Fluoride Action Network

Abstract

Recently, epidemiological studies have suggested that fluoride is a human developmental neurotoxicant that reduces measures of intelligence in children, placing it into the same category as toxic metals (lead, methylmercury, arsenic) and polychlorinated biphenyls. If true, this assessment would be highly relevant considering the widespread fluoridation of drinking water and the worldwide use of fluoride in oral hygiene products such as toothpaste. To gain a deeper understanding of these assertions, we reviewed the levels of human exposure, as well as results from animal experiments, particularly focusing on developmental toxicity, and the molecular mechanisms by which fluoride can cause adverse effects. Moreover, in vitro studies investigating fluoride in neuronal cells and precursor/stem cells were analyzed, and 23 epidemiological studies published since 2012 were considered. The results show that the margin of exposure (MoE) between no observed adverse effect levels (NOAELs) in animal studies and the current adequate intake (AI) of fluoride (50 µg/kg b.w./day) in humans ranges between 50 and 210, depending on the specific animal experiment used as reference. Even for unusually high fluoride exposure levels, an MoE of at least ten was obtained. Furthermore, concentrations of fluoride in human plasma are much lower than fluoride concentrations, causing effects in cell cultures. In contrast, 21 of 23 recent epidemiological studies report an association between high fluoride exposure and reduced intelligence. The discrepancy between experimental and epidemiological evidence may be reconciled with deficiencies inherent in most of these epidemiological studies on a putative association between fluoride and intelligence, especially with respect to adequate consideration of potential confounding factors, e.g., socioeconomic status, residence, breast feeding, low birth weight, maternal intelligence, and exposure to other neurotoxic chemicals. In conclusion, based on the totality of currently available scientific evidence, the present review does not support the presumption that fluoride should be assessed as a human developmental neurotoxicant at the current exposure levels in Europe.

*Abstract online at https://link.springer.com/article/10.1007%2Fs00204-020-02725-2

References

  1. Adamek E, Pawlowska-Goral K, Bober K (2005) In vitro and in vivo effects of fluoride ions on enzyme activity. Ann Acad Med Stetin 51(2):69–85

    CAS  PubMed  Google Scholar

  2. AFSSA (2003) Rapport du comité d’experts spécialisé “eaux” concernant la proposition de fixation d’une valeur limite du fluor dans les eaux minérales naturelles. Agence Française de Sécurité Sanitaire des Aliments, Maisons-Alfort

    Google Scholar

  3. Aggeborn L, Oehman M (2017) The effects of fluoride in drinking water. Uppsala: Institute for Evaluation of Labour Market and Education Policy, p. 1–83. https://www.ifau.se/globalassets/pdf/se/2017/wp2017-20-the-effects-of-fluoride-in-the-drinking-water.pdf.

  4. Anuradha CD, Kanno S, Hirano S (2001) Oxidative damage to mitochondria is a preliminary step to caspase-3 activation in fluoride-induced apoptosis in HL-60 cells. Free Radic Biol Med 31(3):367–373

    CAS  PubMed  Article  Google Scholar

  5. Aravind A, Dhanya RS, Narayan A, Sam G, Adarsh VJ, Kiran M (2016) Effect of fluoridated water on intelligence in 10–12-year-old school children. J Int Soc Prev Community Dent 6(3):S237–S242

    CAS  PubMed  PubMed Central  Article  Google Scholar

  6. ATSDR (1993) Agency for toxic substances and disease registry; toxicological profile for fluorides, hydrogen fluoride, and fluorine (F). TP-91/17. US Department of Health and Human Services. Public Health Service, Atlanta, GA. https://books.google.de/books?id=GU8Lj0_pWLsC&printsec=frontcover&hl=de&source=gbs_ge_summary_r&cad=0#v=onepage&q&f=false.

  7. ATSDR (2003) Agency for toxic substances and disease registry; toxicological profile for fluorides, hydrogen fluoride, and fluorine. US Department of Health and Human Services. Public Health Service, Atlanta, GA. https://www.atsdr.cdc.gov/toxprofiles/tp11.pdf.

  8. Barbier O, Arreola-Mendoza L, Del Razo LM (2010) Molecular mechanisms of fluoride toxicity. Chem Biol Interact 188(2):319–333

    CAS  PubMed  Article  Google Scholar

  9. Bartos M, Gumilar F, Gallegos CE et al (2018) Alterations in the memory of rat offspring exposed to low levels of fluoride during gestation and lactation: Involvement of the alpha7 nicotinic receptor and oxidative stress. Reprod Toxicol 81:108–114

    CAS  PubMed  Article  Google Scholar

  10. Basha PM, Rai P, Begum S (2011) Fluoride toxicity and status of serum thyroid hormones, brain histopathology, and learning memory in rats: a multigenerational assessment. Biol Trace Elem Res 144(1–3):1083–1094

    CAS  PubMed  Article  Google Scholar

  11. Bashash M, Thomas D, Hu H et al (2017) Prenatal fluoride exposure and cognitive outcomes in children at 4 and 6–12 years of age in Mexico. Environ Health Perspect 125(9):097017

    PubMed  PubMed Central  Article  Google Scholar

  12. Becker W, Bruce A (1981) Fluoride intake from food. Vår Föda 33:198–261

    Google Scholar

  13. Bencherif M, Lukas RJ (1991) Differential sensitivity of phosphoinositide metabolism to sodium fluoride and carbachol treatments in PC12 cells. Mol Cell Neurosci 2(5):377–383

    CAS  PubMed  Article  Google Scholar

  14. Bergmann R (1994) Fluorid in der Ernährung des Menschen. Biologische Bedeutung für den wachsenden Organismus. Habilitationsschrift Medical Faculty, Free University Berlin, Berlin

    Google Scholar

  15. BMG/UBA (2015) Bericht des Bundesministeriums für Gesundheit und des Umweltbundesamtes an die Verbraucherinnen und Verbraucher über die Qualität von Wasser für den menschlichen Gebrauch (Trinkwasser) in Deutschland. Berichtszeitraum: 1. Jan. 2011 bis 31. Dez. 2013. In: Umweltbundesamt (Hrsg.): Umwelt & Gesundheit, 02/2015 (https://www.umweltbundesamt.de/sites/default/files/medien/378/publikationen/umwelt_und_gesundheit_02_2015_trinkwasserbericht_des_bmg.pdf).

  16. Boink AB, Wemer J, Meulenbelt J, Vaessen HA, de Wildt DJ (1994) The mechanism of fluoride-induced hypocalcaemia. Hum Exp Toxicol 13(3):149–155

    CAS  PubMed  Article  Google Scholar

  17. Bouaziz H, Croute F, Boudawara T, Soleilhavoup JP, Zeghal N (2007) Oxidative stress induced by fluoride in adult mice and their suckling pups. Exp Toxicol Pathol 58(5):339–349

    CAS  PubMed  Article  Google Scholar

  18. Bouchard MF, Sauve S, Barbeau B et al (2011) Intellectual impairment in school-age children exposed to manganese from drinking water. Environ Health Perspect 119(1):138–143

    CAS  PubMed  Article  Google Scholar

  19. Broadbent JM, Thomson WM, Ramrakha S et al (2015) Community water fluoridation and intelligence: prospective study in New Zealand. Am J Public Health 105(1):72–76

    PubMed  PubMed Central  Article  Google Scholar

  20. Buzalaf MA, Whitford GM (2011) Fluoride metabolism. Monogr Oral Sci 22:20–36

    PubMed  Article  Google Scholar

  21. Caldera R, Chavinie J, Fermanian J, Tortrat D, Laurent AM (1988) Maternal-fetal transfer of fluoride in pregnant women. Biol Neonate 54(5):263–269

    CAS  PubMed  Article  Google Scholar

  22. Carrington C, Devleesschauwer B, Gibb HJ, Bolger PM (2019) Global burden of intellectual disability resulting from dietary exposure to lead, 2015. Environ Res 172:420–429

    CAS  PubMed  Article  Google Scholar

  23. Chan JT, Koh SH (1996) Fluoride content in caffeinated, decaffeinated and herbal teas. Caries Res 30(1):88–92

    CAS  PubMed  Article  Google Scholar

  24. Chen J, Niu Q, Xia T et al (2018) ERK1/2-mediated disruption of BDNF-TrkB signaling causes synaptic impairment contributing to fluoride-induced developmental neurotoxicity. Toxicology 410:222–230

    CAS  PubMed  Article  Google Scholar

  25. Chen K, Didsbury M, van Zwieten A et al (2018) Neurocognitive and educational outcomes in children and adolescents with CKD. A systematic review and meta-analysis. Clin J Am Soc Nephrol 13(3):387–397

    PubMed  PubMed Central  Article  Google Scholar

  26. Chen J, Shan KR, Long YG, Wang YN, Nordberg A, Guan ZZ (2003) Selective decreases of nicotinic acetylcholine receptors in PC 12 cells exposed to fluoride. Toxicology 183(1–3):235–242

    CAS  PubMed  Article  Google Scholar

  27. Chen L, Ning H, Yin Z et al (2017) The effects of fluoride on neuronal function occurs via cytoskeleton damage and decreased signal transmission. Chemosphere 185:589–594

    CAS  PubMed  Article  Google Scholar

  28. Chen R, Zhao LD, Liu H et al (2017) Fluoride induces neuroinflammation and alters wnt signaling pathway in BV2 microglial cells. Inflammation 40(4):1123–1130

    CAS  PubMed  Article  Google Scholar

  29. Chinoy NJ, Patel TN (2001) Effects of sodium fluoride and aluminum chloride on ovary and uterus of mice and their reversal by some antidotes. Fluoride 34(1):9–20

    CAS  Google Scholar

  30. Chlubek D, Grucka-Mamczar E, Birkner E, Polaniak R, Stawiarska-Pi?ta B, Duliban H (2003) Activity of pancreatic antioxidative enzymes and malondialdehyde concentrations in rats with hyperglycemia caused by fluoride intoxication. J Trace Elem Med Bio 17(1):57–60

    CAS  Article  Google Scholar

  31. Choi AL, Sun G, Zhang Y, Grandjean P (2012) Developmental fluoride neurotoxicity: a systematic review and meta-analysis. Environ Health Perspect 120(10):1362–1368

    CAS  PubMed  PubMed Central  Article  Google Scholar

  32. Choi AL, Zhang Y, Sun G et al (2015) Association of lifetime exposure to fluoride and cognitive functions in Chinese children: a pilot study. Neurotoxicol Teratol 47:96–101

    CAS  PubMed  Article  Google Scholar

  33. Cicek E, Aydin G, Akdogan M, Okutan H (2005) Effects of chronic ingestion of sodium fluoride on myocardium in a second generation of rats. Hum Exp Toxicol 24(2):79–87

    CAS  PubMed  Article  Google Scholar

  34. Collins TF, Sprando RL, Black TN et al (2001a) Multigenerational evaluation of sodium fluoride in rats. Food Chem Toxicol 39(6):601–613

    CAS  PubMed  Article  Google Scholar

  35. Collins TF, Sprando RL, Black TN et al (2001) Developmental toxicity of sodium fluoride measured during multiple generations. Food Chem Toxicol 39(8):867–876

    CAS  PubMed  Article  Google Scholar

  36. Collins TF, Sprando RL, Shackelford ME et al (1995) Developmental toxicity of sodium fluoride in rats. Food Chem Toxicol 33(11):951–960

    CAS  PubMed  Article  Google Scholar

  37. Das K, Mondal NK (2016) Dental fluorosis and urinary fluoride concentration as a reflection of fluoride exposure and its impact on IQ level and BMI of children of Laxmisagar, Simlapal Block of Bankura District, W.B., India. Environ Monit Assess 188(4): 218.

  38. Dirks OB, Jongeling-Eijndhoven JM, Flissebaalje TD, Gedalia I (1974) Total and free ionic fluoride in human and cow’s milk as determined by gas-liquid chromatography and the fluoride electrode. Caries Res 8(2):181–186

    CAS  PubMed  Article  Google Scholar

  39. Dong Y-T, Wei N, Qi X-L et al (2017) Attenuating effect of vitamin E on the deficit of learning and memory of rats with chronic fluorosis: The mechanism may involve muscarinic acetylcholine receptors. Fluoride 50(3):354–364

    CAS  Google Scholar

  40. Duan Q, Jiao J, Chen X, Wang X (2018) Association between water fluoride and the level of children’s intelligence: a dose-response meta-analysis. Public Health 154:87–97

    CAS  PubMed  Article  Google Scholar

  41. Dunipace AJ, Brizendine EJ, Zhang W et al (1995) Effect of aging on animal response to chronic fluoride exposure. J Dent Res 74(1):358–368

    CAS  PubMed  Article  Google Scholar

  42. EFSA (2005) Opinion of the scientific panel on dietetic products, nutrition and allergies on a request from the Commission related to the tolerable upper intake level of fluoride (Request No EFSA-Q-2003-018). EFSA J 192:1–65

    Google Scholar

  43. EFSA (2008) Calcium fluoride as a source of fluoride added for nutritional purposes to food supplements. EFSA J 882:1–15

    Google Scholar

  44. EFSA (2012) Scientific Committee; Guidance on selected default values to be used by the EFSA Scientific Committee, Scientific Panels and Units in the absence of actual measured data. EFSA J 10(3):2579

    Google Scholar

  45. EFSA (2013) Panel on dietetic products, nutrition; scientific opinion on dietary reference values for fluoride. EFSA J 11(8):3332

    Article  CAS  Google Scholar

  46. Eichler HG, Lenz K, Fuhrmann M, Hruby K (1982) Accidental ingestion of NaF tablets by children–report of a poison control center and one case. Int J Clin Pharmacol Ther Toxicol 20(7):334–338

    CAS  PubMed  Google Scholar

  47. Ekstrand J, Alvan G, Boreus LO, Norlin A (1977) Pharmacokinetics of fluoride in man after single and multiple oral doses. Eur J Clin Pharmacol 12(4):311–317

    CAS  PubMed  Article  Google Scholar

  48. Ekstrand J, Boreus L, De Chateau P (1981) No evidence of transfer of fluoride from plasma to breast milk. Br Med J 283(6294):761–762

    CAS  Article  Google Scholar

  49. Ekstrand J, Whitford G (1988) Fluoride metabolism. In: Ekstrand J, Fejerskov O, Silverstone LM (eds) Fluoride in dentistry. Munksgaard, Copenhagen, pp 150–170

    Google Scholar

  50. EPA (2010) Fluoride: exposure and relative source contribution analysis. 820-R-10–015. Washington: US Environmental ProtectionAgency. Office of Water, Health and Ecological Criteria Division. https://www.epa.gov/sites/production/files/2019-03/documents/fluoride-exposure-relative-report.pdf.

  51. EVM (2001) Review of fluoride. Expert group on vitamins and minerals. EVM/01/03/P.

  52. Feldman V (2014) Neurodevelopmental toxicity: still more questions than answers. Lancet Neurol 13(7):645–646

    PubMed  Article  Google Scholar

  53. Fisher SK, McEwen E, Kunkle C, Thompson AK, Slowiejko D (1993) Contribution of G protein activation to fluoride stimulation of phosphoinositide hydrolysis in human neuroblastoma cells. J Neurochem 60(5):1800–1805

    CAS  PubMed  Article  Google Scholar

  54. Flora SJ, Mittal M, Mishra D (2009) Co-exposure to arsenic and fluoride on oxidative stress, glutathione linked enzymes, biogenic amines and DNA damage in mouse brain. J Neurol Sci 285(1–2):198–205

    CAS  PubMed  Article  Google Scholar

  55. Flores-Mendez M, Ramirez D, Alamillo N, Hernandez-Kelly LC, Del Razo LM, Ortega A (2014) Fluoride exposure regulates the elongation phase of protein synthesis in cultured Bergmann glia cells. Toxicol Lett 229(1):126–133

    CAS  PubMed  Article  Google Scholar

  56. FSAI (2018) Total diet study 2014–2016: Assessment of dietary exposure to fluoride in adults and children in Ireland. Report of the Scientific Committee of the Food Safety Authority of Ireland. https://www.fsai.ie/news_centre/tds_fluoride_30042018.html.

  57. Fu X, Xie FN, Dong P, Li QC, Yu GY, Xiao R (2016) High-dose fluoride impairs the properties of human embryonic stem cells via JNK signaling. PLoS ONE 11(2):e0148819

    PubMed  PubMed Central  Article  CAS  Google Scholar

  58. Garcia-Montalvo EA, Reyes-Perez H, Del Razo LM (2009) Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress. Toxicology 263(2–3):75–83

    CAS  PubMed  Article  Google Scholar

  59. Gardiner IM, de Belleroche J (1990) Modulation of gamma-aminobutyric acid release in cerebral cortex by fluoride, phorbol ester, and phosphodiesterase inhibitors: differential sensitivity of acetylcholine release to fluoride and K+ channel blockers. J Neurochem 54(4):1130–1135

    CAS  PubMed  Article  Google Scholar

  60. Ge Y, Chen L, Yin Z et al (2018) Fluoride-induced alterations of synapse-related proteins in the cerebral cortex of ICR offspring mouse brain. Chemosphere 201:874–883

    CAS  PubMed  Article  Google Scholar

  61. Gelinas J, Allukian M Jr (2014) Neurodevelopmental toxicity: still more questions than answers. Lancet Neurol 13(7):647–648

    PubMed  Article  Google Scholar

  62. Grandjean P, Landrigan PJ (2014) Neurobehavioural effects of developmental toxicity. Lancet Neurol 13(3):330–338

    CAS  PubMed  PubMed Central  Article  Google Scholar

  63. Green R, Lanphear B, Hornung R et al (2019) Association between maternal fluoride exposure during pregnancy and IQ scores in offspring in Canada. JAMA Pediatr 173(10):940–948

    PubMed Central  Article  Google Scholar

  64. Guo H, Kuang P, Luo Q et al (2017) Effects of sodium fluoride on blood cellular and humoral immunity in mice. Oncotarget 8(49):85504–85515

    PubMed  PubMed Central  Article  Google Scholar

  65. Gutknecht J, Walter A (1981) Hydrofluoric and nitric acid transport through lipid bilayer membranes. Biochim Biophys Acta 644(1):153–156

    CAS  PubMed  Article  Google Scholar

  66. Haojun Z, Yaoling W, Ke Z, Jin L, Junling W (2012) Effects of NaF on the expression of intracellular Ca2+ fluxes and apoptosis and the antagonism of taurine in murine neuron. Toxicol Mech Methods 22(4):305–308

    PubMed  Article  CAS  Google Scholar

  67. Heindel JJ, Bates HK, Price CJ, Marr MC, Myers CB, Schwetz BA (1996) Developmental toxicity evaluation of sodium fluoride administered to rats and rabbits in drinking water. Fundam Appl Toxicol 30(2):162–177

    CAS  PubMed  Article  Google Scholar

  68. Hibbeln JR, Davis JM, Steer C et al (2007) Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study. Lancet 369(9561):578–585

    PubMed  Article  Google Scholar

  69. Horgan AM, Lagrange MT, Copenhaver PF (1994) Developmental expression of G proteins in a migratory population of embryonic neurons. Development 120(4):729–742

    CAS  PubMed  Google Scholar

  70. IARC (1982) International Agency for Research on Cancer; Some aromatic amines, anthraquinones and nitroso compounds, and inorganic fluorides used in drinking-water and dental preparations. Lyon

  71. IPCS (2002) International programme on chemical safety; fluorides (Environmental Health Criteria 227). World Health Organization, Geneva

    Google Scholar

  72. Izquierdo-Vega JA, Sanchez-Gutierrez M, Del Razo LM (2008) Decreased in vitro fertility in male rats exposed to fluoride-induced oxidative stress damage and mitochondrial transmembrane potential loss. Toxicol Appl Pharmacol 230(3):352–357

    CAS  PubMed  Article  Google Scholar

  73. Jha M, Susheela AK, Krishna N, Rajyalakshmi K, Venkiah K (1982) Excessive ingestion of fluoride and the significance of sialic acid: glycosaminoglycans in the serum of rabbit and human subjects. J Toxicol Clin Toxicol 19(10):1023–1030

    CAS  PubMed  Article  Google Scholar

  74. Jortner BS (2006) The return of the dark neuron. A histological artifact complicating contemporary neurotoxicologic evaluation. Neurotoxicology 27(4):628–634

    CAS  PubMed  Article  Google Scholar

  75. Karimzade S, Aghaei M, Mahvi AH (2014) Investigation of intelligence quotient in 9–12-year-old children exposed to high and low-drinking water fluoride in West Azerbaijan province. Iran Fluoride 47(1):9–14

    Google Scholar

  76. Ke L, Zheng X, Sun Y, Ouyang W, Zhang Z (2016) Effects of sodium fluoride on lipid peroxidation and PARP, XBP-1 expression in PC12 cell. Biol Trace Elem Res 173(1):161–167

    CAS  PubMed  Article  Google Scholar

  77. Khan SA, Singh RK, Navit S et al (2015) Relationship between dental fluorosis and intelligence quotient of school going children in and around Lucknow district: a cross-sectional study. J Clin Diagn Res 9(11):10–15

    Google Scholar

  78. Knox EG (1985) Fluoridation of water and cancer: A review of the epidemiological evidence: Report of the working party. Her Majesty’s Stationery Office

  79. Koparal E, Ertugrul F, Oztekin K (2000) Fluoride levels in breast milk and infant foods. J Clin Pediatr Dent 24(4):299–302

    CAS  PubMed  Article  Google Scholar

  80. Kubota K, Lee DH, Tsuchiya M et al (2005) Fluoride induces endoplasmic reticulum stress in ameloblasts responsible for dental enamel formation. J Biol Chem 280(24):23194–23202

    CAS  PubMed  Article  Google Scholar

  81. Kundu H, Basavaraj P, Singla A, Gupta R, Singh K, Jain S (2015) Effect of fluoride in drinking water on children’s intelligence in high and low fluoride areas of Delhi. J Indian Assoc Public Health Dent 13(2):116–121

    Article  Google Scholar

  82. Lee J-H, Jung J-Y, Jeong Y-J et al (2008) Involvement of both mitochondrial-and death receptor-dependent apoptotic pathways regulated by Bcl-2 family in sodium fluoride-induced apoptosis of the human gingival fibroblasts. Toxicology 243(3):340–347

    CAS  PubMed  Article  Google Scholar

  83. Lee J, Han YE, Favorov O, Tommerdahl M, Whitsel B, Lee CJ (2016) Fluoride induces a volume reduction in CA1 hippocampal slices via map kinase pathway through volume regulated anion channels. Exp Neurobiol 25(2):72–78

    PubMed  PubMed Central  Article  Google Scholar

  84. Li H, Huang H, Xu Y, Gao Y, Liu Z (2010) Toxic effects of fluoride on rat cerebral cortex astrocytes in vitro. Wei Sheng Yan Jiu 39(1):86–88

    CAS  PubMed  Google Scholar

  85. Li X, Zhang J, Niu R, Manthari RK, Yang K, Wang J (2019) Effect of fluoride exposure on anxiety- and depression-like behavior in mouse. Chemosphere 215:454–460

    CAS  PubMed  Article  Google Scholar

  86. Lidbeck WL, Hill IB, Beeman JA (1943) Acute sodium fluoride poisoning. JAMA 121(11):826–827

    CAS  Article  Google Scholar

  87. Liu YJ, Guan ZZ, Gao Q, Pei JJ (2011) Increased level of apoptosis in rat brains and SH-SY5Y cells exposed to excessive fluoride–a mechanism connected with activating JNK phosphorylation. Toxicol Lett 204(2–3):183–189

    CAS  PubMed  Article  Google Scholar

  88. Marthaler TM (2013) Salt fluoridation and oral health. Acta Med Acad 42(2):140–155

    PubMed  Article  Google Scholar

  89. McPherson CA, Zhang G, Gilliam R et al (2018) An evaluation of neurotoxicity following fluoride exposure from gestational through adult ages in long-evans hooded rats. Neurotox Res 34(4):781–798

    CAS  PubMed  PubMed Central  Article  Google Scholar

  90. Mendoza-Schulz A, Solano-Agama C, Arreola-Mendoza L et al (2009) The effects of fluoride on cell migration, cell proliferation, and cell metabolism in GH4C1 pituitary tumour cells. Toxicol Lett 190(2):179–186

    CAS  PubMed  Article  Google Scholar

  91. Mesram N, Nagapuri K, Banala RR, Nalagoni CR, Karnati PR (2017) Quercetin treatment against NaF induced oxidative stress related neuronal and learning changes in developing rats. J King Saud Univ Sci 29:221–229

    Article  Google Scholar

  92. Mondal D, Dutta G, Gupta S (2016) Inferring the fluoride hydrogeochemistry and effect of consuming fluoride-contaminated drinking water on human health in some endemic areas of Birbhum district. West Bengal Environ Geochem Health 38(2):557–576

    CAS  PubMed  Article  Google Scholar

  93. Mustafa DE, Younis UM, Elhaga SAA (2018) The relationship between the fluoride levels in drinking water and the schooling performance of children in rural areas of Khartoum State. Sudan Fluoride 51(2):102–113

    CAS  Google Scholar

  94. Nagarajappa R, Pujara P, Sharda AJ et al (2013) Comparative assessment of intelligence quotient among children living in high and low fluoride areas of Kutch, India-a pilot study. Iran J Public Health 42(8):813–818

    PubMed  PubMed Central  Google Scholar

  95. Naik SP, Bankur PK, Sathe S, Haris PMM, Kadar N, Satyanarayan A (2018) Impact of fluoridated water on intelligence quotient levels of school children: a exploratory study. Int J Oral Care Res 6(1):63–66

    Google Scholar

  96. Nakamoto T, Rawls HR (2018) Fluoride exposure in early life as the possible root cause of disease in later life. J Clin Pediatr Dent 42(5):325–330

    PubMed  Article  Google Scholar

  97. Narayana MV, Chinoy NJ (1994) Effect of fluoride on rat testicular steroidogenesis. Fluoride 27(1):7–12

    CAS  Google Scholar

  98. Neelam K, Suhasini R, Sudhakar R (1987) Incidence of prevalence of infertility among married male members of endemic fluorosis district of Andhra Pradesh. In: Proceedings of a conference of the international society of fluoride research, Switzerland (Nyon) (Abstract)

  99. Nguyen Ngoc TD, Son YO, Lim SS et al (2012) Sodium fluoride induces apoptosis in mouse embryonic stem cells through ROS-dependent and caspase- and JNK-mediated pathways. Toxicol Appl Pharmacol 259(3):329–337

    CAS  PubMed  Article  Google Scholar

  100. NHMRC (2017a) National Health and Medical Research Council. Australian drinking water guidelines 6. Version 3.4. Updated October 2017. https://www.nhmrc.gov.au/sites/default/files/documents/reports/aust-drinking-water-guidelines.pdf.

  101. NHMRC (2017b) Water fluoridation and human health in Australia. National Health and Medical Research Council. Public Statement. https://www.nhmrc.gov.au/about-us/publications/2017-public-statement-water-fluoridation-and-human-health#block-views-block-file-attachments-content-block-1.

  102. NRC (2006) National Research Council; Fluoride in Drinking Water: A Scientific Review of EPA’s Standards. Committee on Fluoride in Drinking Water. Board on Environmental Studies and Toxicology. Division on Earth and Life Studies. The National Academy Press, Washington

  103. NTP (1990) National Toxicology Program. NTP technical report on the toxicology and carcinogenesis studies of sodium fluoride in F344/N Rats and B6C3F1 mice (drinking water studies). Washington, DC: Department of Health, Education, and Welfare, National Toxicology Program. NTP TR 393, NIH publication no. 90–2848.

  104. NTP (2015) National Toxicology Program. Neurobehavioral testing specifications. Research Triangle Park: National Toxicology Program. https://ntp.niehs.nih.gov/ntp/test_info/finalntp_neurospecs090415_508.pdf.

  105. NTP (2016) National Toxicology Program. Systematic literature review on the effects of fluoride on learning and memory in animal studies. NTP Research Report 1. Research Triangle Park, NC: National Toxicology Program.

  106. OECD (2007) Test No. 426: Developmental Neurotoxicity Study, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris.

  107. PHS (2015) U.S. Department of Health and Human Services Federal Panel on Community Water Fluoridation; U.S. Public Health Service recommendation for fluoride concentration in drinking water for the prevention of dental caries. Public Health Reports 130(4):318–331.

  108. Pratap SV, Singh CD, Sandeep T et al (2013) A correlation between Serum Vitamin, acetylcholinesterase activity and iq in children with excessive endemic fluoride exposure in Rajasthan. India Int Res J Medical Sci 1(3):12–16

    Google Scholar

  109. Pulungan ZSA, Sofro ZM, Partadiredja G (2018) Sodium fluoride does not affect the working memory and number of pyramidal cells in rat medial prefrontal cortex. Anat Sci Int 93(1):128–138

    CAS  PubMed  Article  Google Scholar

  110. Razdan P, Patthi B, Kumar JK, Agnihotri N, Chaudhari P, Prasad M (2017) Effect of fluoride concentration in drinking water on intelligence quotient of 12–14-year-old children in Mathura District: a cross-sectional study. J Int Soc Prev Community Dent 7(5):252–258

    PubMed  PubMed Central  Google Scholar

  111. Reddy PS, Pushpalatha T, Reddy PS (2007) Suppression of male reproduction in rats after exposure to sodium fluoride during early stages of development. Naturwissenschaften 94(7):607–611

    CAS  PubMed  Article  Google Scholar

  112. Rugg-Gunn AJ, Villa AE, Buzalaf MR (2011) Contemporary biological markers of exposure to fluoride. Monogr Oral Sci 22(37–5):1

    Google Scholar

  113. Sabour S, Ghorbani Z (2013) Developmental fluoride neurotoxicity: clinical importance versus statistical significance. Environ Health Perspect 121(3):70

    Article  Google Scholar

  114. Saxena S, Sahay A, Goel P (2012) Effect of fluoride exposure on the intelligence of school children in Madhya Pradesh. India J Neurosci Rural Pract 3(2):144–149

    PubMed  Article  Google Scholar

  115. SCHER (2011) Scientific Committee on Health and Environmental Risks of the European Union; Critical review of any new evidence on the hazard profile, health effects, and human exposure to fluoride and the fluoridating agents of drinking water.

  116. Schleyer R, Kerndorf H (1992) Die Grundwasserqualität westdeutscher Trinkwasserreserven. VCH, Weinheim

    Google Scholar

  117. Schmidt C, Funke U (1984) Renale Fluoridausscheidung nach Belastung mit Schwarzem Tee. Z Aerztl Fortbild 78:364–367

    Google Scholar

  118. Schwarz K, Milne DB (1972) Fluorine requirement for growth in the rat. Bioinorg Chem 1(4):331–338

    Article  Google Scholar

  119. Schwarze PE, Lag M, Becher R et al (2000) Role of signal transduction pathways in lung inflammatory responses. Toxicol Lett 112–113:165–170

    PubMed  Article  Google Scholar

  120. Sebastian ST, Sunitha S (2015) A cross-sectional study to assess the intelligence quotient (IQ) of school going children aged 10–12 years in villages of Mysore district, India with different fluoride levels. J Indian Soc Pedod Prev Dent 33(4):307–311

    PubMed  Article  Google Scholar

  121. Seraj B, Shahrabi M, Shadfar M et al (2012) Effect of high water fluoride concentration on the intellectual development of children in makoo/iran. J Dent (Tehran) 9(3):221–229

    CAS  Google Scholar

  122. Shan KR, Qi XL, Long YG, 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(2–3):169–177

    CAS  PubMed  Article  Google Scholar

  123. Sharma C, Suhalka P, Bhatnagar M (2018) Curcumin and resveratrol rescue cortical-hippocampal system from chronic fluoride-induced neurodegeneration and enhance memory retrieval. Int J Neurosci 128(11):1007–1021

    CAS  PubMed  Article  Google Scholar

  124. Sharma C, Suhalka P, Bhatnagar M (2018) Curcumin and resveratrol rescue cortical-hippocampal system from chronic fluoride-induced neurodegeneration and enhance memory retrieval. Int J Neurosci 2018:1–15

    Google Scholar

  125. Sharma P, Bhardwaj AK, Singh M, Kumar D, Sharma A, Grover A (2018) Does fluorosis affect the intelligence profile of children? A cross sectional analysis of school children of district Una, Himachal Pradesh, India. Int J Community Med Public Health 5(3):1047–1053

    Article  Google Scholar

  126. Sharma P, Singh M, Kumar D, Grover A, Bhardwaj AK (2016) Effect of fluoride exposure through drinking water on the oral health status and intelligence profile of school children of District Una, Himachal Pradesh: an interim analysis. J Evol Med Dent Sci 5(102).

    Article  Google Scholar

  127. Shashi A, Kumar J (2016) Neuropathological changes in hippocampus in albino rat in fluoride toxicity. Inter J Basic and Appl Med Sc 6:17–25

    Google Scholar

  128. Shen YW, Taves DR (1974) Fluoride concentrations in the human placenta and maternal and cord blood. Am J Obstet Gynecol 119(2):205–207

    CAS  PubMed  Article  Google Scholar

  129. Shuhua X, Ziyou L, Ling Y, Fei W, Sun G (2012) A role of fluoride on free radical generation and oxidative stress in BV-2 microglia cells. Mediators Inflamm 2012(2–3):Article ID 102954.

    Article  CAS  Google Scholar

  130. Simpson E, Rao LG, Evans RM, Wilkie W, Rodger JC, Lakhani A (1980) Calcium metabolism in a fatal case of sodium fluoride poisoning. Ann Clin Biochem 17(1):10–14

    CAS  PubMed  Article  Google Scholar

  131. Sprando RL, Collins TF, Black T, Olejnik N, Rorie J (1998) Testing the potential of sodium fluoride to affect spermatogenesis: a morphometric study. Food Chem Toxicol 36(12):1117–1124

    CAS  PubMed  Article  Google Scholar

  132. Sprando RL, Collins TF, Black TN, Rorie J, Ames MJ, O’Donnell M (1997) Testing the potential of sodium fluoride to affect spermatogenesis in the rat. Food Chem Toxicol 35(9):881–890

    CAS  PubMed  Article  Google Scholar

  133. Sun Z, Zhang Y, Xue X, Niu R, Wang J (2018) Maternal fluoride exposure during gestation and lactation decreased learning and memory ability, and glutamate receptor mRNA expressions of mouse pups. Hum Exp Toxicol 37(1):87–93

    CAS  PubMed  Article  Google Scholar

  134. Susheela AK, Das TK (1988) Chronic fluoride toxicity: a scanning electron microscopic study of duodenal mucosa. J Toxicol Clin Toxicol 26(7):467–476

    CAS  PubMed  Article  Google Scholar

  135. Susheela AK, Jain SK (1983) Fluoride-induced haematological changes in rabbits. Bull Environ Contam Toxicol 30(4):388–393

    CAS  PubMed  Article  Google Scholar

  136. Susheela AK, Kumar A (1991) A study of the effect of high concentrations of fluoride on the reproductive organs of male rabbits, using light and scanning electron microscopy. J Reprod Fertil 92(2):353–360

    CAS  PubMed  Article  Google Scholar

  137. Sutton M, Kiersey R, Farragher L, Long J (2015) Health effects of water fluoridation. An evidence review. Health Research Board, Ireland. https://www.hrb.ie/fileadmin/publications_files/Health_Effects_of_Water_Fluoridation.pdf.

  138. Tang S, Zhang S, Chen W et al (2017) Effects of fluoride on autophagy level in human neuroblastoma SH-SY5Y cells. Wei Sheng Yan Jiu 46(3):472–480

    PubMed  Google Scholar

  139. Taves DR (1983) Dietary intake of fluoride ashed (total fluoride) v. unashed (inorganic fluoride) analysis of individual foods. Br J Nutr 49(3):295–301

    CAS  PubMed  Article  Google Scholar

  140. Taves DR, Forbes N, Silverman D, Hicks D (1983) Inorganic fluoride concentrations in human and animal tissues. Fluorides: Effects on Vegetation, Animals and Humans Ed Shupe J, Peterson, H, Leone, N Paragon Press, Salt Lake City, Utah, USA:189–193.

  141. Teng Y, Zhang J, Zhang Z, Feng J (2018) The effect of chronic fluorosis on calcium ions and CaMKIIalpha, and c-fos expression in the rat hippocampus. Biol Trace Elem Res 182(2):295–302

    CAS  PubMed  Article  Google Scholar

  142. Tu W, Zhang Q, Liu Y et al (2018) Fluoride induces apoptosis via inhibiting SIRT1 activity to activate mitochondrial p53 pathway in human neuroblastoma SH-SY5Y cells. Toxicol Appl Pharmacol 347:60–69

    CAS  PubMed  Article  Google Scholar

  143. Villa A, Anabalon M, Zohouri V, Maguire A, Franco AM, Rugg-Gunn A (2010) Relationships between fluoride intake, urinary fluoride excretion and fluoride retention in children and adults: an analysis of available data. Caries Res 44(1):60–68

    CAS  PubMed  Article  Google Scholar

  144. Wang J, Zhang Y, Guo Z et al (2018) Effects of perinatal fluoride exposure on the expressions of miR-124 and miR-132 in hippocampus of mouse pups. Chemosphere 197:117–122

    CAS  PubMed  Article  Google Scholar

  145. Wei N, Li Y, Deng J, Xu S, Guan Z (2014) The effects of comprehensive control measures on intelligence of school-age children in coal-burning borne endemic fluorosis areas. Chin J Endem 33(3):320–322

    Google Scholar

  146. Whitford GM (1990) The physiological and toxicological characteristics of fluoride. J Dent Res 69(2):539–549 (Discussion 556-547)

    CAS  PubMed  Article  Google Scholar

  147. Whitford GM (1996) Soft tissue distribution of fluoride. In: The Metabolism and Toxicity of Fluoride. Monogr Oral Sci. Myers H.M. (Ed); Basel, Karger, vol 16.

  148. Whitford GM, Pashley DH, Reynolds KE (1979) Fluoride tissue distribution: short-term kinetics. Am J Physiol 236(2):F141–F148

    CAS  PubMed  Google Scholar

  149. Whitford GM, Sampaio FC, Pinto CS, Maria AG, Cardoso VE, Buzalaf MA (2008) Pharmacokinetics of ingested fluoride: lack of effect of chemical compound. Arch Oral Biol 53(11):1037–1041

    CAS  PubMed  Article  Google Scholar

  150. WHO (2011) World Health Organization. Guidelines for drinking-water quality. Fourth edition. https://www.who.int/water_sanitation_health/publications/2011/dwq_guidelines/en/.

  151. WHO (2017) Guidelines for drinking-water quality. Fourth Edition incorporating the first Addendum. https://apps.who.int/iris/bitstream/handle/10665/254637/9789241549950-eng.pdf?sequence=1.

  152. Xia T, Zhang M, He WH, He P, Wang AG (2007) Effects of fluoride on neural cell adhesion molecules mRNA and protein expression levels in primary rat hippocampal neurons. Zhonghua Yu Fang Yi Xue Za Zhi 41(6):475–478

    CAS  PubMed  Google Scholar

  153. Xu B, Xu Z, Xia T et al (2011) Effects of the Fas/Fas-L pathway on fluoride-induced apoptosis in SH-SY5Y cells. Environ Toxicol 26(1):86–92

    CAS  PubMed  Article  Google Scholar

  154. Xu Z, Xu B, Xia T et al (2013) Relationship between intracellular Ca(2)(+) and ROS during fluoride-induced injury in SH-SY5Y cells. Environ Toxicol 28(6):307–312

    CAS  PubMed  Article  Google Scholar

  155. Yan L, Liu S, Wang C et al (2013) JNK and NADPH oxidase involved in fluoride-induced oxidative stress in BV-2 microglia cells. Mediators Inflamm 2013:895975

    PubMed  PubMed Central  Article  CAS  Google Scholar

  156. Yan N, Liu Y, Liu S et al (2016) Fluoride-induced neuron apoptosis and expressions of inflammatory factors by activating microglia in rat brain. Mol Neurobiol 53(7):4449–4460

    CAS  PubMed  Article  Google Scholar

  157. Yan Q, Zhang Y, Li W, Denbesten PK (2007) Micromolar fluoride alters ameloblast lineage cells in vitro. J Dent Res 86(4):336–340

    CAS  PubMed  Article  Google Scholar

  158. Yang L, Jin P, Wang X, Zhou Q, Lin X, Xi S (2018) Fluoride activates microglia, secretes inflammatory factors and influences synaptic neuron plasticity in the hippocampus of rats. Neurotoxicology 69:108–120

    CAS  PubMed  Article  Google Scholar

  159. Yu X, Chen J, Li Y et al (2018) Threshold effects of moderately excessive fluoride exposure on children’s health: A potential association between dental fluorosis and loss of excellent intelligence. Environ Int 118:116–124

    CAS  PubMed  Article  Google Scholar

  160. Zhang M, Wang A, He W et al (2007) Effects of fluoride on the expression of NCAM, oxidative stress, and apoptosis in primary cultured hippocampal neurons. Toxicology 236(3):208–216

    CAS  PubMed  Article  Google Scholar

  161. Zhang M, Wang A, Xia T, He P (2008) Effects of fluoride on DNA damage, S-phase cell-cycle arrest and the expression of NF-kappaB in primary cultured rat hippocampal neurons. Toxicol Lett 179(1):1–5

    CAS  PubMed  Article  Google Scholar

  162. Zhang S, Jiang C, Liu H et al (2013) Fluoride-elicited developmental testicular toxicity in rats: roles of endoplasmic reticulum stress and inflammatory response. Toxicol Appl Pharmacol 271(2):206–215

    CAS  PubMed  Article  Google Scholar

  163. Zhang S, Niu Q, Gao H et al (2016) Excessive apoptosis and defective autophagy contribute to developmental testicular toxicity induced by fluoride. Environ Pollut 212:97–104

    CAS  PubMed  Article  Google Scholar

  164. Zhang S, Zhang X, Liu H et al (2015) Modifying effect of COMT gene polymorphism and a predictive role for proteomics analysis in children’s intelligence in endemic fluorosis area in Tianjin. China Toxicol Sci 144(2):238–245

    CAS  PubMed  Article  Google Scholar

  165. Zhang S, Zheng X, Sun Y, Wang Y, Zhang Z (2015) Alterations in oxidative stress and apoptosis in cultured PC12 cells exposed to fluoride. Fluoride 48(3):213–222

    CAS  Google Scholar

  166. Zhao L, Zhang S, An X et al (2015) Sodium fluoride affects dna methylation of imprinted genes in mouse early embryos. Cytogenet Genome Res 147(1):41–47

    PubMed  Article  CAS  Google Scholar

  167. Zhao Q, Niu Q, Chen J et al (2019) Roles of mitochondrial fission inhibition in developmental fluoride neurotoxicity: mechanisms of action in vitro and associations with cognition in rats and children. Arch Toxicol 93(3):709–726

    CAS  PubMed  Article  Google Scholar

  168. Zhu JQ, Si YJ, Cheng LY et al (2014) Sodium fluoride disrupts DNA methylation of H19 and Peg3 imprinted genes during the early development of mouse embryo. Arch Toxicol 88(2):241–248

    CAS  PubMed  Article  Google Scholar

Acknowledgements

Open Access funding provided by Projekt DEAL. This study was an activity of the Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG). The authors wish to thank the DFG for their continuous support of the SKLM Commission.