Fluoride exposure from the Odense Child Cohort (OCC)
While the addition of fluoride to drinking water is not legal in Denmark, elevated fluoride concentrations up to 1.5 mg/l naturally occur in groundwater in parts of the country,¹³ and some types of tea, especially black tea, constitute an additional source of exposure.¹⁴ In Odense municipality, the fluoride concentration in drinking water is rather low, i.e. 0.2–0.3 mg/l.¹³ Given the retention in and continuous mobilization from calcified tissues, the maternal U-F concentration reflects the level in the blood that is available for passage through the placenta to reach the fetus.¹ …

Discussion
Experimental and cross-sectional studies have provided evidence of fluoride neurotoxicity, especially during early brain development.^1,20 Jointly with two prospective epidemiology studies on populations exposed to fluoridated water or fluoridated salt and other sources,^5,6 both of them rated as low risk of bias,¹ the present study adds new, comparable evidence from a population exposed to low waterfluoride levels. In the absence of other important fluoride sources, U-F concentrations will often be similar to the concentration in drinking water,^21,22 but substantial elevations can occur from tea drinking.⁴ The two studies from North America showed creatinine-adjusted U-F concentrations averaging 0.89 mg/l (Mexico City) and 0.85 and 0.44 mg/l in fluoridated and nonfluoridated cities (Canada), respectively. Ranges of U-F levels from these two prior studies overlapped with the exposures encountered in the OCC study that reflected the low fluoride concentrations of 0.2– 0.3 mg/l in the local drinking water,¹³ as likely increased by tea drinking and other sources of exposure (figure 1). We calculated regression values for linear and, for comparison, piecewise linear dose–response functions for the new, low-exposure study so that it could be compared and merged with the previous findings.⁹

In the OCC study, we did not find evidence of fluoride neurotoxicity at low maternal U-F concentrations in the third trimester. This finding is consistent with the trimester-specific MIREC results,²³ as possibly affected by the imprecision of U-F measured in a single spot sample. Given the overlapping ranges of exposure, the fluoride–IQ relationships in the three studies were similar. Although the fluoride association was not statistically significant in the OCC cohort by itself, the joint association was significant when combined with information from the other two cohorts. This result can be explained by a relatively high variability in the OCC result, whereas the combined result is based on a larger sample size.

The joint BMC was found to be 0.45 mg/l (BMCL, 0.28 mg/l), i.e. slightly higher than previously found (BMC, 0.33 mg/l; BMCL, 0.20 mg/l) for the two North American cohorts alone.9 Also, if instead relying on the GCI as a marker of child intelligence with the slightly larger Mexican sample, the results are similar (Supplementary table S3), as also seen previously.⁹ Given the combined observations on more than 1500 mother–child pairs, the overall BMC results likely reflect a threshold for adverse cognitive effects of prenatal fluoride exposure that occur at levels prevalent in many countries.²¹

…  The OCC study focused on the FSIQ as a cognitive function indicator. Although fluoride neurotoxicity may not affect all cognitive domains equally,^10,23 the abbreviated WISC-V used in the OCC was not separated into subdomains. In addition to FSIQ as a main outcome, the ELEMENT cohort found that elevated maternal U-F concentrations were also associated with higher parent ratings of inattention on the Conners’ Rating Scale, a common symptom of Attention-Deficit/Hyperactivity Disorder (ADHD).¹⁶ Other studies on attention outcomes found an association between water fluoridation and diagnosis of ADHD in Canada, although cross-sectional data on child U-F did not replicate this association,³⁰ perhaps reflecting water-fluoride as a more stable proxy of early-life exposure compared with U-F measured in a later spot sample.

… The pooling of results from three prospective cohorts conducted in areas with wide ranges of overlapping exposure levels offers strong evidence of prenatal neurotoxicity, and these findings should inspire a revision of water-fluoride recommendations aimed at protecting pregnant women and young children. For example, the World Health Organization’s recommendation of 1.5 mg/l as an upper limit for fluoride in drinking water²¹ does not consider developmental neurotoxicity.

… The present study contributes new information on the weak association between fairly low levels of prenatal fluoride exposure and cognitive function at school age in a Danish birth cohort. A possible negative association could not be confirmed within the exposures measured in the OCC. When merged with data from two previous prospective studies at higher exposures, a revised BMCL fluoride concentration of about 0.3 mg/l in maternal pregnancy urine suggests that elevated fluoride intakes, whether from drinking water, black tea, or other sources, during pregnancy may require public health attention.

Funding
The OCC was supported by the Danish Council for Independent Research, Medical Sciences (4004-00352B and 8020-00123B) and the Novo Nordisk Foundation (NNF15OC00017734 and
NNF17OC0029404). P.G. was supported by the National Institte of Environmental Health Sciences (NIEHS) Superfund ResearchProgram (P42ES027706). The ELEMENT study6 and the MIREC study⁷ were supported by grants from the NIEHS (R01ES021446,R01ES007821). H.H. was supported by the Flora L. Thornton Endowed Chair at the University of Southern California. The OCC also had support from Odense University Hospital, Region of Southern Denmark, the Municipality of Odense, Odense University Hospital Research Foundation, Odense Patient data Exploratory Network (OPEN), Helsefonden, the HBM4EU and other independent funding.

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