Plasma fluoride and systemic biomarkers in U.S. children: an instrumental variable analysis using household tap water fluoride

Plasma fluoride reflects fluoride exposure from multiple sources. Fluoride exposure and health outcome observational studies are susceptible to confounding. We estimated the systemic effects of plasma fluoride attributable to drinking-water fluoride exposure in U.S. children and adolescents using an instrumental variable (IV) approach. We analyzed National Health and Nutrition Examination Survey (NHANES) 2013–2016 data consisting of 4470 participants aged 6 to 19 years with measurements of plasma fluoride and household tap-water fluoride. Household tap-water fluoride was used as an IV for plasma fluoride to reduce unmeasured confounding. Survey=weighted two-stage least squares (2SLS) regression was applied: (1) plasma fluoride modeled as a function of tap-water fluoride; (2) each systemic biomarker regressed on predicted plasma fluoride. Biomarkers represented cardiovascular, metabolic, electrolytes, hormones, renal, and hepatic function. Models were adjusted for age, sex, body mass index, race/ethnicity, Income poverty ratio, health insurance status, food security, birthweight, and US Born status. We evaluated effect modification by age, sex, and race/ethnicity. Mean plasma fluoride was 0.40 µmol/L and tap-water fluoride 0.50 mg/L. Each 1 µmol/L increase in predicted plasma fluoride was associated with lower systolic blood pressure (− 7.91 mmHg; 95% Confidence Interval [CI]: −15.15, − 0.68), lower testosterone (geometric mean ratio: 0.49; 0.30, 0.80), higher uric acid (0.92 mg/dL; 0.02, 1.82), and higher sodium (3.41 mmol/L; 1.18, 5.64). Estimates for estimated glomerular filtration rate were lower but imprecise; other biomarkers showed no association. Interactions were significant for multiple biomarkers, most often by sex and age, without indicating direction. Plasma fluoride attributable to tap-water exposure was associated with lower systolic blood pressure, testosterone, and renal function, and with higher serum sodium and uric acid, alongside heterogeneity across demographic subgroups.