In this prospective study we found that patella bone lead was associated with a significantly increased rate of all-cause mortality over an average follow-up of almost 10-years. This association appeared to be driven largely by cardiovascular causes of death as patella bone lead was even more strongly associated with these outcomes, in particular ischemic heart disease. These findings were among a population of men with blood lead levels only slightly higher than US averages for men of a similar age,17
and likely well within the range that would be seen around the world, particularly in countries that banned leaded gasoline more recently than the US or have not banned leaded gasoline at all.
While there was little association between patella bone lead and cancer or non-ischemic heart disease, we found that, compared to participants in the lowest tertile of patella bone lead, those in the highest tertile were at a 2 and one half-fold greater risk of all-cause mortality, almost 6-fold greater risk of cardiovascular mortality, and over 8-fold greater risk of ischemic heart disease, although in this last category the confidence interval was very wide and so the specific point estimate should be interpreted with caution. The increase in hazard ratio with increasing tertile of bone lead exposure was relatively monotonic for all three of these endpoints, suggesting linear dose-response relations, and this was also supported by the significant p-values for linear trend. This was also borne out by smoothing analyses in which the generally monotonic trend was apparent (), and in none of which did the non-linear components reach statistical significance. However, for all-cause and ischemic heart disease mortality, there was the suggestion that the increasing risk with increasing bone lead lessens at higher lead levels, although the confidence intervals were very wide in this range of lead exposures. For all-cause and all cardiovascular mortality the associations with patella bone lead were stronger in analyses excluding participants with heart disease or stroke at baseline than in analyses including such participants. This suggests that having those conditions changes the lead exposure profile, either by alterations in behavior or physiology. Major strengths of our study include the prospectively followed community-dwelling cohort, and having both blood and bone lead data. Bone lead levels provide a better indicator of cumulative exposure to lead than do blood lead levels because of the much longer half-life of lead in bone.9
There are several limitations to this study that should be recognized. First, our study is restricted to men, the majority of whom are Caucasian. Thus, whether the results generalize to women or minorities remains a question. Additionally, bone lead measurements are not perfectly precise and are made with some error. This measurement error, however, is most likely unrelated to overall or cause specific mortality and thus would be likely to bias results towards the null rather than induce a spurious association. We also adjusted for several covariates that might confound the association between lead and cardiovascular mortality, but, as with any observational study, the possibility of residual confounding by these variables or confounding by other unmeasured variables cannot be completely ruled out. Although 32% of active NAS participants did not participate in bone lead measurements, this group was generally similar to those who did, in particular in blood lead level, which suggests that little bias would be introduced from the non-participation. Finally, in comparison to recent studies examining blood lead data in NHANES,7, 8
the present study was substantially smaller. While the increase in strength of the association between patella lead and ischemic heart disease mortality after adjustment is driven by the inverse association between patella lead and age in the oldest NAS participants, this negative confounding is likely exacerbated by the small number of ischemic heart disease deaths. Overall, though, the fact that we still found significant associations between bone lead and mortality in a sample with over 6 times fewer deaths, however, suggests that bone lead is a particularly good biomarker for these outcomes.
As in this study, bone lead has been found in other studies to be a stronger predictor than blood lead of several other health endpoints (e.g. hypertension,12, 18, 19
), and suggest that this biomarker should be strongly consider for monitoring environmental exposures relevant for health. Currently blood lead is the only lead biomarker assessed in NHANES and current Occupational Safety and Health Administration (OSHA) standards regarding exposure to lead relate only to blood lead.26
Bone lead, however, may be a more relevant biomarker and a more important indicator of subsequent health events, at least when the exposure assessment is done only once.
No previous studies have examined the association between bone lead and mortality, although several have reported associations with blood lead in data from NHANES.6–8, 27
In the most recent studies from the third (1988–1994) NHANES, blood lead levels were associated with an increased rate of all-cause, cardiovascular, and, in the study not restricted to those with lower blood lead levels, cancer mortality.7, 8
Among adults 20 years of age and older with blood lead concentrations below 0.48 μmol/L (10 μg/dL), the hazard ratio for those with blood lead concentrations in the highest tertile (≥ 0.175 μmol/L [3.63 μg/dL]) was 25% higher than those with blood lead in the lowest tertile (<0.093 μmol/L [1.93 μg/dL]) for all-cause mortality and 55% higher for cardiovascular mortality.7
Among adults 40 years of age and older, the hazard ratio for those with blood lead concentrations of 0.48 μmol/L (10 μg/dL) or more was 59% higher than those with blood lead below 0.24 μmol/L (5 μg/dL) for all-cause mortality and 55% higher for cardiovascular mortality.8
The average age at baseline in one of these studies7
was more than 20 years younger than in the current study, which, given the difference from our findings for blood lead, could suggest that blood lead at earlier ages is more predictive than blood lead at older ages. The other recent paper on blood lead,8
however, found associations even among older participants, although the findings appeared slightly less robust at older ages. In a study of mostly non-fatal ischemic heart disease (70 of 83 cases) in the NAS, however, both blood lead and patella bone lead were significantly associated with myocardial infarction or angina pectoris, although patella lead appeared to be the stronger predictor.10
Three prior studies with only blood lead data, however, did not see an association with that biomarker.28–30
An alternative explanation for the differences in findings for blood lead in our cohort and the NHANES studies is that if exposures to lead in the Greater Boston area were more varied at the time of blood lead assessment than they were for the more national NHANES cohorts (as is possibly suggested by the slightly higher blood lead levels in our cohort), this could result in more fluctuation in blood lead levels. If this were the case, then any single blood lead measure would be less correlated with overall lead exposure in our cohort and show a reduced effect estimate for mortality if it is truly cumulative exposure that is important for mortality outcomes.
There are several mechanisms by which exposure to lead may result in cardiovascular mortality in particular (for review see 2
). Lead can have direct effects on the excitability and contractility of the heart, and increase vascular tone and peripheral resistance via effects such as stimulating the renin-angiotensin system, reductions in nitric oxide availability and guanylate cyclase, or increased oxidative stress.31–33
Lead has been found to induce proliferation of vascular smooth cells and fibroblasts and induce atherosclerosis in animal models.34, 35
In addition, neurotoxic effects of lead can affect autonomic control of the heart.36
The most extensive data in humans relates to the association between lead exposure and higher blood pressure or hypertension, but lead exposure has also been associated with many other cardiovascular endpoints,2, 3
including pulse-pressure (an indicator of arterial stiffening),21
and ischemic heart disease10
in this same cohort. The association with heart disease deaths persisted after control for blood pressure suggesting that other mechanisms likely mediate the effect of lead on heart disease. Given the mechanisms of these effects of lead on the cardiovascular system, it is not surprising that a cumulative biomarker of lead—exposure such as bone lead—would be a better predictor of cardiovascular mortality than blood, which is a more acute exposure biomarker.
Cardiovascular disease is the leading cause of death in the US and one of the most significant contributors to mortality worldwide.37, 38
Projections of future trends in cardiovascular mortality have important health care planning implications. Cardiovascular mortality has generally shown a steady decrease over the past several decades in developed countries, although the opposite is seen in some developing countries.37, 39, 40
These trends tend to be paralleled by trends in traditional cardiovascular risk factors such as blood pressure, cholesterol levels, and smoking.41, 42
These trends, however, do not explain all the change in cardiovascular mortality, and, at least in some cases, cardiovascular mortality continues to decline despite a leveling off of changes in traditional risk factors.42
Lead exposure has not been considered in this equation, but in the US and many other developed countries environmental exposures have been declining since the mid-1970s.43
These declines may well have contributed to declining cardiovascular mortality rates. Because of the long residence time of lead in bone—a storage site from which it can later re-enter circulation9
—and the aging of the population, the full effects of reducing environmental levels of lead may continue for some time.
In summary, we found that in a population of community-dwelling elderly men with biomarkers of both blood and bone lead, bone lead, but not blood lead, was associated with an increased mortality rate that was particularly evident for cardiovascular disease, and specifically between patella lead and ischemic heart disease.