic fluorosis.

A Physiologically Based Pharmacokinetic Model for Fluoride Uptake by Bone

A sex-specific, physiologically based pharmacokinetic (pbpk) model has been developed to describe the absorption, distribution, and elimination of fluorides in rats and humans. Growth curves generated by plotting mean body weights (kg) against age (weeks or years) are included in the simulation model to allow the integration of chronic fluoride exposure from birth to old age. The model incorporates age and body weight dependence of the physiological processes that control the uptake of fluoride by bone and the elimination of fluoride by the kidneys. Six compartments make up the model. These are lung, liver, kidney, bone, and slowly and rapidly perfused compartments. The model also includes two bone subcompartments: a small, flow-limited, rapidly exchangeable surface bone compartment and a bulk virtually nonexchangeable inner bone compartment. The inner bone compartment contains nearly all of the whole body content of fluoride, which, in the longer time frame, may be mobilized through the process of bone modeling and remodeling. The model has been validated by comparing the model predictions with experimental data gathered in rats and humans after drinking water and dietary ingestion of fluoride. This physiological model description of absorption, distribution, and elimination of fluoride from the body permits the analysis of the combined effect of ingesting and inhaling fluorides on the target organ, bone. Estimates of fluoride concentrations in bone are calculated and related to chronic fluoride toxicity. The model is thus useful for predicting some of the long-term metabolic features and tissue concentrations of fluoride that may be of value in understanding positive or negative effects of fluoride on human health. In addition, the pbpk model provides a basis for across-species extrapolation of the effective fluoride dose at the target tissue, bone, in the assessment of risk from different exposure conditions.

Reversible impairment of glucose tolerance in patients with endemic fluorosis

Endemic fluorosis is a condition resulting from prolonged ingestion of drinking water which contains excess fluoride. Studies on rats have suggested that fluoride toxicity may produce glucose intolerance and abnormalities in insulin secretion. We studied glucose and insulin profiles following an oral glucose load in patients with endemic fluorosis. Twenty-five young adults (age range, 15-30 years) with endemic fluorosis, and an equal number of matched healthy control subjects with normal fluoride intake were studied. Impaired glucose tolerance was demonstrated in 10 of 25 (40%) patients with endemic fluorosis. Patients with impaired glucose tolerance had significantly higher fasting serum immunoreactive insulin (p < 0.05), higher fasting serum fluoride (p < 0.001), and a significantly lower fasting glucose to insulin ratio than that in patients with normal glucose tolerance (p < 0.001) or control subjects (p < 0.05). The fasting serum fluoride levels correlated positively with the area under the glucose curve (r = 0.80, p < 0.01) in patients with impaired glucose tolerance. Interestingly these abnormalities could be reversed when the village was provided drinking water with fluoride levels within acceptable limits. The present study shows that chronic fluoride toxicity in humans could result in significant abnormalities in glucose tolerance which are reversible upon removal of the excess fluoride.

Effect of Long-Term Administration of Sodium Fluoride on Plasma Calcium Level in Relation to Intestinal Absorption and Urinary Excretion in Rabbits

The present study was undertaken to determine the effect of chronic fluoride toxicity on calcium metabolism. Rabbits ( n = 10) were orally administered an aqueous solution of 10 mg NaF/kg body wt daily for 18 months. Equal numbers (n = 10) of age-, sex- and weight-matched rabbits kept under identical laboratory conditions, but not treated, with NaF solution, served as control. The fasting plasma calcium concentrations of fluoride-treated rabbits were significantly lower ( P < 0.001) than those of control animals. In contrast to the decrease in plasma calcium level, an increase in intestinal radioactive calcium ( 45Ca) absorption was observed ( P < 0.001) in all fluoride-treated animals. However, urinary calcium excretion levels were found to be reduced ( P = not significant) in fluoride-treated rabbits. It is therefore concluded that long-term fluoride poisoning alters the calcium homeostatic mechanism, thereby affecting calcium metabolism.

Acute and chronic fluoride toxicity.

Compared with the latter half of the 19th century and the first half of the 20th century, the frequency of fatalities stemming from the ingestion of fluoride compounds has declined dramatically. Since 1978, there have been four fatalities caused by the ingestion of fluoride, all in dental products. The numbers of exposures to fluoride doses that cause concern, however, has increased, as judged by the annual reports of the American Association of Poison Control Centers. The number of reports made to poison control centers has increased from approximately 7700 in 1984 to 10,700 in 1989. Over 3700 persons have been treated in health care facilities for exposure to fluoride during this period, and there have been 133 cases for which the medical outcomes were classified as moderate or major. The sources of fluoride have been limited almost exclusively to fluoride-containing vitamins and dental products. Based on a review of the doses involved in the four fatalities, three of which involved young children, the "probably toxic dose" of fluoride has been set at 5 mg F/kg body weight. For children who are 6 years of age or less, the PTD can be found in single containers of several kinds of dental products. Recommendations that should reduce the frequency of over-exposures to fluoride are described. Regarding adverse effects due to the chronic intake of fluoride (excluding dental fluorosis), there is no evidence for risk in the US up to the level of intake that is associated with drinking water containing 4 ppm. This statement is based on 1990 or 1991 reports by the NY State Department of Health, the USPHS, and the National Cancer Institute. Two new reports, however, have implicated chronic fluoride intake at relatively low levels in a higher incidence of bone fractures. This relationship requires further study.

Red blood cell glucose metabolism in human chronic fluoride toxicity

Fluoride is a well known inhibitor of many enzyme systems in vitro. The most widely studied classic example of fluoride inhibition is its potent inhibition of glycolysis, specifically its action on the enzyme enolase. Despite the plethora of in vitro studies on the effects of fluoride on the enzyme activity, there is a paucity of information concerning the in vivo metabolic lesions caused by the chronic toxic doses of fluoride in humans. The present study has been undertaken with a view to assess the changes in glucose metabolism and related enzymes in erythrocytes of humans consuming toxic doses of fluoride for prolonged periods.

Chronic fluoride toxicity: a scanning electron microscopic study of duodenal mucosa.

The effects of chronic fluoride toxicity on duodenal mucosa of rabbits were investigated using scanning electronmicroscope on materials obtained from rabbits subjected to oral administration of sodium fluoride at the dose of 10 mg/kg body weight per day for a period of 24 months. Significant morphological abnormalities were observed in the mucosa of all the fluoride treated animals [n = 9] when compared to that of control rabbits. The surface of the microvilli of duodenal epithelium revealed a "cracked-clay" appearance in fluoride treated rabbits. Besides, abrasion on the villus surface due to epithelial cell degeneration was also noticed. Mucus probably coating the degenerated cells formed strands over the villi in fluoride treated animals.