Prenatal exposure to fluoride has been associated with adverse neurodevelopmental outcomes. However, the neuropsychological profile of fluoride’s developmental neurotoxicity at low levels and the stability of this relationship across childhood has not been characterized. We investigated the longitudinal and domain specific effect of prenatal fluoride exposure on IQ among children ages 4, 5, and 6–12 years in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort.
We measured the average of maternal urinary fluoride at each trimester of pregnancy adjusted for creatinine (MUFCRE). Children were administered the McCarthy Scales of Children’s Abilities at ages 4 (N = 386) and 5 (N = 308), and the Wechsler Abbreviated Scale of Intelligence at age 6–12 (N = 278). We used generalized estimating equation (GEE) models to estimate the population averaged effect of MUFCRE concentration on longitudinal General Cognitive Index (GCI)/Full-Scale IQ (FSIQ), Verbal IQ (VIQ), and Performance IQ (PIQ) scores (N = 348). We tested for possible interactions between MUFCRE and child sex as well as for MUFCRE and time point on children’s IQ. All models controlled for relevant available covariates.
The mean/median MUFCRE concentration was 0.90/0.83 mg/L (SD = 0.39; IQR, 0.64–1.11 mg/L). A 0.5 mg/L increase in MUFCRE predicted an average 2.12-point decrease in GCI/FSIQ (95% CI: -3.49, -0.75) and 2.63-point decrease in PIQ (95% CI: -3.87, -1.40). MUFCRE was marginally associated with VIQ across time (B = -1.29, 95% CI: -2.60, 0.01). No interactions between MUFCRE and child sex or MUFCRE and time were observed.
The negative association between prenatal fluoride exposure and longitudinal IQ was driven by decrements in non-verbal intelligence (i.e. PIQ), suggesting that visual-spatial and perceptual reasoning abilities may be more impacted by prenatal fluoride exposure as compared to verbal abilities.
Fluoride is added to drinking water and salt for the prevention of dental caries (CDC, 2016). Other sources of fluoride include fluoridated dental products and supplements, certain foods that absorb naturally occurring fluoride, such as green and black tea, and foods that are sprayed with fluoride-containing pesticides (i.e., grapes; Nutrient Data Laboratory, 2015; Zohoori et al., 2013). Recent studies conducted in the United States (Abduweli Uyghurturk et al., 2020), Canada (Till et al., 2018), and Mexico (Thomas et al., 2016a,b; Castiblanco-Rubio et al., 2021) have reported positive associations between fluoride from dietary sources, including drinking water and salt, and urinary fluoride levels in pregnant women. Because of its ubiquity and its ability to pass through the placenta and blood-brain barrier to reach the fetal brain (Agency for Toxic Substances and Disease Registry, 2003), the safety of fluoride exposure in pregnancy has received much attention, both in endemic fluorosis areas (Jiménez et al., 2017) and communities that have fluoridation programs (Green et al., 2019; Bashash et al., 2017).
While it is not disputed that fluoride is a developmental neurotoxicant at high exposure levels, there are relatively few studies that have assessed fluoride’s potential neurotoxicity at levels found in fluoridated areas (i.e., 0.7 mg/L), particularly for pregnant women and young infants. In 2021, the National Toxicology Program (National Toxicology Program, 2020) conducted a systematic review on the impact of fluoride on neurodevelopmental outcomes. The NTP identified two high-quality prospective birth cohort studies that were conducted in Mexico City where salt is fluoridated at 250 ppm (Bashash et al., 2017) and in Canada where drinking water is fluoridated at 0.7 mg/L (Green et al., 2019). Both cohort studies found a 4-to 6-point lower Full-Scale IQ score in children per 1 mg/L increase in maternal urinary fluoride level; in the Canadian cohort the effect of maternal urinary fluoride on IQ was only found in boys while the effect of drinking water fluoride level on IQ was found in both boys and girls.
Most human developmental toxicology studies focus on global or composite test scores, such as Full-Scale IQ, which are derived from a diverse set of tasks (Kamphaus, 2019). While global outcomes are considered highly significant from a public health (Lanphear, 2015) and economic standpoint (Gould, 2009), a low composite score does not convey specific information about the child’s intellectual and cognitive profile. When there are strengths and weaknesses in a cognitive profile, the use of a composite score may have high sensitivity, but at the cost of low specificity (Fiorello et al., 2007). Partitioning Full-Scale IQ into domain specific intellectual abilities, such as verbal and nonverbal skills, may reveal particular cognitive domains that are more sensitive to neurotoxic exposures or may be differentially affected over time (Bellinger et al., 2016). For example, studies have demonstrated that prenatal and early-life lead exposure is more strongly associated with non-verbal intelligence compared to verbal intelligence between the ages of 2–7 (Bellinger et al., 1991; Desrochers-Couture et al., 2018; Dietrich et al., 1991, 1993; Factor-Litvak et al., 1999; Jusko et al., 2008; Wasserman et al., 1997). Similarly, prenatal and early-life fluoride exposure has been associated with greater deficits in non-verbal abilities than verbal abilities in preschool years (Till et al., 2020; Farmus et al., 2021; Cantoral et al., 2021); however, other studies examining early-life exposure to fluoride did not find observe this profile (Ibarluzea et al., 2021) or did not report verbal and non-verbal intelligence (Bashash et al., 2017). Whether non-verbal intelligence is associated with early life exposure to fluoride over the course of child development has not been examined.
In the present study, we examined the longitudinal and domain specific effects (i.e., verbal and nonverbal intelligence) of prenatal fluoride exposure on IQ in mother-child dyads from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort. Since our prior publication on this cohort (Bashash et al., 2017), we received additional maternal urinary fluoride and creatinine data enabling us to examine children’s IQ at three separate time points (age 4, 5, and 6–12 years) and using a larger sample size at each time point relative to our prior work. We also examined the potential for sex-specific effects based on findings that boys may be more susceptible to prenatal exposure than girls (Cantoral et al., 2021; Comfort and Re, 2017; Green et al., 2019, 2020; Torres-Rojas and Jones, 2018).
The ELEMENT project enrolled mother-child pairs from three hospitals in Mexico City serving low to middle income families. Participants were recruited as part of four longitudinal birth cohort studies and are described in a recent cohort profile paper (see Perng et al., 2019). Of the four cohorts, cohorts 2A and 3 had prenatal information and archived maternal urine samples collected during pregnancy. Cohort 2A included 327 women recruited between 1997 and 1999 for an observational study of
Out of the 997 mothers from cohorts 2A and 3, 971 were at least 18 years of age. Of the 971, 585 had urinary fluoride and urinary creatinine measured for at least one trimester (6 were excluded for having MUFCRE concentrations greater than 3.5 standard deviations from the mean). Of the 585 mothers with MUFCRE data, 391 had MSCA data at age 4, 314 had MSCA data at age 5, and 282 had WASI data at age 6–12. The final sample included 348 mother-child dyads with complete covariate, MUFCRE, and
We examined the association between prenatal fluoride exposure and IQ scores in children of mothers included in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study. Consistent with past research conducted on a smaller number of mother-child dyads from this cohort (Bashash et al., 2017), an increment of 0.5 mg/L in maternal urinary fluoride concentration was associated with a 2-point decrement in children’s Full-Scale IQ scores. Results remained consistent when we
A limitation of our study is that fluoride exposure was estimated through maternal non-fasting spot urine samples. Urinary fluoride has a short half-life (approximately 5 hours), and measurement of fluoride may be diluted by lack of control for behaviours that could contribute to acute changes in fluoride levels, such as consumption of fluoride-free bottled water prior to urine sampling. We minimized these limitations by collecting serial urine samples across more than one trimester of
In conclusion, prenatal exposure to fluoride is associated with sustained impacts on IQ. Non-verbal abilities may be more susceptible to impairment from prenatal fluoride exposure as compared to verbal abilities. These results were found among mother-child pairs living in a region of Mexico in which fluoride is added to salt. These findings contribute to the growing body of evidence on fluoride’s neurotoxicity, and indicate a need to develop recommendations for pregnant women. Future research
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
The authors gratefully acknowledge: The American British Cowdray Hospital for providing facilities for the ELEMENT research and Dr. David Bellinger for his collaboration on the design and execution of the ELEMENT study’s cognitive testing.
Funding: This data was supported by the U.S. National Institutes of Health (NIH; grants R01ES021446 and R01-ES007821); the National Institute of Environmental Health Sciences/the U.S. Environmental Protection Agency (NIEHS/EPA; grant P01ES022844, 83543601),
D.C. Bellinger. Effect modification in epidemiologic studies of low-level neurotoxicant exposures and health outcomes. Neurotoxicol. Teratol. (2000)
D.C. Bellinger et al.. A developmental perspective on early-life exposure to neurotoxicants. Environ. Int. (2016)
J. Bernal. Thyroid hormones and brain development. Vitam. Horm. (2005)
A. Cantoral et al. Dietary fluoride intake during pregnancy and neurodevelopment in toddlers: a prospective study in the PROGRESS cohort. Neurotoxicology (2021)
M. Desrochers-Couture et al. Prenatal, concurrent, and sex-specific associations between blood lead concentrations and IQ in preschool Canadian children. Environ. Int. (2018)
K.N. Dietrich et al. The developmental consequences of low to moderate prenatal and postnatal lead exposure: intellectual attainment in the Cincinnati Lead Study Cohort following school entry. Neurotoxicol. Teratol. (1993)
K.N. Dietrich et al. Lead exposure and the cognitive development of urban preschool children: the Cincinnati Lead Study cohort at age 4 years. Neurotoxicol. Teratol. (1991)
L. Farmus et al. Critical Windows of Fluoride Neurotoxicity in Canadian Children. (2021)
M.K.M. Ferreira et al. Fluoride exposure during pregnancy and lactation triggers oxidative stress and molecular changes in hippocampus of offspring rats. Ecotoxicol. Environ. Saf. (2021)
T.I. Korevaar et al. Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinol. (2016)
R. Niu et al. Effects of fluoride on synapse morphology and myelin damage in mouse hippocampus. Chemosphere (2018)
D.B. Thomas et al. Urinary and plasma fluoride levels in pregnant women from Mexico City. Environ. Res. (2016)
C. Till et al. Fluoride exposure from infant formula and child IQ in a Canadian birth cohort. Environ. Int. (2020)
D.B. Thomas et al. Urinary and plasma fluoride levels in pregnant women from Mexico City. Environ. Res. (2016)
F.V. Zohoori et al. Total fluoride intake and excretion in children up to 4 years of age living in fluoridated and non-fluoridated areas. Eur. J. Oral Sci. (2013)
D. Wechsler. WPPSI-R: Wechsler Preschool and Primary Scale of Intelligence-Revised. (1989)
D. Wechsler. Wechsler Abbreviated Scale of Intelligence (WASI) (1999)
B. Weiss. Vulnerability of children and the developing brain to neurotoxic hazards. Environ. Health Perspect. (2000)
G.A. Wasserman et al. Lead exposure and intelligence in 7-year-old children: the Yugoslavia prospective study. Environ. Health Perspect. (1997)
H. Wang et al. Fluoride-induced thyroid dysfunction in rats: roles of dietary protein and calcium level. Toxicol. Ind. Health (2009)
D. Wahlstrom et al. The Wechsler Preschool and Primary Scale of Intelligence—Fourth Edition, Wechsler Intelligence Scale for Children—Fifth Edition, and Wechsler Individual Achievement. (2018)
C. Torres-Rojas et al. Sex differences in neurotoxicogenetics. Front. Genet. (2018)
C. Till et al. Community water fluoridation and urinary fluoride concentrations in a national sample of pregnant women in Canada. Environ. Health Perspect. (2018)
J.G. Thorpe-Beeston et al. Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. N. Engl. J. Med. (1991)
J.P. Shonkoff et al. From Best Practices to Breakthrough Impacts a Science-Based Approach to Building a More Promising Future for Young Children and Families. (2016)
W. Qian et al. Effect of selenium on fluoride-induced changes in synaptic plasticity in rat hippocampus. Biol. Trace Elem. Res. (2013)
W. Perng et al. Early life exposure in Mexico to ENvironmental Toxicants (ELEMENT) project. BMJ Open (2019)
USDA National Fluoride Database of Selected Beverages and Foods – Release 2 (2005). Nutrient Data Laboratory, Beltsville Human Nutrition Research Center, ARS (2015)
Revised Draft NTP Monograph on the Sytematic Review of Fluoride Exposure and Neurodevelopmental and Cognitive Health Effects (2020)
D. Mulualem et al. Efficacy of calcium-containing eggshell powder supplementation on urinary fluoride and fluorosis symptoms in women in the Ethiopian rift valley. Nutrients (2021)
G. Morreale de Escobar. The role of thyroid hormone in fetal neurodevelopment. J. Pediatr. Endocrinol. Metab.: JPEM (2001)
A. Morawska et al. Promoting self-regulation in young children: the role of parenting interventions. Clin. Child Fam. Psychol. Rev. (2019)
C.A. McPherson et al. An evaluation of neurotoxicity following fluoride exposure from gestational through adult ages in Long-Evans hooded rats. Neurotox. Res. (2018)
Prenatal exposure to fluoride and neuropsychological development in early childhood: 1-to 4 years old children.
Highlights Maternal fluoride levels were associated with better cognitive scores in childhood. The neuropsychological association is gender dependent; only seen in boys. Positive associations do not disappear after adjustment by different covariates. A potential positive neuropsychological association at low fluoride levels cannot be excluded. Background Cross-sectional and prospective studies have provided
Effect of Endemic Fluorosis on Cognitive Function of School Children in Alappuzha District, Kerala: A Cross Sectional Study.
Background: Exposure to high fluoride levels in drinking water can lead to a number of adverse effects in children, including cognitive dysfunction. Despite being endemic for fluorosis, studies on its effect on the cognitive function of children are lacking in Kerala. Aims: The aim of this study
Fluoride exposure and intelligence in school-age children: evidence from different windows of exposure susceptibility.
Study Retracted on November 8, 2022. Retraction Note: BMC Public Health 20, 1657 (2020) https://doi.org/10.1186/s12889-020-09765-4 The Editor has retracted this article. After publication, concerns were raised regarding the data analysis and conclusions in the paper. The authors have provided raw data, and post-publication review found inconsistencies in methodology and major misinterpretation of the
Effects of High-Water Fluoride Exposure on IQ Levels in School-Age Children: A Cross-Sectional Study in Jiangsu, China
This cross-sectional research aimed to investigate the potential effects of elevated fluoride levels in drinking water on children’s intelligence quotient (IQ). A total of 721 children from rural Jiangsu, China, were included in the study and divided into two groups based on the fluoride concentration in their drinking water: a
The relationships between thyroid-stimulating hormone and/or dopamine levels in peripheral blood and IQ in children with different urinary iodine concentrations.
Highlights TSH is not related IQ in children with different urinary iodine concentrations. Dopamine in plasma is unrelated to IQ in children with adequate or excessive iodine. Dopamine has positive correlation with intelligence in iodine deficiency group. The interaction between dopamine in plasma and TSH is not related to
Related Studies :
Fluoride Affects Learning & Memory in Animals
An association between elevated fluoride exposure and reduced intelligence has now been observed in 65 IQ studies. Although a link between fluoride and intelligence might initially seem surprising or random, it is actually consistent with a large body of animal research. This animal research includes the following 45 studies (out
Fluoride & IQ: 76 Studies
• As of July 18, 2022, a total of 85 human studies have investigated the relationship between fluoride and human intelligence. • Of these investigations, 76 studies have reported that elevated fluoride exposure is associated with reduced IQ in humans. • The studies which reported an association of reduced IQ with exposure
Fluoride's Effect on Fetal Brain
The human placenta does not prevent the passage of fluoride from a pregnant mother's bloodstream to the fetus. As a result, a fetus can be harmed by fluoride ingested pregnancy. Based on research from China, the fetal brain is one of the organs susceptible to fluoride poisoning. As highlighted by the excerpts
Fluoride's Direct Effects on Brain: Animal Studies
The possibility that fluoride ingestion may impair intelligence and other indices of neurological function is supported by a vast body of animal research, including over 40 studies that have investigated fluoride's effects on brain quality in animals. As discussed by the National Research Council, the studies have consistently demonstrated that fluoride, at widely varying concentrations, is toxic to the brain.
NRC (2006): Fluoride's Neurotoxicity and Neurobehavioral Effects
The NRC's analysis on fluoride and the brain.
Related FAN Content :