Our findings in these two separate large prospective cohorts do not support clinically apparent adverse effects of chronic methylmercury exposure on development of hypertension at usual exposure levels seen in these men and women. In the top quintile, median mercury exposures were about 1.7-fold – and in the top decile, about 2.5-fold – higher than the US EPA reference dose.27
Findings were similar in men, women, and various stratified subgroups.
These ranges of mercury exposure are comparable to those in national US surveys28
and prior European studies.29, 30
In the NHS, median exposure was 0.23 μg/g, or about 0.62 μg/g in hair, similar to the 75th
percentile exposure among US women age 40–49 (hair mercury 0.55 μg/g; 95% CI: 0.40, 0.69).28
In the top decile of NHS, median exposure was 0.76 μg/g, or about 2.05 μg/g in hair, similar to the top decile among white US females age 16–49 (hair mercury 1.84 μg/g; 95% CI: 0.82, 2.86).28
Exposure was even higher in the top decile of the HPFS cohort, consistent with their higher fish consumption compared to the average population, and also suggesting a greater selection of higher mercury fish (e.g., bluefin sushi, swordfish, shark, etc.) in these individuals. Overall, the similar or higher methylmercury exposure levels in our cohorts makes the absence of evidence for higher risk of hypertension more robust.
For assessing population health effects, the primary mercury species of interest is methylmercury, derived principally from fish intake.31
In the absence of unusual occupational exposures, toenail mercury concentration is a useful biomarker of usual methylmercury exposure.32–34
We excluded dentists from measurements, so it is unlikely that any meaningful number of these health professionals were exposed to appreciable sources of occupational mercury. Consumption of tuna and other saltwater fish are the main dietary factors positively associated with toenail mercury.32–34
In addition, when we speciated toenail mercury concentrations in a subset of 29 participants, total mercury and methylmercury concentrations correlated nearly perfectly: Spearman correlation (r)=0.97.8
Toenail mercury concentrations at one time point also predict future exposure, with a correlation of 0.56 for levels assessed in clippings obtained 6 years apart,32
similar to correlations over time for widely used epidemiologic measures such as BP or blood cholesterol.35, 36
Toenail selenium concentrations are also valid biomarkers of selenium exposure, responding to long-term changes in diet and correlating with whole blood and serum selenium.37, 38
Reliability of toenail selenium levels over time is also reasonable, with a correlation of 0.48 for levels in clippings obtained 6 years apart.32
Among prior cross-sectional studies, 4 studies,12–15
but not 2 others,16, 17
suggested a link between higher methylmercury exposure and higher BP or prevalent hypertension. Most of these studies were relatively small, including only a few hundred participants; and several focused on specific ethnicities such as Nunavik Inuits, Cree Indians, French Polynesians, or Brazil Amazonians, potentially limiting generalizability. Perhaps due to their small size, most of these studies also adjusted for a limited set of potential confounders. Additionally, all these studies could be limited by reverse causation, as a cross-sectional design cannot distinguish whether methylmercury exposure is related to higher BP, or whether persons with higher BP may have reasons to consume more fish and thus have higher methylmercury levels. In an initial prospective follow-up of a Faroese birth cohort at 7 years, prenatal methylmercury exposure was associated with higher childhood BP after adjustment for body weight.18
However, this relationship was equivocal and not statistically significant after additional follow-up to age 14 years.19
Overall, prior literature suggested a potential link between methylmercury exposure and hypertension, but with mixed findings across studies and multiple relevant limitations including cross-sectional design, low statistical power, and potential for residual confounding due to limited covariate adjustment. Interestingly, in unadjusted cross-sectional analyses at baseline in our cohorts, mercury levels were positively associated with diastolic BP, as well as with hypercholesterolemia, suggesting that persons with more cardiovascular risk factors may choose to consume more fish (i.e., reverse causation). However, mercury exposure was not related with higher risk of hypertension longitudinally. Adjustment for self-reported fish consumption at baseline did not materially alter these results, although such adjustment may incompletely account for residual confounding due to potential benefits of fish intake. Our findings provide the most robust evidence to-date that chronic methylmercury exposure, at least at doses commonly seen in the US and many other countries, does not increase risk of hypertension.
For some environmental toxins, such as lead or bisphenol A, harms can be assessed independent of any potential health benefits derived from the source of exposure. In comparison, the major source of methylmercury exposure is fish consumption, which provides several cardiovascular and potentially other benefits.39
Thus, population recommendations for methylmercury exposure should simultaneously consider both potential harms and benefits of fish consumption, including of fish that contain methylmercury.3
Guidelines regarding fish intake exist for women who may become pregnant, infants, and young children to optimize brain development during gestation and infancy, aiming to balance benefits of fish consumption versus the effects of methylmercury exposure.3
However, no corresponding guidelines exist for the general adult population, largely due to insufficient evidence for any significant long-term effects of chronic methylmercury exposure in adults. Although we found no adverse association between toenail mercury and hypertension risk, we cannot exclude residual confounding due to benefits of fish or omega-3 consumption on BP,40, 41
even though we adjusted for and stratified by fish consumption and estimated dietary omega-3 consumption. Such benefits, for example, could account for trends toward lower incidence of hypertension with higher mercury exposure in both cohorts. This trend was especially evident in younger adults (<50 years), in whom fewer competing risks from other causes of hypertension might make it easier to detect a clinically relevant BP-lowering effect of fish intake. Overall, our findings do not provide support that chronic methylmercury exposure from seafood consumption increases risk of hypertension.
Our analysis has potential limitations. Our findings were based on toenail measurements at baseline, and changes in methylmercury exposure over time could attenuate true relationships toward the null. Conversely, a single toenail mercury concentration provides an excellent biomarker of integrated usual methylmercury exposure over the past year, and a reasonable correlation between concentrations in nails collected six years apart indicates that a single measure also represents exposure over longer periods. Our findings were also similar in sensitivity analyses limited to shorter durations of follow-up. Our secondary analysis of participant-reported BP could be limited by imperfect measurements and reporting that would attenuate findings toward the null. On the other hand, given that these cohorts comprised educated health professionals, the reported measures are likely reasonably valid, at least within the broad categories that were assessed. Although we adjusted for a range of demographic, clinical, and lifestyle risk factors, residual confounding cannot be excluded, particularly from other benefits of fish consumption. Whereas findings were similar in two separate cohorts and there is little reason to believe that biological effects of methylmercury in these populations would be different than among women and men in general, these cohorts comprised largely white, educated US adults, potentially limiting generalizability.