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DIRECTORY: FAN > Health > Newsletter > Issue # 12

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FAN SCIENCE-WATCH

June 25, 2004

Issue #12: Yet more research on fluoride & the brain

by Michael Connett

A new study has just been published which further elucidates how fluoride may damage the brain.

The study, published in the August 2004 issue of the journal Toxicology, is the latest by a team of Chinese and Swedish scientists, members of which have been researching the impact of fluoride on brain for the past 8 years.

The team, headed up by neurotoxicologist Dr. Zhizhong Guan from the Karolinska Institute in Sweden, has probably investigated the impact of fluoride on brain more thoroughly than any other team in the world. Dr. Guan himself has researched the issue since as far back as 1986, although most of his research on the issue has been published since 1997.

The latest study from the Guan team investigates an important finding they first reported in 2002: namely, that rats drinking fluoride in water for 7 months had a decrease in “nicotinic acetylcholine receptors”, or “nAChRs”, in their brains.

The Potential Implications of Reduced nAChRs in the Brain

The potential implications of the Guan team’s finding can be gleaned from a recent review by Dr. Agneta Nordberg, a Swedish neurotoxicologist and expert on nAChRs.

According to Nordberg (who is now working with Dr. Guan on his fluoride/brain research):

“The neuronal nicotinic acetylcholine receptors (nAChRs) in the brain are important for functional processes, including cognitive and memory functions... The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy. The exact role of nAChRs and their full potential as a therapeutic target in these diseases have yet to be clarified.”

In regards to the relationship between decreased nAChRs and alzheimers disease, Nordberg writes:

“A consistent, significant loss of nAChRs has been observed in cortical autopsy brain tissue from [alzheimers] patients relative to age-matched healthy subjects. More recently, we have found that the nAChR deficits in [alzheimers] brains probably represent an early phenomenon in the course of the disease, which can be detected in vivo by positron emission tomography.” (Ref: Nordberg. Biological Psychiatry 2001; vol. 49; pp. 200-10.)

In 2002, when it was first reported (in the journal Neurotoxicology & Teratology) that fluoride could decrease nAChRs in rat brain, Dr. Guan, Dr. Nordberg and colleagues stated:

“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.”

In the new 2004 study, Dr. Guan, Dr. Nordberg, and colleagues, report on how fluoride might be causing the reduction in these nAChRs.

Their tentative conclusion is that the reduction is connected to a fluoride-induced increase in oxidative stress. Supporting this conclusion was the finding that pre-treating the rats with anti-oxidants seemed to prevent the reduction in nAChRs caused by fluoride.

The conclusion is also supported by a series of earlier studies from the Guan team which found that oxidative stress plays an important role in fluoride toxicity, not only in the brain, but in the liver and kidney as well.

The dose is the poison

For the skeptical-minded out there, I can imagine the question about dose is coming to the fore: How much fluoride did the rats in these studies receive, and how do these doses compare with what humans receive?

In their studies on fluoride toxicity, Guan and colleagues use 3 groups of rats. 1 group receives no fluoride in their water, 1 group receives 30 ppm fluoride, while 1 group receives 100 ppm fluoride. The duration of the studies is usually 7 months.

Among the 3 groups of rats, Guan has found that – while the damage is consistently greatest in the 100 ppm group – damage also occurs in the 30 ppm group as well. Damage in the 30 ppm group includes increased oxidative stress (as reflected by reduced lipid content) and reductions of some (but not all) nAChRs.

Relevance to humans?

On the face of it, it would seem that rats drinking 30 ppm fluoride in water are receiving roughly 30 times more fluoride than humans drinking fluoridated water (1 ppm). However, upon closer inspection, this assumption does not hold true.

Why?

Because rats are more resistant to fluoride toxicity than humans. The increased resistance of rats to fluoride toxicity seems to stem from the ‘reduced intestinal absorption’ of fluoride found in the rat. In other words, when rats ingest fluoride, less of the ingested fluoride actually makes it into their bloodstream. Because of this, rats are known to have far lower levels of fluoride in their blood than humans when consuming the same level of fluoride in water.

Indeed, while Guan and colleagues do not provide data on the level of fluoride in the rats’ blood, the blood levels normally found in rats drinking ~30 ppm fluoride in water (range = ~76-143 ppb) are actually overlapped and exceeded on a chronic basis by a portion of the human population (particularly those with kidney disease) living in fluoridated, and even unfluoridated, areas.

Moreover, the lower range of the levels normally found in rat’s blood drinking 30 ppm fluoride are also reached by young children (albeit for short duration) after ingesting fluoridated toothpaste and/or fluoride supplements. And, on a less frequent basis, young children’s blood can temporarily be infused with fluoride levels which far surpass (by up to a factor of 10) the levels found in rats drinking 30 ppm. The occasion? Use of high concentration acidulated fluoride gels in the dental chair.

Thus, for reasons that should become even more apparent in future Science-Watch bulletins, any damage found in rats drinking water with just 30 ppm fluoride should be taken very seriously.

A Tale of Two Worlds?

Finally, it is heartening to note that the Guan team has apparently not had any problems securing financial support to continue their research. Their research has consistently received ample funds from branches of the Chinese Government and China’s National Natural Science Foundation.

I mention this fact because it stands in rather stark contrast to the experience of US scientists who have also attempted to investigate fluoride’s impact on the brain.

The most notable example, of course, is the experience of Dr. Phyllis Mullenix, former chair of Toxicology at the prestigious Dental Forsythe Center. Ever since publishing her findings (in 1995) indicating neurotoxic effects of fluoride in rats, Mullenix was not only fired from her job, she has been unable to receive any money from government sources to continue her research. (Chris Bryson discusses Dr. Mullenix’s experience in great detail in his new book The Fluoride Deception from Seven Stories Press, May 2004).

Hopefully, however, with more and more research on fluoride and brain coming in from overseas and being published in western journals, some independent US scientists will become emboldened to start investigating the issue themselves, and will find ways of securing the funds to do so.

In the mean time, it is encouraging to know that there are scientists such as Dr. Guan in China and Sweden, actively researching fluoride’s neurotoxicity and publishing their findings. They are no doubt well ahead of the curve.

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ADDENDUM:

The Growing Body of Evidence that Fluoride Damages the Brain

Included below are excerpts from recent studies investigating fluoride’s impact onthe brain.

The studies are organized into 3 categories:

1) Animal Studies from Dr. Guan & Colleagues
2) Animal Studies from other research teams
3) HUMAN Studies

1) Animal Studies from Dr. Guan & Colleagues (back to top)

Shan KR, Qi XL, Long YG, Wang YN, Nordberg A, Guan ZZ. (2004). Decreased nicotinic receptors in PC12 cells and rat brains influenced by fluoride toxicity—a mechanism relating to a damage at the level in post-transcription of the receptor genes. Toxicology 200: 169–177.

“Recently, we have detected the alterations of nicotinic acetylcholine receptors (nAChRs) in rat brains and PC12 cells affected by fluoride toxicity... [O]xidative stress, including protein oxidation of the receptors and lipid peroxidation in cellular membrane, might be a mechanism of the deficit of the receptors.”

Chen J, Shan KR, Long YG, Wang YN, Nordberg A, Guan ZZ. (2003). Selective decreases of nicotinic acetylcholine receptors in PC12 cells exposed to fluoride. Toxicology 183: 235-42.

“These findings suggest that selective decreases in the number of nAChRs may play an important role in the mechanism(s) by which fluoride causes dysfunction of the central nervous system.”

Long YG, Wang YN, Chen J, Jiang SF, Nordberg A, Guan ZZ. (2002). Chronic fluoride toxicity decreases the number of nicotinic acetylcholine receptors in rat brain. Neurotoxicology and Teratology 24:751-7.

“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... 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.”

Shao Q, Wang Y, Guan Z. (2000). [Influence of free radical inducer on the level of oxidative stress in brain of rats with fluorosis]. Zhonghua Yu Fang Yi Xue Za Zhi 34:330-2.

“Over uptake of fluoride for a long term could cause potential increase in the level of oxidative stress in the brain tissue.”

Guan ZZ, Wang YN, Xiao KQ, Dai DY, Chen YH, Liu JL, Sindelar P, Dallner G. (1998). Influence of chronic fluorosis on membrane lipids in rat brain. Neurotoxicology and Teratology 20: 537-542.

“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.”

Wang Y, Guan Z, Xiao K. (1997). [Changes of coenzyme Q content in brain tissues of rats with fluorosis]. Zhonghua Yu Fang Yi Xue Za Zhi. 31: 330-3.

“Coenzyme Q content of brain tissue in rats fed with fluorine-containing water decreased at early stage of fluorosis, but increased significantly at late stage. It is speculated that changes in content of coenzyme Q could correlate with changes in free radical levels induced by fluorine.”

Guan Z, Wang Y, Xiao K. (1997). [Influence of experimental fluorosis on phospholipid content and fatty acid composition in rat brain]. Zhonghua Yi Xue Za Zhi. 77: 592-6.

“The metabolism of brain phospholipid might be interfered by fluoride accumulated in brain tissue, which is related with the degeneration of neuron. The changes of brain phospholipid could be involved in the pathogenesis of chronic fluorosis.”

Guan ZZ. (1986). [Morphology of the brain of the offspring of rats with chronic fluorosis]. Zhonghua Bing Li Xue Za Zhi. 15: 297-9. Chinese.

No abstract available.

2) Animal Studies from other research teams (back to top)

Shen X, Zhang Z, Xu X. (2004). [Influence of combined iodine and fluoride on phospholipid and fatty acid composition in brain cells of rats] Wei Sheng Yan Jiu. 33:158-61.

“Fluorosis had obvious influence on phospholipid and fatty acid composition in brain cells of rats, and its mechanism might be associated with action of lipid peroxidation, and 0.03 mg/L KI (potassium iodine) is the optimal concentration for the antagonistic action with this influence from fluorosis.”

Shashi A. (2003). Histopathological investigation of fluoride-induced neurotoxicity in rabbits. Fluoride 36: 95-105.

“These neurotoxic changes in the brain suggested that there was a direct action of fluoride upon the nerve tissue which was responsible for central nervous system problems such as tremors, seizures, and paralysis indicating brain dysfunction seen at the two highest doses."

Zhai JX, et al. (2003). [Studies on fluoride concentration and cholinesterase activity in rat hippocampus]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 21(2):102-4.

“CONCLUSION: Fluoride may go through the blood-brain barrier and accumulate in rat hippocampus, and inhibit the activity of cholinesterase.”

Bhatnagar M, et al. (2002). Neurotoxicity of fluoride: neurodegeneration in hippocampus of female mice. Indian Journal of Experimental Biology 40: 546-54.

“Light microscopic study of hippocampal sub-regions demonstrated significant number of degenerated nerve cell bodies in the CA3, CA4 and dentate gyrus(Dg) areas of sodium fluoride administered adult female mice. Ultrastructural studies revealed neurodegenerative characteristics like involution of cell membranes, swelling of mitochondria, clumping of chromatin material etc, can be observed in cell bodies of CA3, CA4 and dentate gyrus (Dg). Fluoride intoxicated animals also performed poorly in motor co-ordination tests and maze tests. Inability to perform well increased with higher fluoride concentration in drinking water.”

Chen J, Chen X, Yang K, Xia T, Xie H. (2002). [Studies on DNA damage and apoptosis in rat brain induced by fluoride]. Zhonghua Yu Fang Yi Xue Za Zhi 36: 222-224.

“The DNA damage in pallium neurons in rats of the fluoride group was much more serious compared with those of the control group...Sodium fluoride could induce DNA damage and apoptosis in rats brain.”

Shivarajashankara YM , et al. (2002). Brain lipid peroxidation and antioxidant systems of young rats in chronic fluoride intoxication. Fluoride 35: 197-203.

“These results suggest that fluoride enhances oxidative stress in the brain, thereby disturbing the antioxidant defense of rats. Increased oxidative stress could be one of the mediating factors in the pathogenesis of fluoride toxicity in the brain.”

Shivarajashankara YM , et al. (2002). Histological changes in the brain of young fluoride-intoxicated rats. Fluoride 35(1): 12-21.

“rats exposed to 100 ppm fluoride showed significant neurodegenerative changes in the hippocampus, amygdala, motor cortex, and cerebellum... These histological changes suggest a toxic effect of high-fluoride intake during the early developing stages of life on the growth, differentiation, and subcellular organization of brain cells in rats.”

Ekambaram P, Paul V. (2001). Calcium preventing locomotor behavioral and dental toxicities of fluoride by decreasing serum fluoride level in rats. Environmental Toxicology and Pharmacology 9(4):141-146.

“Administration of sodium fluoride with drinking water produced both behavioural and dental toxicities and not lethality in the present study. A suppression of spontaneous motor activity, a shortening of rota-rod endurance time, a decreased body weight gain and food intake, a suppression of total cholinesterase and acetylcholinesterase activities and dental lesion were observed in test animals.”

Zhang Z, et al. (2001). [Effects of selenium on the damage of learning-memory ability of mice induced by fluoride]. Wei Sheng Yan Jiu. 30(3):144-6.

“The main results showed that the learning capability of mice drinking higher concentration of fluoride presented remarkable deterioration.”

Chen J, Chen X, Yang K. (2000). [Effects of selenium and zinc on the DNA damage caused by fluoride in pallium neural cells of rats]. Wei Sheng Yan Jiu. 29: 216-7.

“The extent of DNA damage in the fluoride + selenium + zinc group was significantly slighter than that in the fluoride group (P < 0.05). It suggested that fluoride and selenium could induce DNA damage in pallium neural cells of rats respectively.”

Lakshmi Vani M, Pratap Reddy K. (2000). Effects of fluoride accumulation on some enzymes of brain and gastrocnemius muscle of mice. Fluoride 33: 17-26.

“This study therefore shows that both brain and muscle are affected by fluoride with inhibition of some enzymes associated with free-radical metabolism, energy production and transfer, membrane transport, and synaptic transmission, but with an enhanced activity of XOD.”

Lu XH, et al. (2000). Study of the mechanism of neurone apoptosis in rats from the chronic fluorosis. Chinese Journal of Epidemiology 19: 96-98.

“There is a tendency for neurone apoptosis in chronic fluorosis in rats. It is most evident with changes in pathology. It is not likely that only one form of neurone damage exist in the process of chronic fluorosis. There are recessive changes and apoptosis in the process at the same time.”

Sun ZR, et al. (2000). Effects of high fluoride drinking water on the cerebral functions of mice. Chinese Journal of Epidemiology 19: 262-263.

“Results: Learning and memory abilities of high-fluoride exposed groups were significantly lower than that of the control group, while the brain ChE activities of high-fluoride exposed groups were significantly higher. Conclusions: High fluoride concentration in drinking water can decrease the cerebral functions of mice. Fluoride is a neurotoxicant.”

van der Voet GB, et al. (1999). Fluoride enhances the effect of aluminium chloride on interconnections between aggregates of hippocampal neurons. Archives of Physiology and Biochemistry 107(1):15-21.

“It was concluded that aluminium interferes with the metabolism of the neuronal cytoskeleton and that this interference is potentiated by fluoride.”

Zhang Z, et al. (1999). [Effect of fluoride exposure on synaptic structure of brain areas related to learning-memory in mice] [Article in Chinese]. Wei Sheng Yan Jiu 28(4):210-2.

“The main results are as follows: the learning ability of mice drinking high concentration of fluoride presented remarkable deterioration, the thickness of post-synaptic density (PSD) was decreased, and the width of synaptic cleft was remarkably increased. The results suggested that the impairment on the learning capability induced by fluorosis may be closely related with the pathological changes of synaptic structure in the brain of mice.”

Paul V, et al. (1998). Effects of sodium fluoride on locomotor behavior and a few biochemical parameters in rats. Environmental Toxicology and Pharmacology 6: 187–191.

“Sodium fluoride treatment suppressed spontaneous motor activity. But no change was observed in the motor coordination of these animals. A suppression of spontaneous motor activity suggests that fluoride has, by a central action, inhibited motivation of these animals to exhibit locomotor behavior.”

Varner JA, et al. (1998). Chronic administration of aluminum-fluoride and sodium-fluoride to rats in drinking water: Alterations in neuronal and cerebrovascular integrity. Brain Research 784: 284-298.

“While the small amount of AlF in the drinking water of rats required for neurotoxic effects is surprising, perhaps even more surprising are the neurotoxic results of NaF at the dose given in the present study 2.1 ppm... The results of the present study indicate that more intensive neuropathological evaluations of F effects on brain may prove to be of value... In summary, chronic administration of AlF and NaF in the drinking water of rats resulted in distinct morphological alterations in the brain, including effects on neurons and cerebrovasculature.”

Zhao XL, Wu JH. (1998). Actions of sodium fluoride on acetylcholinesterase activities in rats. Biomedical and Environmental Sciences 11(1):1-6.

“These results indicate that fluoride may penetrate the blood brain barrier, interact with AChE located on cell membranes, and interfere with their physiological functions thus induce the neurotoxicities.”

Issacson R, et al. (1997). Toxin-induced blood vessel inclusions caused by the chronic administration of aluminum and sodium fluoride and their implications for dementia. Annals of the New York Academy of Science 825: 152-166.

“Neuronal abnormalities were observed in the NaF treated animals- especially in the deeper cell layers... The NaF treatment also produced distortions of cells and, in some rats, cell losses could be demonstrated in particular brain regions. Both AlF3 and NaF induced vascular inclusions, although of a different character...”

Mullenix P, et al. (1995). Neurotoxicity of Sodium Fluoride in Rats. Neurotoxicology and Teratology 17:169-177.

“This study demonstrates a link between certain fluoride exposures and behavioral disruption in the rat. The effect on behavior varied with the timing of exposure during CNS development. Behavioral changes common to weanling and adult exposures were different from those after prenatal exposures... Experience with other developmental neurotoxicants prompts expectations that changes in behavioral function will be comparable across species, especially humans and rats... [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.”

Li Y, et al. (1994). [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. 25(2):188-91.

“Excessive fluoride intake decreased 5-hydroxy indole acetic acid and increased norepinephrine in rat brain.”

Shashi A, et al. (1994). Effect of long-term administration of fluoride on levels of protein, free amino acids and RNA in rabbit brain. Fluoride 27: 155-159.

“The results reported here indicate that fluoride has a specific effect on the synthesis of proteins in the brain which may lead to degenerative changes in the form of ballooning degeneration of neurons, various degrees of loss of nisal substance, and changes in the purkinje cells of the cerebellar cortex. Such changes would provide a plausible explanation for some of the diverse neruological complaints in arms and legs such as numbness, muscle spasms and pains, tenaniform convulsions, and spastic paraplegia, encountered in patients with skeletal fluorosis."

Shashi A. (1992). Studies on alterations in brain lipid metabolism following experimental fluorosis. Fluoride 25(2):77-84.

“The neurotoxic effect of fluoride on lipid content of brain was assessed in rabbits during experimental fluorosis... Fluoride exerts an inhibitory effect on the free fatty acids in brain of both sexes. The relevance of these results in experimental fluorosis is discussed.”

III. HUMAN Studies (back to top)

Xiang Q, et al. (2003). Effect of fluoride in drinking water on children's intelligence. Fluoride 36: 84-94.

“Higher drinking water fluoride levels were significantly associated with higher rates of mental retardation (IQ <70) and borderline intelligence (IQ 70-79)... In endemic fluorosis areas, drinking water fluoride levels greater than 1.0 mg/L may adversely affect the development of children's intelligence.”

Calderon J, et al. (2000). Influence of fluoride exposure on reaction time and visuospatial organization in children. Epidemiology 11(4): S153.

“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.”

Lu Y, et al (2000). Effect of high-fluoride water on intelligence of children. Fluoride 33:74-78.

“The IQ of the 60 children in the high-fluoride area was significantly lower than that of the 58 children in the low-fluoride area... More children in the high-fluoride area were in the retardation or borderline categories of IQ than children in the low fluoride area. An inverse relationship was also present between IQ and the urinary fluoride level. Exposure of children to high levels of fluoride may therefore carry the risk of impaired development of intelligence.”

Calvert GM, et al. (1998). Health effects associated with sulfuryl fluoride and methyl bromide exposure among structural fumigation workers. American Journal of Public Health 88(12):1774-80.

“Sulfuryl fluoride exposure over the year preceding examination was associated with significantly reduced performance on the Pattern Memory Test and on olfactory testing... CONCLUSIONS: Occupational sulfuryl fluoride exposures may be associated with subclinical effects on the central nervous system, including effects on olfactory and some cognitive functions.”

Zhao LB, et al (1996). Effect of high-fluoride water supply on children's intelligence. Fluoride 29: 190-192.

“In Shanxi Province, China, children living in the endemic fluoride village of Sima located near Xiaoyi City had average IQ significantly lower than children living to the north in the nonendemic village of Xinghua.”

Li XS. (1995). Effect of Fluoride Exposure on Intelligence in Children. Fluoride 28(4):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 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. A high fluoride intake was associated with a lower intelligence.”

Li Y, et al. (1994). [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. 25(2):188-91.

“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...”

Du L. (1992). [The effect of fluorine on the developing human brain]. Chung-hua Ping Li Hsueh Tsa Chih. 21(4):218-20.

“Fifteen therapeutically aborted fetuses at the 5th-8th gestation month from the endemic fluorosis area were compared with those from the non-endemic area. Stereological study of the brains showed that the numerical density of volume of the neurons and the undifferentiated neuroblasts as well as the nucleus-cytoplasm ratio of the neurons were increased. The mean volume of the neurons was reduced. The numerical density of volume, the volume density and the surface density of the mitochondria were significantly reduced. The results showed that chronic fluorosis in the course of intrauterine fetal life may produce certain harmful effects on the developing brain of the fetus.”

Lin Fa-Fu; et al (1991). The relationship of a low-iodine and high-fluoride environment to subclinical cretinism in Xinjiang. Iodine Deficiency Disorder Newsletter Vol. 7. No. 3.

“The significant differences in IQ among these regions suggests that fluoride can exacerbate central nervous lesions and somatic developmental disturbance caused by iodine deficiency. This may be in keeping with fluoride's known ability to cause degenerative changes in central nervous system cells and to inhibit the activities of many enzymes, including choline enzymes, causing disturbance of the nerve impulse.”