Focus on cognitive impairment induced by excessive fluoride: an update review.

Based on the route of intake, endemic fluorosis can be classified into the following three types: drinking water type endemic fluorosis, coal-burning type endemic fluorosis, and drinking brick-tea type endemic fluorosis. Excessive fluoride intake adversely affects the physical and mental health of local residents, regardless of the route of intake or distribution of fluorosis. Excessive exposure to fluoride during the pre-natal period can cause developmental delays in infants and young children. Post-natal effects include attention deficits and reduced IQ in children, with reported memory loss in older adults. Excessive fluoride exposure is also a risk factor for Alzheimer’s disease (Court et al., 2001, Varner et al., 1998). Notably, neurological impairments associated with excessive fluoride exposure vary with age.

A meta-analysis of the association between excess fluoride exposure and IQ in children over the past 20 years reported that children living in fluoridated areas were five times more likely to have a low IQ than those living in non-fluoridated or mildly fluoridated areas (Tang et al., 2008). A 2018 study on the relationship between water fluoride and IQ in children showed that excessive water fluoride exposure was associated with lower IQ levels in subgroups stratified by country, age, sex, fluoride dose, and cognitive status (Duan et al., 2018). Children in high-fluoride areas have a lower IQ, indicating a dose-response relationship between the fluoride dose and IQ levels (Veneri et al., 2023, Yu et al., 2018). An analysis of the intelligence of children aged 8–12 years in coal-burning type of endemic fluorosis areas specific to China demonstrated that the intelligence level of children in the coal-burning type of endemic fluorosis areas differed significantly from that in non-patient areas. In addition, urinary fluoride concentrations were negatively correlated with intelligence level(Lou et al., 2021). A significant association between early-life fluoride exposure and cognitive deficits has been reported (Ando et al., 2001, Choi et al., 2012). The mental development index (MDI) and psychomotor development index (PDI) were significantly lower in 1-, 3-, 6-, and 12-month-old infants born to pregnant women in areas with coal-burning type of endemic fluorosis than in newborns born to pregnant women in unaffected areas (Wei et al., 2022). An ecological study in the United States showed that the prevalence of parent-reported attention-deficit hyperactivity disorder was positively correlated with the prevalence of state community water fluoridation (Malin & Till 2015). However, the Canadian Health Measures Survey data for children aged 3–12 years shows that the negligible but statistically significant association was no longer observed when using creatinine- and specific gravity-adjusted urinary fluoride as dilution corrections for urinary fluoride levels (Barberio et al. 2017). Furthermore, higher maternal urinary fluoride adjusted for creatinine (MUFcr) levels in pregnant women are associated with a lower risk of cognitive problems (lack of concentration) at 11 years of age, which is inconsistent with previous findings(Ibarluzea et al., 2023). This may be related to the quality of family background or sensitivity to other toxic levels during pregnancy; other population-based studies are needed to confirm or contradict these results (Ibarluzea et al., 2023). The discrepant results could be attributed to variations in race, dietary patterns, and educational levels. From the perspective of etiology, all the aforementioned cross-sectional studies demonstrate a correlation between fluoride and children’s intelligence; however, prospective studies are needed to further analyze the causal correlation(Gopu et al., 2022).

Because most research on the detrimental effects of fluoride exposure is initiated after birth, exposure during pregnancy is often overlooked, thereby missing the critical windows of fluoride neurotoxicity (Farmus et al., 2021). The ability of fluoride to pass through the placenta and blood-brain barrier to reach the fetal brain causes accumulation, thereby leading to adverse effects in the fetus (Dec et al., 2019, ?ukomska et al., 2020). In a prospective birth cohort in Spain, a positive correlation between MUFcr in the third trimester and measures of cognitive function, such as verbal, memory, and GCI scores, was observed among boys, whereas non-significant effects were observed in girls (p for interaction < 0.05) (Ibarluzea et al., 2022). Goodman et al. collected maternal urine samples in early pregnancy and adjusted for urinary creatinine to obtain maternal urinary fluoride exposure, excluding changes in urinary dilution, focusing not only on general cognitive indices (GCI) and Full-Scale IQ (FSIQ) but also on the McCarthy Scales of Children’s Abilities to examine differences in fluoride on the verbal scale (VIQ) and the perceptual-performance scale (PIQ) (Goodman et al., 2022). The results showed statistically significant negative associations between MUFcr concentrations and longitudinal GCI/FSI scores, mainly for nonverbal ability (Cantoral et al., 2021). No sex-specific effects were found in the Environmental Toxicants (ELEMENT) cohort of Mexico(Green et al., 2020). Two high-quality prospective birth cohort studies identified by the NTP are consistent with these results (Grandjean et al., 2022). At the 12-year visit, the researchers found that urinary fluoride concentrations in children were significantly associated with increased internalizing symptoms, particularly somatization. The association between fluoride concentration and internalizing symptoms was stronger in men when the exposure levels were similar (Adkins et al., 2022). Excessive exposure to fluoride via different routes adversely affects children at different growth stages.

Future research should focus on whether fluoride exposure is sex-sensitive and whether the effects of fluoride exposure have a dose-response relationship, particularly whether low levels of fluoride exposure are beneficial (Kumar et al., 2023). To help formulate a more reasonable public policy to achieve a balance between accruing dental benefits while minimizing the risk of detrimental effects, future research should focus more on school-age children, not only on composite scores but also on domain-specific intellectual abilities (CADTH, 2020, Grandjean, 2019). Furthermore, owing to the presence of several harmful substances in the environment and humans are co-exposed to multiple environmental contaminants, monitoring co-exposure to other pollutants (e.g., arsenic, mercury, lead, and aluminum) in addition to fluoride exposure is essential (Kinawy, 2019, Russ et al., 2019). Prospective studies can provide stronger evidence than ecological investigations. However, when conducting birth cohort studies, parental intelligence, education, diet, and medication intake during pregnancy may be innate factors affecting the intelligence of the offspring. In addition, acquired factors such as an unhealthy lifestyle, lack of essential nutrients (e.g., protein and iodine), and adverse drug reactions may have a negative impact on children’s neurological development (Wang et al., 2020). Considering the differences in renal function between individual researchers, adjusted indices should be used to reflect urinary fluoride levels and other biomarkers that can reflect long-term fluoride status, such as fingernails and deciduous milk teeth, in addition to collecting 24-h urine samples from the mother and child, especially for measuring the child’s fluoride exposure. Adjusting for covariates and collecting individual information can help researchers mitigate confounding variables (Guth et al., 2020, Sabour and Ghorbani, 2013). Sufficient and reliable evidence is needed to confirm whether excessive fluoride is a cognitive neurodevelopmental hazard in humans.

A study on the effects of fluoride exposure on cognitive function in older adults aged ? 60 years. This study conducted in Xuzhou City, Jiangsu Province, China, with different water fluoride concentrations (Ren et al., 2021) included 444 individuals who met the inclusion criteria. Cognitive assessment was analyzed using the Montreal Cognitive Assessment Basic (MoCA-B) and the Self-Assessment of Memory Impairment Scale (AD-8). The results showed that fluoride concentration was a risk factor for cognitive impairment in older adults, and the risk of cognitive impairment was higher among older adults in areas with high-fluoride drinking water. A simple mental status examination (MMSE) conducted in 511 older adults in Heilongjiang, Qinghai, Inner Mongolia, and Xinjiang Uyghur Autonomous Regions of China, reported that excessive fluoride exposure was a potential risk factor for cognitive impairment. In addition, intake of certain doses of low fluoride may have a potential protective effect on cognitive function (Li et al., 2016).

The current status survey of the population does not allow clarification of individual exposure levels. Factors such as breastfeeding, socioeconomic status, parental intelligence level, and other neurotoxic chemicals, were not given adequate focus. Only common confounders were excluded from the analysis to influence the results, which concluded that fluoride exposure was associated with neurological damage (Ren et al., 2022). Although the above findings support the idea that excessive fluoride exposure may be a risk factor for nerve injury, they are mostly cross-sectional investigations and lack direct evidence of fluoride-induced neuronal damage. Ethical constraints make it difficult to draw definitive conclusions about fluoride exposure and neurological injury in population studies; therefore, it is important to validate this effect using appropriate fluorosis models.