NTP monograph on the state of the science concerning fluoride exposure and neurodevelopment and cognition: a systematic review.

Background: Fluoride is a common exposure in our environment that comes from a variety of sources and is widely promoted for its dental and overall oral health benefits. Contributions to an individual's total exposure come primarily from fluoride in drinking water, food, beverages and dental products. A 2006 evaluation by the National Research Council (NRC) found support for an association between consumption of high levels of naturally occurring fluoride in drinking water and adverse neurological effects in humans and recommended further investigation. The evidence reviewed at that time was from dental and skeletal fluorosis-endemic regions of China. Since the NRC evaluation, the number and location of studies examining cognitive and neurobehavioral effects of fluoride in humans have grown considerably, including several recent North American prospective cohort studies evaluating prenatal fluoride exposure. In 2016, the National Toxicology Program (NTP) published a systematic review of the evidence from experimental animal studies on the effects of fluoride on learning and memory. That systematic review found a low-to-moderate level of evidence that deficits in learning and memory occur in non-human mammals exposed to fluoride.

Objective: To conduct a systematic review of the human, experimental animal, and mechanistic literature to evaluate the extent and quality of the evidence linking fluoride exposure to neurodevelopmental and cognitive effects in humans.

Method: A systematic review protocol was developed and utilized following the standardized OHAT systematic review approach for conducting literature-based health assessments. This monograph presents the current state of evidence associating fluoride exposure with cognitive or neurodevelopmental health effects and incorporated predefined assessments of study quality and confidence levels. Benefits of fluoride with respect to oral health are not addressed in this monograph.

Results: The bodies of experimental animal studies and human mechanistic evidence do not provide clarity on the association between fluoride exposure and cognitive or neurodevelopmental human health effects. Human mechanistic studies were too heterogenous and limited in number to make any determination on biological plausibility. This systematic review identified studies that assessed the association between estimated fluoride exposure and cognitive or neurodevelopmental effects in both adults and children, which were evaluated separately. The most common exposure assessment measures were drinking water concentrations and estimates of total fluoride exposure, as reflected in biomarkers such as urinary fluoride. In adults, only two high-quality cross-sectional studies examining cognitive effects were available. The literature in children was more extensive and was separated into studies assessing intelligence quotient (IQ) and studies assessing other cognitive or neurodevelopmental outcomes. Eight of nine high-quality studies examining other cognitive or neurodevelopmental outcomes reported associations with estimated fluoride exposure. Seventy-two studies assessed the association between fluoride exposure and IQ in children. Nineteen of those studies were considered to be high quality; of these, 18 reported an inverse association between estimated fluoride exposure and IQ in children. The 18 studies, which include 3 prospective cohort studies and 15 cross-sectional studies, were conducted in 5 different countries. Forty-six of the 53 low-quality studies in children also found evidence of an inverse association between estimated fluoride exposure and IQ in children.

Discussion: Existing animal studies provide little insight into the question of whether fluoride exposure affects IQ. In addition, studies that evaluated fluoride exposure and mechanistic data in humans were too heterogenous and limited in number to make any determination on biological plausibility. The body of evidence from studies in adults is also limited and provides low confidence that fluoride exposure is associated with adverse effects on adult cognition. There is, however, a large body of evidence on associations between fluoride exposure and IQ in children. There is also some evidence that fluoride exposure is associated with other neurodevelopmental and cognitive effects in children; although, because of the heterogeneity of the outcomes, there is low confidence in the literature for these other effects. This review finds, with moderate confidence, that higher estimated fluoride exposures (e.g., as in approximations of exposure such as drinking water fluoride concentrations that exceed the World Health Organization Guidelines for Drinking-water Quality of 1.5 mg/L of fluoride) are consistently associated with lower IQ in children. More studies are needed to fully understand the potential for lower fluoride exposure to affect children's IQ.