Categories
Appraisal Neurodevelopmental Disorders

Appraisal of prenatal fluoride IQ study


Publication reviewed:

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.
Prenatal fluoride IQ study plot

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.

STRENGTHS

• 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.

WEAKNESSES

• 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.

Categories
Appraisal Endocrine Disorders

Fluoride thyroid exposure study indicates no association


Publication reviewed:

Fluoride exposure and indicators of thyroid functioning in the Canadian population: implications for community water fluoridation

Barberio AM, Hosein FS, Quiñonez C, McLaren L — Journal of Epidemiology and Community Health


The Fluoride Science editorial board appraised a key fluoride thyroid research study finding no association between fluoride and hypothyroidism indicators in Canada.

Fluoride thyroid study used Canadian Health Measures Survey data

WHAT THE RESEARCH FOUND

The authors conducted this cross-sectional study using data from the latest (2009-2013) Canadian Health Measures Survey (CHMS) to examine the association between fluoride exposure and thyroid outcomes.

Both thyroid outcome and fluoride exposure were measured at individual level as follows:

Fluoride exposure measures

  • Fluoride level in spot urine sample
  • Fluoride concentration in primary drinking water (mg/L) + self-report on residential history (at least 3 years of consecutive residence)
  • Self-reported use of fluoride containing toothpaste and or mouthwash as well as history of fluoride treatment at dental office

Thyroid outcome measures

  • Self-reported diagnosis of thyroid condition (yes/no)
  • Serum thyroid stimulating hormone (TSH) level (low/normal/high)

No significant association was found between fluoride exposure measured in urine and tap water samples and self-reported diagnosis of a thyroid condition or altered (low or high) TSH levels. Fluoride exposure, in a time and place where multiple sources of fluoride including community water fluoridation exist, is not associated with impaired thyroid functioning in a representative sample of the Canadian population.

Canada has fluoridation program guidelines that are similar to the US, and the findings are relevant to the US and other countries with similar populations and CWF schemes.

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.

STRENGTHS

The association between fluoride exposure and thyroid outcomes was examined using the individual-level data collected from the nationally representative sample of Canadian and adjusted for potential demographic confounders (age, gender, household education and income).

In addition to self-reported data of thyroid condition diagnosis and indicators of fluoride exposures along with the sample of tap water to determine fluoride concentration of subjects’ primary drinking water, the authors used biomarkers of contemporary fluoride exposure (urinary fluoride level) and thyroid functions (serum TSH, thyroid stimulating hormone).

Data from the latest Canadian national health surveillance program (2009-2013), which implements extensive data validation and quality control measures

WEAKNESSES

The use of self-reported thyroid condition diagnosis is subject to misclassification. Spot urine samples do not provide cumulative measures of fluoride exposure over time.

Cross-sectional study design, thus causation could not be discerned.

Potential confounders such as iodine intake (although Canada has adopted mandatory iodisation of all food-grade salt since 1949 and reportedly has adequate population iodine status), smoking, and family history of thyroid disease were not adjusted.

RELEVANCE AND VALIDITY

As a previous study on this topic by Peckham and colleagues reported an ecological association between fluoride and hypothyroidism (both exposure and outcome measured at medical practice-level in England), the findings of this study, which used data of exposure and outcomes measured at the individual-level, offers a design that overcomes the concern that an ecological fallacy is at play. Although each method of measuring fluoride exposure has some underlying limitations—misclassification due to fluctuation of spot urine sample; reporting/recall bias in self-reported use of fluoride products/fluoride treatment; unknown amount of actual fluoride exposure from primary drinking water—the use of multiple sources of information is a good strategy to identify individual-level fluoride exposure.
The overall prevalence of hypothyroidism or hyperthyroidism at the population-level is low (less than 5%) in Canada, thus the raw number of subjects who had altered serum TSH level or self-reported diagnosis of thyroid condition was small (nearly 95% of subjects had normal TSH level or no diagnosis of thyroid condition).
The study provides sound individual-level evidence that fluoride exposure levels experienced by the general population do not confer risk for disrupted thyroid function.