Dose-response analyses of the 27 human developmental neurotoxicity studies ranked highest quality by National Toxicology Program (NTP) systematic review

Abstract

BACKGROUND AND AIM: The National Toxicology Program (NTP) has been conducting a systematic review of the evidence for fluoride’s neurotoxicity. Drafts of the NTP report conclude fluoride is a presumed hazard for developmental neurotoxicity, but have not included rigorous dose-response analyses to estimate a safe dose. This is of great public health importance because millions of people are exposed to fluoride added to public water supplies or table salt; or naturally elevated fluoride in drinking water. METHODS: We conducted several dose-response analyses using data extracted by NTP from 27 human studies NTP ranked high quality. The number of studies finding adverse effects were counted at three exposure levels: 0.7, 0.7–1.5, 1.5mg/L. Meta-analyses were performed with the 14 studies having individual-level exposure data, in two subgroups by mean exposure: ≤1.5mg/L or 1.5mg/L. The same 14 studies were then assessed using meta-regression of IQ loss at mean exposure against mean exposure. RESULTS:Of the 27 higher quality studies, 25 found adverse neurocognitive effects with 11 at exposures below 0.7mg/L; 4 at 0.7–1.5mg/L; and 10 at 1.5mg/L. None found significant beneficial effects. In the meta-analysis, all 14 studies found loss of IQ, including the 7 in subgroup ≤1.5mg/L which had a pooled effect size of -4.0 (95%CI -6.03, -2.05) IQ points per 1mg/L fluoride. The meta-regression fit a linear dose-response with pooled effect size of -2.94 (95%CI -4.03, -1.84) IQ points per 1mg/L. CONCLUSIONS:Dose-response analyses of 27 studies ranked high quality by NTP found a remarkable consistency of adverse effects down to very low doses. The magnitude of predicted IQ loss is of considerable concern. Pregnant women and infants should limit exposure to fluoride. KEYWORDS: fluoride, developmental neurotoxicity, dose-response, IQ, National Toxicology Program, meta-analysis