Abstract
Highlights
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- Urine fluoride was inversely associated with IQ.
- DRD2 Taq 1A polymorphism was not related to IQ in children exposed to high fluoride.
- Urine fluoride had a stronger association with IQ in children with TT genotype.
- The threshold of urine fluoride affecting IQ in children with TT genotype existed.
Objective: We aimed to study the association of urine fluoride with intelligence quotient (IQ) in children with a careful consideration of up to 30 potential confounding factors as well as possible heterogeneity of the relation between urine fluoride levels and IQ scores across children with different dopamine receptor-2 (DRD2) Taq 1A genotypes (CC, CT, and TT).
Methods: A school-based cross-sectional study design was applied. A total of 323 children (2014–2015, 7–12 years old) were enrolled from four schools in both historical endemic and non-endemic areas of fluorosis in Tianjin of China using a cluster sampling method. Urine fluoride levels and age-specific IQ scores in children were measured at the enrollment. Polymerase chain reaction-restriction fragment length polymorphism methods were used to genotype DRD2 Taq 1A polymorphism with genomic DNA isolated from whole blood collected at the enrollment. Multiple linear regression models were applied to evaluate the relationship between urine fluoride levels and IQ scores overall and within the DRD2 Taq 1A SNP = CC/CT and TT subgroups. Model robustness was tested through bootstrap, sensitivity analysis, and cross-validation techniques. A safety threshold of urine fluoride levels for IQ impairment was determined in the subgroup TT.
Results: In overall participants, the DRD2 Taq 1A polymorphism itself was not related to IQ scores in children who had a high level of urine fluoride. In the CC/CT subgroup, urine fluoride levels and IQ scores in children were unrelated (adjusted ß (95% confidence interval (CI)) = – 1.59 (- 4.24, 1.05), p = 0.236). Among the participants carrying the TT genotype, there was a strong and robust negative linear relationship between log-urine fluoride and IQ scores in children (adjusted ß (95% CI) = – 12.31 (- 18.69, – 5.94), p<0.001). Urine fluoride levels had a stronger association with IQ in children carrying the TT genotype (adjusted ß = – 12.31, bootstrapped standard error (SE) = 1.28), compared to that in overall participants (adjusted ß = – 2.47, bootstrapped SE = 3.75) (Z = 2.483 and bootstrapped p = 0.007). The safety threshold of urine fluoride levels in the subgroup TT was 1.73 mg/L (95% CI = (1.51, 1.97) (mg/L)).
Conclusions: There is heterogeneity in the relation between urine fluoride and IQ across children carrying different DRD2 Taq 1A genotypes. Large-scale epidemiological studies are needed to confirm our findings.
Original abstract online at https://www.sciencedirect.com/science/article/abs/pii/S0147651318308674
EXCERPTS
… In China, endemic fluorosis is classified into drinking-water type, drinking-tea type, and coal-burning type. Humans are exposed to high fluoride mainly through drinking groundwater with high fluoride content (Barbier et al., 2010). When fluorine is absorbed, it enters the blood and distributes throughout the body, mainly in bones and teeth (Barbier et al., 2010). In addition, 50–80% inhaled fluoride can be excreted through the urinary system, and thus, urine fluoride concentration as an internal exposure index can systematically reflect the burden of fluoride exposure in drinking water (Ding et al., 2011).
… We also determined a safety threshold of urine fluoride on intelligence impairment in the subgroup TT as 1.73 mg/L urine fluoride with a 95% CI of (1.51 mg/L, 1.97 mg/L). According to WHO Drinking water Quality 4th edition (2011), fluoride in drinking water quality standard is 1.5 mg/L (WHO, 2011). In China, the water fluoride limits for large centralized and small centralized or decentralized water supplies are 1.0 mg/L and 1.2 mg/L, respectively (Liu et al., 2016). However,
these standards were set based on both drink water fluoride levels and general health significance. To date, no national or international intelligence impairment-based safety threshold of urine fluoride levels (an internal exposure index) is available. Thus, the IQ-based safety threshold of urine fluoride levels that we identified in the subgroup TT may be considered as an initial testing value to be refined at multilevels of the laboratory, epidemiological, and clinical studies.
Strengths of our study include using urine fluoride as an internal exposure index and thus minimizing the measurement error of exposure, adjusting up to 30 potential confounding covariates including child age and gene polymorphismin regressing IQ on urine fluoride in children, and careful modeling with applications of cross-validation, bootstrap techniques, and sensitivity analysis. Meanwhile, we were also limited by a cross-sectional study design, no data on breastfeeding which might influence both urine fluoride levels and IQ scores in children, possible residual confounding of covariates, and relatively small sample size of the subgroup TT.
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