Abstract
As a guide to establishing a safe exposure level for fluoride exposure in pregnancy, we applied benchmark dose modeling to data from two prospective birth cohort studies. We included mother-child pairs from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort in Mexico and the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort in Canada. Maternal urinary fluoride concentrations (U-F, in mg/L, creatinine-adjusted) were measured in urine samples obtained during pregnancy. Children were assessed for intelligence quotient (IQ) at age 4 (n = 211) and between six and 12 years (n = 287) in the ELEMENT cohort, and three to four years (n = 407) in the MIREC cohort. We calculated covariate-adjusted regression coefficients and their standard errors to assess the association of maternal U-F concentrations with children’s IQ measures. Assuming a benchmark response of 1 IQ point, we derived benchmark concentrations (BMCs) and benchmark concentration levels (BMCLs). No deviation from linearity was detected in the dose-response relationships, but boys showed lower BMC values than girls. Using a linear slope for the joint cohort data, the BMC for maternal U-F associated with a 1-point decrease in IQ scores was 0.31 mg/L (BMCL, 0.19 mg/L) for the youngest boys and girls in the two cohorts, and 0.33 mg/L (BMCL, 0.20 mg/L) for the MIREC cohort and the older ELEMENT children. Thus, the joint data show a BMCL in terms of the adjusted U-F concentrations in the pregnant women of approximately 0.2 mg/L. These results can be used to guide decisions on preventing excess fluoride exposure in pregnant women.
*Original abstract online at https://doi.org/10.1111/risa.13767
Excerpt:
Discussion
… The increased precision using the average maternal U-F concentration as an indicator of prenatal fluoride exposure results in stronger statistical evidence of fluoride-associated deficits, compared with using cross-sectional or retrospective studies. Still, the amount of fluoride that reaches the brain during early brain development is unknown, and even the maternal U-F concentration measurements may be considered somewhat imprecise as dose indicators. Such imprecision, likely occurring at random, will tend to underestimate fluoride neurotoxicity (Grandjean & Budtz-Jørgensen, 2010).
The prospective studies offer strong evidence of prenatal neurotoxicity, and the benchmark results should inspire a revision of water-fluoride recommendations aimed at protecting pregnant women and young children. While systemic fluoride exposure has been linked to dental health benefits in early studies (Iheozor-Ejiofor et al., 2015), these benefits occur in the oral cavity after teeth have erupted (Featherstone, 2000), thus suggesting that use of toothpaste and other topical treatment should be considered for alternative caries prevention…
Funding
The ELEMENT study was supported by U.S. NIH R01ES021446, NIH R01-ES007821, NIEHS/EPA P01ES022844, NIEHS P42-ES05947, NIEHS Center Grant P30ES017885 and the National Institute of Public Health/Ministry of Health of Mexico. The MIREC study was supported by the Chemicals Management Plan at Health Canada, the Ontario Ministry of the Environment, and the Canadian Institutes for Health Research (grant # MOP-81285). PG is supported by the NIEHS Superfund Research Program (P42ES027706). CT is supported by the NIEHS (grants R21ES027044; R01ES030365-01).
References
1.Aggeborn, L., & Ohman, M. (2017). The effects of fluoride in drinking water. Uppsala, Sweden: Institute for Evaluation of Labour Market and Education Policy.
2. Arbuckle, T. E., Fraser, W. D., Fisher, M., Davis, K., Liang, C. L., Lupien, N., … Ouellet, E. (2013). Cohort profile: The maternal-infant research on environmental chemicals research platform. Paediatric and Perinatal Epidemiology, 27(4), 415-425.
3. Bartos, M., Gumilar, F., Gallegos, C. E., Bras, C., Dominguez, S., Monaco, N., … Minetti, A. (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. Reproductive Toxicology, 81, 108-114.
4. Bashash, M., Marchand, M., Hu, H., Till, C., Martinez-Mier, E. A., Sanchez, B. N., … Téllez-Rojo, M. M. (2018). Prenatal fluoride exposure and attention deficit hyperactivity disorder (ADHD) symptoms in children at 6-12years of age in Mexico City. Environment International, 121(Pt 1), 658-666.
5. Bashash, M., Thomas, D., Hu, H., Martinez-Mier, E. A., Sanchez, B. N., Basu, N., … Hernández-Avila, M. (2017). Prenatal fluoride exposure and cognitive outcomes in children at 4 and 6-12 years of age in Mexico. Environmental Health Perspectives, 125(9), 097017.
6. Bergman, A., Heindel, J. J., Kasten, T., Kidd, K. A., Jobling, S., Neira, M., … Woodruff, T. J. (2013). The impact of endocrine disruption: A consensus statement on the state of the science. Environmental Health Perspectives, 121(4), A104-106.
7. Broadbent, J. M., Thomson, W. M., Ramrakha, S., Moffitt, T. E., Zeng, J., Foster Page, L. A., & Poulton, R. (2015). Community Water Fluoridation and Intelligence: Prospective Study in New Zealand. American Journal of Public Health, 105(1), 72-76.
8. Budtz-Jørgensen, E., Bellinger, D., Lanphear, B., & Grandjean, P., & International Pooled Lead Study Investigators. (2013) An international pooled analysis for obtaining a benchmark dose for environmental lead exposure in children. Risk Analysis, 33(3), 450-461.
9. Budtz-Jørgensen, E., Keiding, N., & Grandjean, P. (2001). Benchmark dose calculation from epidemiological data. Biometrics, 57(3), 698-706.
10. Choi, A. L., Sun, G., Zhang, Y., & Grandjean, P. (2012). Developmental fluoride neurotoxicity: A systematic review and meta-analysis. [Research Support, Non-U.S. Gov’t]. Environmental Health Perspectives, 120(10), 1362-1368.
11. Choi, A. L., Zhang, Y., Sun, G., Bellinger, D. C., Wang, K., Yang, X. J., … Grandjean, P. (2015). Association of lifetime exposure to fluoride and cognitive functions in Chinese children: A pilot study. Neurotoxicology and Teratology, 47, 96-101.
12. Crump, K. S. (1995). Calculation of benchmark doses from continuous data. Risk Analysis, 15(1), 79-89.
13. Cui, Y., Zhang, B., Ma, J., Wang, Y., Zhao, L., Hou, C., …Liu, H. (2018). Dopamine receptor D2 gene polymorphism, urine fluoride, and intelligence impairment of children in China: A school-based cross-sectional study. Ecotoxicol. Environ. Saf., 165, 270-277.
14. 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.
15. Ekstrand, J., & Ehrnebo, M. (1983). The relationship between plasma fluoride, urinary excretion rate and urine fluoride concentration in man. Journal of Occupational Medicine, 25(10), 745-748.
16. European Food Safety Authority. (2009). Guidance of the Scientific Committee on Use of the benchmark dose approach in risk assessment. EFSA Journal, 1150, 1-72.
17. European Food Safety Authority. (2010). EFSA Panel on Contaminants in the Food Chain (CONTAM); Scientific Opinion on Lead in Food. EFSA Journal, 8(4), 1570.
18. Featherstone, J. D. (2000). The science and practice of caries prevention. Journal of the American Dental Association, 131(7), 887-899.
19. Gould, E. (2009). Childhood lead poisoning: Conservative estimates of the social and economic benefits of lead hazard control. Environmental Health Perspectives, 117(7), 1162-1167.
20. Grandjean, P. (2013). Only one chance: How environmental pollution impairs brain development – and how to protect the brains of the next generation. New York: Oxford University Press.
21. Grandjean, P. (2019). Developmental fluoride neurotoxicity: An updated review. Environmental Health, 18(1), 110.
22.Grandjean, P., & Budtz-Jørgensen, E. (2010). An ignored risk factor in toxicology: The total imprecision of exposure assessment. Pure and Applied Chemistry, 82(2), 383-391.
23. Green, R., Lanphear, B., Hornung, R., Flora, D., Martinez-Mier, E. A., Neufeld, R., …Till, C. (2019). Association between maternal fluoride exposure during pregnancy and IQ scores in offspring in Canada. JAMA Pediatr, 173(10), 940-948.
24. Green, R., Rubenstein, J., Popoli, R., Capulong, R., & Till, C. (2020). Sex-specific neurotoxic effects of early-life exposure to fluoride: A review of the epidemiologic and animal literature. Current Epidemiology Reports, 7, 263-273.
25. Hirzy, J. W., Connett, P., Xiang, Q. Y., Spittle, B. J., & Kennedy, D. C. (2016). Developmental neurotoxicity of fluoride: A quantitative risk analysis towards establishing a safe daily dose of fluoride for children. Fluoride, 49(4), 379-400.
26. Iheozor-Ejiofor, Z., Worthington, H. V., Walsh, T., O’Malley, L., Clarkson, J. E., Macey, R., … Glenny, A. M. (2015). Water fluoridation for the prevention of dental caries. Cochrane Database of Systematic Reviews (Online)(6), CD010856.
27. Kaplan, R. M., & Sacuzzo, D. P. (2010). Psychological testing: Principles, applications, & issues, eighth edition. Belmont, CA: Wadsworth.
28. Krishnankutty, N., Jensen, T. S., Kjaer, J., Jørgensen, J. S., Nielsen, F., & Grandjean, P. (2021). Public health risks from tea drinking: Fluoride exposure. Scandinavian Journal of Public Health, https://doi.org/10.1177/1403494821990284. https://www.ncbi.nlm.nih.gov/pubmed/33557697.
29. Levin, E. D., Dow-Edwards, D., & Patisaul, H. (2021). Introduction to sex differences in neurotoxic effects. Neurotoxicology and Teratology, 83, 106931.
30. Malin , A. J., Riddell, J., McCague, H., & Till, C. (2018). Fluoride exposure and thyroid function among adults living in Canada: Effect modification by iodine status. Environment International, 121(Pt 1), 667-674.
31. Malin, A. J., & Till, C. (2015). Exposure to fluoridated water and attention deficit hyperactivity disorder prevalence among children and adolescents in the United States: An ecological association. Environmental Health, 14, 17.
32. Martinez-Mier, E. A., Cury, J. A., Heilman, J. R., Katz, B. P., Levy, S. M., Li, Y., … Zohouri, V. (2011). Development of gold standard ion-selective electrode-based methods for fluoride analysis. Caries Research, 45(1), 3-12.
33. Mullenix, P. J., Denbesten, P. K., Schunior, A., & Kernan, W. J. (1995). Neurotoxicity of sodium fluoride in rats. Neurotoxicology and Teratology, 17(2), 169-177.
34. National Research Council. (1989). Recommended Dietary Allowances (10 ed.). Washington, DC: National Academy Press.
35. National Research Council. (2006). Fluoride in drinking water: A scientific review of EPA’s standards. Washington, DC: National Academy Press.
36. National Toxicology Program. (2020). Revised draft NTP monograph on the systematic review of fluoride exposure and neurodevelopmental and cognitive health effects. Research Triangle Park, NC: National Institute of Environmental Health Sciences.
37. Nilsen, F. M., J. D. C. Ruiz, and N. S. Tulve. 2020. A Meta-Analysis of Stressors from the Total Environment Associated with Children’s General Cognitive Ability. Int J Environ Res Public Health 17 (15). https://doi.org/10.3390/ijerph17155451. https://www.ncbi.nlm.nih.gov/pubmed/32751096.
38. Opydo-Symaczek, J., & Borysewicz-Lewicka, M. (2005). Urinary fluoride levels for assessment of fluoride exposure of pregnant women in Poznan, Poland. Fluoride, 38(4), 312-317.
39. Perng, W., Tamayo-Ortiz, M., Tang, L., Sanchez, B. N., Cantoral, A., Meeker, J. D., … Peterson, K. E. (2019). Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) Project. BMJ Open, 9(8), e030427.
40. Perrott, K. W. (2018) Fluoridation and attention deficit hyperactivity disorder-A critique of Malin and Till (2015). British Dental Journal, 223(11), 819-822.
41. Reuben, A., Caspi, A., Belsky, D. W., Broadbent, J., Harrington, H., Sugden, K., … Moffitt, T. E. (2017). Association of Childhood Blood Lead Levels With Cognitive Function and Socioeconomic Status at Age 38 Years and With IQ Change and Socioeconomic Mobility Between Childhood and Adulthood. Jama, 317(12), 1244-1251.
42. Riddell, J. K., Malin, A. J., Flora, D., McCague, H., & Till, C. (2019). Association of water fluoride and urinary fluoride concentrations with attention deficit hyperactivity disorder in Canadian youth. Environment International, 133(Pt B), 105190.
43. Rodríguez, I., Burgos, A., Rubio, C., Gutiérrez, A. J., Paz, S., Rodrigues da Silva Júnior, F. M., … Revert, C. (2020). Human exposure to fluoride from tea (Camellia sinensis) in a volcanic region-Canary Islands, Spain. Environmental Science and Pollution Research, 27, 43917-43928..
44. Tang, Q., Du, J., Ma, H., Jiang, S., & Zhou, X. (2008). Fluoride and children’s intelligence: A meta-analysis. Bio Trace Elem Res, 126, 115-120.
45. Thomas, D. B., Basu, N., Martinez-Mier, E. A., Sanchez, B. N., Zhang, Z., Liu, Y., … Téllez-Rojo, M. M. (2016). Urinary and plasma fluoride levels in pregnant women from Mexico City. Environmental Research, 150, 489-495.
46. Till, C., Green, R., Flora, D., Hornung, R., Martinez-Mier, E. A., Blazer, M., … Lanphear, B. (2019). Fluoride exposure from infant formula and child IQ in a Canadian birth cohort. Environment International, 134, 105315.
47. Till, C., Green, R., Flora, D., Hornung, R., Martinez-Mier, E. A., Blazer, M., … Lanphear, B. (2020). Fluoride exposure from infant formula and child IQ in a Canadian birth cohort. Environment International, 134, 105315.
48. Till, C., Green, R., Grundy, J. G., Hornung, R., Neufeld, R., Martinez-Mier, E. A., … Lanphear, B. (2018). Community water fluoridation and urinary fluoride concentrations in a national sample of pregnant women in Canada. Environmental Health Perspectives, 126(10), 107001.
49. U.S. Environmental Protection Agency. (1985). National Primary Drinking Water Regulations: Fluoride Final Rule and Proposed Rule.
50. U.S. Environmental Protection Agency. (2010). Fluoride: Exposure and relative source contribution analysis. Washington, DC: Health and Ecological Criteria Division, Office of Water, U.S. EPA.
51. U.S. Environmental Protection Agency. (2012). Benchmark dose technical guidance. Washington, DC: Risk Assessment Forum, U.S. EPA.
52. Valdez Jimenez, L., Lopez Guzman, O. D., Cervantes Flores, M., Costilla-Salazar, R., Calderon Hernandez, J., Alcaraz Contreras, Y., & Rocha-Amador, D. O. (2017). In utero exposure to fluoride and cognitive development delay in infants. Neurotoxicology, 59, 65-70.
53. Wang, M., Liu, L., Li, H., Li, Y., Liu, H., Hou, C., … Wang, A. (2020). Thyroid function, intelligence, and low-moderate fluoride exposure among Chinese school-age children. Environment International, 134, 105229.
54. Waugh, D. T., Godfrey, M., Limeback, H., & Potter, W. (2017). Black Tea Source, Production, and Consumption: Assessment of Health Risks of Fluoride Intake in New Zealand. J Environ Public Health, 2017, 5120504.
55. Wechsler, D. 1991. Wechsler Intelligence Scale for Children, 3rd ed. WISC-III Manual. San Antonio, TX: The Psychological Corporation.
56.World Health Organization. (2006). Fluoride in drinking-water. London, UK: IWA Publishing.
57. Xiang, Q., Liang, Y., Chen, L., Wang, C., Chen, B., Chen, X., & Zhou, M. (2003). Effect of fluoride in drinking water on children’s intelligence. Fluoride, 36(2), 84-94.
58. Yu, X., Chen, J., Li, Y., Liu, H., Hou, C., Zeng, Q., … Wang, A. (2018). Threshold effects of moderately excessive fluoride exposure on children’s health: A potential association between dental fluorosis and loss of excellent intelligence. Environment International, 118, 116-124.
59. Zhang, S., Zhang, X., Liu, H., Qu, W., Guan, Z., Zeng, Q., … Wang, A. (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. Toxicological Sciences, 144(2), 238-245.
*Original abstract online at https://doi.org/10.1111/risa.13767
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