Many uncertainties still surround the possible harmful effect of fluoride exposure on cognitive neurodevelopment in children. The aim of this systematic review and meta-analysis was to characterize this relation through a dose-response approach, by comparing the intelligence quotient (IQ) scores in the highest versus the lowest fluoride exposure category with a random-effects model, within a one-stage dose-response meta-analysis based on a cubic spline random-effects model.
Out of 1996 potentially relevant literature records, 33 studies were eligible for this review, 30 of which were also suitable for meta-analysis. The summary mean difference of IQ score, comparing highest versus lowest fluoride categories and considering all types of exposure, was ?4.68 (95% confidence interval-CI ?6.45; ?2.92), with a value of ?5.60 (95% CI ?7.76; ?3.44) for drinking water fluoride and ?3.84 (95% CI ?7.93; 0.24) for urinary fluoride. Dose-response analysis showed a substantially linear IQ decrease for increasing water fluoride above 1 mg/L, with ?3.05 (95% CI ?4.06; ?2.04) IQ points per 1 mg/L up to 2 mg/L, becoming steeper above such level. A weaker and substantially linear decrease of ?2.15 (95% CI ?4.48; 0.18) IQ points with increasing urinary fluoride emerged above 0.28 mg/L (approximately reflecting a water fluoride content of 0.7 mg/L). The inverse association between fluoride exposure and IQ was particularly strong in the studies at high risk of bias, while no adverse effect emerged in the only study judged at low risk of bias. Overall, most studies suggested an adverse effect of fluoride exposure on children’s IQ, starting at low levels of exposure. However, a major role of residual confounding could not be ruled out, thus indicating the need of additional prospective studies at low risk of bias to conclusively assess the relation between fluoride exposure and cognitive neurodevelopment.
The trace element fluoride (F) has been used since 1930 for the prevention and management of dental caries, which is considered a global health issue, especially in pediatric populations (ten Cate and Buzalaf, 2019; World Health Organisation, 2021). In nature, this mineral can be found in different amounts in water, plants, and food. Fluoride compounds are also used in aluminum, petroleum, chemical, and plastics industries, therefore workers in such industries may be exposed to higher levels of fluoride than the standard population (Choubisa and Choubisa, 2016). As a dental caries preventive approach, fluoride can be delivered through topical self- or professional applications (e.g. toothpastes, mouth rinses, gels, and varnishes), which are considered safe and cost-effective at the recommended amount, thus many scientific health authorities have endorsed their use (Iheozor-Ejiofor et al., 2015; NHS – National Health System, 2021; NIH – National Institute of Health, 2021; World Health Organization, 2017). Community-based strategies (e.g. water, salt, and milk fluoridation), as well as individually prescribed drops or tablet supplementation, however, raise concerns on their efficacy and safety both for dental and general health (European Commission, 2011; U.S. Department of Health and Human Services Federal Panel on Community Water Fluoridation, 2015). Also, since a considerable amount of fluoridated water is not actually used for direct oral uptake and rather ends up in the environment, contamination from fluoride is addressed as a possible source of biohazard for plants and animals (Aguirre-Sierra et al., 2013; Banerjee et al., 2021; Ranjan et al., 2008). Most fluoride consumption comes from fluoridated water and from foods and beverages prepared with fluoridated water, although a small part also comes from the accidental ingestion of fluoride-containing dental products (CDC – Center for Disease Control and Prevention, 2021). One of the public health policies that has been adopted to supplement children and adults with fluoride has been community water fluoridation (CWF), consisting of the controlled addition of fluoride to the public water supply, typically at concentrations ranging from 0.7 mg/L to 1.2 mg/L. However, in 2015 the Centers for Disease Control and Prevention (CDC) updated its water fluoridation guidelines setting such level at 0.7 mg/L in the U.S. (U.S. Department of Health and Human Services Federal Panel on Community Water Fluoridation, 2015). CWF policy was first introduced in the United States in 1945 and is currently applied in many regions worldwide, covering approximately 400 million people in over 25 countries (British Fluoridation Society, 2013; CDC – Center for Disease Control and Prevention, 2021). In addition to the beneficial effects of fluoride on dental caries, some adverse health effects deriving from the chronic overexposure to this element have long been documented (Dhar and Bhatnagar, 2009; European Commission, 2011; Vieira, 2022). Among these, dental and skeletal fluorosis are well known and supported by a strong body of evidence (Abanto Alvarez et al., 2009; Saldarriaga et al., 2021; Srivastava and Flora, 2020). In addition, a possible neurotoxic effect of excess fluoride exposure in children has been reported by the U.S. Environmental Protection Agency (EPA) and U.S. National Research Council (NRC) and has continued to be investigated (Bashash et al., 2017; Broadbent et al., 2015; Lu et al., 2000; National Research Council, 2006; Neurath, 2020). These effects could be due to the capacity of fluoride to accumulate in brain regions responsible for memory and learning, affecting them through oxidative stress. In fact, while the blood-brain barrier, to some extent, can protect the adult brain from various toxic agents, it is less efficient in the fetus, newborn, and young child (Grandjean, 2019; Srivastava and Flora, 2020). In addition, fluoride exposure has been linked to hypothyroidism, which negatively affects early neurodevelopment both in fetuses and newborn children (Peckham et al., 2015; Prezioso et al., 2018). Two previous published systematic reviews have investigated the relation between fluoride exposure and neurocognitive development in humans, yielding somewhat inconsistent results, and only one of them performed a dose-response meta-analysis, focusing their assessment on fluoride exposure through drinking water (Duan et al., 2018), while the other only conducted a high-versus-low fluoride analysis (Duan et al., 2018; Miranda et al., 2021). Also, a draft systematic review by the National Toxicology Program (NTP) analyzed such a relationship, but did not perform a meta-analysis (NTP – National Toxicology Program, 2020).
Therefore, the aim of this study was to investigate the relation between exposure to inorganic fluoride, in all forms, and neurodevelopmental toxicity in children, through a comprehensive, updated systematic review and meta-analysis with a dose-response approach.
Protocol and registration
This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines (Page et al., 2021). The protocol was registered in the PROSPERO database (registration no. CRD42022321899).
Search strategy and study selection
The research framework was defined by the following question: “What is the effect of early or prenatal fluoride exposure on the risk of abnormal neurodevelopment according to a dose-response relation?” According to the PECOS
The literature search retrieved 1996 potentially relevant records. After the removal of duplicate records (n = 162) and the screening of titles and abstracts of the remaining 1834 records, 1773 records were discarded. After a full text evaluation of the remaining 61 records, additional 32 records were excluded since 3 of them addressed a wrong outcome, 3 were not eligible as publication types, 2 did not have their full texts available, 8 addressed overlapping cohorts of subjects, 10 did not
What is new in this work, as compared to the other systematic reviews and meta-analyses on this topic, is that we applied a recent and novel statistical approach that allows the full modeling of the dose-response relation between fluoride and cognitive endpoints, yielding its shape across the entire range of exposure, considering both exposure from fluoride in drinking water and urinary fluoride as biomarkers of exposure, conducting such analysis separately and allowing a comparison between the
Credit author statement
Federica Veneri: conceptualization of the research protocol, methodology, data collection, data analysis, writing-original draft preparation; Marco Vinceti: conceptualization of the research protocol, methodology, data analysis, writing-reviewing and editing; Luigi Generali: supervision, writing-reviewing and editing; Maria Edvige Giannone: methodology, data collection and data synthesis; Elena Mazzoleni: methodology, data collection and data synthesis; Linda Birnbaum: writing-reviewing and
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
*Original article online at: https://www.sciencedirect.com/science/article/abs/pii/S0013935123000312