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JECH Online First, published on October 9, 2017 as 10.1136/jech-2017-209956 PostScript

Letter

Fluoride exposure and indicators of thyroid functioning: study design and data analysis considerations Barberio et al1 reported that there was no evidence of a relationship between fluoride exposure and the diagnosis of a thyroid condition among a subsample of respondents available from Statistics Canada’s Canadian Health Measures Survey. On review, however, their data show that the mean urinary fluoride (UF) level in patients with primary hypothyroidism was 0.60  mg/L compared with 0.55  mg/L for individuals without this condition. In other words, the mean UF levels in respondents with primary hypothyroidism were higher than without. However, it is the reported ranges of UF levels from either groups that is particularly revealing. For example, among individuals with primary hypothyroidism, UF levels were found to range from 0.22 to 0.98 mg/L. The range reported in the controls was 0.49 to 0.61 mg/L.1 What these data show is that among patients with primary hypothyroidism, a subgroup of patients had very low UF levels with another subgroup demonstrating elevated UF above the normal range. The differences may seem insignificant; however, Chen et al2 observed that UF levels were strongly associated with abnormal endocrine function. Specifically, when UF levels exceeded 0.38 mg/L, abnormal expression of calcitonin (CT), a hormone produced by the thyroid, was found to occur. Moreover, when UF levels exceeded 0.62 mg/L, abnormal expression of osteocalcin (OC), an osteoblast-derived hormone, was observed. It is important to be aware that elevated CT is associated with thyroid

disorders3 and overexpression of OC is involved in diabetes onset, by promoting glucose intolerance, or early-stage diabetes.4 This leads us to the next observation. Studies have shown that UF excretion in patients with chronic kidney disease (CKD) are significantly lower than that in patients with normal renal function resulting in a significantly higher retention of fluoride.5 Notably, Montenegro et al6 reported that glomerular filtration rate (GFR) is reduced (by about 40%) in more than 55% of adults with hypothyroidism. It is also widely acknowledged that the prevalence of primary hypothyroidism, mainly in the subclinical form, increases as GFR decreases.7 Hill et al8 reported that the prevalence of CKD (stages 1 to 5) in North America was 15.45%, ranging from 11.71% to 19.20%. Thus, evidence suggests that the lower range of UF observed among individuals with primary hypothyroidism may be more representative of individuals with CKD. Given the high prevalence of CKD in Canada, and the significantly higher prevalence of hypothyroidism among CKD patients compared with the general population, it is evident that using UF as a biomarker of fluoride exposure in hypothyroidism is highly questionable and may lead to unsubstantiated conclusions about causality particularly when confounding factors are not properly examined. For a more accurate analysis, serum/plasma fluoride levels should have been examined. Finally, the wide range of reported CIs in this study suggest the results must be interpreted with a high degree of uncertainty. Choosing a more precise biomarker would improve quantitative uncertainty and may lead to radically different outcomes. Declan Timothy Waugh Correspondence to Declan Timothy Waugh, EnviroManagement Services, Cork, Ireland; ​declan@​ enviro.​ie

Contributors  DTW is the sole contributor. Funding  This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors. Competing interests  None declared. Provenance and peer review  Not commissioned; internally peer reviewed. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

To cite Waugh DT. J Epidemiol Community Health Published Online First: [please include Day Month Year]. doi:10.1136/jech-2017-209956 Received 7 September 2017 Accepted 17 September 2017 J Epidemiol Community Health 2017;0:1. doi:10.1136/jech-2017-209956

References

1 Barberio AM, Hosein FS, Quiñonez C, et al. Fluoride exposure and indicators of thyroid functioning in the Canadian population: implications for community water fluoridation. J Epidemiol Community Health 2017;71:1019–25. 2 Chen S, Li B, Lin S, et al. Change of urinary fluoride and bone metabolism indicators in the endemic fluorosis areas of southern China after supplying low fluoride public water. BMC Public Health 2013;13:156. 3 Oishi S, Shimada T, Tajiri J, et al. Elevated serum calcitonin levels in patients with thyroid disorders. Acta Endocrinol 1984;107:476–81. 4 Aoki A, Muneyuki T, Yoshida M, et al. Circulating osteocalcin is increased in early-stage diabetes. Diabetes Res Clin Pract 2011;92:181–6. 5 Spencer H, Kramer L, Gatza C, et al. Fluoride metabolism in patients with chronic renal failure. Arch Intern Med 1980;140:1331–5. 6 Montenegro J, González O, Saracho R, et al. Changes in renal function in primary hypothyroidism. Am J Kidney Dis 1996;27:195–8. 7 Lo JC, Chertow GM, Go AS, et al. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int 2005;67:1047–52. 8 Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease - a systematic review and metaanalysis. PLoS One 2016;11:e0158765.

Waugh DT. J Epidemiol Community Health Month 2017 Vol 0 No 0

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Fluoride exposure and indicators of thyroid functioning: study design and data analysis considerations Declan Timothy Waugh J Epidemiol Community Health published online October 9, 2017

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Fluoride exposure and indicators of thyroid functioning: study design and data analysis considerations.

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