Prenatal and childhood exposure to fluoride and cognitive development: findings from the longitudinal MINIMat cohort in rural Bangladesh.

PREPRINT

Background:

There are indications that fluoride exposure considered to be beneficial for dental health may not be safe from a neurodevelopmental perspective.

Objectives:

To assess the impact of prenatal and childhood fluoride exposure on cognitive abilities at 5 and 10 years of age.

Methods:

We studied 500 mother-child pairs from the MINIMat (Maternal and Infant Nutrition Interventions in Matlab) birth cohort in rural Bangladesh. Urinary fluoride concentrations were measured in the pregnant women at gestational week 8 and in their children at 5 and 10 years, using an ion-selective electrode and adjusting for specific gravity. Cognitive abilities were assessed using the Wechsler Preschool and Primary Scale for Intelligence-Third Edition and the Wechsler Intelligence Scale-Fourth Edition at age 5 and 10 years, respectively. Associations of urinary fluoride concentrations (log2-transformed) with cognitive abilities (raw scores) were assessed with multivariable-adjusted linear or spline regression models. Water fluoride concentrations were measured at the 10-year-old visit.

Results:

Maternal urinary fluoride concentrations (median: 0.63 mg/L, 5th–95th percentiles: 0.26–1.41 mg/L) were inversely associated with full-scale raw scores at 5 and 10 years (B [95% confidence interval]: -2.8 [-5.1, -0.6] and -4.9 [-8.0, -1.8], respectively, by exposure doubling). In cross-sectional analysis at 10 years, child urinary fluoride (overall median: 0.66 mg/L, 5th–95th percentiles: 0.34–1.26 mg/L) above -0.47 on the log2-scale (corresponding to 0.72 mg/L) was inversely associated with full-scale raw scores (B [95% CI]: -12.1 [-21.2, -3.0]). The association at 5 years was also negative but non-significant. For both prenatal and childhood exposure, associations were most noticeable with perceptual reasoning, but also verbal scores. The estimate for the association between urinary fluoride at 10 years and perceptual reasoning became 18% lower after adjustment for prenatal exposure. Non consistent sex-specific differences were observed.

Conclusion:

Urinary fluoride concentrations measured prenatally and during childhood (child urinary fluoride concentrations above -0.47 on the log2 scale (corresponding to 0.72 mg/L) were associated with lower cognitive abilities, especially perceptual reasoning and verbal abilities, in Bangladeshi children.

EXCERPTS:

Study population

This study was based on a mother-child cohort, 16-19 nested in a community-based randomized
controlled trial (Maternal and Infant Nutrition Interventions in Matlab [MINIMat trial];reg#ISRCTN16581394). The MINIMat trial was conducted in Matlab, a rural sub-district in  Bangladesh, about 57 km southeast of the capital Dhaka, with the overarching objective to assess effects of prenatal food and multiple micronutrient supplementation on gestational and child health.²⁰ The trial enrolled 4436 pregnant women from November 2001 throughout October 2003, and this resulted in 3625 live births. The pregnant women were randomly allocated to receive one of two food supplementations and one of three different multiple micronutrient supplementations.²⁰

The food supplementation was initiated either directly after recruitment (around 9 weeks’ gestation)
or during the usual care invitation at 20 weeks’ gestation. The micronutrient supplementation was
initiated at gestational week 14, and consisted of: 1) 30 mg iron and 400 µg folic acid; or 2) 60 mg
iron and 400 µg folic acid, or 3) the UNICEF/WHO/UNU preparation with 15 micronutrients.²⁰

The initial aim of the nested mother-child cohort was to assess the potential impact of elevated
arsenic concentrations in drinking water 21 and, subsequently, the impact of other environmental
toxicants and also nutrients on child health and development.^{18, 22} Singleton children born from May
2002 through December 2003 were invited to participate in the cognitive development assessment
at 5 years of age (n=2853) and 2260 children were assessed (Supplemental Figure S1).¹⁶ For the
follow-up assessment of cognitive development at 10 years of age, we invited those who were born
between October 2002 and December 2003 and were still registered as residents in the study area
(n=1607), and 95% of them agreed to participate (n=1530).^{18, 22-24} For the present study on the
association of urinary fluoride with child cognition at 5 and 10 years of age, we selected the first 500
tested children (born from October 2002 throughout May 2003) with urine samples collected both
from the mothers during enrollment (median: gestational week 8) and from their children at 10 years
of age (Figure S1). Since 423 of these 500 selected children also had urine samples collected at 5
years old, we decided to include urinary fluoride from the same children at 5 years. The prospective
analyses of gestational urinary fluoride concentrations with outcomes at 10 years included all 500
children, and the models of outcomes at 5 years included 457 children (because of missing data in
HOME scores for 43 children). Prospective models of child urinary fluoride concentrations at 5 years with outcomes at 10 years included 423 children (missing urine sample at 5 years for 77 children).
Out of these, 388 were included in the cross-sectional analyses at 5 years (missing HOME scores for
35 children). The cross-sectional analyses at 10 years included all 500 children. Comparison of the
included children (n=500 and n=423) with the remaining children born within the MINIMat trial
(n=3125 and n=3202) suggested no major differences regarding maternal background characteristics,
except for number of years of maternal education during pregnancy (4.1 versus 5.2 years; p<0.001)
(Table S1)…

Maternal urinary fluoride and cognitive abilities at 5 and 10 years of age

In the adjusted analyses, the inverse associations of maternal urinary fluoride concentrations during
pregnancy (median: 0.63 mg/L) with cognitive outcomes at 5 years of age were markedly strengthened compared to the unadjusted associations (Table 4). Maternal urinary fluoride
concentrations were inversely associated with full-scale, verbal, and performance raw scores (B [95%
CI]: -2.8 [-5.1, -0.6], -1.4 [-2.6, -0.3], and -0.8 [-1.6, 0.1], respectively; per doubling of exposure). The
interaction between fluoride and child sex was not statistically significant (P=0.7–0.9), and
stratification by sex did not indicate any clear differences between boys and girls.

Associations of maternal urinary fluoride concentrations with cognitive abilities at 10 years of age
were also markedly stronger in the adjusted than the unadjusted models (Table 4). Maternal urinary
fluoride concentrations during pregnancy were inversely associated with full-scale raw scores (B
[95% CI]: -4.9 [-8.0, -1.8]; per exposure doubling), mainly driven by lower perceptual reasoning raw
scores (-2.4 [-3.5, -1.3]; per doubling). The interaction between fluoride and child sex was not
significant in any of the models (P=0.2–0.7), but after stratification by sex (Table 4), the inverse
associations of maternal urinary fluoride concentrations with full-scale and perceptual reasoning raw
scores appeared more pronounced in girls (B [95% CI]: -7.3 [-12.2, -2.3] and -3.4 [-5.1, -1.7]; per
doubling of exposure) than in boys (-3.2 [-7.3, 0.9] and -1.4 [-2.9, 0.0]; per doubling).
In sensitivity analysis, further adjustment for maternal urinary arsenic, cadmium, or iodine
concentrations, season of urine sampling or food and micronutrient supplementations resulted only
in minor changes of the estimates (Table S6 and S7). When additionally adjusting for maternal
erythrocyte lead concentrations, the association of maternal fluoride with the full-scale raw scores at
5 years became moderately stronger (21%; Table S6), while the association at 10 years was only
marginally strengthened (Table S7). In sensitivity analyses with a simpler adjustment set, including
only some basic a priori selected factors and true confounders, the estimates were slightly stronger
at 5 and weaker at 10 years (Table S6-S7).

Children’s urinary fluoride and cognitive abilities at 5 and 10 years of age

In the cross-sectional analyses at 5 years, the children’s urinary fluoride concentrations (median: 0.62
mg/L) were inversely associated with cognitive outcomes, but the associations were not statistically
significant, neither in the unadjusted nor in the adjusted models (Table 5). The interaction with sex was not statistically significant in any of the models (P=0.4–0.9). However, when models were
stratified by sex, the inverse association with full-scale raw scores appeared more pronounced in girls
(B [95% CI]: -2.5 [-7.1, 2.0]; per doubling) than in boys (-0.3 [-3.8, 3.2]; per doubling), but none of the
associations were statistically significant.

In the prospective analyses, associations of child urinary fluoride concentrations at 5 years with
cognitive outcomes at 10 years were statistically non-significant in all models (Table 5). There was a
significant interaction of fluoride with child sex for perceptual reasoning raw scores (P=0.009), and
the stratified analysis showed an inverse association for boys only (B [95% CI]: -2.5 [-4.3, -0.6]; per
doubling). Overall, when stratifying by sex, associations of urinary fluoride concentrations with all
cognitive abilities were inverse in boys, but positive in girls (Table 5), although not statistically
significant.

In the cross-sectional analyses at 10 years, children’s urinary fluoride concentrations (log 2 –
transformed) were non-linearly associated with full-scale raw scores in both the unadjusted and
adjusted models (Table 6). After covariate adjustment, the estimates became stronger and child
urinary fluoride concentrations above -0.47 on the log2 scale (corresponding to 0.72 mg/L) were
inversely associated with full-scale raw scores (B [95% CI]: -12.1 [-21.2, -3.0]; per doubling), which
was mainly driven by lower perceptual reasoning (-4.4 [-7.7, -1.1]; per doubling) and verbal
comprehension raw scores (-3.8 [-6.8, -0.8]; per doubling), both of which were also evaluated non-
linearly. We did not observe any significant interaction with sex (P=0.3–0.9) or differences between
estimates for boys and girls in the stratified models (Table 6).

In sensitivity analysis, further adjustment for children’s urinary arsenic, cadmium, or iodine
concentrations, season of urine sampling, or food and micronutrient supplementation did not
considerably change the estimates in the models mentioned above (Tables S8-S10). Further
adjustment by child urinary lead concentrations, however, strengthened the cross sectional and
prospective 5-year fluoride exposure estimates, but they were still not significant. Additional
adjustment of the child fluoride exposure models (5 years) for the prenatal exposure changed the
estimates to variable degrees and all models remained non-significant (Table S11). In the cross-
sectional models at 10 years the additional adjustment for prenatal exposure resulted in less than
20% attenuation of the estimates (Table 7). After adjustment for prenatal exposure, child urinary
fluoride concentrations had an inverse association with full-scale raw scores at 10 years of age [-10.5
(95% CI: -19.7, -1.4)], compared to the previously observed difference in raw scores [-12.1 (95% CI: –
21.2, -3.0)]. When the associations were adjusted for the minimal adjustment set, including only
some basic a priori selected factors and true confounders (Table S8-S10), the estimates were weaker,
but the associations observed in the main models remained robust.

Discussion

In this longitudinal cohort study, urinary fluoride concentrations, during both gestation and
childhood, were inversely associated with the measures of child cognition. Maternal urinary fluoride
in early pregnancy was inversely associated with the children’s cognitive scores both at 5 and 10
years of age, with no apparent threshold below which there appeared to be no effect. Similarly, the
children’s contemporary fluoride exposure at 10 years of age was inversely associated with cognition,
but only at urinary concentrations above -0.47 on the log 2 scale (corresponding to 0.72 mg/L).
Concerning the affected cognitive domains, both prenatal and childhood exposure appeared to
predominantly affect perceptual reasoning and verbal comprehension. We did not observe any
consistent sex differences.

The finding that maternal urinary fluoride concentrations in early pregnancy (median: 0.63 mg/L,
range: 0.07–7.5 mg/L) were inversely associated with child cognition measured at 5 and 10 years of
age is in accordance with results reported from other prospective cohort studies with similar
exposure levels.^{5, 7, 12, 39} The ELEMENT study in Mexico reported that maternal urinary fluoride
concentrations during pregnancy (median during pregnancy: 0.82–0.90 mg/L, range: 0.02–2.4 mg/L
in two different evaluations; n=299–348) were inversely associated with the children’s intelligence
scores at ages 4, 5, and 6–12 years.^{5, 39} In the Canadian MIREC study, maternal urinary fluoride
concentrations (median across all trimesters: 0.41–0.44 mg/L, range: 0.06–2.5 mg/L; n=512–596)
were inversely associated with child intelligence at 3 to 4 years of age.7, 12 In line with the prospective
studies from Canada and Mexico,^{5, 12} we also found that the prenatal fluoride exposure was
associated primarily with perceptual reasoning, representing non-verbal reasoning, spatial
processing, and visual motor skills at 10 years of age. Additionally, we found that the children’s verbal
skills (reasoning and comprehension) seemed to be impacted. This was also shown in the Mexican
updated ELEMENT study,³⁹ but not in the Canadian MIREC study.¹¹ Also, a small ecological Chinese
study (n=99) observed lower verbal skills in children aged 8-12 years with dental fluorosis in
comparison to a control group without dental fluorosis.⁴⁰ It can be speculated that the domain-
specific neurotoxicity of fluoride varies across populations.

We also found that the children’s contemporary fluoride exposure was inversely associated with
their cognitive abilities at 10 years of age, although at higher exposure levels. Like with prenatal
fluoride exposure, the association was mainly driven by lower scores of perceptual reasoning and
verbal comprehension. A doubling of the exposure above 0.72 mg/L was associated with a decrease
in full-scale raw score by 12, which corresponds to 0.35 standard deviation. Adjusting for the
prenatal exposure decreased the full-scale estimate by about 13% only, suggesting a contribution of
childhood exposure to the overall impact on child cognition. In our study, the correlation between
maternal and child urinary fluoride was weak. To our knowledge, there is only one previous
longitudinal study, based on the MIREC cohort, investigating the association with child cognition of
both prenatal and childhood fluoride exposure. They found significant inverse associations of urinary
fluoride concentrations during pregnancy, estimated infants’ intake of fluoride, and children’s urinary
concentrations (median: 0.39 mg/L at 1.9–4.4 years) with performance intelligence quotient (IQ) at
3–4 years of age.¹² In a cross-sectional study of 2886 Chinese children aged 7–13 years, like in our
study, there was evidence of a threshold for the association of child urinary fluoride with intelligence
at a concentration of 1.6 mg/L.⁴¹ Another cross-sectional Chinese study reported that children (aged
6–13 years, n=709) in the fourth quartile of urinary fluoride had about 20% increased odds of
developing dental fluorosis or having an IQ below 120, compared to children in the first quartile
(overall range in urinary fluoride: 0.02–5.4 mg/L).⁴²

Notably, we found no clear association of urinary fluoride at 5 years of age (median: 0.62 mg/L,
range: 0.11–3.6 mg/L) with cognition, neither cross-sectionally, nor at 10 years. Possibly, the shorter
childhood exposure time at 5 years resulted in a milder impact on cognition than that at 10 years.
Also, the fluoride concentration in a single spot urine sample at 5 years of age may be less reliable as
an exposure biomarker than that in later childhood, due to the rapid linear growth.⁴³ In young
children, more than half of the ingested amount of fluoride may be retained in the skeleton.³
Obviously, such retention differs between individuals, resulting in varying urinary excretion in
relation to the ingested amount. This was supported by the weak correlation of urinary fluoride at 5
years with water fluoride (samples collected at 10-year follow-up), compared to urinary fluoride at
early gestation and at 10 years of age.

The overall findings regarding sex differences in cognitive abilities in relation to fluoride exposure
are inconsistent. In the present study, the impact of prenatal exposure on cognition seemed
somewhat more pronounced in girls than in boys, though the difference was not significant and was
observed mainly at 10 years of age. Similarly, a study in Calgary, Canada, found that women who
used fluoridated drinking water (at 0.7 mg/L) during pregnancy gave birth to children with poorer
cognitive flexibility, particularly in girls, compared to those using non-fluoridated water⁴⁴
. Also, a Chinese study involving 512 children aged 8–13 years reported lower cognition scores in girls
compared to boys in an endemic fluorosis region, but not in a similar region with low water fluoride
concentrations. 45 In the Canadian MIREC study, however, maternal urinary fluoride concentrations
were inversely associated with child intelligence mainly in boys.⁷ In contrast, no sex differences were
observed in the Mexican ELEMENT cohort.^{5, 39} As to childhood exposure, we found no sex-related
difference in the associations of the children’s contemporary fluoride exposure at 10 years of age
with cognitive abilities. Similarly, the MIREC study found no sex-related difference in the association
of childhood fluoride exposure and performance IQ.¹² The diverse findings in relation to child sex and
critical windows of exposure highlight the need for more and larger prospective studies.

During fetal development, fluoride ingested by the mother crosses the placenta and thereafter
the undeveloped fetal blood-brain barrier.^{4, 14} For example, passage of fluoride across the fetal blood-
brain barrier is indicated by brain tissue analysis of aborted human fetuses.⁴⁶ There are also
experimental studies in rodents with long-term oral fluoride exposure in adult life indicating that
fluoride crosses the mature blood-brain barrier.⁴⁷ However, despite increasing evidence that fluoride
has neurotoxic properties,¹⁴ there is no consensus on underlying mechanisms of action. Several
possible mechanisms have been suggested, including oxidative stress and mitochondrial
dysfunction,^47-49 neuroinflammation, neuronal apoptosis, and neurotransmitter imbalance.⁴⁷ Besides
a possible direct toxic effect on the central nervous system, fluoride has also been postulated to
function as an endocrine disruptor.¹⁴ In the Canadian MIREC cohort, a 0.5 mg/L increase in water
fluoride concentrations in pregnant women was associated with a 65% increased odds of primary
hypothyroidism.⁵⁰ Also, boys born to women with primary hypothyroidism had lower full-scale
intelligence scores than children of euthyroid women.⁵⁰ In a Chinese study, including 571 children
aged 7-13 years, fluoride exposure altered thyroid hormones and thyroid stimulating hormone (TSH)
evels, which modified the association between fluoride and intelligence.⁵¹

Drinking water is an important source of fluoride exposure in many parts of the world.² The
drinking water fluoride concentrations measured at the 10-year-old follow-up visit (median: 0.20
mg/L, range: 0.04–0.74 mg/L) were comparable to those in the Canadian MIREC study (fluoridated
area: median: 0.56 mg/L, range: 0.41–0.87 mg/L and non-fluoridated area median: 0.13, range:
0.04–0.20 mg/L).⁵² We believe that drinking water was an important source of fluoride in the present
study as people drink several liters per day due to the hot climate.⁵³ Also, the children’s urinary
fluoride concentrations at 10 years of age were moderately correlated with their drinking water
concentrations (rho=0.44). A stronger correlation was found between the mothers’ urinary fluoride
in early gestation and the water fluoride concentrations at the children’s 10-year-old visit (rho=0.55)
providing potential support for fairly stable exposure through drinking water over time. However, we
did not measure water fluoride concentrations during early gestation nor during the 5-year-old visit,
and several of the wells (mainly private wells) were renewed or abandoned due to the elevated
arsenic concentrations found in 2002–2003.⁵⁴ There is a paucity of data on exposure from other
dietary and non-dietary sources, though exposure to fluoride from black tea may be considerable. 55
However, tea consumption is low in rural Bangladesh.⁵⁶ A recent study reported that the fluoride
concentrations in two commercial toothpastes for children in Bangladesh contained 803 and 1042
mg/kg⁵⁷ which is within the concentration range recommended by WHO (1000–1500 mg/kg).¹ Still,
dental care products could contribute to the total daily intake, especially for small children who are
likely to swallow some toothpaste during brushing.⁵⁸

The main strengths of the study include the prospective population-based design, and a broad range of individual urinary fluoride concentrations measured during gestation and at 5 and 10 years of age. Child cognition was comprehensively and repeatedly measured at 5 and 10 years with reliable and widely used psychometric tools, and we were able to adjust the models for multiple potential confounders, including SES, HOME, maternal non-verbal reasoning, and maternal and child education, which have been found to influence child cognition. A limitation is that we used a single spot urine sample at each exposure assessment time point, which may have introduced exposure misclassification, given the short half-life of fluoride in plasma, approximately 6 hours.³ Such exposure misclassification is expected to bias the observed results towards null.⁵⁹ As earlier studies have indicated that urinary fluoride concentrations increase slightly as pregnancy progresses,^{12, 52, 60} it is possible that we may have underestimated the prenatal fluoride exposure since we measured the urinary fluoride concentrations in the first trimester. On the other hand, urinary fluoride is probably more stable in early pregnancy than in late pregnancy, when increased bone resorption is more
prominent due to the prioritized transport of calcium to the fetus,⁶¹ leading to increased release of
fluoride from bone. Because the WPPSI-III and WISC-IV were not standardized in the Bangladeshi
population, we used raw intelligence scores, which limits the comparability of the effect sizes of the
dentified associations with other studies and between the various studied cognitive outcomes. We
did not adjust for methylmercury exposure, as we have previously found it not to be associated with
the children’s cognitive abilities at 10 years in the present cohort.⁶² Finally, although our associations
are adjusted for multiple potential confounders, unmeasured residual confounding may exist.

To conclude, this study adds to the growing evidence that even low-level fluoride exposure early
in life may adversely impact child cognition. Prenatal exposure was associated with lower cognitive
abilities, with no indication of a threshold. Also, childhood fluoride exposure was inversely associated
with child cognition, although at higher exposure levels. Both perceptual reasoning and verbal ability
appeared to be affected. Because even minor changes in cognition at a population level have
important implications for public health, the overall results raise concerns about the existing
guidelines and standards for fluoride in drinking water…

Acknowledgments

We thank all participating families, and everyone involved in cognitive testing, collection of samples
and data generation. This work was supported by grants from the Swedish Research Council Formas
(grant 2019-00909 and 210–2013– 751), the Swedish Research Council (grants 2022-00753, 2017–
01172, 2015–03206, and 521–2013–02269), the Swedish International Development Cooperation
Agency (grant SWE-186), the European Commission [Public health impact of long-term, low-level
mixed element exposure in susceptible population strata (PHIME)], and Karolinska Institutet. The
Maternal and Infant Nutrition Interventions in Matlab (MINIMat) supplementation trial in pregnancy
was funded by UNICEF, Sida, the UK Medical Research Council, the Swedish Research Council, the UK
Department for International Development, the International Centre for Diarrhoeal Disease
Research, Bangladesh, the Global Health Research Fund (Japan), the Child Health and Nutrition
Research initiative, Uppsala University, and the U.S. Agency for International Development.

References

1. O’Mullane DM, Baez RJ, Jones S, et al. 2016. Fluoride and Oral Health. Community Dent Health 33(2):69-99, PMID: 27352462, https://doi.org/10.1922/CDH_3707O’Mullane31
2. World Health Organization. 2022. Guidelines for Drinking-water Quality: Fourth Edition Incorporating the First and Second Addenda. 4th ed + 1st + 2nd. World Health Organization. https://iris.who.int/handle/10665/352532
3. Buzalaf MAR, Whitford GM. 2011. Fluoride metabolism. Monogr Oral Sci 22:20-36, PMID: 21701189, https://pubmed.ncbi.nlm.nih.gov/21701189/
4. Grandjean P. 2019. Developmental fluoride neurotoxicity: an updated review. Environ Health. 18(1):110, PMID: 31856837, https://doi.org/10.1186/s12940-019-0551-x
5. 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, PMID:28937959, https://doi.org/10.1289/EHP655
6. Cantoral A, Téllez-Rojo MM, Malin AJ, et al. 2021. Dietary fluoride intake during pregnancy and neurodevelopment in toddlers: A prospective study in the progress cohort. Neurotoxicology 87:86-93, PMID: 34478773, https://doi.org/10.1016/j.neuro.2021.08.015
7. 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, PMID: 31424532, https://doi.org/10.1001/jamapediatrics.2019.1729
8. Ibarluzea J, Gallastegi M, Santa-Marina L, et al. 2022. Prenatal exposure to fluoride and neuropsychological development in early childhood: 1-to 4 years old children. Environ Res 207:112181, PMID:34627799, https://doi.org/10.1016/j.envres.2021.112181
9. Grandjean P, Meddis A, Nielsen F, et al. 2024. Dose dependence of prenatal fluoride exposure associations with cognitive performance at school age in three prospective studies. Eur J Public Health 34(1):143-149, PMID: 37798092,
   https://doi.org/10.1093/eurpub/ckad170.
10. Kampouri M, Zander E, Gustin K, et al. 2024. Associations of gestational and childhood exposure to lead, cadmium, and fluoride with cognitive abilities, behavior, and social communication at 4 years of age: NICE birth cohort study. Environ Res 263(Pt 2):120123. PMID: 39389199, https://doi.org/10.1016/j.envres.2024.120123
11. Till C, Green R, Flora D, et al. 2020. Fluoride exposure from infant formula and child IQ in a Canadian birth cohort. Environ Int 134:105315, PMID:31743803, https://doi/10.1016/j.envint.2019.105315
12. Farmus L, Till C, Green R, et al. 2021. Critical windows of fluoride neurotoxicity in Canadian children. Environ Res 200:111315. PMID: 34051202, https://doi.org/10.1016/j.envres.2021.111315
13. 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. PMID: 24832151, https://doi.org/10.2105/AJPH.2013.301857
14. NTP. 2023. NTP Board of Scientific Counselors Working Group Report on the Draft State of the Science Monograph and the Draft Meta-Analysis Manuscript on Fluoride. Final Report: Approved by the NTP Board of Scientific counselors on May 16, 2023. https://ntp.niehs.nih.gov/sites/default/files/2023-05/BSC_WG_Report_Final_Version_BSC_approved051623_508.pdf
15. Hoque AKMF, Khaliquzzaman M, Hossain MD, Khan AH. 2003. Fluoride levels in different drinking water sources in Bangladesh. Fluoride 36:38-44, https://www.researchgate.net/publication/286982904_Fluoride_levels_in_different_drinking_water_sources_in_Bangladesh
16. Hamadani JD, Tofail F, Nermell B, et al. 2011. Critical windows of exposure for arsenic-associated impairment of cognitive function in pre-school girls and boys: a population-based cohort study. Int J Epidemiol 40(6):1593-1604, PMID: 22158669, https://doi.org/10.1093/ije/dyr176.
17. Kippler M, Tofail F, Hamadani JD, et al. 2012. Early-life cadmium exposure and child development in 5-year-old girls and boys: a cohort study in rural Bangladesh. Environ Health Perspect 120(10):1462-1468, PMID: 22759600, https://doi.org/10.1289/ehp.1104431
18. Gustin K, Tofail F, Vahter M, Kippler M. 2018. Cadmium exposure and cognitive abilities and behavior at 10 years of age: A prospective cohort study. Environ Int 113:259-268, PMID: 29459184, https://doi.org/10.1016/j.envint.2018.02.020
19. Kampouri M, Tofail F, Rahman SM, et al. 2023. Gestational and childhood urinary iodine concentrations and children’s cognitive function in a longitudinal mother-child cohort in rural Bangladesh. Int J Epidemiol 52(1):144-155, PMID: 35613019, https://doi.org/10.1093/ije/dyac110
20. Persson L, Arifeen S, Ekström EC, et al. 2012. Effects of prenatal micronutrient and early food supplementation on maternal hemoglobin, birth weight, and infant mortality among children in Bangladesh: the MINIMat randomized trial. JAMA 307(19):2050-2059, PMID: 22665104, https://doi.org/10.1001/jama.2012.4061
21. Vahter ME, Li L, Nermell B, Rahman A, et al. 2006. Arsenic exposure in pregnancy: a population-based study in Matlab, Bangladesh. J Health Popul Nutr 24(2):236-245. PMID: 17195565.
22. Skröder H, Kippler M, Tofail F, Vahter M. 2017. Early-Life Selenium Status and Cognitive Function at 5 and 10 Years of Age in Bangladeshi Children. Environ Health Perspect 125(11):117003, PMID: 29116931, https://doi.org/10.1289/EHP1691
23. Rahman SM, Kippler M, Tofail F, et al. 2017. Manganese in Drinking Water and Cognitive Abilities and Behavior at 10 Years of Age: A Prospective Cohort Study. Environ Health Perspect 125(5):057003. PMID: 28564632 https://doi.org/10.1289/EHP631
24. Vahter M, Skröder H, Rahman SM, et al. 2020. Prenatal and childhood arsenic exposure through drinking water and food and cognitive abilities at 10 years of age: A prospective cohort study. Environ Int 139:105723, PMID: 32298878,
    https://doi.org/10.1016/j.envint.2020.105723
25. Nermell B, Lindberg AL, Rahman M, et al. 2008. Urinary arsenic concentration adjustment factors and malnutrition. Environ Res 106(2):212-218, PMID: 17900556, https://doi.org/10.1016/j.envres.2007.08.005
26. Wechsler D. 2002. Wechsler Preschool and Primary Scale of Intelligence-Third edition (WPPSI-III). San Antonio, TX; The Psychological Corporation.
27. Wechsler D. 2003. Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV). San Antonio, TX: Psychological Corporation.
28. Arifeen SE, Ekström E-C, Frongillo EA, et al. 2018. Cohort profile: the maternal and infant nutrition interventions in Matlab (MINIMat) cohort in Bangladesh. International journal of epidemiology, 47(6):1737-1738e. PMID: 29868907, https://doi.org/10.1093/ije/dyy102
29. Gwatkin DR, Rustein S, Pande J, RP W. 2000. Socio-Economic Differences in Health, Nutrition, and Population in Bangladesh. World Bank, Washington, DC.
30. Raven J. 1989. The Raven Progressive Matrices: A Review of National Norming Studies and Ethnic and Socioeconomic Variation within the United States. J Educ Meas 26(1):1-16.
31. Bradley RH, Caldwell BM, Corwyn RF. 2003. The Child Care HOME Inventories: assessing the quality of family child care homes. Early Child Res Q 18(3):294-309. https://doi.org/10.1016/S0885-2006(03)00041-3
32. Caldwell BM. 1967. Descriptive evaluations of child development and of developmental settings. Pediatrics 40(1):46-54. PMID: 6028898.
33. Rydbeck F, Bottai M, Tofail F, et al. 2014. Urinary iodine concentrations of pregnant women in rural Bangladesh: A longitudinal study. J Expo Sci Environ Epidemiol 24(5):504-509. https://doi.org/10.1038/jes.2013.79.
34. Bergkvist C, Kippler M, Hamadani JD, et al. 2010. Assessment of early-life lead exposure in rural Bangladesh. Environ Res 110(7):718-724. PMID: 20656285, https://doi.org/10.1016/j.envres.2010.07.004
35. Textor J, van der Zander B, Gilthorpe MS, et al. 2016. Robust causal inference using directed acyclic graphs: the R package “dagitty.” Int J Epidemiol 45(6):1887-1894. PMID: 28089956, https://doi.org/10.1093/ije/dyw341
36. Dewey KG, Begum K. 2011. Long-term consequences of stunting in early life. Maternal & Child Nutrition, 7(s3):5-18. PMID: 21929633 https://doi.org/10.1111/j.1740-8709.2011.00349.x
37. Lanphear BP, Hornung R, Khoury J, et al. 2005. Low-level environmental lead exposure and children’s intellectual function: an international pooled analysis. Environ Health Perspect 113(7):894-899. PMID: 16002379, https://doi.org/10.1289/ehp.7688
38. Goodman CV, Hall M, Green R, et al. 2022. Iodine Status Modifies the Association between Fluoride Exposure in Pregnancy and Preschool Boys’ Intelligence. Nutrients 14(14): 2920, PMID: 35889877, https://doi.org/10.3390/nu14142920
39. Goodman CV, Bashash M, Green R, et al. 2022. Domain-specific effects of prenatal fluoride exposure on child IQ at 4, 5, and 6-12 years in the ELEMENT cohort. Environ Res 211:112993. PMID: 35276192, https://doi.org/10.1016/j.envres.2022.112993
40. Lou D, Luo Y, Liu J, et al. 2021. Refinement Impairments of Verbal-Performance Intelligent Quotient in Children Exposed to Fluoride Produced by Coal Burning. Biol Trace Elem Res 199(2):482-489, PMID: 32363519, https://doi.org/10.1007/s12011-020-02174-z
41. 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. PMID: 29870912, https://doi.org/10.1016/j.envint.2018.05.042
42. Wang S, Zhao Q, Li G, et al. 2021. The cholinergic system, intelligence, and dental fluorosis in school-aged children with low-to-moderate fluoride exposure. Ecotoxicol Environ Saf 228:112959. PMID: 34808511, https://doi.org/10.1016/j.ecoenv.2021.112959
43. Black RE, Liu L, Hartwig FP, et al. 2022. Health and development from preconception to 20 years of age and human capital. The Lancet 399(10336):1730-1740, PMID: 35489357, https://doi.org/10.1016/S0140-6736(21)02533-2
44. Dewey D, England-Mason G, Ntanda H, et al. 2023. Fluoride exposure during pregnancy from a community water supply is associated with executive function in preschool children: A prospective ecological cohort study. Science of The Total Environment 891:164322. PMID: 37236475, https://doi.org/10.1016/j.scitotenv.2023.164322
45. Xiang Q, Liang Y, Chen L, et al. 2003. Effect of fluoride in drinking water on children’s intelligence. Fluoride 36(2):84-94, https: https://www.researchgate.net/publication/237230677_Effect_of_fluoride_in_drinking_water on_children’s_intellige
46. Du L. 1992. [The effect of fluorine on the developing human brain]. Zhonghua Bing Li Xue Za Zhi 21(4):218-220. PMID: 1473206.
47. Ren C, Li HH, Zhang CY, Song XC. 2022. Effects of chronic fluorosis on the brain. Ecotoxicol Environ Saf. 244:114021. PMID: 36049331, https://doi.org/10.1016/j.ecoenv.2022.114021
48. Adkins EA, Brunst KJ. 2021. Impacts of Fluoride Neurotoxicity and Mitochondrial Dysfunction on Cognition and Mental Health: A Literature Review. Int J Environ Res Public Health 18(24), PMID: 34948493, https://doi.org/10.3390/ijerph18241288
49. Zhang KL, Lou DD, Guan ZZ. 2015. Activation of the AGE/RAGE system in the brains of rats and in SH-SY5Y cells exposed to high level of fluoride might connect to oxidative stress. Neurotoxicol Teratol 48:49-55, PMID: 25666879, https://doi.org/10.1016/j.ntt.2015.01.007
50. Hall M, Lanphear B, Chevrier J, et al. 2023. Fluoride exposure and hypothyroidism in a Canadian pregnancy cohort. Sci Total Environ 869:161149, PMID: 36764861, https://doi.org/10.1016/j.scitotenv.2022.161149
51. Wang M, Liu L, Li H, et al. 2020. Thyroid function, intelligence, and low-moderate fluoride exposure among Chinese school-age children. Environ Int 134:105229, PMID: 31698198, https://doi.org/10.1016/j.envint.2019.105229
52. Till C, Green R, Grundy JG, et al. 2018. Community Water Fluoridation and Urinary Fluoride Concentrations in a National Sample of Pregnant Women in Canada. Environ Health Perspect 126(10):107001, PMID: 30392399, https://doi.org/10.1289/EHP3546
53. Milton AH, Rahman H, Smith W, et al. 2006. Water consumption patterns in rural Bangladesh: are we underestimating total arsenic load? J Water Health. 4(4):431-6. PMID: 17176814.
54. Kippler M, Skröder H, Rahman SM, et al. 2016. Elevated childhood exposure to arsenic despite reduced drinking water concentrations — A longitudinal cohort study in rural Bangladesh. Environ Int 86:119-125, PMID: 26580026, https://doi.org/10.1016/j.envint.2015.10.017
55. Krishnankutty N, Storgaard Jensen T, Kjær J, et al. 2022. Public-health risks from tea drinking: Fluoride exposure. Scand J Public Health 50(3):355-361, PMID: 33557697, https://doi.org/10.1177/1403494821990284.
56. Hossain MM. 2010. Changing consumption patterns in rural Bangladesh. Intl J Consum Stud 34(3):349-356, https://doi.org/10.1111/j.1470-6431.2010.00866.x
57. Paul CC, Khan MdAS, Sarkar PK, et al. 2019. Assessment of the Level and Health Risk of Fluoride and Heavy Metals in Commercial Toothpastes in Bangladesh. Indones J Chem 20(1):150-159. https://doi.org/10.22146/ijc.43266
58. Zohoori FV, Buzalaf MA, Cardoso CA, et al. 2013. Total fluoride intake and excretion in children up to 4 years of age living in fluoridated and non-fluoridated areas. Eur J Oral Sci 121(5):457-464. PMID: 24028594, https://doi.org/10.1111/eos.12070
59. Blair A, Stewart P, Lubin JH, Forastiere F. 2007. Methodological issues regarding confounding and exposure misclassification in epidemiological studies of occupational exposures. Am J Ind Med 50(3):199-207, PMID: 17096363, https://doi.org/10.1002/ajim.20281
60. Malin AJ, Hu H, Martínez-Mier EA, et al. 2023. Urinary fluoride levels and metal co-exposures among pregnant women in Los Angeles, California. Environ Health 22(1):74, PMID: 37880740, https://doi.org/10.1186/s12940-023-01026-2
61. Salles JP. Bone metabolism during pregnancy. 2016. Ann Endocrinol (Paris) 77(2): 163-168, PMID:27157104, https://doi.org/10.1016/j.ando.2016.04.004
62. Gustin K, Tofail F, Mehrin F, et al. 2017. Methylmercury exposure and cognitive abilities and behavior at 10years of age. Environ Int 102:97-105, PMID: 28216013. https://doi.org/10.1016/j.envint.2017.02.004

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