In this well-characterized population of U.S. men and women, multiple independent determinants of toenail selenium levels were identified. It would be expected that selenium levels in the body should be affected by dietary factors and supplement use, and both were identified here as independent determinants. However, although the magnitude of these observed relationships is likely to be underestimated due to some misclassification in estimation of diet, even so these dietary factors explained only a modest relative proportion of overall variation in selenium levels. Notably, several other demographic and lifestyle factors were independent determinants of selenium levels, including smoking, alcohol intake, age, and sex. Furthermore, geographic residence remained a strong independent predictor, even after adjustment for types of foods consumed and each of the other independent determinants of toenail selenium.
Beef and bread products are recognized as good sources of selenium [26
], and bioavailability of selenium from these foods is relatively high [27
]. However, consumption of white rice was also negatively correlated with selenium levels in our study. This could be explained by findings that consumption of high glycemic index (GI) foods leads to higher oxidative stress [29
]. Selenoproteins are important components of several critical antioxidant systems, such as glutathione peroxidase, that actively protect against damage from free radicals and reactive oxygen species [31
]. Thus, it is possible that consuming foods that induce oxidative stress, such as high GI foods, could deplete selenium levels. It is also possible that foods such as white rice, which are typically refined and depleted of phytochemicals, could be replacing other higher-selenium foods in the diet. Interestingly, intakes of coffee, dairy products, and eggs were each inversely associated with selenium levels. No prior study has evaluated intakes of these foods in relation to selenium levels. Our findings support the need for further study of potential effects of these foods on selenium levels.
We observed a dose-response relationship between the number of cigarettes currently smoked and toenail selenium levels, consistent with findings from previous studies [3
], even after multivariable adjustment for dietary habits, demographics, and other lifestyle factors. However, why cigarette smokers have lower levels of selenium has not been established. Swanson et al. [6
] and van den Brandt et al. [5
] reported that compared to nonsmokers, current smokers have lower consumption of selenium as estimated from dietary questionnaires, suggesting that lower selenium levels in smokers could at least partly reflect dietary differences. However, we identified current smoking as a significant predictor of lower selenium levels even after adjustment for other dietary and non-dietary determinants. Although residual confounding from unmeasured dietary factors and measurement error in the observed dietary factors cannot be excluded, the magnitude and observed dose-response support biological plausibility of a causal relationship. Cigarette smoking is known to increase oxidative stress [33
], with a positive dose-response relationship per number of cigarettes smoked [36
], and biomarkers of oxidative stress are reduced substantially within 2 weeks of smoking cessation [34
]. These results support our findings of lower selenium levels in current but not former smokers, and the lowest levels among those who smoked the most cigarettes per day. Our findings indicate that factors which promote oxidative stress, such as current smoking, may directly affect tissue selenium levels, for example by increasing selenium utilization and causing depletion of tissue selenium stores. This concept of selenium depletion is further supported by the relationships we found between some other non-dietary characteristics and selenium levels. For example, older age was associated with lower toenail selenium levels, consistent with previous reports [3
], which may be explained by increased oxidative damage as a function of aging [38
]. In addition, we observed alcohol-related reductions in selenium levels, a finding supported by reports that alcohol consumption induces oxidative stress [40
]. Thus, our findings together support a new hypothesis, in which factors that promote oxidative stress may deplete selenium levels in the body.
Prior studies of selenium levels have found inconsistent sex differences [4
]. The sex differences we observed should be interpreted conservatively since these were two separately recruited cohorts. Interestingly, prior findings have also been inconsistent in terms of whether oxidative stress levels are higher in men or women [45
]. The reasons for these discrepancies in relationships between sex and both selenium and oxidative stress status are unknown, and further investigation of these issues is warranted.
Although the extensive transport system of food products in the United States is thought to reduce variability in the selenium contents of foods in different regions, significant geographic heterogeneity in selenium levels was observed, even after accounting for dietary habits, demographics, and other lifestyle factors. This could be due to significant variation in the selenium contents of foods in different U.S. regions, or to residual confounding from unmeasured differences in other dietary habits or lifestyle characteristics between regions. Whereas our findings cannot definitively distinguish between these two possibilities, our evaluation and adjustment for multiple dietary habits, demographic characteristics, and lifestyle factors suggests that the former explanation may be more plausible. Previous studies have shown inconsistent geographic distributions of selenium in crops and human levels in the U.S. [3
], and most prior studies in humans [3
] have not reported the independent effect of geographic variation adjusted for other potential selenium determinants, including diet and lifestyle factors. Our study provides unique geographic information about the distribution of selenium levels, adjusted for other major determinants, in two large U.S. cohorts.
This analysis has several strengths. Rather than measuring selenium content in foods and estimating exposure, we assessed actual tissue biomarkers of selenium levels in 3,902 free-living men and women from across the U.S., providing a better estimate of actual exposure to selenium in the population. Selenium levels were evaluated in toenails using well-established methods, providing a valid and reproducible biomarker of long-term levels. The cohort size and standardized assessment of a wide variety of participant characteristics allowed multivariable-adjustment for several demographic, lifestyle, and dietary factors, including multiple potential dietary sources of selenium, minimizing residual confounding. We concurrently evaluated multiple potential determinants, providing the best evidence to-date of how each of these demographic, lifestyle, and dietary factor may independently influence long-term selenium levels.
Limitations should also be considered. The participants were Americans of higher socioeconomic status and mostly white, and our findings may not be generalizable to other socioeconomic groups or nations. On the other hand, there is little reason to expect that the biological effects on selenium levels of some factors, such as smoking, might vary substantially in other socioeconomic groups, races, or countries. These cohorts do not represent random samples of the U.S. population, and thus the geographic findings should be viewed qualitatively rather than as definitive for the U.S. population. Although extensive covariate information was collected using validated instruments, some residual confounding due to unmeasured or imperfectly measured factors may remain.
In summary, we identified several independent dietary, and interestingly, non-dietary predictors of selenium levels in the U.S. population. For many of the non-dietary factors, the findings were consistent with expected effects of oxidative stress, suggesting that tissue selenium, and potentially selenium-related anti-oxidant defenses, may depend on the balance between dietary consumption vs. depletion by oxidant stressors. Geographic variation was also an independent determinant, suggesting that even in the U.S. substantial regional differences in the selenium contents of foods may be present. Finally, although we identified a number of independent determinants of selenium-providing critical information for future studies examining selenium levels and chronic disease - a large proportion of the total variance was left unexplained. Future studies, including the examination of genetic factors, are needed to better understand the biological pathways through which environmental and genetic determinants affect selenium concentrations in the human population.