Fluoride exposure from infant formula and child IQ in a Canadian birth cohort.

Abstract

Highlights:

• Consumption of formula reconstituted with fluoridated water can lead to excessive fluoride intake.
• Breastfed infants receive very low intake of fluoride.
• We compared IQ scores in 398 children who were formula-fed versus breastfed during infancy.
• IQ scores were lower with higher levels of fluoride in tap water.
• The effect was more pronounced among formula-fed children, especially for nonverbal skills.

Background

Infant consumption of formula reconstituted with fluoridated water can lead to excessive fluoride intake. We examined the association between fluoride exposure in infancy and intellectual ability in children who lived in fluoridated or non-fluoridated cities in Canada.

Methods

We examined 398 mother-child dyads in the Maternal-Infant Research on Environmental Chemicals cohort who reported drinking tap water. We estimated water fluoride concentration using municipal water reports. We used linear regression to analyze the association between fluoride exposure and IQ scores, measured by the Wechsler Primary and Preschool Scale of Intelligence-III at 3–4 years. We examined whether feeding status (breast-fed versus formula-fed) modified the impact of water fluoride and if fluoride exposure during fetal development attenuated this effect. A second model estimated the association between fluoride intake from formula and child IQ.

Results

Thirty-eight percent of mother-child dyads lived in fluoridated communities. An increase of 0.5 mg/L in water fluoride concentration (approximately equaling the difference between fluoridated and non-fluoridated regions) corresponded to a 9.3- and 6.2-point decrement in Performance IQ among formula-fed (95% CI: -13.77, -4.76) and breast-fed children (95% CI: -10.45, -1.94). The association between water fluoride concentration and Performance IQ remained significant after controlling for fetal fluoride exposure among formula-fed (B = -7.93, 95% CI: -12.84, -3.01) and breastfed children (B = -6.30, 95% CI: -10.92, -1.68). A 0.5 mg increase in fluoride intake from infant formula corresponded to an 8.8-point decrement in Performance IQ (95% CI: -14.18, -3.34) and this association remained significant after controlling for fetal fluoride exposure (B = -7.62, 95% CI: -13.64, -1.60).

Conclusions

Exposure to increasing levels of fluoride in tap water was associated with diminished non-verbal intellectual abilities; the effect was more pronounced among formula-fed children.

Excerpts:

3.3. Model 2: IQ scores and fluoride intake from formula

Fluoride intake from formula was not significantly associated with FSIQ (B = ?2.69, 95% CI: 7.38, 2.01, p= .26) or VIQ (B = 3.08, 95% CI: ?1.40, 7.55, p = .18) (Table 2). In contrast, a 0.5 mg increase in fluoride intake predicted an 8.76-point decrement in PIQ score (95% CI:  14.18,  3.34, p = .002; Fig. 1B). Adding MUF to the PIQ model slightly attenuated the association between fluoride intake and PIQ (B =??7.62, 95% CI:  13.64, 1.60, p = .01) (Table 2). Removing two cases with extreme IQ scores did not appreciably alter the association between fluoride intake and PIQ score, with and without adjustment for MUF (Table S3).4.

Discussion

For each 0.5 mg/L increase in water fluoride concentration, we found a decrease of 4.4 FSIQ points among preschool children who were formula-fed in the first six months of life; 0.5 mg/L is the approximate difference in mean water fluoride level between fluoridated (0.59 mg/L) and non-fluoridated (0.13?mg/L) regions. In contrast, we did not find a significant association between water fluoride concentration and FSIQ among exclusively breastfed children. The association between water fluoride concentration and FSIQ must be interpreted with caution, however, because the association became non-significant when two outliers were removed.

We observed an even stronger association between water fluoride and PIQ (non-verbal intelligence). A 0.5 mg/L increase in water fluoride level predicted a decrement in PIQ in both the formula-fed (9.3-points) and the breastfed groups (6.2-points). Adjusting for fetal exposure or removing two extreme scores did not appreciably alter these results.We observed converging results using fluoride intake from formula, which is a continuous, time-weighted exposure estimate. For each 0.5 mg/day of fluoride intake, we found an 8.8-point decrement in PIQ; adjusting for fetal exposure using MUF attenuated the association only slightly (7.6-point decrement in PIQ). MUF was also negatively associated with PIQ (2.4-point decrement for each 0.5 mg/L increase in MUF). The fluoride intake estimate may reflect a more refined measure of exposure in infancy because it captures differences in both water fluoride level and the proportion of time each child was given formula over the first year of life. Yet, our binary classification of whether a child was exclusively breastfed for 6 months may better capture children who are most vulnerable to neurotoxic effects of fluoride because it subsets those exposed to fluoride during the early infancy period when the brain undergoes significant development (Huttenlocher and Dabholkar, 1997, Kostovic, 2006). Taken together, these findings suggest that using optimally fluoridated water (0.7 mg/L) to reconstitute infant formula may diminish the development of intellectual abilities in young children, particularly for non-verbal abilities. The findings also suggest that both prenatal and postnatal fluoride exposure affect the development of non-verbal intelligence to a greater extent than verbal intelligence. Prior studies examining prenatal exposure to fluoride and IQ showed a similar pattern (Bashash et al., 2017, Green et al., 2019).

Consistent with prior studies showing a positive effect of breastfeeding on cognition (Horta et al., 2015), children in the breastfed group had higher FSIQ and VIQ scores relative to the formula-fed group, regardless of fluoridation status (Table 1); higher education and income levels in the breastfed group likely accounts for part of this association (Walfisch et al., 2013). In contrast, the breastfed group did not differ significantly from the formula-fed group with respect to PIQ score. Children who lived in non-fluoridated regions showed higher PIQ scores than children who lived in fluoridated regions, though this difference was significant only for the formula-fed group, perhaps reflecting a higher vulnerability of nonverbal abilities to fluoride exposure in infancy.

Most studies of fluoride exposure from infant formula consumption have focused on risk for later development of dental enamel fluorosis (Brothwell and Limeback, 2003, Hong et al., 2006, Berg et al., 2011). Beyond fluorosis, the safety of fluoride exposure from infant formula has not been rigorously tested, despite warnings of overexposure (Diesendorf and Diesendorf, 1979). A recent study showed that up to 59% of infants younger than four months exceed the upper limit (0.1 mg/kg/day) (Institutes of Medicine, 1997) when optimally fluoridated water is used to reconstitute infant formula (Harriehausen et al., 2019); 33% and 14.3% of six- and nine-month old infants exceeded the upper limit threshold, respectively. Conversely, breastfed infants receive very low fluoride intake (generally less than 0.01 mg/L), even in communities with fluoridated water (Dabeka et al., 1986, Ekstrand, 1981, Fomon et al., 2000). Our estimate of fluoride intake (0.34 mg F/day) among formula-fed infants who live in a fluoridated region is an underestimate of actual fluoride intake because we did not include fluoride from other sources, such as the fluoride found in the formula or foods; thus, the association between fluoride intake and IQ scores among formula-fed infants may be stronger than the association obtained in our analysis.

Our results, which showed that higher fluoride exposure in infancy was associated with diminished IQ scores in young children, are consistent with two longitudinal birth cohort studies. In one study involving 299 mother–child pairs living in Mexico City, there was a decrement of 3.2 IQ points in preschool aged children for every 0.5 mg/L of MUF level during pregnancy (Bashash et al., 2017). In the other study, which we conducted using the same Canadian cohort, we reported a decrement of 2.2 IQ points among preschool aged boys for every 0.5?mg/L of MUF level during pregnancy (Green et al., 2019). When MUF was included as a covariate in the current study, the association between MUF and FSIQ was not significant (see Table 2, note a). This discrepancy arises because (1) Green et al. (2019) did not include fluoride exposure in infancy as a covariate and (2) Green et al. (2019) estimated sex-specific MUF effects whereas the current study estimated an overall MUF effect.

The beneficial effects of fluoride predominantly occur at the tooth surface, after teeth have erupted (Limeback, 1999). Fluoride contributes to the prevention of dental caries primarily when it is topically applied to teeth, such as brushing with fluoridated toothpaste (Featherstone, 2001, Limeback, 1999, National Research Council (NRC), 2006, Pizzo et al., 2007, Warren and Levy, 2003). Because fluoride is not essential for growth and development (Scientific Committee on Health and Environmental Risks (SCHER), 2011), there is no recommended intake level of fluoride during fetal development or in the first six months of life before teeth have erupted. Accordingly, the Canadian Pediatric Society recommends administering supplemental fluoride (i.e. systemic exposure) only when primary teeth begin to erupt (American Dental Association) (at approximately 6?months) and only if the child is susceptible to high caries activity and is not exposed to other fluoride-based interventions, such as toothbrushing or water fluoridation (Godel, 2002).

The American Dental Association (Berg et al., 2011, American Dental Association, 2018) advises parents to use optimally fluoridated drinking water to reconstitute concentrate infant formulas, while being cognizant of the potential risk of mild enamel fluorosis development. This recommendation is echoed by the Centers for Disease Control and Prevention (Community Water Fluoridation. Infant Formula) as well as the U.S. Department of Health and Human Services (2015). The Canadian Dental Association (2019) recommends using water with low fluoride concentration (or ready-to-feed formula) when the fluoride level in drinking water is above the optimal level. In addition to tap water, which is reportedly used by 93% of caregivers who feed formula to infants (Brothwell and Limeback, 2003), “nursery” water (which may contain up to 0.7?mg F/L) is marketed for reconstituting formula and sold in Canada and the United States. The availability of fluoridated nursery water gives the false impression that fluoride exposure during early infancy is beneficial prior to teeth eruption.

Formula-fed infants who reside in fluoridated areas have a 70-fold higher intake of fluoride than exclusively breastfed infants (Ekstrand, 1981, Zohoori et al., 2018, United States Environmental Protection Agency, 2010). Formula-fed infants also retain more fluoride than breastfed infants (Zohoori et al., 2018, Ekstrand and Hardell, 1984) because infants have a limited capacity to excrete fluoride before renal function reaches its full capacity at about two years of age (National Research Council (NRC), 2006, Zohoori et al., 2018). Fluoride absorption also depends on the presence of other nutrients (Health Canada, 2010); when fluoride intake is exclusively from reconstituted formula, the bioavailability of fluoride is 65%, whereas a varied diet reduces fluoride absorption in tissues and bone to about 47% (Ekstrand and Ehrnebo, 1979). These factors place formula-fed infants at an even higher risk of fluoride toxicity.

Our study has some limitations. First, infant formulas vary in fluoride content. Ready-to-use formulas typically have less fluoride than powdered formula (Dabeka and McKenzie, 1987, Fomon et al., 2000); information about formula type was only available for 100 of 198 (50.5%) participants in the formula group; of those, 75% reported using powdered formula, which is the most common type of formula used by the general population (Infant Feeding Practices Survey II, xxxx, Fomon et al., 2000). Variability in fluoride content is also seen across different types of powdered formula (United States Environmental Protection Agency, 2010, Harriehausen et al., 2019, Mahvi et al., 2010). Additionally, soy-based formula reconstituted with distilled water has more fluoride (0.24–0.30?mg/L depending on whether it is ready-to-feed or concentrated) than milk-based powdered formulas (0.12–0.17?mg/L) (Harriehausen et al., 2019, Van Winkle et al., 1995). Although we lacked data on brand of formula, we have no reason to expect that use of powdered versus ready-to-feed or soy- versus milk-based formula would differ by fluoridation status. Moreover, our effects were primarily based on water fluoride content, which is the major source of fluoride (Buzalaf et al., 2001). Second, we did not have specific information on the type of water (bottled versus tap) used to reconstitute formula. However, mothers typically report using tap water for reconstituting formula (Van Winkle et al., 1995) and we only included children of women who reported drinking tap water in our analyses. Third, there is potential for non-differential misclassification of the feeding status variable because mothers may have been confused by the definition of exclusive breastfeeding on the questionnaire or the responses may have been affected by recall or response bias. As with any survey, women could be confused by the question, but given the demographic of the sample – highly educated, English speaking, and non-teenage mothers – confusion seems less likely. Fourth, our method of estimating infant fluoride intake has not been validated. Finally, children were tested between 3 and 4 years of age and we have no information regarding other possible sources of fluoride that occurred between post-weaning and the age of testing. Thus, other sources of fluoride (e.g. dental products) or more frequent brushing, might differ between participants who lived in fluoridated versus non-fluoridated communities or among those in the breastfeeding versus formula-feeding group. To control for these potential differences, we included maternal education in all models. In addition, the design of our study compares water fluoride level and IQ scores in the formula-fed children using the breast-fed children as a control.

In summary, fluoride intake among infants younger than 6 months may exceed the tolerable upper limits if they are fed exclusively with formula reconstitued with fluoridated tap water. After adjusting for fetal exposure, we found that fluoride exposure during infancy predicts diminished non-verbal intelligence in children. In the absence of any benefit from fluoride consumption in the first six months, it is prudent to limit fluoride exposure by using non-fluoridated water or water with lower fluoride content as a formula diluent.

Funding source

This study was funded by a grant from the National Institute of Environmental Health Science (NIEHS) (grant #R21ES027044). The MIREC Study was supported by the Chemicals Management Plan at Health Canada, the Ontario Ministry of the Environment, and the Canadian Institutes for Health Research (grant #MOP-81285).

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