# Mechanisms of Fluoride Toxicity: From Enzymes to Underlying Integrative Networks
## 4 The Implication of Fluoride Toxicity on Human Health
### Fluoride-Induced Neurotoxicity
#### 4.5.2 Developmental Neurotoxicity of Fluoride in Children  
Since the evidence of fluoride in the cerebrospinal fluid of patients with fluorosis in 1988 [142], imaging studies of radioactive fluoride showed that fluoride passes the blood-brain barrier (BBB) [94]. Based on the research from China, the fetal brain is highly susceptible to fluoride poisoning since the fetal BBB is immature and readily permeable to fluoride. A study by [PERSON] et al., performed in 1992, revealed the effects of fluoride on the brains of 15 fetuses from an endemic fluorosis area compared with those from a non-endemic area [143]. These studies showed delayed brain development in endemic fluorosis areas. [PERSON] et al. concluded that the passage of fluoride through the placenta of mothers impacts brain development. The effect of fluoride chronic exposure on children's intelligence quotient (IQ) has been used as an indication of the neurotoxic effect of fluoride. Several studies published in China, Iran, India, and Mexico found an association between lowered IQ and exposure to fluoride [136; 144; 145; 146; 147; 148; 149; 150]. Most of the robust evidence has been gathered in China. In many communities the daily intake of fluoride exceeds two milligrams [151]. A meta-analysis of 16 studies carried out in China between 1998 and 2008 found that children living in an endemic area have five times higher odds of developing a statistically lower IQ than those who live in a low fluoride level area [152]. In 2012, [PERSON] et al. [153] assessed a meta-analysis of 27 research reports published over 22 years. The last prospective birth cohort studies from Mexico and Canada provided evidence that intrauterine exposure to fluoride is most important in developmental fluoride neurotoxicity. The effects of prenatal fluoride exposure and development of children's cognitive abilities were followed in 299 Mexican mother-children pairs of the Early Life Exposures to Environmental Toxicants birth cohort study [150]. Higher levels of fluoride in mothers' urine during pregnancy were associated with lower cognitive and IQ scores in their children. The authors estimated that each 0.5 mg F/L increase in maternal urinary concentration was associated with an average decrease of 3.15 and 2.50 points in cognitive and IQ scores, respectively. A further study on 213 mother-child pairs of the same project in Mexico City found that higher prenatal fluoride exposures during pregnancy were associated with global measures of Attention Deficit Hyperactivity Disorder (ADHD) and more symptoms of inattention in the offspring [154]. In the Canadian study, maternal exposure to higher levels of fluoride during pregnancy was associated with lower IQ scores in children at 3-4 years [155]. An increase of fluoride in maternal urine for 1 mg/L was associated with a 4.5 point decrease of IQ score in boys. A recent 2020 study by [PERSON] et al. of Canadian cohort children compared IQ scores in 398 children who were formula-fed versus breastfed during infancy [156]. This detailed analysis indicates that fluoride intake among infants younger than six months may exceed the tolerable upper limits if they are fed exclusively with formula reconstituted with fluoridated tap water. After adjusting for fetal exposure, the investigators found that fluoride exposure during infancy predicts diminished non-verbal intelligence in children. [PERSON] et al. [4] used data from a study by [PERSON] et al. of more than 500 children in China [157] and estimated a safe daily dose of fluoride. Based on their calculations, a protective daily dose should be no higher than 0.05 mgF/day, or 0.0010 mgF/kg-day for children. The fluoride-induced lowered IQ quotient among children remains the most widely discussed adverse effect of fluoride by the scientific community [29; 94; 158]. [PERSON] concluded that recent epidemiological results support the notion that elevated fluoride intake during early development can result in IQ deficits that may be considerable [94]. On the other hand, [PERSON] et al.