Three studies have now examined the safe exposure level to fluoride in pregnancy using benchmark dose analysis. In 2016, Hirzy et al. found that, for a benchmark response (BMR) of 1 IQ point, the lower confidence limit of the benchmark dose (BMDL) was a daily intake of approximately 0.27 mg/day, corresponding to a drinking water fluoride concentration of 0.22 mg/L. In 2019, Grandjean found the BMDL for the maternal urinary fluoride concentration to be about 0.2 mg/L or below, a level that was similar to the result calculated by Hirzy et al., and considered that a protective limit for fluoride in drinking water would likely require that the current maximum contaminant level goal (MCLG) of the Environmental Protection Agency (EPA) in the United States of America of 4.0 mg/L MCGL should be reduced by a more than a 10-fold factor, i.e., to less than 0.4 mg/L, below the level currently achieved by fluoridation of approximately 0.7 mg/L. On November 4, 2020, a preprint of a benchmark dose analysis for maternal pregnancy urine fluoride and IQ in children by Grandjean et al.3 was posted online. The authors included authors from the Mexican (Early Life Exposure in Mexico to Environmental Toxicants, ELEMENT) and Canadian (Maternal-Infant Research on Environmental Chemicals, MIREC) studies by Bashash et al. and Green et al., respectively, as well as two biostatisticians. The joint data from the ELEMENT and MIREC studies showed that the two prospective studies, which had maternal urine fluoride exposure at levels commonly occurring in the general population, showed benchmark concentration level (BMCL) results, for a BMR of 1 IQ point, for the maternal urinary fluoride level of about 0.2 mg/L. With the proviso that the preprint had not yet been certified by peer review and that it should not be used to guide clinical practice until this had been done, the authors concluded that the results can be used to guide decisions on preventing excess fluoride exposure in vulnerable populations. They also observed that the two prospective studies offered strong evidence of prenatal neurotoxicity and should inspire a revision of water fluoride regulations based on the benchmark results, especially for pregnant women and young children. They considered that although systemic fluoride exposure may be associated with some benefits in dental health, these benefits appeared to be small and non-essential prior to tooth eruption and other means of caries prevention, such as fluoridated toothpaste and other topical treatment, might be considered.
Keywords: Benchmark dose analysis; Drinking water fluoride; Fluoride in pregnancy; Maternal urinary fluoride; Safe exposure level.
Fluoride (F) is not an essential trace element in humans or necessary for the
development of healthy teeth and bones.9,10 It is likely that there is no threshold for fluoride-induced developmental neurotoxicity in drinking water, and the only
assuredly safe level of fluoride in drinking water is zero.10,11,12 The currently
recommended level of 0.7 mg F/L for community water systems10,11 and the
provision of fluoridated salt are no longer appropriate for preventing dental caries
because they will result in pregnant women and children having a fluoride intake
above the estimated safe daily intakes of approximately 0.04 mg F/day (0.0007 mg F/kg bw/day for a 56 kg woman) and 0.15 mg F/day (0.003 mg F/kg bw/day for a 45 kg child, the 90th percentile children’s body mass at 8–13 yr), respectively.10,11 The oral reference value for longer-term (up to 10% of an average life span) exposure (RfVLO) can be calculated to be approximately 0.0007 mg/kg bw/day (0.04÷56=0.00071). Preventing fluoride-induced developmental neurotoxicity in children by lowering the dietary fluoride intake to the estimated safe level for pregnant women and children may not be easily achievable but a start could be made by relatively simple measures such as avoiding fluoridated water, fluoride-rich foods, and fluoridated dental products.
A pea-sized amount of fluoridated toothpaste (250 mg), with 1000 ppm of F (1 mg
of F/1000 mg of toothpaste), contains 0.25 mg of F, a smear or rice grain-sized
amount of fluoridated toothpaste (100 mg) contains 0.1 mg of F, and a large strip of fluoridated toothpaste (1000 mg) contains 1 mg of F.10,13,14 If a child younger than 3 years brushed their teeth twice daily, morning and night, with a rice grain-sized amount of fluoridated toothpaste with 1000 ppm of F they would be placing
0.1×2=0.2 mg of F in their oral cavity and would exceed the estimated safe daily dose of 0.15 mg F if more than 75% of the toothpaste was swallowed. Similarly, a 3–6-year-old child brushing with a pea-sized amount twice daily (2×0.25=0.5 mg) would have to not swallow not more than 30% of the toothpaste to avoid exceeding the safe daily dose. A pregnant woman using a large strip of toothpaste twice daily (1×2=2 mg) would need to avoid swallowing more than 2% of the toothpaste to stay within estimated safe daily F intake. Thus, the use of fluoridated toothpaste by children up to the age of 6 years and pregnant women is problematic and would best be avoided if IQ loss in children is to be prevented.
Prevention will also be assisted by having an adequate dietary intake of vitamins,
antioxidants, and selenium: e.g., vitamin C, vitamin E, and other antioxidants, from fruits and vegetables, which are seen to be able to protect against F-poisoning and fluorosis.10,15,16 Selenium can improve mitochondrial membrane stability and protect against fluoride toxicity in skeletal muscles10,17 although at higher levels selenium is synergistic with fluoride and arsenic in causing toxicity.10,18
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2 Grandjean P. Developmental fluoride neurotoxicity: an updated review [review]. Environ Health 2019;18(1):110. doi: 10.1186/s12940-019-0551-x. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=grandjean . [abstract in Fluoride 2020;53(1 Pt1):97].
3 Grandjean P, Hu H, Till C, Green R, Bashash M, Flora D, et al. A benchmark dose analysis for maternal pregnancy urine-fluoride and IQ in children. medRxiv2020 Nov 4;2020.10.31.20221374 preprint doi:
https://doi.org/10.1101/2020.10.31.20221374; Available from: https://pubmed.ncbi.nim.nih.gov/33173917/
4 Xiang Q, Liang Y, Chen L, Wang C, Chen B, Chen X, et al. Effect of fluoride in drinking water on children’s intelligence. Fluoride 2003;36:84-94. Erratum in Fluoride 2004;37(4):320.
5 Bashash M, Thomas D, Hu H, Martinez-Mier EA, Sanchez BN, Basu N, Peterson KE, Ettinger AS, Wright R, Zhang ZZ, Liu Y, Schnaas L, Mercado-Garcia A, Téllez-Rojo MM, Hernández-Avita M. Prenatal fluoride exposure and cognitive outcomes in children at 4 and 6–12 years of age in Mexico. Environ Health Perspect 2017 Sept 19;125(9):097017. doi: 10.1289/EHP655. Available from: https://www.thelancet.com/journals/laneur/article/PIIS1474-4422%2813%2970278-3/fulltext
6 Green R, Lanphear B, Hornung R, Flora D, Angeles Martinez-Mier E, Neufeld R, Ayotte P, Muckle G, Till C. Association between maternal fluoride exposure during pregnancy and IQ scores in offspring in Canada. JAMA Pediatr. doi:10.1001/jamapediatrics.2019.1729. Published online August 19, 2019.
[abstract in Fluoride 2019;52(4);580].
7 Iheozor-Ejiofor Z, Worthington HV, Walsh T, O’Malley, Clarkson JE, Macey R, et al. Water fluoridation for the prevention of dental caries. Cochrane Database Syst Rev 2015;2015(6): CD010856. Available
from: https://doi.org/10.1002/14651858.CD010856.pub2 . https://www.ncbi.nlm.nih.gov/pubmed/26092033 .
8 Featherstone JD. The science and practice of caries prevention. J Am Dent Assoc 2000;131(7): 887-99. https://doi.org/10.14219/jada.archive.2000.0307 . Available from: https://www.ncbi.nlm.nih.govpubmed/10916327 .
9 Scientific Committee on Health and Environmental Risks (SCHER). Opinion of critical review of any new evidence on the hazard profile, health effects, and human exposure to fluoride and the fluoridating agents of drinking water. Brussels, Belgium: Directorate General for Health and Consumers, European
Commission; 2011 May 16. pp. 2-4.
10 Spittle B. Prevention of fluoride ion-induced IQ loss in children [editorial]. Fluoride 2017;50(4):385-92.
11 Spittle B. The effect of the fluoride ion on reproductive parameters and an estimate of the safe daily dose of fluoride to prevent female infertility and miscarriage, and foetal neurotoxicity [editorial]. Fluoride 2017;50(3):287-91.
12 Spittle B Neurotoxic effects of fluoride [editorial]. Fluoride 2011;44930:117-24.
13 Limeback H, Robinson C. Fluoride therapy. In: Limeback H, editor. Comprehensive preventive dentistry. Ames, Iowa, USA, and Chichester, West Sussex, UK: Wiley-Blackwell, an imprint of John Wiley & Sons; 2012. pp. 251-82.
14 American Dental Association Council on Scientific Affairs. Fluoride toothpaste use for young children. JADA 2014;145(2):190-1.
15 Susheela AK. A treatise on fluorosis. Revised 3rd ed. Delhi, India: Fluorosis Research and Rural Development Foundation; 2000. pp. 89-92.
16 Susheela AK. Anemia in pregnancy: an easily rectifiable problem [guest editorial]. Fluoride 2010;43(2):104-7.
17 Pang YX, Guo YQ, Zhu P, Fu KW, Sun YF, Tang RQ. The effects of fluoride, alone and in combination with selenium, on the morphology and histochemistry of skeletal muscle. Fluoride 1996;29(2):59-62.
18 Li Y, Sun M, Wu D, Chen X. The toxicity of combination of selenium, fluoride and arsenic on rat embryos. Wei Sheng Yan Jiu 1999;28(2):74-6. [in Chinese].
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