Alzheimers, Dementia, Attention Deficit Disorder, reduced IQ in children and more Neurotoxicity of fluoride, Fluoride, 1996, 29:2, 57-58 (Editorial by AWB and JC) The August 1995 issue of this journal contained an abstract (pages 151-152) of an interesting paper by Dr Phyllis Mullenix and her collaborators.1 They recorded behavioral changes in rats after ingestion of fluoride, and found that the severity of the effect on behavior increased directly with plasma fluoride levels and fluoride concentration in specific brain regions. A reading of the full paper is well worthwhile. In their Introduction, after referring to the increase in dental fluorosis in humans after decades of water fluoridation, the authors comment: "One concern that has not been fully investigated is the link between fluoride and effects an the central nervous system (CNS).... Many years of ubiquitous fluoride exposure have not resulted in obvious CNS problems such as seizures, lethargy, salivation, tremors, paralysis, or sensory deficits. Still unexplored, however, is the possibility that fluoride exposure is linked with subtle brain dysfunction." The carefully designed animal experiment which they report revealed subtle but very real changes in behavior patterns following fluoride ingestion: hyperactivity after prenatal exposure, and cognitive deficits after weanling and adult exposure. Fluoride accumulation in important regions of the rat brain, especially the hippocampus, was found to increase as the drinking water fluoride levels increased. These effects, and the sex differences observed, corresponded to those observed in other studies of hippocampal brain damage. The authors point out that the plasma fluoride levels recorded in the rats were the same as those sometimes recorded in humans - for example, in children one hour after receiving topical fluoride treatment of their teeth. In their conclusion calling for further rat and human studies they state: "Experience with other developmental neurotoxicants prompt expectations that changes in behavioral function will be comparable across species, especially humans and rats. Of course behaviors per se do not extrapolate, but a generic behavioral pattern disruption as found in this rat study can be indicative of a potential for motor dysfunction, IQ deficits and/or learning disabilities in humans." The authors draw attention to reports from Chinese investigators that high levels of fluoride in drinking water (3-11 ppm) affect the central nervous system directly without first causing the physical deformations of skeletal fluorosis.2-4 Readers of Fluoride will recall the recent (November 1995) research report from China indicating adverse neurological effects on the brain from fluoride exposure.5 This work also suggested that children with dental fluorosis are at greater risk of decreased mental acuity. One can only wonder whether the effects of fluoridated water might extend beyond the appearance of the teeth and include neurotoxicity among children afflicted with dental fluorosis. Some of our readers may recall also pertinent early clinical findings reported by our founding editor, Dr G L Waldbott, of which Dr Mullenix and her co-workers do not appear to have been aware. These involved a wide range of reversible toxic effects of fluoridated drinking water, including diminished mental acuity and impairment of memory.6-8 In a separate report, Dr Waldbott even gave an account, supported by laboratory data, of a case of tetaniform convulsions induced by drinking fluoridated drinking water.9 For decades proponents of water fluoridation have questioned the validity of these reports without, however, offering objective evidence to refute them. But in the light of the human research in China and now the animal research in the United States, these clinical observations by Dr Waldbott on the neurotoxicity of fluoride in drinking water clearly deserve greater attention and credence. [references not scanned] Jaqueline Calderon, Machado Blenda, Navarro Marielena, Carrizales Leticia, Ortiz Maria Deogracias, Diaz-Barriga F. Influence of Fluoride Exposure on Reaction Time and Visuospatial Organization in Children, Epidemiology July 2000, Volume 11, Number 4 Supplement S153. Fluoride exposure is an important public health problem in several Mexican states. In the city of San Luis Potosi, Mexico, above 90% of the children have some degree of dental fluorosis. The main source of exposure to fluoride is tap water. The objective of the study was to evaluate the influence of chronic exposure to fluoride on neuropsychological development in children. Sixty-one children aged 6 to 8 years were included. Fluoride concentration in tap water ranged from 1.2 to 3 mg/L. Fluoride exposure was measured in urine samples by electrothermal ion selective method. Blood lead (PbB) was measured as indicator of lead exposure by atomic absorption spectrophotometry. Height for age index (HAI) was calculated as indicator of past nutritional status. Three tests were used to evaluate the neuropsychological development: (1) Wechsler Intelligence Scale for Children Revisited version for Mexico (WISC-RM), (2) Rey Osterrelth-Complex Figure test and (3) Continuos Performance Test (CPT). Mean value of fluoride in urine was 4.3 mgF/g creatinine (1.6-10.8). Mean PhB value was 6.2 ug/dl (2.0-15.6). After controlling by significant confounders, urinary fluoride correlated positively with reaction time and inversely with the scores in visuospatial organization. IQ scores were not influenced by fluoride exposure. An increase in reaction time could affect the attention process, also the low scores in visuospatial organization could be affecting the reading and writing abilities in these children. University of North Carolina. Email: Jaqueline.Calderon@sph-unc.edu Guan ZZ, Wang YN, Xiao KQ, Dai DY, Chen YH, Liu JL, Sindelar P, Dallner G, Influence of chronic fluorosis on membrane lipids in rat brain. Neurotoxicol Teratol 1998 Sep-Oct;20(5):537-42 Brain membrane lipid in rats were analyzed after being fed either 30 or 100 ppm fluoride for 3, 5, and 7 months. The protein content of brain with fluorosis decreased, whereas the DNA content remained stable during the entire period of investigation. After 7 months of fluoride treatment, the total brain phospholipid content decreased by 10% and 20% in the 30 and 100 ppm fluoride groups, respectively. The main species of phospholipid influenced by fluorosis were phosphatidylethanolamine, phosphatidylcholine, and phosphatidylserine. The fatty acid and aldehyde compositions of individual phospholipid classes were unchanged. No modifications could be detected in the amounts of cholesterol and dolichol. After 3 months of fluoride treatment, ubiquinone contents in brain were lower; however, at 7 months they were obviously increased in both groups of fluoride treatment. The results demonstrate that the contents of phospholipid and ubiquinone are modified in brains affected by chronic fluorosis and these changes of membrane lipids could be involved in the pathogenesis of this disease. Department of Pathology, Guiyang Medical College, Guizhou, China. jialiul@public.gy.gz.cn Jope RS, Modulation of phosphoinositide hydrolysis by NaF and aluminum in rat cortical slices. J Neurochem 1988 Dec;51(6):1731-6 NaF stimulated phosphoinositide hydrolysis in rat cortical slices. The production of [3H]inositol monophosphate was rapid for the first 15 min of incubation with NaF, followed by a plateau. The major product detected was [3H]inositol monophosphate, although significant amounts of [3H]inositol bisphosphate and [3H]inositol trisphosphate were also produced. The stimulation of [3H]inositol monophosphate production by NaF was concentration dependent between 2 and 20 mM NaF. Addition of 10 or 100 microM AlCl3 or aluminum maltol did not alter the effect of NaF, whereas at 500 microM, these aluminum preparations resulted in significant inhibition. Increasing the concentration of K+ from 5 to 20 mM potentiated [3H]inositol monophosphate production induced by carbachol but not by NaF. Incubation with 1 microM phorbol 12-myristate 13-acetate, a phorbol ester, inhibited carbachol-induced, but not NaF-induced, [3H]inositol monophosphate production. These results further support the hypothesis that a guanine nucleotide binding protein that can be activated by NaF is involved in phosphoinositide hydrolysis in brain. The use of NaF provides a means to bypass receptors to study intracellular regulatory sites of phosphoinositide metabolism without disrupting cells. Department of Pharmacology and Neuropsychiatry Research Program, University of Alabama, Birmingham. Kay AR, Miles R, Wong RK, Intracellular fluoride alters the kinetic properties of calcium currents facilitating the investigation of synaptic events in hippocampal neurons. J Neurosci 1986 Oct;6(10):2915-20 We have attempted to suppress voltage-dependent conductances in hippocampal neurons by introducing various intracellular agents. Voltage-clamp studies were carried out using acutely dissociated hippocampal neurons from adult guinea pigs. Synaptic events were examined using intracellular recordings in the slice preparation. Sodium conductance was suppressed when the quaternary lidocaine derivative QX 314 was introduced intracellularly. Potassium conductances were blocked by intracellular cesium or Tris. We also found that the anion fluoride could affect calcium conductance by an intracellular action. When anions other than fluoride were used for intracellular recordings, the voltage-dependent calcium current inactivated slowly and showed persistent activation at membrane potentials between -40 and -10 mV. In contrast, when fluoride was present intracellularly, the inactivation kinetics of the calcium current were accelerated and the persistent component of the current was largely suppressed. Intracellular recordings in the hippocampal slice showed that when electrodes contained cesium, QX 314, and fluoride, the spiking and nonlinear responses of the neuronal membrane to depolarization were blocked. In these conditions the time course and voltage-dependence of EPSPs could be examined in detail without complications due to voltage-dependent currents of the postsynaptic cell. Li Y, Li X, Wei S, Effect of excessive fluoride intake on mental work capacity of children and a preliminary study of its mechanism, Hua Hsi I Ko Ta Hsueh Hsueh Pao,1994 Jun, 25 :2, 188-191 (Translated from Chinese) We made an investigation in 157 children, aged 12-13, born and grew up in a coal burning pattern endemic fluorosis area and an experiment on excessive fluoride intake in rat. The results showed: (1) Excessive fluoride intake since early childhood would reduce mental work capacity (MWC) and hair zinc content: (2) The effect on zinc metabolism was a mechanism of influence on MWC by excessive fluoride intake; (3) Excessive fluoride intake decreased 5-hydroxy indole acetic acid and increased norepinephrine in rat brain; whether this is also a mechanism of the influence on MWC awaits confirmation. Li XS, Zhi JL, Gao RO, Effect of Fluoride Exposure on Intelligence in Children, Fluoride, 1995 Nov, 28:4, pp 189-192 The intelligence was measured of 907 children aged 8-13 years living in areas which differed in the amount of fluoride present in the environment. The Intelligence Quotient (IQ) of children living in areas with a medium or severe prevalence of fluorosis was lower than that of children living in areas with only a slight fluorosis or no fluorosis. The development of intelligence appeared to be adversely affected by fluoride in the areas with a medium or severe prevalence of fluorosis but to a minor extent only in areas with only a slight prevalence of fluorosis. A high fluoride intake was associated with a lower intelligence. No correlation was found between age and intelligence in the areas with a medium and severe prevalence of fluorosis. The effect of exposure to a high level of fluoride on intelligence may occur at an early stage of development of the embryo and infant when the differentiation of brain nerve cells is occurring and development is most rapid. Liu WX, Experimental study of behavior and cerebral morphology of rat pups generated by fluorotic female rat, Chung-hua Ping Li Hsueh Tsa Chih, 1989 Dec, 18:4, 290-292 (Article in Chinese) In order to study the effects of fluoride on the central nervous system, 33-42-day old rat pups generated by three groups of female Wistar rats, which were given distilled water containing 0, 30 and 60 ppm NaF respectively beforehand as drinking water for 85 days, were used for behavior test and cerebral morphological examination. The results of behavior test showed that the latent period of pain reaction and that of conditioned reflex in the 30 ppm F and 60 ppm F groups were longer than that in the control group (P less than 0.05 or P less than 0.01). morphological examination of the pup brains showed that the nerve cell density of the 60 ppm F group was higher than that of the control group (P less than 0.05). Electronmicroscopically, mild degeneration of organelles of the nerve cells was observed in those brains of the 60 ppm F group. Masters RD and Coplan M, Study finds correlation between fluorides in water and lead levels, Dartmouth College News Release, and Poisoning the Well: Neurotoxic Metals, Water Treatment, and Human Behavior - Plenary Address to the Annual Conference of the Association for Politics and the Life Sciences Mattsson JL, Albee RR, Eisenbrandt DL Chang LW, Subchronic neurotoxicity in rats of the structural fumigant, sulfuryl fluoride, Neurotoxicol-Teratol, 1988 Mar-Apr, 10:2, 127-133 Inhalation exposure of male and female Fischer 344 rats to sulfuryl fluoride [Vikane (Dow Chemical Company) gas fumigant] at 300 ppm for 6 hr/day, 5 days week, for 13 weeks caused diminished wight gain, dental fluorosis, a slight decrease in grooming, decreased flicker fusion threshold, slowing of flash, auditory and somatosensory evoked potentials, mild nasal and pulmonary inflammation, mild kidney effects, and mild vacuolation in the brain. Auditory brainstem responses (ABRs) and brain histology were evaluated two months postexposure in 2 male and 2 female rats. Both the ABRs and brain histology were within normal limits at this time, indicating that these treatment effects were, to at least a great extent, reversible. Exposure to 100 ppm resulted in dental fluorosis and very minor slowing of some evoked responses; all other measures, including brain histology, were normal. No treatment effects were noted at 30 ppm. Mullenix PJ, Denbesten PK, Schunior A, Kernan WJ, Neurotoxicity of sodium fluoride in rats, Neurotoxicology Teratology, 1995 March,17(2):169-177.Fluoride (F) is known to affect mineralizing tissues, but effects upon the developing brain have not been previously considered. This study in Sprague-Dawley rats compares behavior, body weight, plasma and brain F levels after sodium fluoride (NaF) exposures during late gestation, at weaning or in adults. For prenatal exposures, dams received injections (SC) of 0.13 mg/kg NaF or saline on gestational days 14-18 or 17-19. Weanlings received drinking water containing 0, 75, 100, or 125 ppm F for 6 or 20 weeks, and 3 month-old adults received water containing 100 ppm F for 6 weeks. Behavior was tested in a computer pattern recognition system that classified acts in a novel environment and quantified act initiations, total times and time structures. Fluoride exposures caused sex- and dose-specific behavioral deficits with a common pattern. Males were most sensitive to prenatal day 17-19 exposure, whereas females were more sensitive to weanling and adult exposures. After fluoride ingestion, the severity of the effect on behavior increased directly with plasma F levels and F concentrations in specific brain regions. Such association is important considering that plasma levels in this rat model (0.059 to 0.640 ppm F) are similar to those reported in humans exposed to high levels of fluoride. [emphasis added] See also Effects on Brain II by Dr. P.J. Mullenix. Spittle B, Psychopharmacology of fluoride: a review, Int Clin Psychopharmacol, 9:2, 1994 Summer, 79-82 Although the blood-brain barrier is relatively impermeable to fluoride, it does not pose an absolute barrier and fluoride has the ability to enter the brain. The literature was examined to assess the quality of the evidence for cerebral impairment occurring due to exposure to fluoride from therapeutic or environmental sources. Several surveys of persons chronically exposed to industrial fluoride pollution reported symptoms related to impaired central nervous system functioning with impaired cognition and memory. Examination of individual case reports showed the evidence for aetiological relationships between symptoms and fluoride exposure to be of variable quality. The evidence was seen as being suggestive of a relationship rather than being definitive. The difficulties with concentration and memory described in relation to exposure to fluoride did not occur in isolation but were accompanied by other symptoms of which general malaise and fatigue were central. Possible mechanisms whereby fluoride could affect brain function include influencing calcium currents, altering enzyme configuration by forming strong hydrogen bonds with amide groups, inhibiting cortical adenylyl cyclase activity and increasing phosphoinositide hydrolysis. [editor's note: this review was published before Mullenix et al ., completed their ground-breaking study. The blood-brain barrier is penetrated by fluoride] Strunecká A, Patočka J , Pharmacological implications of aluminofluoride complexes, a review of the evidence for pathophysiological effects of aluminium and fluoride on living organism Varner JA, Jensen KF, Horvath W, Isaacson RL, Chronic administration of aluminum-fluoride or sodium-fluoride to rats in drinking water: alterations in neuronal and cerebrovascular integrity. Brain Res 1998 Feb 16;784(1-2):284-98This study describes alterations in the nervous system resulting from chronic administration of the fluoroaluminum complex (AlF3) or equivalent levels of fluoride (F) in the form of sodium-fluoride (NaF). Twenty seven adult male Long-Evans rats were administered one of three treatments for 52 weeks: the control group was administered double distilled deionized drinking water (ddw). The aluminum-treated group received ddw with 0.5 ppm AlF3 and the NaF group received ddw with 2.1 ppm NaF containing the equivalent amount of F as in the AlF3 ddw. Tissue aluminum (Al) levels of brain, liver and kidney were assessed with the Direct Current Plasma (DCP) technique and its distribution assessed with Morin histochemistry. Histological sections of brain were stained with hematoxylin & eosin (H&E), Cresyl violet, Bielschowsky silver stain, or immunohistochemically for beta-amyloid, amyloid A, and IgM. No differences were found between the body weights of rats in the different treatment groups although more rats died in the AlF3 group than in the control group. The Al levels in samples of brain and kidney were higher in both the AlF3 and NaF groups relative to controls. The effects of the two treatments on cerebrovascular and neuronal integrity were qualitatively and quantitatively different. These alterations were greater in animals in the AlF3 group than in the NaF group and greater in the NaF group than in controls. Copyright 1998 Elsevier Science B.V. Psychology Department, Binghamton University, Binghamton, NY, USA. Varner JA, Jensen KF, Horvath W, Issacson RL, The Neurotoxicological Evaluation Of The Chronic Administration Of Aluminum-Fluoride and Sodium-Fluoride, Society for Neuroscience Annual Meeting; San Diego, CA, 1995 Nov, abstract. This study examined the neurotoxic consequences of the chronic ingestion of AlF3 and the equivalent fluoride concentration given as low doses of NaF in drinking water. Twenty seven male LE rats, 3.5 - 4.5 months of age, were studied. The animals were divided into 3 groups based on the contents of the drinking water: control, NaF, or AlF3. Water was available ad libium for 52 weeks. Significantly more rats died in the AlF3 group than the control group during the study. Histological examinations involved the following stains: Cresy Violet, Bielschowsky silver, H&E, Morin Aluminum fluorescence, Beta Amyloid, Amyloid A, and IgM. Overall, neuronal loss was more prominent in the AlF3 group than the NaF and control groups in the left hemisphere and in the dentate gyrus of both hemispheres. Toxin-induced abnormalities in the AlF3 group were more apparent in the left hemisphere cortex but changes were found in the right hemisphere hippocampus. Hippocampal argentophillic reactions were common in both treated groups. Beta amyloid reaction product was enhanced in the thalamus in both toxin groups. More IgM antibody reaction product was found in the right hemisphere cortices of rats in both treated groups. Overall brain and kidney Al content was higher in both toxin groups relative to controls. Indications of glomerular disease were found in both treated groups. This reduction and/or abnormal appearance of cells, the presence of beta-amyloid, IgM, and Al indicate that AlF3 is neurotoxic when chronically administered in the drinking water of rats. The abnormal appearance of cells and the presence of beta-amyloid, IgM, and Al suggest that NaF also induces neurotoxicity, although somewhat different than that found after AlF3.
Varner JA, Huie C, Horvath W, Jensen KF, Issacson RL, Chronic AlF3 Administration: II. Selected Histological Observations, Neuroscience Research Communications, 1993, 13:2, 99-104.
[editor's note this study shows that the bioavailability of Al from drinking water is increased in the presence of fluoride. The Al content in the brain doubled in treated animals. According to an October 28, 1992 Wall Street Journal Article: "Rats fed the highest doses developed irregular mincing steps characteristic of senile animals.... Post mortem examination of the rat brains disclosed 'substantial cell loss in structures associated with dementia -- the neo-cortex and hippocampus'."] Yang Y, Wang X, Guo X, Effects of high iodine and high fluorine on children's intelligence and the metabolism of iodine and fluorine, Chung Hua Liu Hsing Ping Hsueh Tsa Chih, 1994 Oct, 15 (5), 296-298 (Translated from Chinese). An investigation on children's intelligence and the metabolism of iodine and fluorine in high iodine and fluorine regions was carried out. The results were as follows. In high iodine and high fluorine areas, the thyroid enlargement prevalence rate among inhabitants and that among children were 3.8% and 29.8%, respectively. The dental fluorosis prevalence rate among inhabitants and that among children was 35.48% and 72.9%, respectively. The pupils' average intelligence quotient (IQ) was 76.67 ± 7.75, slightly lower than the control point, but that of low intelligent pupils was 16.7%. The urinary iodine and urinary fluoride were 816.25 ± 1.80 micrograms/L and 2.08 ± 1.03 mg/L, respectively, markedly higher than the control point. The thyroid iodine-131 (131I) uptake rate was markedly lower than the control point. The values at 3 h and 24 h were 9.36 ± 1.55% and 9.26 ± 4.63%, respectively. The serum TSH was obviously higher than the control point. These results indicate that high iodine and high fluorine exert severe damage to human body. Zhao LB, Liang GH, Zhang DN, Wu XR, Effect of a high fluoride water supply on children's intelligence, Fluoride, 1996, 29:4, 190-192
Abstract: In Shanxi Province, China, children living in the endemic fluoride village of Sima (water supply F=4.12 mg/L) located near Xiaoyi City had average IQ (97.69) significantly lower (p<0.02) mg/L; average IQ = 105.21). These differences were not associated with gender, but the IQ scores were directly related to educational level of the parents.
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