The continuous rise of autism spectrum disorder (ASD) prevalent in the past few decades is causing an increase in public health and socioeconomic concern. A consensus suggests the involvement of both genetic and environmental factors in the ASD etiopathogenesis. Fluoride (F) is rarely recognized among the environmental risk factors of ASD, since the neurotoxic effects of F are not generally accepted. Our review aims to provide evidence of F neurotoxicity. We assess the risk of chronic F exposure in the ASD etiopathology and investigate the role of metabolic and mitochondrial dysfunction, oxidative stress and inflammation, immunoexcitotoxicity, and decreased melatonin levels. These symptoms have been observed both after chronic F exposure as well as in ASD. Moreover, we show that F in synergistic interactions with aluminum's free metal cation (Al3+) can reinforce the pathological symptoms of ASD. This reinforcement takes place at concentrations several times lower than when acting alone. A high ASD prevalence has been reported from countries with water fluoridation as well as from endemic fluorosis areas. We suggest focusing the ASD prevention on the reduction of the F and Al3+ burdens from daily life.

The Institute of Technology and Business Okružní 517 10 370 01 České Budějovice Czech Republic

See more in PubMed

American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-5®) [(accessed on 23 May 2019)]; Available online: https://books.google.cz/books?id=-JivBAAAQBAJ.

World Health Organization Autism Spectrum Disorders. [(accessed on 23 May 2019)]; Available online: https://www.who.int/news-room/fact-sheets/detail/autism-spectrum-disorders.

Centers for Disease Control and Prevention (CDC) Data & Statistics on Autism Spectrum Disorder. U.S. Department of Health & Human Services; Atlanta, GA, USA: 2018.

World Health Organization ICD-11 for Mortality and Morbidity Statistics. [(accessed on 25 May 2019)]; Available online: https://icd.who.int/browse11/l-m/en.

Kogan M.D., Vladutiu C.J., Schieve L.A., Ghandour R.M., Blumberg S.J., Zablotsky B., Perrin J.M., Shattuck P., Kuhlthau K.A., Harwood R.L., et al. The prevalence of parent-reported autism spectrum disorder among US children. Pediatrics. 2018;142:e20174161. doi: 10.1542/peds.2017-4161. PubMed DOI PMC

Almandil N.B., Alkuroud D.N., Abdul Azeez S., Al Sulaiman A., Elaissari A., Borgio J.F. Environmental and genetic factors in autism spectrum disorders: Special emphasis on data from arabian studies. Int. J. Environ. Res. Public Health. 2019;16:658. doi: 10.3390/ijerph16040658. PubMed DOI PMC

Strunecká A., Strunecký O., Guan Z. The resemblance of fluorosis pathology to that of autism spectrum disorder: A mini-review. Fluoride. 2019;52:105–115.

Elsabbagh M., Divan G., Koh Y.-J., Kim Y.S., Kauchali S., Marcín C., Montiel-Nava C., Patel V., Paula C.S., Wang C., et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 2012;5:160–179. doi: 10.1002/aur.239. PubMed DOI PMC

Øzerk K. The issue of prevalence of autism. IEJEE. 2017;9:263–306.

European Commission Health & Consumer Protection Directorate-General . Some Elements About the Prevalence of Autism Spectrum Disorders (ASD) in the European Union. European Commission; Luxembourg: 2005. 16p

Strunecka A., Blaylock R.L., Patocka J., Strunecky O. Immunoexcitotoxicity as the central mechanism of etiopathology and treatment of autism spectrum disorders: A possible role of fluoride and aluminum. Surg. Neurol. Int. 2018;9:74. doi: 10.4103/sni.sni_407_17. PubMed DOI PMC

Strunecka A., Patocka J. Pharmacological and toxicological effects of aluminofluoride complexes. Fluoride. 1999;32:230–242.

Strunecka A., Strunecky O., Patocka J. Fluoride plus aluminum: The useful tools in laboratory investigations, but messengers of the false information. Physiol. Res. 2002;51:557–564. PubMed

Strunecka A., Patocka J., Blaylock R., Chinoy N. Fluoride interactions: From molecules to disease. Curr. Signal Transduct. Ther. 2007;2:190–213. doi: 10.2174/157436207781745300. DOI

European Food Safety Authority . Dietary Reference Values for Nutrients Summary Report. European Food Safety Authority; Parma, Italy: 2017. DOI

Luke J. Ph.D. Thesis. University of Surrey; Guildford, UK: 1997. The Effect of Fluoride on the Physiology of the Pineal Gland.

Pagan C., Delorme R., Callebert J., Goubran-Botros H., Amsellem F., Drouot X., Boudebesse C., Le Dudal K., Ngo-Nguyen N., Laouamri H., et al. The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders. Transl. Psychiatry. 2014;4:e479. doi: 10.1038/tp.2014.120. PubMed DOI PMC

Burgstahler A.W. Paradoxical dose-response effects of fluoride. Fluoride. 2002;35:143–147.

Strunecka A., Blaylock R.L., Hyman M.A., Paclt I. Cellular and Molecular Biology of Autism Spectrum Disorders. Bentham e Books Bentham Science; Sharjah, UEA: 2010. DOI

Hassan M.H., Desoky T., Sakhr H.M., Gabra R.H., Bakri A.H. Possible metabolic alterations among autistic male children: Clinical and biochemical approaches. J. Mol. Neurosci. 2019;67:204–216. doi: 10.1007/s12031-018-1225-9. PubMed DOI

Delhey L., Kilinc E.N., Yin L., Slattery J., Tippett M., Wynne R., Rose S., Kahler S., Damle S., Legido A., et al. Bioenergetic variation is related to autism symptomatology. Metab. Brain Dis. 2017;32:2021–2031. doi: 10.1007/s11011-017-0087-0. PubMed DOI PMC

Rose S., Niyazov D.M., Rossignol D.A., Goldenthal M., Kahler S.G., Frye R.E. Clinical and Molecular Characteristics of Mitochondrial Dysfunction in Autism Spectrum Disorder. Mol. Diagn. Ther. 2018;22:571–593. doi: 10.1007/s40291-018-0352-x. PubMed DOI PMC

Bennuri S.C., Rose S., Frye R.E. Mitochondrial dysfunction is inducible in lymphoblastoid cell lines from children with autism and may involve the TORC1 pathway. Front. Psychiatry. 2019;10:269. doi: 10.3389/fpsyt.2019.00269. PubMed DOI PMC

Sternweis P.C., Gilman A.G. Aluminum: A requirement for activation of the regulatory component of adenylate cyclase by fluoride. Proc. Natl. Acad. Sci. USA. 1982;79:4888–4891. doi: 10.1073/pnas.79.16.4888. PubMed DOI PMC

Chabre M. Aluminofluoride and beryllofluoride complexes: New phosphate analogues in enzymology. Trends Biochem. Sci. 1990;15:6–10. doi: 10.1016/0968-0004(90)90117-T. PubMed DOI

Wittinghofer A. Aluminum fluoride for molecule of the year. Curr. Biol. 1997;7:682–690. doi: 10.1016/S0960-9822(06)00355-1. PubMed DOI

Tesmer J.J., Berman D.M., Gilman A.G., Sprang S.R. Structure of RGS4 bound to AlF4- activated Gi1: stabilization of the transition state for GTP hydrolysis. Cell. 1997;89:251–261. doi: 10.1016/S0092-8674(00)80204-4. PubMed DOI

Schlichting I., Reinstein J. pH influences fluoride coordination number of the AlFx phosphoryl transfer transition state analog. Nat. Struct. Biol. 1999;8:721–723. doi: 10.1038/11485. PubMed DOI

Sondek J., Lambright D.G., Noel J.P., Hamm H.E., Sigler P.B. GTPase mechanism of G proteins from the 1.7-Åcrystal structure of transducing α-GDP·AlF4−. Nature. 1994;372:276–279. doi: 10.1038/372276a0. PubMed DOI

Rosenbaum D.M., Rasmussen S.G.F., Kobilka B.K. The structure and function of G-protein-coupled receptors. Nature. 2009;459:356. doi: 10.1038/nature08144. PubMed DOI PMC

Rossignol D.A., Frye R.E. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front. Physiol. 2014;5:150. doi: 10.3389/fphys.2014.00150. PubMed DOI PMC

Rose S., Melnyk S., Pavliv O., Bai S., Nick T.G., Frye R.E., James S.J. Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl. Psychiatry. 2012;2:e134. doi: 10.1038/tp.2012.61. PubMed DOI PMC

Frye R.E., James S.J. Metabolic pathology of autism in relation to redox metabolism. Biomark. Med. 2014;8:321–330. doi: 10.2217/bmm.13.158. PubMed DOI

Strunecka A., editor. Cellular and Molecular Biology of Autism Spectrum Disorders. Bentham e Books Bentham Science; Sharjah, UEA: 2010. Biochemical Changes in ASD; pp. 100–120. DOI

Guan Z., Yang P., Su Y., Wang Y. Changed levels of lipid peroxidation and anti-oxidation in blood of children in the area of fluoride and aluminium toxication in Shuichen County of Guizhou. J. Guiyang Med. Coll. 1991;16:198–200. (In Chinese)

Belardo A., Gevi F., Zolla L. The concomitant lower concentrations of vitamins B6, B9 and B12 may cause methylation deficiency in autistic children. J. Nutr. Biochem. 2019;70:38–46. doi: 10.1016/j.jnutbio.2019.04.004. PubMed DOI

Nardone S., Sams D.S., Reuveni E., Getselter D., Oron O., Karpuj M., Elliott E. DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Transl. Psychiatry. 2014;4:e433. doi: 10.1038/tp.2014.70. PubMed DOI PMC

Blaylock R.L. The Cerebellum in Autism Spectrum Disorders. In: Strunecka A., editor. Cellular and Molecular Biology of Autism Spectrum Disorders. Bentham e Books Bentham Science; Sharjah, UEA: 2010. pp. 17–31. DOI

Vargas D.L., Nascimbene C., Krishnan C., Zimmerman A.W., Pardo C.A. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 2005;57:67–81. doi: 10.1002/ana.20315. PubMed DOI

Blaylock R.L. Excitotoxicity: A possible central mechanism in fluoride neurotoxicity. Fluoride. 2004;37:301–314.

Blaylock R.L. A possible central mechanism in autism spectrum disorders, part 1. Altern. Ther. Health M. 2008;14:46–53. PubMed

Strunecka A., Blaylock R.L., Strunecky O. Fluoride, aluminum, and aluminofluoride complexes in pathogenesis of the autism spectrum disorders: A possible role of immunoexcitotoxicity. J. Appl. Biomed. 2016;14:171–176. doi: 10.1016/j.jab.2016.04.001. DOI

Luke J. Fluoride deposition in the aged human pineal gland. Caries Res. 2001;35:125–128. doi: 10.1159/000047443. PubMed DOI

Veatch O.J., Goldman S.E., Adkins K.W., Malow B.A. Melatonin in children with autism spectrum disorders: How does the evidence fit together? J. Nat. Sci. 2015;1:e125. PubMed PMC

Pagan C., Goubran-Botros H., Delorme R., Benabou M., Lemiere N., Murray K., Amsellem F., Callebert J., Chaste P., Jamain S., et al. Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders. Sci. Rep. 2017;7:2096. doi: 10.1038/s41598-017-02152-x. PubMed DOI PMC

Lu F., Zhang Y., Trivedi A., Jiang X., Chandra D., Zheng J., Nakano Y., Abduweli Uyghurturk D., Jalai R., Onur S.G., et al. Fluoride related changes in behavioral outcomes may relate to increased serotonin. Physiol. Behav. 2019;206:76–83. doi: 10.1016/j.physbeh.2019.02.017. PubMed DOI PMC

Ho B.T., McIsaac W.M., Tansey L.W. Hydroxyindole-O-methyltransferase III: Influence of the phenyl moiety on the inhibitory activities of some n-acyltryptamines. J. Pharm. Sci. 1969;58:563–566. doi: 10.1002/jps.2600580508. PubMed DOI

Tordjman S., Anderson G.M., Bellissant E., Botbol M., Charbuy H., Camus F., Graignic R., Kermarrec S., Fougerou C., Cohen D., et al. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology. 2012;37:1990–1997. doi: 10.1016/j.psyneuen.2012.04.013. PubMed DOI

Johansson A.E.E., Dorman J.S., Chasens E.R., Feeley C.A., Devlin B. Variations in genes related to sleep patterns in children with autism spectrum disorder. Biol. Res. Nurs. 2019;21:335–342. doi: 10.1177/1099800419843604. PubMed DOI

UNICEF Fluoride in water: An overview. WATERfront. 1999;13:11–13.

Spittle B. Fluoride Fatigue: Fluoride Poisoning: Is Fluoride in your Drinking Water, and from Other Sources, Making you Sick? Paua Press Limited; Dunedin, New Zealand: 2008. p. 78.

McClure F.J. A review of fluorine and its physiological effects. Physiol. Rev. 1933;13:277–300. doi: 10.1152/physrev.1933.13.3.277. DOI

Waldbott G., Burgstahler A., McKinney H. Fluoridation: The great dilemma. Ann. Intern. Med. 1979;90:291. doi: 10.7326/0003-4819-90-2-291_7. DOI

Carlsson A. Current problems of the pharmacology and toxicology of fluorides. Lakartidningen. 1978;75:1388–1392. PubMed

Mullenix P.J., Denbesten P.K., Schunior A., Kernan W.J. Neurotoxicity of sodium fluoride in rats. Neurotoxicol. Teratol. 1995;17:169–177. doi: 10.1016/0892-0362(94)00070-T. PubMed DOI

Du L. The effect of fluorine on the developing human brain. Chin. J. Pathol. 1992;21:218–220. PubMed

Tang Q.Q., Du J., Ma H.H., Jiang S.J., Zhou X.J. Fluoride and children’s intelligence: A meta-analysis. Biol. Trace. Elem. Res. 2008;126:115–120. doi: 10.1007/s12011-008-8204-x. PubMed DOI

Choi A.L., Sun G., Zhang Y., Grandjean P. Developmental fluoride neurotoxicity: A systematic review and meta-analysis. Environ. Health Perspect. 2012;120:1362–1368. doi: 10.1289/ehp.1104912. PubMed DOI PMC

Grandjean P., Landrigan P.J. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014;13:330–338. doi: 10.1016/S1474-4422(13)70278-3. PubMed DOI PMC

Rocha-Amador D., Navarro M.E., Carrizales L., Morales R., Calderon J. Decreased intelligence in children and exposure to fluoride and arsenic in drinking water. Cad. Saude Publ. 2007;23(Suppl. 4):S579–S587. doi: 10.1590/S0102-311X2007001600018. PubMed DOI

Seraj B., Shahrabi M., Shadfar M., Ahmadi R., Fallahzadeh M., Eslamlu H.F., Kharazifard M.J. Effect of high water fluoride concentration on the intellectual development of children in Makoo-Iran. J. Dent. (Tehran) 2012;9:221–229. PubMed PMC

Aravind A., Dhanya R.S., Narayan A., Sam G., Adarsh V.J., Kiran M. Effect of fluoridated water on intelligence in 10–12-year-old school children. J. Int. Soc. Prev. Community Dent. 2016;6:S237–S242. doi: 10.4103/2231-0762.197204. PubMed DOI PMC

Yu X., Chen J., Li Y., Liu H., Hou C., Zeng Q., Cui Y., Zhao L., Li P., Zhou Z., et al. Threshold effects of moderately excessive fluoride exposure on children’s health: A potential association between dental fluorosis and loss of excellent intelligence. Environ. Int. 2018;118:116–124. doi: 10.1016/j.envint.2018.05.042. PubMed DOI

Razdan P., Patthi B., Kumar J.K., Agnihotri N., Chaudhari P., Prasad M. 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. 2017;7:252–258. doi: 10.4103/jispcd.JISPCD_201_17. PubMed DOI PMC

Duan Q., Jiao J., Chen X., Wang X. Association between water fluoride and the level of children’s intelligence: A dose-response meta-analysis. Public Health. 2018;154:87–97. doi: 10.1016/j.puhe.2017.08.013. PubMed DOI

Bashash M., Thomas D., Hu H., Martinez-Mier E.A., Sanchez B.N., Basu N., Peterson K.E., Ettinger A.S., Wright R., Zhang Z., et al. Prenatal Fluoride Exposure and Cognitive Outcomes in Children at 4 and 6–12 Years of Age in Mexico. Environ. Health Perspect. 2017;125:097017. doi: 10.1289/EHP655. PubMed DOI PMC

Green R., Lanphear B., Hornung R., Flora D., Martinez-Mier E.A., Neufeld R., Ayotte P., Muckle G., Till C. Association between maternal fluoride exposure during pregnancy and IQ scores in offspring in Canada. JAMA Pediatr. 2019 doi: 10.1001/jamapediatrics.2019.1729. PubMed DOI PMC

Hirzy J.W., Connett P., Xiang Q., Spittle B., Kennedy D. Developmental Neurotoxicity of Fluoride: A Quantitative Risk Analysis Toward Establishing a Safe Dose for Children. In: McDuffie J.E., editor. Neurotoxins. IntechOpen; London, UK: 2017. pp. 115–132. DOI

Bellinger D.C. Environmental chemical exposures and neurodevelopmental impairments in children. Ped. Med. 2018;1:9. doi: 10.21037/pm.2018.11.03. DOI

Onaolapo A.Y., Onaolapo O.J. Global Data on Autism Spectrum Disorders Prevalence: A Review of Facts, Fallacies and Limitations. Univ.J. Clin. Med. 2017;5:14–23. doi: 10.13189/ujcm.2017.050202. DOI

Adak B., Halder S. Systematic review on prevalence for autism spectrum disorder with respect to gender and socio-economic status. J. Ment. Dis. Treat. 2017;3 doi: 10.4172/2471-271X.1000133. DOI

Baio J., Wiggins L., Christensen D.L., Maenner M.J., Daniels J., Warren Z., Kurzius-Spencer M., Zahorodny W., Robinson Rosenberg C., White T., et al. Prevalence of autism spectrum disorder among children aged 8 years—Autism and developmental disabilities monitoring network, 11 Sites, United States, 2014. MMWR Surveill. Summ. 2018;67:1–23. doi: 10.15585/mmwr.ss6706a1. PubMed DOI PMC

Wiener R.C., Shen C., Findley P., Tan X., Sambamoorthi U. Dental fluorosis over time: A comparison of national health and nutrition examination survey data from 2001–2002 and 2011–2012. J. Dent. Hyg. 2018;92:23–29. PubMed PMC

Neurath C., Limeback H., Osmunson B., Connett M., Kanter V., Wells C.R. Dental fluorosis trends in US oral health surveys: 1986 to 2012. JDR Clin. Trans. Res. 2019 doi: 10.1177/2380084419830957. PubMed DOI

Autism Spectrum Disorder Among Children and Youth in Canada. [(accessed on 1 June 2019)]; Available online: https://www.canada.ca/en/public-health/services/publications/diseases-conditions/autism-spectrum-disorder-children-youth-canada-2018.html.

Prevalence of Autism Spectrum Disorder Among Children in Select Countries Worldwide as of 2018 (per 10,000 Children) [(accessed on 9 August 2019)]; Available online: https://www.statista.com/statistics/676354/autism-rate-among-children-select-countries-worldwide/

Australian Institute of Health and Welfare Autism in Australia. [(accessed on 25 June 2019)]; Available online: https://www.aihw.gov.au/reports/disability/autism-in-australia/contents/autism.

Ministries of Health and Education . New Zealand Autism Spectrum Disorder Guideline. Ministry of Health; Wellington, New Zealand: 2016. 343p

Spittle B. Green light for water fluoridation in New Zealand. Fluoride. 2015;48:271–273.

Waugh D.T., Godfrey M., Limeback H., Potter W. Black tea source, production, and consumption: Assessment of health risks of fluoride intake in New Zealand. J. Environ. Public Health. 2017;2017:5120504. doi: 10.1155/2017/5120504. PubMed DOI PMC

Sun D.J., Gao Y.H., Zhao L.J. Epidemic and control of endemic fluorosis in China; Proceedings of the XXXIVth conference of the International Society for Fluoride Research; Guiyang, China. 18–20 October 2018; Fluoride2019, 52, 79–80.

Jin T.X., Hua Z., Guan Z.Z. The historical review and development strategies on prevention and control of coal-burning type of endemic fluorosis in Liupanshui, Guizhou of China; Proceedings of the XXXIVth conference of the International Society for Fluoride Research; Guiyang, China. 18–20 October 2018; Fluoride2019, 52, 94–95.

Wang F., Lu L., Wang S.-B., Zhang L., Ng C.H., Ungvari G.S., Cao X.-L., Lu J.-P., Hou C.-L., Jia F.-J., et al. The prevalence of autism spectrum disorders in China: A comprehensive meta-analysis. Int. J. Biol. Sci. 2018;14:717–725. doi: 10.7150/ijbs.24063. PubMed DOI PMC

Sun X., Allison C., Wei L., Matthews F., Auyeung B., Yu Wu Y., Griffiths S., Zhang J., Baron-Cohen S., Brayne C. Autism prevalence in China is comparable to Western prevalence. Mol. Autism. 2019;10 doi: 10.1186/s13229-018-0246-0. PubMed DOI PMC

Saito M., Hirota T., Sakamoto Y., Adachi M., Takahashi M., Osato-Kaneda A., Kim Y.S., Leventhal B., Shui A., Kato S., et al. Prevalence and cumulative incidence of autism spectrum disorders and the patterns of co-occurring neurodevelopmental disorders in a total population sample of 5-years-old children. [(accessed on 28 March 2019)];Lancet. 2019 in press. Available online: https://ssrn.com/abstract=3360118. PubMed PMC

Dean H.T. Endemic fluorosis and its relation to dental caries, 1938. Public Health Rep. 2006;121(Suppl. 1):213–219; discussion 212. PubMed

Komiyama K., Kimoto K., Taura K., Sakai O. National survey on school-based fluoride mouth-rinsing programme in Japan: Regional spread conditions from preschool to junior high school in 2010. Int. Dent. J. 2014;64:127–137. doi: 10.1111/idj.12068. PubMed DOI PMC

Hossain M.D., Ahmed H.U., Jalal Uddin M.M., Chowdhury W.A., Iqbal M.S., Kabir R.I., Chowdhury I.A., Aftab A., Datta P.G., Rabbani G., et al. Autism spectrum disorders (ASD) in South Asia: A systematic review. BMC Psychiatry. 2017;17:281. doi: 10.1186/s12888-017-1440-x. PubMed DOI PMC

Rudra A., Belmonte M.K., Soni P.K., Banerjee S., Mukerji S., Chakrabarti B. Prevalence of autism spectrum disorder and autistic symptoms in a school-based cohort of children in Kolkata, India. Autism Res. 2017;10:1597–1605. doi: 10.1002/aur.1812. PubMed DOI PMC

Kim Y.S., Leventhal B.L., Koh Y.J., Fombonne E., Laska E., Lim E.C., Cheon K.A., Kim S.J., Kim Y.K., Lee H., et al. Prevalence of autism spectrum disorders in a total population sample. Am. J. Psychiatry. 2011;168:904–912. doi: 10.1176/appi.ajp.2011.10101532. PubMed DOI

Department of Health Estimating Prevalence of Autism Spectrum Disorders (ASD) in the Irish Population: A Review of Data Sources and Epidemiological Studies. [(accessed on 10 June 2019)]; Available online: https://health.gov.ie/wp-content/uploads/2018/12/ASD-Report-Final-19112018-For-publication.pdf.

National Autistic Society Autism Facts and History. [(accessed on 10 May 2019)]; Available online: https://www.autism.org.uk/about/what-is/myths-facts-stats.aspx.

European Commission . Autism Spectrum Disorders in the European Union (ASDEU) European Commission; Luxembourg: 2018. 13p

Waugh D.T., Potter W., Limeback H., Godfrey M. Risk assessment of fluoride intake from tea in the republic of Ireland and its implications for public health and water fluoridation. Int. J. Environ. Res. Public Health. 2016;13:259. doi: 10.3390/ijerph13030259. PubMed DOI PMC

Aggebornb L., Öhmanc M. The Effects of Fluoride in the Drinking Water. Department of Government at Uppsala University; Upsalla, Sweden: 2017. p. 81.

Campbell J. Countries with Lowest Autism Rates That May Surprise You. [(accessed on 15 May 2019)]; Available online: https://newmiddleclassdad.com/countries-with-lowest-autism-rates/

Van Bakel M.M., Delobel-Ayoub M., Cans C., Assouline B., Jouk P.S., Raynaud J.P., Arnaud C. Low but increasing prevalence of autism spectrum disorders in a French area from register-based data. J. Autism Dev. Disord. 2015;45:3255–3261. doi: 10.1007/s10803-015-2486-6. PubMed DOI

Narzisi A., Posada M., Barbieri F., Chericoni N., Ciuffolini D., Pinzino M., Romano R., Scattoni M.L., Tancredi R., Calderoni S., et al. Prevalence of Autism Spectrum Disorder in a large Italian catchment area: A school-based population study within the ASDEU project. Epidemiol. Psychiatr. Sci. 2018:1–10. doi: 10.1017/S2045796018000483. PubMed DOI PMC

National Toxicology Program . Systematic Literature Review on the Effects of Fluoride on Learning and Memory in Animal Studies. U.S. Department of Health and Human Services; Triangle Park, NC, USA: 2016. PubMed

U. S. Department of Health, 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 Rep. 2015;130:318–331. doi: 10.1177/003335491513000408. PubMed DOI PMC

Consumerlab.com Recommended Daily Intakes and Upper Limits for Vitamin and Minerals. [(accessed on 11 May 2019)]; Available online: https://www.consumerlab.com/RDAs/Fluoride/#rdatable.

Department of Health and Ageing . Nutrient Reference Values for Australia and New Zealand. Commonwealth of Australia; Canberra, Australia: 2006. 309p

EFSA Panel on Dietetic Products, Nutrition, Allergies Scientific opinion on dietary reference values for fluoride. EFSA J. 2013;11:3332. doi: 10.2903/j.efsa.2013.3332. DOI

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. EC; Brussels, Belgium: 2010. 59p

Shen M.D., Piven J. Brain and behavior development in autism from birth through infancy. Dialogues Clin. Neurosci. 2017;19:325–333. PubMed PMC

Leigh J.P., Du J. Brief report: Forecasting the economic burden of autism in 2015 and 2025 in the United States. J. Autism. Dev. Disord. 2015;45:4135–4139. doi: 10.1007/s10803-015-2521-7. PubMed DOI

Modabbernia A., Velthorst E., Reichenberg A. Environmental risk factors for autism: An evidence-based review of systematic reviews and meta-analyses. Mol. Autism. 2017;8:13. doi: 10.1186/s13229-017-0121-4. PubMed DOI PMC

Ng M., de Montigny J.G., Ofner M., Do M.T. Environmental factors associated with autism spectrum disorder: A scoping review for the years 2003–2013. Health Promot. Chronic Dis. Prev. Can. 2017;37:1–23. doi: 10.24095/hpcdp.37.1.01. PubMed DOI PMC

Schofield K. The metal neurotoxins: An important role in current human neural epidemics? Int. J. Environ. Res. Public Health. 2017;14:1511. doi: 10.3390/ijerph14121511. PubMed DOI PMC

Bjørklund G., Skalny A.V., Rahman M.M., Dadar M., Yassa H.A., Aaseth J., Chirumbolo S., Skalnaya M.G., Tinkov A.A. Toxic metal(loid)-based pollutants and their possible role in autism spectrum disorder. Environ. Res. 2018;166:234–250. doi: 10.1016/j.envres.2018.05.020. PubMed DOI

Blaylock R.L. A possible central mechanism in autism spectrum disorders, part 3: The role of excitotoxin food additives and the synergistic effects of other environmental toxins. Altern. Ther. Health. Med. 2009;15:56–60. PubMed

Blaylock R.L., Strunecka A. Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders. Curr. Med. Chem. 2009;16:157–170. doi: 10.2174/092986709787002745. PubMed DOI

Anderson G.M. The potential role for emergence in autism. Autism Res. 2008;1:18–30. doi: 10.1002/aur.2. PubMed DOI