Effect of fluoride exposure on the intelligence of school children in Madhya Pradesh, India

Introduction

Fluoride is known to have both beneficial and adverse effects on humans.[1] Introduction of systemic and topical fluorides into the prevention and control of dental caries denotes the most significant issue in dentistry. Fluorides have brought a considerable decline in the prevalence of dental caries, especially in countries with advanced economies.[2] However, in the 1980s it was established that fluoride controls caries mainly through its topical effect.[3] Drinking water is usually, but not always, the main source of fluoride.[1] Elevated concentration of naturally occurring fluoride in drinking water is a worldwide problem. Many Asian countries including India have reported a concentration of fluoride exceeding the World Health Organization (WHO) guidelines values or their prevailing national standards.[4] Sixty million Indians are living in about 200 districts of 20 states in endemic areas of fluorosis.[5] Dental and skeletal effects associated with fluoride, in humans, are well documented.[45] Also, the existing literature reports the neurological consequences associated with exposure to fluoride. In children, most reported effects are on the cognitive capacities, particularly intelligence reduction.[46–11] On the other hand studies conducted by Hu et al.[8] and Spittle et al.[12] have not found any trend or correlation between fluoride and the intelligence of children.

The majority of studies that show a correlation between a lower Intelligence Quotient (IQ) and elevated fluoride intake are from China. To the best of our knowledge, there is only one piece of literature[9] published from the Indian subcontinent, which shows that fluoride exposure has an effect on the intellectual function of children. Many of the published studies have methodological limitations, like no consideration for the effect of lead, arsenic, iodine deficiency, socioeconomic status (SES) or nutritional status of the children.

Keeping in mind the above-mentioned confounders, the current study has been designed to assess the relationship between exposure to different drinking water fluoride levels and children's intelligence in Madhya Pradesh state, India.

Materials and Methods

Prior to the study, a detailed study protocol was submitted to the Ethics Committee of the Institution. After obtaining the ethical approval, a pilot study was conducted in high and low fluoride areas. Based on the results of a pilot study, to achieve a 5% level of significance and 80% power, the sample size for the present study was calculated using Power and Precision v. 4 (Biostat Inc., Englewood, USA).

Results

The sociodemographic characteristics of the children, with different levels of water fluoride, are presented in Table 1. There were almost an equal number of boys and girls in each group. The SES was between middle and high. Mean years of education of the head of the family were seven. Height for age ratio and weight for height ratio revealed that most of them were in the mild to moderately impaired category. No statistically significant differences were observed in the participant's gender proportion, SES, education of the head of the family, height for age ratio, or weight for height ratio.

Table 1 Sociodemographic characteristics of the children with different levels of water fluoride

Table 2 shows the levels of urinary fluoride, iodine, lead, and arsenic in children with different levels of water fluoride. A statistically significant difference was observed in urinary fluoride levels between four groups. Differences in urinary iodine, urinary lead, and urinary arsenic were not significant.

Table 2 Levels of urinary fluoride, iodine, lead, and arsenic in children with different levels of water fluoride

The mean intelligence grades of the children with different levels of water fluoride are presented in Figure 1. The lowest mean grade was observed with water fluoride level <1.5 PPM. The highest mean grade (worst intelligence) was observed with water fluoride level >4.5 PPM. The differences for intelligence grades were statistically significant between the four groups (ANOVA=22.130, P 0.000). Figure 2 shows simple linear regression analysis, with urinary fluoride as a dependent variable. There was a statistically significant relationship of the water fluoride level with the urinary fluoride level (R=0.995, R² =0.991, ANOVA=17897.210, P 0.000). When simple linear regression analysis was performed, with intelligence grades as the dependent variable, a significant relationship of intelligence grades was observed with the water fluoride level [Figure 3, R=0.534, R² =0.286, ANOVA=67.14, P 0.000] and urinary fluoride level [Figure 4, R=0.542, R² =0.294, ANOVA=69.94, P 0.000]. However, in stepwise multiple linear regression analysis the only significant independent variable was urinary fluoride [Table 3].

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Figure 1

Mean intelligence grades of children with different levels of water fluoride

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Figure 2

Simple linear regression analysis with urinary fluoride as a dependent variable and water fluoride as an independent variable

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Figure 3

Simple linear regression analysis with the intelligence grade as a dependent variable and water fluoride as an independent variable

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Figure 4

Simple linear regression analysis with the intelligence grade as a dependent variable and urinary fluoride as an independent variable

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Table 3 Stepwise multiple linear regression analysis with intelligence grades as dependent variables

Discussion

This study indicates that exposure to fluoride is associated with reduced intelligence in children. We have found a significant inverse relationship between intelligence and the water fluoride level, and intelligence and the urinary fluoride level. After adjusting for confounders, urinary fluoride was the significant predictor for intelligence. The kidneys are the principal organs for the excretion of fluoride. Fluoride in urine is a better indicator for exposure compared to water, as it integrates all the sources.[419] Therefore, the degree of exposure to fluoride in the present study has been checked by analyzing the urinary fluoride level.

The impact of fluoride on intelligence has been reported by a number of studies. Many of them have several shortcomings, like the lack of adjustment for confounders, no biological markers, no quantification for other neurotoxic pollutants, and so on. Despite all of that, these studies suggest that fluoride negatively impacts intelligence.[46–11]

Studies have shown that exposure to lead and arsenic has been associated with a decline in intellectual function in children.[410] Also, the education level of parents, SES of the family,[46–8] nutrition,[2021] and iodine deficiency[79] affect the intellectual ability of children. Therefore, these factors were considered in the present study. In the present study lead and arsenic in urine were within the documented safe zone (Normal human levels — lead ≤80 μg/l,[2223] arsenic ≤100 μg/l[2425] ). Moreover, differences in the urinary lead and arsenic levels of children with different levels of water fluoride were not significant. These findings indicated that the observed deficits in intelligence could not be attributed to lead and arsenic exposure. Data from previous studies could lend support to the hypothesis that interaction between fluoride, lead, and arsenic could worsen the children's intelligence grades,[4] and thus, indicate a need for further investigation. In a low iodine area, impairment of intelligence could occur through the development of hypothyroidism or clinical/subclinical cretinism.[7] In our study, we could not find a significant difference in the urinary iodine levels of children with different levels of water fluoride. Also, as per the WHO criteria, the iodine status of all the children was ‘Adequate’ (>100 μg/l).[2627] Numerous studies in animal and human models demonstrated that suboptimal nutrition in early life affects the cognitive performance.[2021] However, in present study, indices for chronic and acute malnutrition failed to show any relationship with intelligence. Studies conducted by Lu et al.[7] and Xiang et al.[8] showed that the relationship of the SES of the family and the parents’ education level, with the children's IQ, was not significant. These finding were consistent with the findings in the present study. However, Zaho et al. stated that the children's IQ increased with parents education level.[6] In a Mexican study by Rocha-Amador et al., after adjusting for confounders (blood lead, SES, mothers’ education, nutritional status), the fluoride in urine was associated with reduced IQ scores.[4] In a meta analysis Tang et al. concluded that children who lived in an endemic fluoride area had five times higher odds of developing low IQ than those who lived in a non-fluoride area.[11]

It is very well established that fluoride can penetrate the blood brain barrier.[6–91128] Also, it can pass through the placenta to the fetus,[6–91129] and with subsequent continuous exposure to fluoride during childhood, it may have adverse effects on the developing brain, thereby causing decreased intelligence in children.[6–911] The biomechanism of the action of fluoride in reducing intelligence is still not clear. However, there is evidence that it may involve the alteration of the membrane lipid and cause a reduction in the cholinesterase activity in the brain. This may lead to altered utilization of acetylcholine, affecting the transmission of nerve impulses in the brain tissue.[30–32] NaF has been found to alter the levels of dopamine, serotonin, 5-hydroxyindoleacetic acid, homovanille acid, norepinephrine, and epinephrine, in the hippocampus and neocortex regions of the rat brain.[33] Yu et al. demonstrated changes in neurotransmitters and their receptors in the fetal brain from the endemic fluorosis area.[7] Thyroid hormones play an important role in the development of the brain. In a study, Susheela et al. found that elevated fluoride uptake may cause iodine deficiency in fluorotic individuals, even when they reside in non-iodine deficient areas.[34]

Limitations: In this cross-sectional study, we have analyzed the fluoride in urine, a biomarker of recent exposure. We have not analyzed for historical markers such as dental fluorosis. We assume that the exposure scenario has not changed over time and current exposure to fluoride in drinking water can be used as a proxy for past exposure. We have analyzed a single morning urine sample, instead of a 24-hour urine sample. However, the studies of Villa et al.[35] and Opydo-Szymaczek and Borysewicz-Lewicka[36] reveal that there is a close relationship between the concentration of fluoride in the first morning sample and in the 24-hour specimen. Children's intelligence can be influenced by inheritance. Children in our study groups attend school and are therefore exposed to different levels of fluoride, while not at home. Although the children who had changed their water source since birth were excluded in the present study, we could not completely exclude the influence of recall bias. Moreover, fluoride level in a particular water source may change over a period of years. Therefore, we emphasize the need for a more careful evaluation of the effect of fluoride on intelligence.

In conclusion, data from this research supports that children exposed to fluoride are at risk for impaired development of intelligence. Millions of children around the world are exposed to high concentration of fluoride in water, and are therefore, potentially at risk. For the benefit of the upcoming generations, urgent attention needs to be focused on this substantial public health problem.