1. Introduction

Fluoride has significant impact on health. Long-term fluoride deposition in enamel prevents tooth decay. The prevalence of dental caries in developed countries has been declining over the past few decades largely due to widespread fluoride use (Mascarenhas, 2000). Along with beneficial effects on teeth, fluoride deposits in skeletal bone and increases bone mineral density (Vestergaard et al., 2008). To provide these beneficial effects, supplemental fluoride is added to water, supplements, infant formula, and toothpaste (McDonagh, 2000, O’Mullane et al., 2016). However, excessive fluoride can produce negative health consequences, notably dental and skeletal fluorosis (Abanto et al., 2009, Srivastava and Flora, 2020). Elevated fluoride concentrations in groundwater naturally occur in certain parts of the world where it can be a significant cause of disease (Ali et al., 2016, Srivastava and Flora, 2020). Other sources of exposure to high levels of fluoride may include tea consumption, fluoridated drinking water, food, and other supplements, as well as industrial contaminations (Fan et al., 2016, Kabir et al., 2020). The severity of fluorosis depends on what age and how long overexposure to fluoride occurs as well as individual response, weight, degree of physical activity, nutritional factors, and bone growth (Abanto et al., 2009).

Fluoride can impact synthesis, metabolism, and plasma levels of substances in experimental animals and within the human body. For example, plasma albumin and protein are reported to decrease in rats and sheep with chronic fluorosis (Cenesiz et al., 2005, He et al., 2014). Studies have shown a relationship between fluoride and uric acid levels as well (Cenesiz et al., 2005, He et al., 2014, Shivarajashankara et al., 2001a, Shivarajashankara et al., 2001b, Bouaziz et al., 2007, Nabavi et al., 2013, Luo et al., 2017). However, evidence obtained thus far is based predominately on experimental animals with mixed results. Studies showed that exposure to excessive fluoride in experimental animals resulted in renal oxidative damage and elevated levels of serum uric acid (Cenesiz et al., 2005, Nabavi et al., 2013, Luo et al., 2017), while other studies found plasma uric acid levels decreased in rats and mice with fluoride exposure (He et al., 2014, Shivarajashankara et al., 2001a, Bouaziz et al., 2007). The increased serum uric acid levels associated with fluoride exposure can be a measure of renal toxicity. Despite evidence in the relation between fluoride and uric acid in animals, there is a lack of epidemiologic studies with human subjects. A study conducted in a village of India found that children aged 3–10 years with endemic skeletal fluorosis had increased levels of oxidative stress and decreased levels of plasma uric acid (Shivarajashankara et al., 2001b).

Uric acid, a product of the breakdown of purines in the body, could be a protective or risk factor for disease. Chronic high levels of plasma uric acid is a precipitating factor for gout and nephrolithiasis as well as a strong risk factor for metabolic syndrome and cardiovascular disease (Becker and Jolly, 2006, de Oliveira and Burini, 2012, Noone and Marks, 2013). To clarify the potential relationship between fluoride exposure and uric acid levels in humans, we examined both plasma and water fluoride concentrations in association with serum uric acid levels in a large sample of adolescents aged 12–19 years who participated in the 2013–2016 US National Health and Nutrition Examination Survey (NHANES).

2. Materials and methods

3. Results

During the study period of 2013–2016, there were a total of 2748 adolescents, aged 12–19 years. After removing the adolescents who had missing data on plasma and water fluoride (n = 433) and had missing data on serum uric acid (n = 43), the sample size was reduced to 2272. We further excluded female participants who were pregnant (n = 0), and participants with missing covariates included in our models (n = 339). The final sample size was 1933 in the analyses.

The median value of plasma and water fluoride was 0.32 µmol/L (range: 0.09–4.32) and 0.50 mg/L (range: 0.01–7.32), respectively, in the adolescent participants (data not shown). The geometric mean of plasma fluoride was significantly higher in the hyperuricemia group (0.39 µmol/L; p = 0.0002), as compared to that in the non-hyperuricemia group (0.34 µmol/L) (Table 2). The geometric mean of water fluoride concentrations in the households of the hyperuricemia group (0.37 mg/L; p = 0.0304) was also significantly higher than in the non-hyperuricemia group (0.32 mg/L). The mean of uric acid in the total participants was 5.08 mg/dL. As expected, an increased serum levels of uric acid (6.73 mg/dL; p < 0.0001) was seen in the hyperuricemia group, as compared with the non-hyperuricemia group (4.75 mg/dL) (Table 2).

Finally, the relationship between water fluoride and plasma fluoride concentrations was assessed in the study participants. The fit plot for the association is shown in Fig. 1. It can be seen that water fluoride concentrations in the households of the study participants were positively associated with their plasma fluoride concentrations, with a ? of 0.1907 (p < 0.0001).

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Fig. 1. Relationship between water and plasma fluoride concentrations in the study participants (n?=?1933). LOGWFL denotes log-transformed water fluoride concentrations and LOGPFL denotes log-transformed plasma fluoride concentrations; ?: regression coefficient.

4. Discussion

Fluoride offers numerous benefits including dental health (Mascarenhas, 2000, Vestergaard et al., 2008). However, excessive fluoride can lead to negative consequences, especially in children and adolescents. In the present study, we found a statistically significant dose-dependent increase in the prevalence of hyperuricemia among adolescents with increasing plasma fluoride levels. Since water fluoride is the primary source of fluoride exposure in U.S., we additionally included water fluoride in the study and found a significant association of water fluoride concentrations with the increased prevalence of hyperuricemia as well after adjusting for potential confounders. To our knowledge, this is the first study assessing the relationship between fluoride exposure and hyperuricemia in an adolescent population. Although this is a cross-sectional study, the results reveal a potential role of exposure to fluoride in the increased prevalence of hyperuricemia in US adolescents. The findings provide additional evidence on environmental risk factors for hyperuricemia that has been increasingly prevalent in developed countries.

There is lack of evidence on the relationship between fluoride exposure and uric acid levels in a human population. Different from the observations in an earlier study reporting that children aged 3–10 years with endemic skeletal fluorosis had increased levels of oxidative stress and decreased levels of plasma uric acid (Shivarajashankara et al., 2001b), our study found increased uric acid levels with increased fluoride exposure in adolescents. This discrepancy might be due to the differences in the study population with respect to age and the level of fluoride exposure. In support of our findings, several studies provided evidence that exposure to excessive fluoride in experimental animals elevated levels of serum uric acid (Cenesiz et al., 2005, Nabavi et al., 2013, Luo et al., 2017). However, the relationship between uric acid and fluoride in animal studies remains controversial. Further investigations are needed to clarify this relationship and to explore the potential mechanisms underlying the effect of fluoride exposure on serum uric acid levels.

There are several possible reasons that could explain the observed positive association in this study. First, fluoride exposure has been reported in human and experimental animal studies to cause kidney damage (Nabavi et al., 2013, Luo et al., 2017, Xiong et al., 2007, Khandare et al., 2017, Malin et al., 2019), which can lead to a decrease in uric acid excretion and an increase in plasma uric acid levels. A recent study reported that fluoride exposure may contribute to complex changes in kidney and liver parameters among U.S. adolescents (Malin et al., 2019). Second, fluoride could affect endocrine or metabolic conditions that can be associated with higher uric acid production and lower uric acid excretion. Low-to-moderate fluoride exposure from drinking water was associated with impaired thyroid hormones (Kheradpisheh et al., 2018) as well as overweight and obesity in school-age children in a recent study (Liu et al., 2019). It was reported earlier that higher waist circumference and BMI were associated with lower uric acid excretion (Noone and Marks, 2013). Third, a close association between chronic fluoride toxicity and increased oxidative stress has been reported in humans and experimental animals (Shivarajashankara et al., 2001a, Shivarajashankara et al., 2001b, Bouaziz et al., 2007, Nabavi et al., 2013, Luo et al., 2017). This increase in oxidative stress may be a factor in the correlation of uric acid levels and fluoride levels. In this case, uric acid could serve as an antioxidant (Sautin and Johnson, 2008) in response to oxidative stress elicited by fluoride exposure. Uric acid could be a protective or risk factor. Acute elevation may be a protective factor whereas chronic elevation is a risk for disease. Whether or not hyperuricemia or even high normal levels plays a causal role or simply is a marker arising in the course of each related disorder remains unresolved (Becker and Jolly, 2006).

The median level of water fluoride found in the households of the study participants in our study was 0.50?mg/L, which is considered low and meets the optimal water fluoride concentration of 0.7?mg/L recommended by the U.S. Public Health Service (U.S. Department of Health and Human Services, 2015). This level was also lower than the levels found in the endemic skeletal fluorosis regions where the groundwater contains elevated levels of fluoride geographically (Shivarajashankara et al., 2001b, Xiong et al., 2007, Khandare et al., 2017, Kheradpisheh et al., 2018, Liu et al., 2019). However, there was a wide range of fluoride concentrations (0.01–7.32?mg/L) found in the household water of the study participants, which indicates that some residents exposed to higher levels of fluoride from domestic well water that contains naturally-occurring high levels of fluoride or from community water systems that receive higher levels of fluoridation. We found in our study that adolescents who drank the water with fluoride even at relatively low concentrations (?0.73?mg/L; the highest quartile) had increased prevalence of hyperuricemia.

In addition to water fluoride, sources of fluoride exposure during adolescence include dental products such as toothpastes, mouth rinses, and fluoride varnish for prevention of dental carries. Fluoride is additionally found in processed foods and beverages, pesticides, tea drinks, mechanically deboned meat, and Teflon pans. Plasma concentrations of fluoride reflect all sources of exposure, although drinking water is a main source of exposure. Our study confirmed a significantly positive association between water and plasma fluoride concentrations. Exposure to excess fluoride has a significant impact on adolescent health. In addition to consequences on teeth and bone, fluoride exposure may alter kidney and liver functions in adolescents (Malin et al., 2019). Our study revealed that low levels of plasma fluoride (?0.32?µmol/L) was associated with increased odds of hyperuricemia in US adolescents after adjusting for potential confounders. Excess fluoride during development may also impact neural connections leading cognitive complications such as lower IQ and ADHD (Grandjean and Landrigan, 2014, Malin and Till, 2015, Green et al., 2019). There is also evidence of fluoride acting as a carcinogen. One study found a correlation between osteosarcoma and fluoride exposure during childhood (Bassin et al., 2006).

This study has several caveats. Given the cross-sectional nature of this study, the causality of relationships cannot be determined and a reverse causality cannot be ruled out. Further longitudinal studies are needed to determine these associations. Additionally, only one blood sample was collected from each participant at different times during the day in the NHANE, which would potentially affect the level of measurements of exposure and outcome. Multiple samples taken over time would better assess the exposure and the related outcomes. Lastly, we did not examine whether the association between fluoride and uric acid levels differed geographically within U.S. adolescents as geographic locations of individuals were not available in the dataset.

Despite the limitations of this study, there are a number of strengths. First, we explored the association between fluoride exposure using both plasma and water concentrations and hyperuricemia in a large and nationally representative sample of US adolescents who participated in the 2013–2016 NHANES. Second, we were able to adjust for a number of potential confounders while assessing the association, including demographic variables, BMI, physical activity, seafood consumption, as well as serum cotinine levels as biomarker of exposure to tobacco smoke. Third, we analyzed and presented the prevalence of hyperuricemia and fluoride exposure levels in US adolescents for the most recent years that are available in the NHANES. Lastly, this is the first study reporting the potential relationship between fluoride exposure and hyperuricemia in an adolescent population and is among a few studies elucidating how serum uric acid levels change in association with fluoride levels.

5. Conclusion

In summary, our results demonstrate a positive relationship between plasma and water fluoride and uric acid levels. It is suggested that the increase in uric acid levels found in this study might be due to impaired kidney damages or metabolic functions and the need for removal of free radicals produced by fluoride. Further studies are warranted to overcome the limitations of this study and examine the impact of chronic fluoride exposure on adolescent development and health as well as later in life. Increasing bodies of evidence would help in determining the optimal fluoride concentrations for humans.

CRediT authorship contribution statement

Yudan Wei: Conceptualization, Methodology, Formal analysis, Investigation, Validation, Supervision, Writing – original draft, Writing – review & editing; Jianmin Zhu: Methodology, Software, Data curation, Formal analysis, Investigation, Writing – review & editing; Sara Ann Wetzstein: Investigation, Writing – original draft, Writing – review & editing.