Lead Exposure and Cardiovascular Disease—A Systematic Review

1Cardiovascular disease is the leading cause of mortality and a primary contributor to the burden of disease worldwide. Environmental toxicants, including lead and other metals, are potentially preventable exposures that may explain population variation in cardiovascular disease rates. However, after more than 100 years since initial reports suggested a link between lead exposure and cardiovascular outcomes, the contribution of lead to cardiovascular disease is still incompletely understood.

2Population research on the cardiovascular effects of lead has focused largely on the association with blood pressure and hypertension. Several reviews and metaanalyses combining data from more than 30 original studies and around 60,000 participants have examined the evidence relating blood lead to blood pressure or hypertension [;;;;, 1995; ]. All these reviews concluded that there was a positive association between blood lead levels and blood pressure (Table 1). The estimated increase in systolic blood pressure associated with a 2-fold increase in blood lead levels (e.g., from 5 to 10 μg/dL) ranged across reviews from 0.6 to 1.25 mmHg. This epidemiologic relationship is also supported by a large body of experimental and mechanistic evidence. Because lead exposure is widespread, even a modest effect would imply that lead exposure is an important determinant of blood pressure levels and hypertension in human populations.

3The cardiovascular effects of lead, however, are not limited to increased blood pressure and hypertension. Lead exposure has also been associated with an increased incidence of clinical cardiovascular end points such as coronary heart disease, stroke, and peripheral arterial disease, and with other cardiovascular function abnormalities such as left ventricular hypertrophy and alterations in cardiac rhythm.

4In the present article, our objective was to perform a systematic review of the epidemiologic evidence on the association of lead exposure with cardiovascular disease end points. Because previous reviews have examined the connection between lead and blood pressure in depth (Table 1), our systematic review emphasizes other clinical and intermediate cardiovascular outcomes to obtain a broader picture of the impact of lead on cardiovascular disease. Finally, we assessed the causal role of lead on blood pressure and cardiovascular disease by applying the criteria and terminology of the 2004 Surgeon General Report The Health Consequences of Smoking to the available information.

5We aimed to identify all observational studies assessing the association between lead exposure and cardiovascular end points. Using free text and key words (Appendix A), we searched PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed), EMBASE (http://www.embase.com/), and TOXLINE (http://toxnet.nlm.nih.gov/) through August 2006 with no language restrictions. In addition we manually reviewed the reference lists from relevant original research and review articles and documents.

6For lead exposure, we included studies that used biomarkers (lead levels in blood, bone, or other specimens), environmental measures (airborne lead levels), or indirect measures (job titles, job exposure matrices, living in lead-contaminated areas). For cardiovascular end points, we included studies that reported clinical cardiovascular end points (cardiovascular disease, coronary heart disease, stroke, or peripheral arterial disease) and intermediate cardiovascular end points (left ventricular mass, heart rate, heart rate variability, or electrocardiographic abnormalities) other than blood pressure levels or hypertension.

7We excluded publications containing no original research, studies not carried out in humans, case reports, case series, ecologic studies, studies lacking a cardiovascular outcome, and studies lacking data on lead exposure (Figure 1). For studies with multiple publications on the same population, we selected the publication with the longest follow-up. For studies with equivalent follow-up periods, we selected the study with the largest number of cases or the most recent publication. We excluded autopsy studies measuring lead in arterial tissue and studies based on polycardiography and ballistocardiograpy, techniques no longer in use. For consistency, blood lead levels were converted to micrograms per deciliter.

8We adapted the criteria used by to assess study quality for studies of clinical end points and the criteria used by to assess study quality for studies of intermediate end points (Appendices B and C).

9Measures of association (odds ratios, prevalence ratios, standardized mortality ratios, relative risks, relative hazards, comparisons of means, linear regression coefficients, correlation coefficients) and their standard errors were abstracted or derived from published data. For studies reporting measures of association for population subgroups, we pooled the measures of association using an inverse-variance weighted random-effects model.

10Because of substantial heterogeneity and methodologic limitations of the original studies, we considered that quantitative pooling was inappropriate. We thus present a qualitative systematic review of the available evidence.

11Twelve studies met our inclusion criteria (Table 2). Lead was measured in blood in all the prospective cohort studies and in the only cross-sectional study available. Blood lead levels were substantially lower in more recent compared with older studies. Case–control studies assessed lead exposure on the basis of lead levels in blood, plasma, and urine, on a job exposure matrix, and on lead levels in the air of the residential neighborhood of study participants. None of these studies determined lead in bone. Although cohort studies and the cross-sectional study tended to fulfill prespecified quality criteria, case–control studies failed to fulfill some important quality criteria (Appendix B).

12Lead exposure was positively associated with clinical cardiovascular end points in all studies (Table 2). Among prospective studies, the relative risks for coronary heart disease ranged between 1.1 comparing blood lead levels > 24.8 μg/dL versus < 12.4 μg/dL in the British Regional Heart Study and 1.89 comparing blood lead levels ≥ 3.63 μg/dL versus < 1.93 μg/dL in the National Health and Nutrition Examination Survey (NHANES) III Mortality Follow-up Study. The relative risk for stroke in the NHANES III Mortality Follow-up Study was 2.51. There were no prospective studies on the association of blood lead with peripheral arterial disease. However, the relative risk for peripheral arterial disease comparing blood lead levels ≥ 2.47 μg/dL versus < 1.03 μg/dL in a cross-sectional analysis of NHANES 1999–2002 was 1.92.

13Eighteen studies from the United States, Europe, and Australia met our inclusion criteria (Table 3). Battery, ceramic, pigment, refinery, and smelter industries were studied. All studies used job titles to ascertain exposure and death certificates to identify coronary heart disease (12 studies), stroke (15 studies) and overall cardiovascular mortality (9 studies). Most were retrospective cohort studies and used external comparisons to the general population to derive standardized mortality ratios. The exceptions were the study by, two proportional mortality studies and two prospective cohort studies. Occupational studies failed to fulfill most prespecified quality criteria (Appendix B).

14Relative risk estimates across occupational studies varied widely, with positive, inverse, and null associations (Table 3). Several studies reported the associations among workers with the heaviest exposure, by year of hire, and incorporating a latency period. In two of the three studies that reported associations by duration of employment, coronary heart disease and stroke mortality were higher among workers with the highest number of years of employment.

15Five studies evaluated ventricular wall dimensional and functional parameters (Table 4). Increased blood lead levels were associated with an increased prevalence of left ventricular hypertrophy in U.S. adults and with a nonstatistically significant increase in left ventricular mass in U.S. battery workers. Similarly, Polish steel workers had higher left ventricular mass and lower ejection fraction compared to administrative workers from the same factory, and lead-exposed Polish workers had impaired diastolic function compared with nonexposed controls. Chinese refinery workers with blood lead levels > 50 μg/dL had similar interventricular septum and left ventricular wall thickness compared to workers < 50 μg/dL, although lead levels in the reference category are unknown.

16Ten studies measured heart rate variability among lead-exposed workers, and one study measured heart rate variability in Seoul, Korea, public officials not occupationally exposed to lead (Table 4). Most of these studies had limitations in terms of sample size, methods of lead assessment, and lack of adjustment for potential confounders (Table 4; Appendix C). The conditions for electrocardiographic ascertainment and the heart rate variability indices differed widely across studies, making comparisons difficult. The coefficient of variation of the R-R interval was lower in lead-exposed workers compared with other workers in two of five studies in which the coefficient of variation was measured under normal breathing, and in one of three studies in which it was assessed during deep breathing. Among Seoul public officials, increased lead levels were inversely associated with measures of low frequency, high frequency, and total power spectrum in uni-variate analyses, but adjusted results were not presented because lead exposure was dropped from the stepwise regression models used.

17Fifteen studies reported the association of lead with other electrocardiographic parameters and one study with other vascular abnormalities. All studies, except the Normative Aging Study, were conducted in occupational populations in Europe. These types of outcome, including rhythm disorders, ischemic changes and cycle duration, varied widely across studies, and the findings were inconsistent. The Normative Aging Study measured lead in blood, tibia, and patella and identified associations between tibia lead and intraventricular conduction defects (QRS duration) and increased QT duration in subjects < 65 years of age.

18Finally, heart rate was evaluated using different methods in five studies, four in lead-exposed workers and one in elderly men from the Netherlands, with inconsistent findings.

19Chronic lead poisoning was connected to hypertension in the 19th century. With rare exceptions, a major limitation of early reports was the lack of a comparison group. The hypertensive effects of lead have been extensively documented in experimental animals chronically exposed to high lead concentrations and in workers chronically exposed to high lead levels. Generally, the development of hypertension in subjects chronically exposed to high lead levels has been interpreted as a possible consequence of lead nephropathy. At environmental levels of exposure, however, the effect of lead on blood pressure has been controversial. Numerous studies have addressed this question. All reviews have concluded that there is an association between lead and blood pressure, although the strength of this association is modest (Table 1). Substantial evidence, however, implies that this relationship is causal.

20The association between lead exposure and blood pressure has been found in populations with different geographic, ethnic, and socioeconomic background. While residual confounding by socioeconomic status is a concern, studies in homogenous samples and studies that have adjusted for a variety of socioeconomic indicators have still identified an association between lead exposure and blood pressure.

21The association between blood lead and elevated blood pressure has been identified not only in cross-sectional but also in prospective studies that showed that new cases of hypertension and within-person elevations in blood pressure levels over follow-up were related to baseline lead exposure.

22While the strength of the association between lead and blood pressure is modest, it may have been substantially underestimated because of measurement error in both lead and blood pressure determinations. Most studies used single blood lead measurements to assess lead exposure. When bone lead was used as a bio-marker of long-term exposure, lead in cortical or trabecular bone was positively associated with increased systolic blood pressure or hypertension in all prospective and cross-sectional studies. Furthermore, even bone lead is subject to error derived from the sampling site and from the technical difficulties of the measurement. In addition, blood pressure measurements were often conducted using nonstandardized protocols, without repeated measures, or in samples including hypertensive subjects.

23Some studies have demonstrated a progressive dose–response relationship between lead exposure and blood pressure. However, the shape of the dose–response relationship is not completely characterized, particularly at low levels of exposure. It is not known what is the lowest level of lead exposure not associated with blood pressure, although in the available studies there seems to be no evidence of a threshold effect.

24Numerous experimental studies in animals have shown irrefutable evidence that chronic exposure to low lead levels results in arterial hypertension that persists long after the cessation of lead exposure. The precise mechanisms explaining a hypertensive effect of low chronic exposure to environmental lead are unknown. An inverse association between estimated glomerular filtration rate and blood lead has been observed at blood lead levels < 5 μg/dL in general population studies, indicating that lead-induced reductions in renal function could play a major role in hypertension. Other potential mechanisms include enhanced oxidative stress, stimulation of the renin-angiotensin system, and down-regulation of nitric oxide and soluble guanylate cyclase. These mechanisms could result in increased vascular tone and peripheral vascular resistance.

25We conclude that the evidence is sufficient to infer a causal relationship between lead exposure and high blood pressure. Further research is still needed to determine the precise dose–response relationship, the relative importance of short-term versus chronic lead effects, the relevant mechanisms at environmental levels of exposure, and whether the magnitude of the association is different in children or in other vulnerable population subgroups.

26Few cohort studies have evaluated the prospective association of lead with clinical cardiovascular outcomes in general population settings. The findings of the NHANES II and NHANES III Mortality Follow-up studies are remarkable. NHANES are periodic, standardized surveys designed to provide representative health data from the U.S. noninstitutionalized population. Despite a marked decline in lead levels in U.S. adults, both surveys showed statistically significant increases in cardiovascular mortality with increasing blood lead. In addition a cross-sectional analysis of NHANES 1999–2002 data identified an association of blood lead with the prevalence of peripheral arterial disease. The British Regional Heart Study and two other small cohort studies showed positive but nonstatistically significant associations of coronary heart disease or stroke incidence with higher lead levels. The confidence intervals from these studies were wide but included the point estimates of the NHANES studies. Additional studies are needed to determine the consistency of the evidence in diverse populations.

27The associations of blood lead with clinical cardiovascular end points in the NHANES studies were moderately strong, with a clear dose–response gradient. An unresolved issue is the impact of uncontrolled confounding and measurement error on the relative risk estimates in studies of lead and clinical cardiovascular end points. NHANES studies adjusted for race, education, income, and urban versus rural location, which reduces potential confounding by socioeconomic status. Studies with more detailed information on the determinants of lead exposure may contribute to a better understanding of this issue. Similarly, evaluating lead effects using a single blood lead measure may result in measurement error with substantial underestimation of the magnitude of the association. This is particularly problematic when there are marked temporal trends in lead levels, as this source of error adds to within-person variability in blood lead levels to increase regression-dilution bias.

28Lead levels of 0.8 ppm and 0.1 ppm in drinking water induced atherosclerosis in animal models, and lead levels of 0.5–10 μM induced the proliferation of vascular smooth cells and fibroblasts in in vitro models. Lead-related atherosclerosis could be explained by several mechanisms, including increases in blood pressure, impairment of renal function, and induction of oxidative stress, inflammation, and endothelial dysfunction.

29Because of the scarce number of prospective studies and the lack of information on incident nonfatal events, we conclude that the evidence is suggestive but not sufficient to infer a causal relationship with clinical cardiovascular end points. Prospective studies are required to characterize fully the impact of lead on cardiovascular morbidity and mortality. These studies need detailed and repeated assessment of lead exposure and its determinants, standardized assessment of traditional cardiovascular risk factors, and long-term follow-up to identify incident cardiovascular events and trends in subclinical markers of atherosclerosis. Although elevated blood pressure and impaired renal function are proposed mechanisms that mediate the effects of lead on clinical cardiovascular outcomes, other mechanisms are likely to be involved. Future epidemiologic studies should explore in detail the magnitude of the contribution of specific mediators of clinical cardiovascular lead effects.

30The validity of occupational studies of lead and cardiovascular mortality is limited by several methodologic problems. A major limitation is the healthy worker effect. The comparison of exposed workers with the general population is particularly inappropriate for cardiovascular mortality because workers are healthier and their lifestyles and cardiovascular risk factors are likely to differ widely from those of the general population. In addition, cardiovascular diseases are associated with prolonged disability and changes in employment status. Even in studies based on comparisons with unexposed workers, the selection of healthier individuals at time of hire or for specific jobs within an industry may have resulted in biased estimates of the association. Correcting the bias introduced by the healthy worker survivor effect is extremely challenging, and stratifying by duration of employment or time since hire is unlikely to completely account for this source of bias.

31Additional limitations include the assignment of lead exposure based on job titles and of cardiovascular deaths based on death certificates. Misclassification of exposure and outcome may have resulted in further underestimation of the association of lead and cardiovascular end points. Finally, the lack of determinations of established cardiovascular risk factors and of other occupational exposures may have contributed to uncontrolled confounding.

32As a result of these methodologic limitations, and despite many occupational cohort studies published in the literature (Table 3), available information on occupational lead exposure and cardiovascular mortality is inadequate to infer the presence or absence of a causal relationship. Because studies of environmental lead exposure provide evidence of an association between lead and cardiovascular mortality at lower exposures than those experienced by occupationally exposed workers, we expect the impact of lead in exposed workers to be at least as important as in environmentally exposed subjects.

33Several studies, mostly cross-sectional, found an association between increased lead exposure and decreased heart rate variability. The diversity in the methods and conditions used for measuring heart rate variability makes it difficult to compare the association of lead exposure and heart rate variability across studies. In addition, the validity and precision of these studies are often limited by small sample sizes, limitations in the assessment of lead exposure, and lack of control for established cardiovascular risk factors and other confounders.

34Lead, a well-established neurotoxicant, could affect heart rate variability by interfering in autonomic nervous control of the heart. Heart rate variability measures the fluctuation of the heart rate around the mean heart rate. Because the basis of normal cardiac autonomic functioning is the shift from parasympathetic to sympathetic modulation, decreased heart rate variability is a marker of cardiac autonomic dysfunction. Indeed, decreased heart rate variability in supine position and in response to postural change has been associated with increased incident coronary heart disease and all-cause mortality in large prospective cohort studies in populations free of cardiovascular disease.

35We conclude that the evidence is suggestive of but not sufficient to infer a causal relationship of lead exposure with heart rate variability. Large studies with adequate measures of lead exposure and of heart rate variability are needed to better characterize the association between lead exposure and autonomic cardiac control.

36The evidence in this systematic review is sufficient to infer a causal relationship of lead exposure with elevated blood pressure, and it is suggestive of but not sufficient to infer a causal relationship of lead with clinical cardiovascular outcomes and cardiovascular function tests. These associations have been observed at blood lead levels well below 5 μg/dL. Indeed, no lower threshold has been established for any lead-cardiovascular association.

37Although future research will contribute to characterize fully the impact of lead exposure on cardiovascular health, these findings have several important public health implications. First, there is an immediate need to lower the current safety standard of the World Health Organization and the U.S. Occupational Safety and Health Administration for blood lead in workers (currently established at 40 μg/dL). Second, a criterion for elevated blood lead levels in adults needs to be established and screened for in preventive services. In fact, the cardiovascular end points described above plus the substantial evidence that chronic lead exposure affects cognitive function and renal function at levels < 5 μg/dL indicate that the U.S. Centers for Disease Control and Prevention criterion for elevated blood levels in children (10 μg/dL) is too high for adults. Third, the hypertensive effects of lead exposure and its impact on cardiovascular mortality need to be included in risk assessment and in economic analyses of lead exposure impact. Finally, regulatory and public health interventions must be developed and implemented to prevent and reduce lead exposure beyond current levels in adults.