Abstract

This DRAFT Monograph is distributed solely for the purpose of pre-dissemination peer review and does not represent and should not be construed to represent any NTP determination or policy.

Background: Previous reviews of epidemiological studies, including 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 neurological effects in humans and recommended further investigation (NRC 2006). Most of the evidence is from dental and skeletal fluorosis-endemic regions that have higher levels of naturally occurring fluoride than the fluoride concentrations historically added to water in community water fluoridation programs (0.7–1.2 ppm). NTP previously published a systematic review of the evidence from experimental animal studies of the effects of fluoride on learning and memory (NTP 2016). The systematic review found a low-to-moderate level of evidence that learning and memory deficits occur in non-human mammals exposed to fluoride. Studies in animals generally used fluoride drinking water concentrations that far exceeded the levels used in water fluoridation, and the lack of studies at lower fluoride concentrations was identified as a data gap. The evidence for effects on learning and memory was strongest (moderate) in animals exposed as adults, and evidence was weaker (low) in animals exposed during development. Since the publication of the NTP (2016) systematic review of the animal evidence, additional animal studies have been published. This systematic review extends the scope of the 2016 review by including human epidemiological studies, along with updated animal evidence and selected mechanistic information in order to reach hazard identification conclusions for fluoride and neurodevelopmental and cognitive effects.

Objective: To conduct a systematic review of the human, experimental animal, and mechanistic literature to evaluate the evidence and develop hazard conclusions about whether fluoride exposure is associated with neurodevelopmental and cognitive effects.
Method: A systematic review protocol was developed and utilized following the Office of Health Assessment and Translation (OHAT) approach for conducting literature-based health assessments.

Results: The literature search and screening process identified 149 published human studies, 339 published experimental animal studies, and 60 in vitro/mechanistic studies relevant to the objective. Eighty-two of the 149 human studies evaluated the association between fluoride exposure and neurodevelopmental or cognitive effects, and the remaining human studies evaluated thyroid effects or other potential mechanistic data. The majority of the experimental animal studies were mechanistic studies, which were not assessed in the NTP (2016) report. Thirty-five new experimental animal1 studies evaluating effects on learning and memory and/or motor activity and sensory effects of fluoride were identified since the NTP (2016) systematic review.

The human body of evidence provides a consistent pattern of findings that high fluoride exposure is associated with decreased intelligence quotient (IQ) in children. There is a moderate level of evidence from cognitive neurodevelopmental studies in children based on four prospective cohort studies and nine cross-sectional studies that are considered functionally prospective in nature. Because the majority of available studies evaluate cognitive neurodevelopmental effects in children, the focus of the hazard conclusions is on cognitive neurodevelopmental effects. The evidence for cognitive effects in adults is limited, coming from two cross-sectional studies, and is inadequate to evaluate whether fluoride exposure in adults is associated with cognitive effects. The assessment of the new animal data focuses on evaluating a deficiency identified during the prior NTP (2016) review concerning the difficulty in distinguishing potential effects of fluoride on motor and sensory functions from effects specifically on learning and memory functions. Further examination of the animal data, including studies carried out at the NTP, have further highlighted this deficiency in the animal studies. For this reason, the animal body of evidence is now considered inadequate to inform conclusions on whether fluoride exposure is associated with cognitive effects (including cognitive neurodevelopmental effects) in humans primarily due to the inability to separate these effects from the other effects on the nervous system, including motor activity or motor coordination. While the animal data provide evidence of effects of fluoride on neurodevelopment, the human evidence base is primarily focused on cognitive neurodevelopmental effects and is the focus of conclusions.

Conclusions: NTP concludes that fluoride is presumed to be a cognitive neurodevelopmental hazard to humans. This conclusion is based on a consistent pattern of findings in human studies across several different populations showing that higher fluoride exposure is associated with decreased IQ or other cognitive impairments in children. However, the consistency is based primarily on higher levels of fluoride exposure (i.e., >1.5 ppm in drinking water). When focusing on findings from studies with exposures in ranges typically found in the United States (i.e., approximately 0.03 to 1.5 ppm in drinking water, NHANES (Jain 2017)) that can be evaluated for dose response, effects on cognitive neurodevelopment are inconsistent, and therefore unclear. There is inadequate evidence to determine whether fluoride exposure lowers IQ or impairs cognitive function in adults. There are few human studies available that provide data to evaluate whether fluoride exposure is associated with other neurodevelopmental effects, beyond IQ or other cognitive measures. Although conclusions were reached by integrating evidence from human and animal studies with consideration of relevant mechanistic data, the conclusions are based primarily on the human evidence. The evidence from animal studies is inadequate to inform conclusions on cognitive effects, and the mechanisms underlying fluoride-associated cognitive neurodevelopmental effects are not well characterized.

Sources of Support:
National Institute of Environmental Health Sciences (NIEHS)
Division of the National Toxicology Program (DNTP)

Contributors
Evaluation Team

The evaluation team is composed of federal staff and contractor staff support.

Peer Reviewers

The peer reviewers were outside experts selected for their experience with fluoride, developmental neurobehavioral toxicity, and systematic review procedures. Peer reviewers were screened for conflict of interest prior to their service and did not report any conflicts of interest. Service as a peer reviewer does not necessarily indicate that the reviewer endorses the final document.

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