Prenatal fluoride exposure and cognitive outcomes in children at 4 and 6-12 years of age in Mexico
Morteza Bashash, Deena Thomas, Howard Hu et al. — Environmental Health Perspectives
WHAT THE RESEARCH FOUND
The authors analyzed data from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) project to examine if prenatal exposure to fluoride is associated with declined childhood intelligence.
Subjects: The ELEMENT project recruited women who were 14 or less weeks pregnant and free of medical, mental disorders, high-risk pregnancy as well as use of recreational alcohol and drugs use at three clinics of the Mexican Institute of Society Security in Mexico City that serve low-to-moderate income populations.
Exposure measure: Prenatal F exposure was measured as an averaged value of maternal creatinine-adjusted urinary fluoride concentrations (maximum three and minimum one spot urine sample[s] were archived for each woman).
Outcome measure: Offspring’s neurocognitive outcomes were measured as the General Cognitive Index (GCI) score at 4 years and IQ score at 6-12 years.
Covariates: Maternal age, education, marital status, birth order, birth weight, gestational age at delivery, maternal smoking, maternal IQ (estimated using selected subtests of the WAIS-Spanish measured at 6-12 months after birth), and cohort ID. The specific-gravity adjusted urinary fluoride values obtained from offspring at 6-12 years of age were included in the model for prenatal F exposure and IQ.
The study found:
- Significant correlation between GCI and IQ scores.
- No significant correlation between prenatal creatinine-adjusted urinary fluoride and offspring’s specific-gravity adjusted urinary fluoride levels at 6-12 years of age.
- Prenatal creatinine-adjusted urinary fluoride level and GCI at 4 years of age showed mild linear relationship: 0.5mg/L increase in prenatal urinary fluoride was associated with 3.15-point drop in GCI scores (p=0.01, N=287).
- Prenatal urinary fluoride level and IQ at 6-12 years of age showed mild curvilinear relationship: 1) no clear association between prenatal urinary fluoride and IQ scores below approximately 0.8mg/L urinary fluoride levels, and 2) a negative association above prenatal urinary fluoride 0.8mg/L. The authors found 0.5 mg/L increase in prenatal urinary fluoride was associated with -2.5 points in IQ scores (p=0.01, N=211).
- Sensitivity analyses conducted for the subsets of data (N<200) indicated the following:
- The negative associations between prenatal urinary fluoride and GCI or IQ persisted with further adjustment for other potential confounders (family possession, maternal bone lead and blood mercury levels). The effect estimates were attenuated when family possession (SES proxy) and maternal blood mercury values were adjusted in the models relative to unadjusted models, while all of the effect estimates were higher in the subset of subjects with available data of SES, maternal bone lead and blood mercury levels.
- There was no clear, statistically significant, association between contemporaneous children’s urinary fluoride and IQ at 6-12 years of age either unadjusted or adjusted for maternal urinary fluoride during pregnancy.
LEVEL OF RIGOR
- A – Strong methodology and unbiased, appeared in peer-reviewed in respected science journal
- B – Strong methodology and unbiased, not in peer-reviewed journal
- C – Weak methodology and/or biased
- F – Not a scientific finding
SUPPORT FROM OTHER STUDIES
- High – All the peer-reviewed research to date support these findings, and a significant amount of research has been done in this area.
- Medium – Most, but not all, peer-reviewed research to date support these findings, and a significant amount of research has been done in this area.
- Low – Not a lot of research has been done in this area, or some, but not most, other peer-reviewed research supports these findings.
- Not Supported – No other studies support this study’s conclusions.
- Contradicted – Most studies contradict this study’s conclusions.
• Data of childhood neurocognitive outcomes collected in the longitudinal birth cohort research project with various maternal and perinatal covariates data including maternal IQ, education, smoking, and birth outcomes.
• Although sample size of subset data was small, the authors were able to check the effect of SES (although proxy), maternal lead and mercury in the investigated association.
• Urinary fluoride data were adjusted by creatinine and specific gravity for variation in urinary dilution.
• The authors report detail methods and results.
• Limitation of urinary fluoride as a biomarker of fluoride exposure: Urinary fluoride level fluctuates during the day and reflects only recent exposures, and it is unknown if fluoride level measured in spot urine samples during pregnancy is a good measure of prenatal fluoride exposure for fluoride’s neurotoxic effect in children.
• No fluoride data other than urinary fluoride levels were collected or available, thus we do not know the source of fluoride exposure (i.e. fluoride in water, salt, toothpaste, environmental or industrial F exposure etc.) or how such external dose of exposures reflected internal F dose (in urine).
• Lack of data on iodine in salt, other nutritional intake and dietary practices that could influence pregnancy, urinary excretion, and fetus-child cognitive development, and environmental neurotoxicants such as arsenic.
RELEVANCE AND VALIDITY
This study had an advantage of using the data from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) project, which collected data longitudinally from pregnancy to childhood on the exposures to environmental toxicants such as lead and mercury and childhood neurocognitive outcomes. However, this study on fluoride was not planned prior to the ELEMENT data collection, therefore the authors had limited ability to validate fluoride exposures and relied solely on fluoride concentrations in spot urine samples.
Biomarkers of fluoride exposure such as urinary and serum fluoride are considered a marker of recent fluoride exposures. Urinary fluoride fluctuates, thus the value can be influenced by the timing of exposure and sampling, and we do not know if the level captured in a spot urine sample reasonably reflects the usual and/or long-term exposures to fluoride during the prenatal period. In this study, some of the subjects had three spot (second morning void) urine samples obtained from each of trimesters, but approximately 80% of subjects provided only one or two spot urine samples during pregnancy. While the authors adjusted fluoride concentration in spot urine samples with creatinine and specific gravity for dilution factor, there are a number of factors that affect fluoride uptake, retention, and excretion. It is anticipated that fluoride metabolisms would change with gestation, yet we do not know how it changes during the different phases of pregnancy. The authors reported a mean prenatal urinary fluoride value of 0.9 mg/L among the study subjects and thought the value was within normal range, however there are limited population-based data available to determine the reference value of urinary fluoride concentrations during pregnancy. EPA considers urinary fluoride as Group I biomarker for fluoride-related neurotoxicity because there is a lack of established methodology of sampling (i.e. first morning vs. second morning void, spot urine vs. 24-hour urine sampling), analytic strategies, and established relationship between external dose (i.e. supplemental fluoride dose, fluoride concentration in water), internal dose (i.e. in urine), and biological endpoint (i.e. neurotoxicity).
The negative association between prenatal urinary fluoride level and cognitive ability found at 4 and 6-12 years of age in the offspring, no association found between children’s urinary fluoride and IQ at 6-12 years of age, and no significant effect of prenatal urinary fluoride below 0.8 mg/L on childhood IQ in non-linear relationship found in this study all corroborate with a portion of the published literature. A largely spread scatter plot distribution suggests that prenatal fluoride exposure may be a small portion of variations that explain the relationship. We agree with the authors on that additional studies are needed to examine if the association found in this study are replicated in other study populations and if fluoride exposure during pregnancy is indeed a critical window of susceptibility for population’s neurocognitive health. There are only a few studies of relatively small observational studies from Mexico that looked at the fluoride exposure in pregnant women and its association with neurobehavioral outcomes in their offspring (Bashash et al 2017, Valdez Jiménez et al. 2017, and unpublished thesis of Thomas 2014). We also desperately need to learn more about fluoride metabolism during pregnancy and how prenatal urine fluoride concentrations are related to external fluoride doses such as fluoride in drinking water.