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Lead exposure and cardiovascular disease--a systematic review.

OBJECTIVE: This systematic review evaluates the evidence on the association between lead exposure and cardiovascular end points in human populations.

METHODS: We reviewed all observational studies from database searches and citations regarding lead and cardiovascular end points.

RESULTS: A positive association of lead exposure with blood pressure has been identified in numerous studies in different settings, including prospective studies and in relatively homogeneous socioeconomic status groups. Several studies have identified a dose-response relationship. Although the magnitude of this association is modest, it may be underestimated by measurement error. The hypertensive effects of lead have been confirmed in experimental models. Beyond hypertension, studies in general populations have identified a positive association of lead exposure with clinical cardiovascular outcomes (cardiovascular, coronary heart disease, and stroke mortality; and peripheral arterial disease), but the number of studies is small. In some studies these associations were observed at blood lead levels < 5 [micro]g/dL.

CONCLUSIONS: We conclude that the evidence is sufficient to infer a causal relationship of lead exposure with hypertension. We conclude that the evidence is suggestive but not sufficient to infer a causal relationship of lead exposure with clinical cardiovascular outcomes. There is also suggestive but insufficient evidence to infer a causal relationship of lead exposure with heart rate variability.

PUBLIC HEALTH IMPLICATIONS: These findings have immediate public health implications. Current occupational safety standards for blood lead must be lowered and a criterion for screening elevated lead exposure needs to be established in adults. Risk assessment and economic analyses of lead exposure impact must include the cardiovascular effects of lead. Finally, regulatory and public health interventions must be developed and implemented to further prevent and reduce lead exposure.

KEY WORDS: atherosclerosis, blood pressure, cardiovascular disease, heart rate variability, hypertension, lead, systematic review. Environ Health Perspect 115:472-482 (2007). doi:10.1289/ehp.9785 available via http://dx.doi.org/ [Online 22 December 2006]

Background

Cardiovascular disease is the leading cause of mortality and a primary contributor to the burden of disease worldwide (Lopez et al. 2006). Environmental toxicants, including lead and other metals, are potentially preventable exposures that may explain population variation in cardiovascular disease rates (Bhatnagar 2006; Weinhold 2004). However, after more than 100 years since initial reports suggested a link between lead exposure and cardiovascular outcomes (Lancereaux 1881; Lorimer 1886), the contribution of lead to cardiovascular disease is still incompletely understood.

Population 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 [Hertz-Picciotto and Croft 1993; Nawrot et al. 2002; Schwartz 1995; Sharp et al. 1987; Staessen et al. 1994, 1995; U.S. Environmental Protection Agency (U.S. EPA) 2006]. 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 [micro]g/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 (U.S. EPA 2006). 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.

The 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 (Lustberg and Silbergeld 2002; Menke et al. 2006; Navas-Acien et al. 2004; Schober et al. 2006), and with other cardiovascular function abnormalities such as left ventricular hypertrophy and alterations in cardiac rhythm (Cheng et al. 1998; Schwartz 1991).

In 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 [U.S. Department of Health and Human Services (U.S. DHHS) 2004] to the available information.

Methods

Search strategy and data abstraction. We 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.

For 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.

We 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.

We adapted the criteria used by Longnecker et al. (1988) to assess study quality for studies of clinical end points and the criteria used by Appel et al. (2002) to assess study quality for studies of intermediate end points (Appendices B and C).

Statistical methods. Measures 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 (Greenland 1987). For studies reporting measures of association for population subgroups (Cooper et al. 1985; Malcolm 1971), we pooled the measures of association using an inverse-variance weighted random-effects model (Egger et al. 2001).

Because 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.

Results

Lead and clinical cardiovascular disease in general populations. Twelve studies met our inclusion criteria (Table 2). Lead was measured in blood in all the prospective cohort studies (Kromhout 1988; Lustberg and Silbergeld 2002; Menke et al. 2006; Moller and Kristensen 1992; Pocock et al. 1988) and in the only cross-sectional study available (Muntner et al. 2005). 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 (Kosmala et al. 2004), plasma (Mansoor et al. 2000), and urine (Pan et al. 1993; Tsai et al. 2004), on a job exposure matrix (Gustavsson et al. 2001), and on lead levels in the air of the residential neighborhood of study participants (Dulskiene 2003). 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).

Lead 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 [micro]g/dL versus < 12.4 [micro]g/dL in the British Regional Heart Study (Pocock et al. 1988) and 1.89 comparing blood lead levels [grater than or equal to] 3.63 [micro]g/dL versus < 1.93 [micro]g/dL in the National Health and Nutrition Examination Survey (NHANES) III Mortality Follow-up Study (Menke et al. 2006). 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 [grater than or equal to] 2.47 [micro]g/dL versus < 1.03 [micro]g/dL in a cross-sectional analysis of NHANES 1999-2002 was 1.92 (Muntner et al. 2005).

Lead and cardiovascular mortality in occupational populations. Eighteen studies from the United States (Cooper et al. 1985; Michaels et al. 1991; Robinson 1974; Sheffet et al. 1982; Steenland et al. 1992; Tollestrup et al. 1995), Europe (Alexieva et al. 1981; Belli et al. 1989; Carta et al. 2003; Cocco et al. 1997, 1994; Davies 1984; Dingwall-Fordyce and Lane 1963; Gerhardsson et al. 1995; Lundstrom et al. 1997; Malcolm 1971; Wilczynska et al. 1998), and Australia (McMichael and Johnson 1982) 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 Dingwall-Fordyce and Lane (1963), two proportional mortality studies (Alexieva et al. 1981; McMichael and Johnson 1982) and two prospective cohort studies (Robinson 1974; Tollestrup et al. 1995). Occupational studies failed to fulfill most prespecified quality criteria (Appendix B).

Relative 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 (Dingwall-Fordyce and Lane 1963; Lundstrom et al. 1997; Malcolm and Barnett 1982; Steenland et al. 1992), by year of hire (Cooper et al. 1985; Lundstrom et al. 1997), and incorporating a latency period (Lundstrom et al. 1997). In two of the three studies that reported associations by duration of employment, coronary heart disease (Steenland et al. 1992) and stroke (Michaels et al. 1991) mortality were higher among workers with the highest number of years of employment.

Lead and intermediate cardiovascular outcomes. Five studies evaluated ventricular wall dimensional and functional parameters (Beck and Steinmetz-Beck 2005; Kasperczyk et al. 2005; Schwartz 1991; Tepper et al. 2001; Zou et al. 1995) (Table 4). Increased blood lead levels were associated with an increased prevalence of left ventricular hypertrophy in U.S. adults (Schwartz 1991) and with a nonstatistically significant increase in left ventricular mass in U.S. battery workers (Tepper et al. 2001). Similarly, Polish steel workers had higher left ventricular mass and lower ejection fraction compared to administrative workers from the same factory (Kasperczyk et al. 2005), and lead-exposed Polish workers had impaired diastolic function compared with nonexposed controls (Beck and Steinmetz-Beck 2005). Chinese refinery workers with blood lead levels > 50 [micro]g/dL had similar interventricular septum and left ventricular wall thickness compared to workers < 50 [micro]g/dL (Zou et al. 1995), although lead levels in the reference category are unknown.

Ten studies measured heart rate variability among lead-exposed workers (Andrzejak et al. 2004; Bckelmann et al. 2002; Gajek et al. 2004; Gennart et al. 1992; Ishida et al. 1996; Murata et al. 1995; Murata and Araki 1991; Muzi et al. 2005; Niu et al. 1998; Teruya et al. 1991), and one study measured heart rate variability in Seoul, Korea, public officials not occupationally exposed to lead (Jhun et al. 2005) (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 (Jhun et al. 2005), increased lead levels were inversely associated with measures of low frequency, high frequency, and total power spectrum in univariate analyses, but adjusted results were not presented because lead exposure was dropped from the stepwise regression models used.

Fifteen studies reported the association of lead with other electrocardiographic parameters (Cheng et al. 1998; Gatagonova 1995a, 1995c; Kirkby and Gyntelberg 1985; Kosmider 1968; Kosmider and Petelenz 1961, 1962; Kosmider et al. 1965; Kromhout et al. 1985; Krotkiewski et al. 1964; Saric 1981; Shcherbak 1988; Sroczynski et al. 1990, 1985; Stozinic and Colakovic 1980) and one study with other vascular abnormalities (Aiba et al. 1999). All studies, except the Normative Aging Study (Cheng et al. 1998), 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 (Cheng et al. 1998).

Finally, heart rate was evaluated using different methods in five studies, four in lead-exposed workers (Bckelmann et al. 2002; Kosmider and Petelenz 1961; Murata et al. 1995; Zou et al. 1995) and one in elderly men from the Netherlands (Kromhout et al. 1985), with inconsistent findings.

Discussion

Lead exposure and hypertension--sufficient evidence to infer a causal relationship. Chronic lead poisoning was connected to hypertension in the 19th century (Lorimer 1886). With rare exceptions (Vigdortchik 1935), a major limitation of early reports was the lack of a comparison group (Sharp et al. 1987). 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 (Agency for Toxic Substances and Disease Registry 1999; U.S. EPA 2006). 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.

Consistency. The 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 (Martin et al. 2006; Pocock et al. 1984).

Temporality. The 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 (Glenn et al. 2003; Moller and Kristensen 1992; Weiss et al. 1986).

Strength of the association. While 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 biomarker of long-term exposure (Hu et al. 2007), lead in cortical or trabecular bone was positively associated with increased systolic blood pressure or hypertension in all prospective (Cheng et al. 2001; Glenn et al. 2003) and cross-sectional studies (Gerr et al. 2002; Hu et al. 1996; Korrick et al. 1999; Lee et al. 2001; Martin et al. 2006; Rothenberg et al. 2002; Schwartz and Stewart 2000). 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.

Biologic gradient (dose response). Some studies have demonstrated a progressive dose-response relationship between lead exposure and blood pressure (Pocock et al. 1984; Schwartz 1988; Weiss et al. 1986). 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 (Hertz-Picciotto and Croft 1993; Schwartz et al. 2001).

Biologic plausibility and experimental data. Numerous 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 (U.S. EPA 2006). 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 [micro]g/dL in general population studies (Ekong et al. 2006; Muntner et al. 2005), indicating that lead-induced reductions in renal function could play a major role in hypertension. Other potential mechanisms include enhanced oxidative stress (Stohs and Bagchi 1995; Vaziri et al. 2001), stimulation of the renin-angiotensin system (Carmignani et al. 1999; Rodriguez-Iturbe et al. 2005), and down-regulation of nitric oxide (Ding et al. 1998; Dursun et al. 2005) and soluble guanylate cyclase (Farmand et al. 2005). These mechanisms could result in increased vascular tone and peripheral vascular resistance (U.S. EPA 2006).

Causal inference. We 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.

Clinical cardiovascular end points in general populations. Consistency and temporality. Few 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 (Lustberg and Silbergeld 2002; Schober et al. 2006). In addition a cross-sectional analysis of NHANES 1999-2002 data identified an association of blood lead with the prevalence of peripheral arterial disease (Muntner et al. 2005; Navas-Acien et al. 2004). The British Regional Heart Study (Pocock et al. 1988) and two other small cohort studies (Kromhout 1988; M?ller and Kristensen 1992) 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.

Strength of the association and dose response. The 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.

Biologic plausibility and experimental data. Lead levels of 0.8 ppm (Revis et al. 1981) and 0.1 ppm (Minaii et al. 2002) in drinking water induced atherosclerosis in animal models, and lead levels of 0.5-10 [micro]M induced the proliferation of vascular smooth cells and fibroblasts in in vitro models (Fujiwara et al. 1995). Lead-related atherosclerosis could be explained by several mechanisms, including increases in blood pressure, impairment of renal function (Ekong et al. 2006), and induction of oxidative stress (Stohs and Bagchi 1995; Vaziri et al. 2001), inflammation (Heo et al. 1996), and endothelial dysfunction (Vaziri et al. 2001).

Causal inference. Because 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.

Cardiovascular mortality in occupational populations. Adequacy of the evidence. The validity of occupational studies of lead and cardiovascular mortality is limited by several methodologic problems. A major limitation is the healthy worker effect (Arrighi and Hertz-Picciotto 1994). 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 (Choi 1992). 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 (Arrighi and Hertz-Picciotto 1994; Howe et al. 1988).

Additional 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.

Causal inference. As 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.

Lead exposure and heart rate variability. Consistency, temporality, and strength of the association. Several 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.

Biologic plausibility and experimental data. Lead, a well-established neurotoxicant, could affect heart rate variability by interfering in autonomic nervous control of the heart (Chang et al. 2005). Heart rate variability measures the fluctuation of the heart rate around the mean heart rate (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology 1996). 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 (Liao et al. 1997; Tsuji et al. 1996).

Causal inference. We 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 standardized assessment of heart rate variability are needed to better characterize the association between lead exposure and autonomic cardiac control.

Public health implications. The 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 [micro]g/dL (Menke et al. 2006; Nawrot and Staessen 2006). Indeed, no lower threshold has been established for any lead-cardiovascular association.

Although 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 [micro]g/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 (Shih et al. 2007) and renal function (Ekong et al. 2006) at levels < 5 [micro]g/dL indicate that the U.S. Centers for Disease Control and Prevention criterion for elevated blood levels in children (10 [micro]g/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.

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Ana Navas-Acien, (1) Eliseo Guallar, (2,3) Ellen K. Silbergeld, (1) and Stephen J. Rothenberg (4,5)

(1) Department of Environmental Health Sciences, and (2) Departments of Epidemiology and Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA; (3) Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA; (4) Centro de Investigacion y de Estudios Avanzados--Instituto Politecnico Nacional (CINVESTAV-IPN), Merida, Yucatan, Mexico; (5) Instituto Nacional de Salud Publica, Cuernavaca, Morelos, Mexico

This article is part of the mini-monograph "Lead Exposure and Health Effects in Adults: Evidence, Management, and Implications for Policy."

Address correspondence to S. Rothenberg, Departamento, Ecologia Humana, Centro de Investigacion y de Estudios Avanzados--Instituto Politecnico Nacional (CINVESTAV-IPN), Carretera Antigua a Progreso km 6, 97310 Merida, Yucatan, Mexico. Telephone: 52 999 124 2109. Fax: 52 739 395 0662. E-mail: srothenberg@mda.cinvestav.mx

We thank J.M. Samet for his comments to a previous version of this manuscript.

A.N-A. was supported by grant P30 ES 03819 from the National Institute of Environmental Health Sciences Center in Urban Environmental Health.

The authors declare they have no competing financial interests.

Received 3 October 2006; accepted 20 December 2006.
Table 1. Reviews of the association between blood lead levels and blood
pressure.

 Year of
 No. of publication Language
 studies of studies of literature
First author, year Type (a) included (range) search

Sharp et al. 1987 Review 4 1982-1986 English, French
Hertz-Picciotto Review 13 1980-1992 English
 and Croft 1993
Staessen et al. SR, MA 23 1980-1993 English, French,
 1994, 1995 German
Schwartz 1995 SR, MA 15 1985-1993 English
ATSDR 1999 SR 24 1980-1996 No language
 restriction
Nawrot et al. 2002 SR, MA 31 1980-2001 English, French,
 German
U.S. EPA 2006 SR, MA 9 1990-2003 English
 10

 Total Age range of
 no. of participants
First author, year subjects (years) Comparison

Sharp et al. 1987 8,406 24-59 Per 2-fold [up arrow] (b)
Hertz-Picciotto 22,923 12-80 [not equal to] for each
 and Croft 1993 study
Staessen et al. 33,141 10-88 Per 2-fold [up arrow]
 1994, 1995
Schwartz 1995 NR 18-76 Per 2-fold [up arrow] (b)
 Men only
ATSDR 1999 NR All ages [not equal to] for each
 study
Nawrot et al. 2002 58,518 10-90 Per 2-fold [up arrow]
U.S. EPA 2006 27,424 14-93 Per 2-fold [up arrow]
 34,740

 Pooled estimate
 [change in mmHg
First author, year Outcome (95% CI)]

Sharp et al. 1987 SBP --

Hertz-Picciotto SBP --
 and Croft 1993 DBP --
 Hypertension --
Staessen et al. SBP 1.0 (0.4-1.6)
 1994, 1995 DBP 0.6 (0.2-1.0)
Schwartz 1995 SBP 1.25 (0.87-1.63)
ATSDR 1999 SBP --
 DBP --
 Hypertension --
Nawrot et al. 2002 SBP 1.0 (0.5-1.4)
 DBP 0.6 (0.4-0.8)
U.S. EPA 2006 SBP 0.81 (0.46-1.16) (c)
 DBP --

 Median of estimates
 [change in mmHg Conclusions as
First author, year (range)] reported by authors

Sharp et al. 1987 1.9 (0.7 to 2.3) Evidence consistent with
 causation
Hertz-Picciotto 2.0 (-5.9 to 8.0) Evidence strongly
 and Croft 1993 1.7 (-1.6 to 4.0) supports causal
 RR: 1.4 (1.2 to 1.7) association
Staessen et al. 1.0 (-3.0 to 14.0) MA suggests a weak
 1994, 1995 1.0 (-2.0 to 13.0) association
Schwartz 1995 1.45 (0.2 to 3.2) MA consistent with
 causal association
ATSDR 1999 NR Suggestion of [up arrow]
 NR blood pressure, but
 NR evidence is inconclusive
Nawrot et al. 2002 1.0 (-5.0 to 14.0) MA suggests a weak
 1.0 (-2.0 to 14.0) association
U.S. EPA 2006 1.0 (-3.9 to 11) MA suggests an effect
 1.0 (-1.3 to 7.3) of blood lead on SBP

Abbviations: [not equal to], different; [up arrow], increase; CI,
confidence interval; DBP, diastolic blood pressure; MA, meta-analysis;
NHANES, National Health and Nutrition Examination Survey; NR, not
reported; RR, relative risk; SBP, systolic blood pressure; SR,
systematic review; U.S. DHHS, U.S. Department of Health and Human
Services; U.S. EPA, U.S. Environmental Protection Agency.
(a) Systematic review: a search strategy and criteria for manuscript
selection are specified. Meta-analysis: a pooled analysis using meta-
analysis techniques are presented. (b) In the study by Sharp et al.
(1987), we divided by 3 the change per 15 [micro]g/dL (equivalent to
comparing 10 [micro]g/dL vs. 5 [micro]g/dL). The study by Schwartz
et al. (1995) reports the change in mmHg comparing 10 [micro]g/dL vs. 5
[micro]g/dL. (c) Pooled estimate using an inverse variance weighted
random-effects model (Egger et al. 2001) of two pooled estimates for
linear and log-linear estimates, respectively.

Table 2. Epidemiologic studies of lead exposure and clinical
cardiovascular disease in general populations.

First author, Men
year Country Population (%)

Prospective cohort studies
 Pocock et al. U.K. British Regional 100
 1988 Heart Study
 Kromhout 1988 Netherlands Elderly men in Zutphen 100
 Moller and Denmark Survey repondents 48
 Kristensen 4 municipalities
 1992
 Lustberg and U.S. NHANES II 47
 Silbergeld
 2002
 Menke et al. U.S. NHANES III 47
 2006(AAS)

Case-control and cross-sectional studies
 Pan et al. Taiwan Clinic-based 69
 1993
 Mansoor et Sweden Clinic-based 53
 al. 2000
 Gustavsson et Sweden SHEEP Study 68
 al. 2001
 Dulskiene Lithuania Clinic-based 100
 2003
 Tsai et al. Taiwan Clinic-based 57
 2004
 Kosmala et Poland Clinic-based 53
 al. 2004
 Muntner et U.S. NHANES 1999-2002 47
 al. 2005

First author, Age range Lead
year (years) assessment

Prospective cohort studies
 Pocock et al. 40-49 Blood (AAS)
 1988
 Kromhout 1988 57-76 Blood (AAS)
 Moller and 40 Blood (AAS)
 Kristensen
 1992
 Lustberg and 30-74 Blood (AAS)
 Silbergeld
 2002
 Menke et al. [greater than or equal to] 17 Blood (AAS)
 2006

Case-control and cross-sectional studies
 Pan et al. NR Urine (DPASV)
 1993
 Mansoor et Mean Plasma (TRXFS)
 al. 2000 46
 Gustavsson et 45-70 JEM
 al. 2001
 Dulskiene 25-64 Airborne
 2003
 Tsai et al. NR Urine (AAS)
 2004
 Kosmala et Mean Blood (AAS)
 al. 2004 62
 Muntner et [greater than or equal to] 40 Blood (AAS)
 al. 2005

First author, Range of End point
year lead levels ascertainment

Prospective cohort studies
 Pocock et al. < 6.2 to > 35.2 Death certificate or chest
 1988 [micro]g/dL pain, inzyme, ECG (a)
 Death certificate medica record
 Kromhout 1988 < 10.8 (10th p) > 28.0 Death certificate, or chest
 (90th p) [micro]g/dL pain, enzyme, ECG (a)
 Moller and 2 to 60 [micro]g/dL Death certificate hospital
 Kristensen admissions
 1992
 Lustberg and < 10 to 29 [micro]g/dL Death certificate
 Silbergeld
 2002
 Menke et al. < 1 to 10 [micro]g/dL Death certificate
 2006 (AAS)

Case-control and crosssectional studies
 Pan et al. 7.9 to 138.4 NR
 1993 [micro]g/L
 Mansoor et Mean Angiograms
 al. 2000 3.3 ng/g plasma
 Gustavsson et NM Chest pain, ECG enzyme (a)
 al. 2001
 Dulskiene NM Medical records
 2003
 Tsai et al. 5.3 to 123.6 NR
 2004 [micro]g/L
 Kosmala et Mean Coronariography, treadmill
 al. 2004 3.9 [micro]g/dL exercise text
 Muntner et < 0.3 to > 10 Ankle-brachial BP index
 al. 2005 (98th p)
 [micro]g/dL

First author, No. of cases/ Measure of (b)
year Outcome noncases association

Prospective cohort studies
 Pocock et al. CHD, F + NF 316/7,063 OR 1.1 (0.4-1.8)
 1988
 Stroke, 66/7,313 Mean 16.7 [micro]g/dL
 F + NF Mean 15.3 [micro]g/dL
 Kromhout 1988 CHD, F + NF 26/115 HR 1.34 (0.46-3.94)
 Moller and CHD, F + NF 40/1,005 HR 1.58 (0.85-2.95)
 Kristensen CVD, F + NF 54/991 HR 1.10 (0.63-1.93)
 1992
 Lustberg and CVD, F 424/3,766 HR 1.39 (1.01-1.91)
 Silbergeld
 2002
 Menke et al. CVD, F 766/13,198 HR 1.55 (1.08-2.24)
 2006 CHD, F 367/13,597 HR 1.89 (1.04-3.43)
 Stroke, F 141/13,823 HR 2.51 (1.20-5.26)

Case-control and crosssectional studies
 Pan et al. BFD prev. 16/16 30.8 (30.1) [micro]g/L
 1993 17.4 (5.4) [micro]g/L
 Mansoor et PAD prev. 65/65 3.3 (0.4) ng/g plasma
 al. 2000 3.2 (0.3) ng/g plasma
 Gustavsson et AMI inc., 1,335/1,658 OR 1.03 (0.64-1.65)
 al. 2001 NF
 Dulskiene AMI 579/1,777 OR 1.12 (0.76-1.40)
 2003
 Tsai et al. BFD prev. 68/68 33.7 (24.3) [micro]g/L
 2004 22.2 (11.8) [micro]g/L
 Kosmala et Effort angina 33/18 3.9 (1.4) [micro]g/dL
 al. 2004 3.7 (1.2) [micro]g/dL
 Muntner et PAD prev. NR OR 1.92 (1.02-3.61)
 al. 2005

First author,
year Comparison Adjusted for (c)

Prospective cohort studies
 Pocock et al. > 24.8 vs. < 12.4 [micro]g/dL Age, smoking,
 1988 location
 Cases vs. noncases Age, smoking,
 location
 Kromhout 1988 > 23.8 vs. < 13.0 [micro]g/dL Age, smoking, BMI,
 BP, cholesterol
 Moller and Per log unit change Sex, smoking,
 Kristensen alcohol, BP,
1992 cholesterol,
 exercise
 Lustberg and 20-29 vs. < 10 [micro]g/dL Age, sex, race,
 Silbergeld educ., income,
 2002 smoking, BMI,
 exercise, location
 Menke et al. < 1.93 vs. Age, sex, race,
 2006 [greater than or equal to] 3.63 educ., income,
 [micro]g/dL smoking, alcohol,
 BMI, exercise,
 cholesterol, CRP,
 urban residence,
 menopause,
 hypertension,
 kidney function

Case-control and crosssectional studies
 Pan et al. Cases vs. noncases Age, sex
 1993
 Mansoor et Cases vs. noncases Age, sex
 al. 2000
 Gustavsson et [greater than or equal to] 0.04 Age, sex, smoking,
 al. 2001 mg/[m.sup.3] vs. unexp. alcohol, BP, BMI,
 exercise, location
 Dulskiene > 0.225 vs. Age, sex, smoking,
 2003 [less than or equal to] 0.225 BP
 [micro]g/[m.sup.3]
 Tsai et al. Cases vs. noncases Age, sex
 2004
 Kosmala et Cases vs. noncases Crude
 al. 2004

 Muntner et [greater than or equal to] 2.47 Age, sex, race,
 al. 2005 vs. < 1.06 [micro]g/dL educ., insurance,
 smoking, alcohol,
 BMI, diabetes

Abbreviations: AAS, atomic absorption spectrometry; AMI, acute
myocardial infarction; BFD, black foot disease, a form of peripheral
arterial disease endemic in the arseniasis areas of southwestern Taiwan;
BMI, body mass index; BP, blood pressure levels or hypertension; CHD,
coronary heart disease; CI, confidence interval; CVD, cardiovascular
disease; DPASV, differential pulse anodic stripping voltammetry; ECG,
electrocardiogram; educ., education; F, fatal; F+NF, fatal and nonfatal;
HR, hazard ratio; inc., incidence; JEM, job exposure matrix; NF,
nonfatal; NHANES, National Health and Nutrition Examination Survey; NM,
not measured; NR, not reported; OR, odds ratio; PAD, peripheral arterial
disease; p, percentile; prev, prevalence; SHEEP, Stockholm Heart
Epidemiology Study; TRXFS, total-reflection X-ray fluorescence
spectrometry; unexp., unexposed.
(a) Standard World Health Organization criteria for myocardial
infarction. (b) For studies that categorized lead exposure, we report
the HR or OR (with 95% CI in parentheses) comparing the highest with the
lowest lead category. Otherwise, we present the mean (SD) lead levels
for cases and noncases. (c) Blood pressure-unadjusted relative risk is
as follows: a) Menke (2006): cardiovascular mortality 1.64, coronary
heart disease mortality 2.01, stroke mortality 2.61; b) Gustavsson
(2001): acute myocardial infarction 1.17.

Table 3. Epidemiologic studies of cardiovascular mortality in
occupational populations exposed to lead.

First author, year Country Population Men (%)

Prospective cohort studies
 Robinson 1974 U.S. Tetraethyl lead production 100
 workers
 Tollestrup et al. U.S. Orchard workers (lead arsenate) 66
 1995

Retrospective cohort studies
 Dingwall-Fordyce U.K. Lead pensioners and workers 100
 and Lane 1963
 Malcolm 1971, U.K. Lead battery and smelter 99
 Malcolm and pensioners and workers
 Barnett 1982
 Sheffet et al. U.S. Pigment plant workers 100
 1982
 Davies 1984 U.K. Pigment plant workers 100
 Pigment plant workers + lead 100
 poisoning
 Cooper et al. U.S. Lead battery and producing 100
 1985 workers
 Belli et al. 1989 Italy Lead miners 100
 Michaels et al. U.S. Newspaper print workers 100
 1991
 Steenland et al. U.S. Smelter workers 100
 1992
 Cocco et al. 1994 Italy Lead miners 100
 Gerhardsson et Sweden Smelter workers 100
 al. 1995
 Lundstrom et al. Sweden Smelter workers 100
 1997
 Cocco et al. 1997 Italy Smelter workers 100
 Wilczynksa et al. Poland Workers compensated for lead 100
 1998 poisoning
 Carta et al. 2003 Italy Smelter workers 100

Proportional mortality study
 Alexieva et al. Bulgaria Smelter workers 100
 1981
 McMichael and Australia Smelter workers 100
 Johnson 1982

First author, year Age range (years) Outcome

Prospective cohort studies
 Robinson 1974 20-58 CVD
 Tollestrup et al. 8 to [greater than or equal to] 55 CHD
 1995 Stroke

Retrospective cohort studies
 Dingwall-Fordyce [greater than or equal to] 65 Mean 55 Stroke
 and Lane 1963
 Malcolm 1971, < 65 to [greater than or equal to] 65 at CHD
 Malcolm and death Stroke
 Barnett 1982
 Sheffet et al. Mean 27.8 CVD (d)
 1982
 Davies 1984 18-59 Stroke
 18-59 Stroke
 Cooper et al. < 25-74 CVD
 1985 CHD
 Stroke
 Belli et al. 1989 NR CVD
 Michaels et al. 19-83 CHD
 1991 Stroke
 Steenland et al. NR CHD
 1992 Stroke
 CHD
 Stroke
 Cocco et al. 1994 Mean 27.7 CVD
 Gerhardsson et NR CHD
 al. 1995 Stroke
 Lundstrom et al. 15 to [greater than or equal to] 75 at CVD
 1997 death CHD
 Stroke
 Cocco et al. 1997 Mean 30.4 CVD
 CHD
 Stroke
 Wilczynksa et al. < 29 to [greater than or equal to] 50 at CVD
 1998 1st episode CHD
 Stroke
 Carta et al. 2003 NR CVD

Proportional mortality study
 Alexieva et al. Mean at death 61 CHD
 1981 Stroke
 McMichael and 30 to > 60 at death CHD
 Johnson 1982 Stroke

 Follow-
 up No. of
First author, year (years) deaths (a) RR (95% CI) (b) Comparison

Prospective cohort studies
 Robinson 1974 20 57 n = 0.64 (0.54- Production
 1,252 0.75) vs.
 maintenance
 workers
 Tollestrup et al. 45 NR 1.27 (0.72- Workers vs.
 1995 2.23) general
 NR n = 0.82 (0.31- population
 1,097 2.12)

Retrospective cohort studies
 Dingwall-Fordyce 35 51 2.73 (1.31- Assembly,
 and Lane 1963 5.71) (c) plumbers,
 plate
 cutting,
 etc. vs.
 office,
 chemist,
 etc.
 Malcolm 1971, 10 99 1.00 (0.82- Workers vs.
 Malcolm and 1.22) general
 Barnett 1982 population
 51 103 1.31 (0.66- High exposed
 1.91) vs. no
 exposed
 Sheffet et al. 31 139 0.62 (0.52- Workers vs.
 1982 0.73) general
 population
 Davies 1984 30 31 0.94 (0.66- Workers vs.
 1.33) general
 population
 30 9 4.10 (2.12- Workers vs.
 7.86) general
 population
 Cooper et al. 24 984 0.97 (0.99- Workers vs.
 1985 1.06) general
 715 0.85 (0.69- population
 1.05)
 172 1.06 (0.76-
 1.48)
 Belli et al. 1989 36 82 0.95 (0.76- Workers vs.
 1.10) general
 population
 Michaels et al. 23 186 0.63 (0.54- Workers vs.
 1991 0.73) general
 43 1.35 (0.98- population
 1.82)
 Steenland et al. 39 320 0.94 (0.84- Workers vs.
 1992 1.05) general
 74 1.05 (0.82- population
 1.32)
 39 239 0.99 (0.87- High exposed
 1.12) vs. general
 53 1.05 (0.79- population
 1.37)
 Cocco et al. 1994 28 258 0.63 (0.56- Workers vs.
 0.72) general
 population
 Gerhardsson et 20 34 1.72 (1.20- Workers vs.
 al. 1995 2.42) general
 0 0 (0.00-1.23) population
 Lundstrom et al. 32 234 0.90 (0.80- Workers vs.
 1997 1.00) general
 152 0.80 (0.70- population
 1.00)
 36 0.80 (0.60-
 1.20)
 Cocco et al. 1997 48 251 0.70 (0.62- Workers vs.
 0.80) general
 49 0.34 (0.25- population
 0.45)
 105 0.95 (0.77-
 1.15)
 Wilczynksa et al. 22 231 0.91 (0.80- Workers vs.
 1998 1.04) general
 98 0.96 (0.78- population
 1.17)
 33 1.03 (0.71-
 1.45)
 Carta et al. 2003 29 28 0.80 (0.56- Workers vs.
 1.16) general
 population

Proportional mortality study
 Alexieva et al. 10 26 5.60 (1.68- Workers vs.
 1981 18.6) general
 47 0.17 (0.08- population
 0.36)
 McMichael and 40 231 0.95 (0.67- Exposed
 Johnson 1982 1.35) workers vs.
 53 1.45 (0.76- staff
 2.76) workers

 Corrected
 for healthy
First author, year Adjusted for worker effect

Prospective cohort studies
 Robinson 1974 Crude No
 Tollestrup et al. Age, sex No
 1995

Retrospective cohort studies
 Dingwall-Fordyce Age, period No
 and Lane 1963
 Malcolm 1971, Age No
 Malcolm and
 Barnett 1982
 Sheffet et al.
 1982
 Davies 1984 Age, period No
 Age, period No
 Cooper et al. Age (~ findings by year of Partially (e)
 1985 hire and employment
 duration)
 Belli et al. 1989 Age No
 Michaels et al. Age (for stroke, analysis by Partially
 1991 employment duration (f))
 Steenland et al. Age, period (+ analyses by Partially
 1992 employment duration (g))
 Age, period
 Cocco et al. 1994 Age, period (~ findings for No
 surface and underground
 workers)
 Gerhardsson et Age, period (~ findings by No
 al. 1995 year of hire)
 Lundstrom et al. Age, period (~ findings for No
 1997 highest exposure group and
 adding a latency period)
 Cocco et al. 1997 Age, period No
 Wilczynksa et al. Age (~ findings by number of No
 1998 lead poisoning episodes)
 Carta et al. 2003 Age No
Proportional mortality study
 Alexieva et al. Age No
 1981
 McMichael and Age No
 Johnson 1982

Abbreviations: CHD, coronary heart disease; CI, confidence interval;
CVD, cardiovascular; RR, relative risk; SMR, standard mortality ratio.
In all studies, lead exposure was determined through job titles, and
mortality outcomes were assigned through information in death
certificates. (a) Sample size not available in most studies.
(b) Relative risk estimates came from SMRs except Robinson (1974) (RR),
Tollestrup (1995) (HR), Alexieva (1981) (proportional mortality rate),
and McMichael (1982) (proportional mortality rate). (c) The within-
cohort relative risk was estimated by comparing standardized mortality
ratios in the highest versus the lowest category of exposure. (d) A
total of 15% of subjects with unknown cause of death in death
certificate. (e) Partial adjustment indicates that authors conducted
additional analyses by employment duration. (f) For Michaels et al.
(1991), SMRs (95%CI) for stroke by number of years of employment are
< 10 years, 2.52 (0.06-13,93); 10-19 years, 0.32 (0.01-1.74); 20-29
years, 0.65 (0.18-1.68); [greater than or equal to] 30 years, 1.68
(1.18-2.31). (g) For Steenland et al. (1992), SMRs by numbers of years
of employment are as follows: a) CHD: 1-5 years, 1.02; 5-20 years, 0.92;
[greater than or equal to] 20 years, 0.86. b) Stroke: 1-5 years, 0.83;
5-20 years, 1.01; [greater than or equal to] 20 years, 1.41.

Table 4. Epidemiologic studies of lead exposure and intermediate
cardiovascular end points.

 Sample Age
First author, size Men range
year Country Population (no.) (%) (years)

Studies of ventricular mass and function
 Schwartz 1991 U.S. NHANES II < 9,932 ~ 50 25-74
 Zou et al. China Refinery workers 41 81 24-45
 1995
 Tepper et al. U.S. Battery workers 108 51 36-73
 2001
 Kasperczyk et Poland Steel workers 143 NR Mean 44
 al. 2005
 Beck and Poland Lead workers 104 100 32-56
 Steinmetz-
 Beck 2005

Studies of heart rate variability
 Murata and Japan Gun workers 32 100 23-58
 Araki 1991
 Teruya et al. Japan Battery, refinery 172 100 18-57
 1991 workers
 Gennart et Belgium Battery workers 183 100 22-55
 al. 1992
 Murata et al. Japan Glass workers 51 0 21-35
 1995
 Ishida et al. Japan Ceramic painters 128 45 29-75
 1996
 Niu et al. China Lead-exposed 302 NR 20-59
 1998 workers
 Bockelmann et Germany Lead, iron, steel 136 100 Mean 43
 al. 2002 workers
 Gajek et al. Poland Foundry workers 35 100 Mean 42
 2004
 Andrzejak et Poland Copper smelter 86 100 Mean 43
 al. 2004 workers
 Muzi et al. Italy Battery workers 78 96 Mean 38
 2005
 Jhun et al. Korea Public officials 331 55 Mean 38
 2005 and family

Studies of other cardiac function abnormalities
 Kosmider and Poland Lead-poisoned 140 100 18-45
 Petelenz workers
 1961
 Kosmider and Poland Lead-poisoned 76 100 46-65
 Petelenz workers
 1962
 Krotkiewski Poland Lead-poisoned 591 78 20-68
 et al. 1964 workers
 Kosmider et Poland Lead-poisoned 100 100 20-45
 al. 1965 workers
 Kosmider 1968 Poland Lead-poisoned 216 100 18-65
 workers
 Stozinic and Yugoslavia Lead-poisoned 1,000 100 NR
 Colakovic workers
 1980
 Saric 1981 Croatia Residents near to 502 50 26-70
 and far from a
 smelter
 Kromhout et Netherlands Elderly men in 152 100 57-76
 al. 1985 Zutphen
 Kirkby and Denmark Lead smelter 190 89 30-60
 Gyntelberg workers
 1985
 Sroczynski et Poland Lead workers 250 100 Mean 41
 al. 1985
 Shcherbak Russia Lead workers 320 100 20-59
 1988
 Sroczynski et Poland Lead workers 711 100 20-60
 al. 1990
 Gatagonova Russia Lead workers 500 78 20-60
 1995a,b,d
 Gatagonova Russia Lead workers 68 100 NR
 1995c
 Cheng et al. U.S. Normative Aging 775 100 48-93
 1998 Study

Studies of other vascular function abnormalities
 Aiba et al. Japan Refinery workers 48 100 18-69
 1999

First author, Lead Range levels
year assessment ([micro]g/dL) Comparison

Studies of ventricular mass and function
 Schwartz 1991 Blood NR Per 1 [micro]g/dL
 Zou et al. Blood Mean 42.5 > 50 vs. < 50 [micro]g/dL
 1995
 Tepper et al. Blood 12-50 34-50 vs. 12-25
 2001 [micro]g/dL
 Kasperczyk et Blood Mean 23.4 Administrative workers
 al. 2005
 Beck and Blood 19.3-79.8 Lead exposed vs. control
 Steinmetz-
 Beck 2005

Studies of heart rate variability
 Murata and Job title < 16-60 Other workers no lead
 Araki 1991 exp.
 Teruya et al. Blood 5-76 Correlation, > 50 vs.
 1991 < 20 [micro]g/dL
 Gennart et Blood 4.4-75 Other workers (finishing,
 al. 1992 main tenance, etc.)
 Murata et al. Job title NR Textile workers
 1995
 Ishida et al. Blood 2.1-69.5 > 30 vs. < 10 [micro]g/dL
 1996
 Niu et al. Job title NM Healthy controls
 1998
 Bockelmann et Blood Mean lead Iron steel workers
 al. 2002 workers 31.2
 Gajek et al. Blood < 3.6 to Healthy controls
 2004 > 41.0
 Andrzejak et Blood Mean lead Healthy controls matched
 al. 2004 workers 46.8 on age, sex, smoking,
 lipids, BMI
 Muzi et al. Blood < 3.5 to Other workers
 2005 > 31.6
 Jhun et al. Blood < 1.39 to Per natural-log unit
 2005 > 3.45

Studies of other cardiac function abnormalities
 Kosmider and Job title NM Healthy controls
 Petelenz symptoms
 1961
 Kosmider and Job title NM Healthy controls
 Petelenz symptoms
 1962
 Krotkiewski Job title NM Other workers
 et al. 1964 symptoms
 Kosmider et Job title NM Healthy controls
 al. 1965 symptoms
 Kosmider 1968 Job title NM Healthy controls
 symptoms
 Stozinic and Job title NM Healthy controls
 Colakovic symptoms
 1980
 Saric 1981 Area of NM Residents far from smelter
 residency
 Kromhout et Blood < 10.8 Correlation
 al. 1985 > 28.0
 Kirkby and Job title Mean 31 Healthy controls
 Gyntelberg residents in Glostrup
 1985
 Sroczynski et Job title NM Other workers
 al. 1985
 Shcherbak Job title NM Other workers
 1988
 Sroczynski et Job title NM Other workers
 al. 1990
 Gatagonova Job title Mean 67 Other workers
 1995a,b,d
 Gatagonova Job title NM Other workers
 1995c
 Cheng et al. Blood Mean 5.79 Per 10 unit [up arrow]
 1998
 Tibia Mean 22
 [micro]g/g
 Patella Mean 31
 [micro]g/g

Studies of other vascular function abnormalities
 Aiba et al. Job title Mean 43.2 Correlation
 1999

First author, End point
year ascertainment Main findings

Studies of ventricular mass and function
 Schwartz 1991 ECG (Minnesota code) [up arrow] prevalence left
 ventricular hypertrophy
 OR adjusted for age, sex, race =
 1.33 (95% CI, 1.09-1.61)
 Zou et al. US (dimensional and ~ end-diastolic, systolic
 1995 functional internal dimension, wall
 parameters) thickness
 ~ ejection fraction (%), cardiac
 output (mL/sec), index (mL/sec
 x [m.sup.2]
 ~ heart rate
 Tepper et al. US and ECG [up arrow] left ventricular mass
 2001 (g/[m.sup.2]) but NS (p =
 0.20)
 Kasperczyk et US (dimensional and [up arrow] left ventricular mass
 al. 2005 functional (g and g/[m.sup.2])
 parameters) [up arrow] left, ~ right end-
 diastolic internal dimensions
 ~ wall thickness
 (interventricular septum,
 posterior wall, others)
 [down arrow] ejection fraction
 (%)
 Beck and Echo-doppler [down arrow] early mitral inflow
 Steinmetz- peak velocity, [up arrow] late
 Beck 2005 mitral inflow peak velocity
 [down arrow] time velocity
 integral of early vs. late
 diastolic inflow
 ~ time velocity integral of
 early vs. total diastolic
 inflow
 [up arrow] time velocity
 integral of late vs. total
 diastolic inflow
 ~ Isovolumetric relaxation time
 of left ventricle

Studies of heart rate variability
 Murata and ECG: 100 R-R [down arrow] CV of R-R interval;
 Araki 1991 intervals, normal ~ CV of LF component,
 breath [down arrow] CV of HF component
 Teruya et al. ECG: 1 min, normal, ~, [down arrow] mean; ~,
 1991 deep breath [down arrow] SD; and ~,
 [down arrow] CV of R-R
 interval
 ~, [down arrow] maximal
 variation ratio (min/max R-R
 interval)
 ~, [down arrow] maximal
 variation rate ([min/max R-R
 interval]/mean)
 Gennart et ECG: normal, deep ~ CV of R-R interval, ~ CV of
 al. 1992 breath mean square of successive
 differences, and ~ CV of mean
 ratio of shortest to longest
 R-R
 Murata et al. ECG: 100 R-R ~ heart rate
 1995 intervals, normal [down arrow] CV of R-R interval,
 breath [down arrow] CV of LF and
 [down arrow] HF components
 [down arrow] LF/HF ratio
 Ishida et al. ECG: 100 R-R ~ CV of R-R interval
 1996 intervals, normal,
 deep breath
 Doppler: finger blood [down arrow] flow between supine
 flow and standing/supine
 ~ flow drop velocity (supine
 flow/time to the nadir after
 standing)
 Niu et al. ECG: deep breath, ~ R-R interval
 1998 valsalva, stand up
 Bockelmann et ECG: 90 min, 10-step [down arrow] heart rate at rest
 al. 2002 battery test [up arrow] sinus arrhythmia at
 rest
 Lack of recovery of LF and HF
 after test
 Gajek et al. ECG: 24 hr, long- and ~ mean R-R, SDNN, SDNN index,
 2004 short-term SDANN, rMSSD, pNN50
 Short-term only: ~ TP, VLF, LF,
 HF, LF/HF, HF night / HF day
 Andrzejak et ECG: 24 hr ~ heart rate
 al. 2004 Long-term: [down arrow] pNN50,
 ~ mean R-R, SDNN, SDNN index,
 SDANN, rMSSD
 Short-term: all parameters
 [down arrow] included LF and
 HF, except mean R-R and LF:HF
 Muzi et al. ECG: battery tests [down arrow] R-R interval ratios
 2005 for lying-standing, lying-
 standing-lying, deep breaths,
 and valsalva
 Jhun et al. ECG: 3 min, seated [down arrow] LF, HF, and total
 2005 position power spectrum

Studies of other cardiac function abnormalities
 Kosmider and ECG [down arrow] heart rate,
 Petelenz [down arrow] P-Q interval
 1961 [up arrow] heart muscle lesions
 and vegetative disorders
 Kosmider and ECG [up arrow] heart muscle lesions
 Petelenz and vegetative disorders
 1962
 Krotkiewski ECG [up arrow] prevalence of
 et al. 1964 ischemic changes: 32% vs. 13%
 Kosmider et ECG [up arrow] heart muscle lesions
 al. 1965 and vegetative disorders
 Kosmider 1968 ECG [up arrow] heart muscle lesions
 and vegetative disorders
 Stozinic and ECG questionnaire [up arrow] electrocardiographic
 Colakovic abnormalities (including
 1980 [up arrow] S-T segment)
 [up arrow] self-reported
 coronary heart disease and
 intermittent claudication
 Saric 1981 ECG ~ electrocardiographic
 abnormalities
 Kromhout et ECG ~ resting heart rate
 al. 1985
 Kirkby and ECG (Minnesota code) [up arrow] prevalence of
 Gyntelberg ischemic changes: 20% vs. 6%
 1985
 Sroczynski et ECG (Minnesota code) [up arrow] prevalence of
 al. 1985 ischemic changes: 10.0% vs.
 5.3%
 [up arrow] prevalence of rhythm
 disorders: 14% vs. 2.7%
 Shcherbak ECG [up arrow] prevalence of
 1988 ischemic changes: 11.6% vs.
 6.7%
 Sroczynski et ECG (Minnesota code) [up arrow] prevalence systolic
 al. 1990 murmur and rhythm disorders
 [up arrow] prevalence
 ventricular repolarization
 ~ prevalence of ischemic changes
 Gatagonova Integral rehography Changes of intracardial and
 1995a,b,d peripheral hemodynamics
 Disorders of myocardial
 bioelectric activity and
 contractility
 ECG [up arrow] P wave and QT, QRS
 interval; ~ P-Q interval
 Gatagonova Exercise stress test [up arrow] prevalence of
 1995c ischemic changes ([up arrow]
 S-T segment > 1 mm 15.9 vs.
 4.2%)
 Cheng et al. ECG Subjects < 65 years: [up arrow]
 1998 QT, [up arrow] QRS interval
 for tibia and patella, ~ for
 blood
 Subjects
 [greater than or equal to] 65
 years: ~ QT, ~ QRS interval
 for all biomarkers
 ~ conduction defects and
 arrhythmia for all biomarkers,
 indices and age groups, except
 [up arrow] intraventricular
 conduction defect for tibia
 lead in < 65 years

Studies of other vascular function abnormalities
 Aiba et al. Acceleration [down arrow] amplitude ratio of
 1999 plethysmography the second/first systolic wave
 (age adjusted)
 ~ amplitude ratio of the third/
 first and third/first waves
 (age adjusted)

Abbreviations: [up arrow], [down arrow]--indicate increase or decrease
(statistically significant at p < 0.05, unless otherwise specified).
BMI, body mass index; CI, confidence interval; CV, coefficient of
variation; DB, deep breathe; ECG, electrocardiogram; exp., exposed; HF,
high frequency; HRV, heart rate variability; LF, low frequency; NM, not
measured; NR, not reported; NS, not significant; OR, odds ratio; pNN50,
proportion of interval differences of successive normal-to-normal
intervals > 50 msec; RMSSD, square root of the mean-squared differences
of successive NN intervals; SD, standard deviation; SDANN, SD of the
average normal-to-normal interval. SDNN, SD of the normal-to-normal
interval; TP, total power; US ultrasound; V, ventricular; VLF, very low
frequency.


Appendix A. Search strategy.

Free text and key word

Lead, lead poisoning, heavy metals, mortality, atherosclerosis, cardiovascular disease, peripheral arterial disease, peripheral vascular disease, hypertension, blood pressure, heart rate, electrocardiogram, left ventricular hypertrophy.

Search in PubMed

(Lead [MH] OR Lead poisoning [MH] OR (Metals, heavy [MH] NOT (Actinium OR Americium OR Antimony OR Barium OR Berkelium OR Bismuth OR Californium OR Cesium OR Chromium OR Cobalt OR Copper OR Curium OR Einsteinium OR Fermium OR Francium OR Gallium OR Germanium Gold OR Hafnium OR Indium OR Iridium OR Iron OR Lawrencium OR Manganese OR Molybdenum OR Neptunium OR Nickel OR Niobium OR Nobelium OR Osmium OR Palladium OR Platinum OR Plutonium OR Protactinium OR Radium OR Rhenium OR Rhodium OR Rubidium OR Ruthenium OR Silver OR Strontium OR Tantalum OR Technetium OR Thallium OR Thorium OR Tin OR Tungsten OR Uranium OR Vanadium OR Zinc OR Zirconium))) AND (Cardiovascular Disease [MH] OR Mortality OR Myocardial Infarction OR Stroke OR Peripheral Arterial Disease OR Peripheral Vascular Disease OR Hypertension OR Blood pressure OR Systolic OR Diastolic OR Atherosclerosis OR Arteriosclerosis OR Electrocardiography OR Heart Rate OR Ventricular Hypertrophy OR heart failure)

Search in EMBASE

(Lead:de OR (Lead poisoning:de)) AND ((cardiovascular disease:de) OR mortality:ti,ab OR (Myocardial Infarction:ti,ab) OR Stroke:ti,ab OR (Peripheral Arterial Disease:ti,ab) OR (Peripheral Vascular Disease:ti,ab) OR Hypertension:ti,ab OR (Blood pressure:ti,ab) OR Systolic:ti,ab OR Diastolic:ti,ab OR Atherosclerosis:ti,ab OR Arteriosclerosis:ti,ab OR Electrocardiography:ti,ab OR (Heart Rate:ti,ab) OR (Ventricular Hypertrophy:ti,ab) OR (heart failure:ti,ab))

Search in TOXLINE

(Lead [MH] OR Lead poisoning [MH]) AND (Cardiovascular Disease [MH] OR Mortality OR Myocardial Infarction OR Stroke OR Peripheral Arterial Disease OR Peripheral Vascular Disease OR Hypertension OR Blood pressure OR Systolic OR Diastolic OR Atherosclerosis OR Arteriosclerosis OR Electrocardiography OR Heart Rate OR Ventricular Hypertrophy OR heart failure)

Databases: PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed); EMBASE (http://www.embase.com/); TOXLINE (http://toxnet.nlm.nih.gov/).
Appendix B. Criteria for evaluating the design and data analysis of
epidemiologic studies of lead exposure and clinical cardiovascular
disease. (a)

 General populations
 Cohort studies
 Moller and
 Pocock Kromhout Kristensen
 et al. 1988 1988 1992

All studies
 Lead exposure was assessed at Y Y Y
 the individual level
 Exposure was assessed measuring Y Y Y
 lead levels in blood or bone
 Outcomes were based on objective Y Y N
 tests/standard criteria in
 [greater than or equal to] 90%
 of study participants
 Authors presented internal Y Y Y
 comparisons within study
 participants
 Authors controlled for relevant Y N Y
 confounding factors in
 addition
 to age and sex (b)
Cohort studies
 Loss to follow-up was Y Y Y
 independent of lead exposure
 Intensity of search of disease Y Y Y
 was independent of lead
 exposure
Case--control and cross-sectional
 studies
 Response rate among noncases was -- -- --
 at least 70%
 Exclusion criteria and data -- -- --
 collection were similar for
 all participants
 Non cases would have been cases -- -- --
 if they had developed
 cardiovascular disease
 Interviewer was blinded with -- -- --
 respect to the participant
 case or exposure status

 General populations
 Cohort studies CC and
 Lustberg CS studies
 and Menke Pan Mansoor
 Silbergeld et al. et al. et al.
 2002 2006 1993 2000

All studies
 Lead exposure was assessed at Y Y Y Y
 the individual level
 Exposure was assessed measuring Y Y N N
 lead levels in blood or bone
 Outcomes were based on objective N N N Y
 tests/standard criteria in
 [greater than or equal to] 90%
 of study participants
 Authors presented internal Y Y Y Y
 comparisons within study
 participants
 Authors controlled for relevant Y Y N N
 confounding factors in
 addition
 to age and sex (b)
Cohort studies
 Loss to follow-up was Y Y -- --
 independent of lead exposure
 Intensity of search of disease Y Y -- --
 was independent of lead
 exposure
Case--control and cross-sectional
 studies
 Response rate among noncases was -- -- N U
 at least 70%
 Exclusion criteria and data -- -- U Y
 collection were similar for
 all participants
 Non cases would have been cases -- -- U N
 if they had developed
 cardiovascular disease
 Interviewer was blinded with -- -- U U
 respect to the participant
 case or exposure status

 General population
 CC and CS studies
 Gustavsson Dulskiene Tsai et al.
 et al. 2001 2003 2004

All studies
 Lead exposure was assessed at Y N Y
 the individual level
 Exposure was assessed measuring N N N
 lead levels in blood or bone
 Outcomes were based on objective Y N N
 tests/standard criteria in
 [greater than or equal to] 90%
 of study participants
 Authors presented internal Y Y Y
 comparisons within study
 participants
 Authors controlled for relevant N Y N
 confounding factors in
 addition
 to age and sex (b)
Cohort studies
 Loss to follow-up was -- -- --
 independent of lead exposure
 Intensity of search of disease -- -- --
 was independent of lead
 exposure
Case--control and cross-sectional
 studies
 Response rate among noncases was Y U N
 at least 70%
 Exclusion criteria and data Y U U
 collection were similar for
 all participants
 Non cases would have been cases Y U U
 if they had developed
 cardiovascular disease
 Interviewer was blinded with U U U
 respect to the participant
 case or exposure status

 Occupational
 General populations populations
 CC and CS studies Prosp.
 Muntner
 Kosmala et al. Robinson
 et al. 2004 2005 1974

All studies
 Lead exposure was assessed at Y Y N
 the individual level
 Exposure was assessed measuring Y Y N
 lead levels in blood or bone
 Outcomes were based on objective Y Y N
 tests/standard criteria in
 [greater than or equal to] 90%
 of study participants
 Authors presented internal Y Y Y
 comparisons within study
 participants
 Authors controlled for relevant N Y N
 confounding factors in
 addition
 to age and sex (b)
Cohort studies
 Loss to follow-up was -- -- Y
 independent of lead exposure
 Intensity of search of disease -- -- Y
 was independent of lead
 exposure
Case--control and cross-sectional
 studies
 Response rate among noncases was U Y --
 at least 70%
 Exclusion criteria and data Y Y --
 collection were similar for
 all participants
 Non cases would have been cases Y Y --
 if they had developed
 cardiovascular disease
 Interviewer was blinded with U Y --
 respect to the participant
 case or exposure status

 Occupational populations
 Retrospective cohort
 studies
 Prosp. Dingwall- Malcolm
 Tollestrup Fordyce 1971,
 et al. and Lane Malcolm and
 1995 1963 Barnett 1982

All studies
 Lead exposure was assessed at N N N
 the individual level
 Exposure was assessed measuring N N N
 lead levels in blood or bone
 Outcomes were based on objective N N N
 tests/standard criteria in
 [greater than or equal to] 90%
 of study participants
 Authors presented internal Y Y N
 comparisons within study
 participants
 Authors controlled for relevant N N N
 confounding factors in
 addition
 to age and sex (b)
Cohort studies
 Loss to follow-up was N N N
 independent of lead exposure
 Intensity of search of disease N N N
 was independent of lead
 exposure
Case--control and cross-sectional
 studies
 Response rate among noncases was -- -- --
 at least 70%
 Exclusion criteria and data -- -- --
 collection were similar for
 all participants
 Non cases would have been cases -- -- --
 if they had developed
 cardiovascular disease
 Interviewer was blinded with -- -- --
 respect to the participant
 case or exposure status

 Occupational populations
 Retrospective cohort studies
 Sheffet Cooper
 et al. Davies et al. Belli
 1982 1984 1985 et al. 1989

All studies
 Lead exposure was assessed at N N N N
 the individual level
 Exposure was assessed measuring N N N N
 lead levels in blood or bone
 Outcomes were based on objective N N N N
 tests/standard criteria in
 [greater than or equal to] 90%
 of study participants
 Authors presented internal N N N N
 comparisons within study
 participants
 Authors controlled for relevant N N N N
 confounding factors in
 addition
 to age and sex (b)
Cohort studies
 Loss to follow-up was N N N N
 independent of lead exposure
 Intensity of search of disease N N N N
 was independent of lead
 exposure
Case--control and cross-sectional
 studies
 Response rate among noncases was -- -- -- --
 at least 70%
 Exclusion criteria and data -- -- -- --
 collection were similar for
 all participants
 Non cases would have been cases -- -- -- --
 if they had developed
 cardiovascular disease
 Interviewer was blinded with -- -- -- --
 respect to the participant
 case or exposure status

 Occupational populations
 Retrospective cohort studies
 Michaels Steenland Cocco et al.
 1991 et al. 1992 1994

All studies
 Lead exposure was assessed at N N N
 the individual level
 Exposure was assessed measuring N N N
 lead levels in blood or bone
 Outcomes were based on objective N N N
 tests/standard criteria in
 [greater than or equal to] 90%
 of study participants
 Authors presented internal N N N
 comparisons within study
 participants
 Authors controlled for relevant N N N
 confounding factors in
 addition
 to age and sex (b)
Cohort studies
 Loss to follow-up was N N N
 independent of lead exposure
 Intensity of search of disease N N N
 was independent of lead
 exposure
Case--control and cross-sectional
 studies
 Response rate among noncases was -- -- --
 at least 70%
 Exclusion criteria and data -- -- --
 collection were similar for
 all participants
 Non cases would have been cases -- -- --
 if they had developed
 cardiovascular disease
 Interviewer was blinded with -- -- --
 respect to the participant
 case or exposure status

 Occupational populations
 Retrospective cohort studies
 Cocco
 Gerhardsson Lundstrom et al.
 et al. 1995 et al. 1997 1997

All studies
 Lead exposure was assessed at N N N
 the individual level
 Exposure was assessed measuring N N N
 lead levels in blood or bone
 Outcomes were based on objective N N N
 tests/standard criteria in
 [greater than or equal to] 90%
 of study participants
 Authors presented internal N N N
 comparisons within study
 participants
 Authors controlled for relevant N N N
 confounding factors in
 addition
 to age and sex (b)
Cohort studies
 Loss to follow-up was N N N
 independent of lead exposure
 Intensity of search of disease N N N
 was independent of lead
 exposure
Case--control and cross-sectional
 studies
 Response rate among noncases was -- -- --
 at least 70%
 Exclusion criteria and data -- -- --
 collection were similar for
 all participants
 Non cases would have been cases -- -- --
 if they had developed
 cardiovascular disease
 Interviewer was blinded with -- -- --
 respect to the participant
 case or exposure status

 Occupational populations
 Retrospective cohort studies
 Wilczynksa et al. Carta et al.
 1998 2003

All studies
 Lead exposure was assessed at N N
 the individual level
 Exposure was assessed measuring N N
 lead levels in blood or bone
 Outcomes were based on objective N N
 tests/standard criteria in
 [greater than or equal to] 90%
 of study participants
 Authors presented internal N N
 comparisons within study
 participants
 Authors controlled for relevant N N
 confounding factors in
 addition
 to age and sex (b)
Cohort studies
 Loss to follow-up was N N
 independent of lead exposure
 Intensity of search of disease N N
 was independent of lead
 exposure
Case--control and cross-sectional
 studies
 Response rate among noncases was -- --
 at least 70%
 Exclusion criteria and data -- --
 collection were similar for
 all participants
 Non cases would have been cases -- --
 if they had developed
 cardiovascular disease
 Interviewer was blinded with -- --
 respect to the participant
 case or exposure status

 Occupational populations
 PMS
 Alexieva et al. McMichael and
 1981 Johnson 1982

All studies
 Lead exposure was assessed at N Y
 the individual level
 Exposure was assessed measuring N N
 lead levels in blood or bone
 Outcomes were based on objective N N
 tests/standard criteria in
 [greater than or equal to] 90%
 of study participants
 Authors presented internal Y Y
 comparisons within study
 participants
 Authors controlled for relevant N N
 confounding factors in
 addition
 to age and sex (b)
Cohort studies
 Loss to follow-up was -- --
 independent of lead exposure
 Intensity of search of disease -- --
 was independent of lead
 exposure
Case--control and cross-sectional
 studies
 Response rate among noncases was -- --
 at least 70%
 Exclusion criteria and data Y Y
 collection were similar for
 all participants
 Non cases would have been cases N N
 if they had developed
 cardiovascular disease
 Interviewer was blinded with N N
 respect to the participant
 case or exposure status

Abbreviations: --, not applicable; CC, case--control study; CS, cross-
sectional study; N, no; PMS, proportional mortality study, Prosp.,
prospective; U, unclear; Y, yes.
(a) Criteria modified from Longnecker et al. (1988). (b) In occupational
studies, relevant factors included the healthy worker survivor effect.
Studies that adjusted for blood pressure levels were considered not to
fulfill this criterion.

Appendix C. Criteria for evaluating the design and data analysis of
epidemiologic studies of lead exposure and intermediate cardiovascular
end points. (a)

 Ventricular mass and function
 Zou Tepper
 Schwartz et al. et al. Kasperczyk
 1991 1995 2001 et al. 2005

Association estimates based on Y Y Y N
 lead assessed at the
 individual level
Association estimates based on Y Y Y N
 blood or bone lead measures
Cardiovascular tests were Y Y Y Y
 based on a standardized
 protocol
Authors indicate that Y N Y N
 examiners received training
 to conduct cardiovascular
 tests
Inclusion and exclusion Y U Y U
 criteria were similar for
 all participants
Recruitment procedures were Y U Y U
 similar for all participants
Response rate was at least 70% Y U N U
Examiner was blinded with Y U U U
 respect to the participant
 exposure status
Authors controlled for Y Y Y N
 relevant confounding factors
 in addition to age, sex

 Ventricular
 mass and
 function Heart rate variability
 Beck and Teruya Gennart
 Steinmetz- Murata and et al. et al.
 Beck 2005 Araki 1991 1991 1992

Association estimates based on N N Y N
 lead assessed at the
 individual level
Association estimates based on N N Y Y
 blood or bone lead measures
Cardiovascular tests were Y Y Y Y
 based on a standardized
 protocol
Authors indicate that N N N N
 examiners received training
 to conduct cardiovascular
 tests
Inclusion and exclusion Y Y Y N
 criteria were similar for
 all participants
Recruitment procedures were U Y Y Y
 similar for all participants
Response rate was at least 70% U U U Y
Examiner was blinded with U U Y U
 respect to the participant
 exposure status
Authors controlled for N N N N
 relevant confounding factors
 in addition to age, sex

 Heart rate variability
 Murata Ishida Niu and
 et al. et al. Abbritti Bockelmann
 1995 1996 1998 et al. 2002

Association estimates based on N Y N N
 lead assessed at the
 individual level
Association estimates based on N Y N N
 blood or bone lead measures
Cardiovascular tests were Y Y U Y
 based on a standardized
 protocol
Authors indicate that N N N N
 examiners received training
 to conduct cardiovascular
 tests
Inclusion and exclusion Y Y U Y
 criteria were similar for
 all participants
Recruitment procedures were N Y U U
 similar for all participants
Response rate was at least 70% U U U U
Examiner was blinded with U Y U U
 respect to the participant
 exposure status
Authors controlled for N N N N
 relevant confounding factors
 in addition to age, sex

 Heart rate variability
 Gajek Andrzejak Muzi
 et al. et al. et al. Jhun et al.
 2004 2004 2005 2005

Association estimates based on N N N Y
 lead assessed at the
 individual level
Association estimates based on N N N Y
 blood or bone lead measures
Cardiovascular tests were Y Y Y Y
 based on a standardized
 protocol
Authors indicate that N N N N
 examiners received training
 to conduct cardiovascular
 tests
Inclusion and exclusion N Y U Y
 criteria were similar for
 all participants
Recruitment procedures were N Y U Y
 similar for all participants
Response rate was at least 70% U U U U
Examiner was blinded with U U U Y
 respect to the participant
 exposure status
Authors controlled for N N N N
 relevant confounding factors
 in addition to age, sex

 Other cardiac abnormalities
 Kosmider and Kosmider Krotkiewski
 Petelenz 1961 1962 et al. 1964

Association estimates based on N N N
 lead assessed at the
 individual level
Association estimates based on N N N
 blood or bone lead measures
Cardiovascular tests were N N Y
 based on a standardized
 protocol
Authors indicate that N N N
 examiners received training
 to conduct cardiovascular
 tests
Inclusion and exclusion U U U
 criteria were similar for
 all participants
Recruitment procedures were U U U
 similar for all participants
Response rate was at least 70% U U U
Examiner was blinded with U U U
 respect to the participant
 exposure status
Authors controlled for N N N
 relevant confounding factors
 in addition to age, sex

 Other cardiac abnormalities
 Kosmider Stozinic and
 et al. Kosmider Colakovic Saric
 1965 1968 1980 1981

Association estimates based on N N N N
 lead assessed at the
 individual level
Association estimates based on N N N N
 blood or bone lead measures
Cardiovascular tests were N N N N
 based on a standardized
 protocol
Authors indicate that N N N N
 examiners received training
 to conduct cardiovascular
 tests
Inclusion and exclusion U U U N
 criteria were similar for
 all participants
Recruitment procedures were U U U N
 similar for all participants
Response rate was at least 70% U U U U
Examiner was blinded with U U U U
 respect to the participant
 exposure status
Authors controlled for N N N N
 relevant confounding factors
 in addition to age, sex

 Other cardiac abnormalities
 Kirkby and
 Kromhout Gyntelberg Sroczynski
 et al. 1985 1985 et al. 1985

Association estimates based on Y N N
 lead assessed at the
 individual level
Association estimates based on Y N N
 blood or bone lead measures
Cardiovascular tests were Y Y Y
 based on a standardized
 protocol
Authors indicate that Y Y N
 examiners received training
 to conduct cardiovascular
 tests
Inclusion and exclusion Y Y U
 criteria were similar for
 all participants
Recruitment procedures were Y Y U
 similar for all participants
Response rate was at least 70% Y Y U
Examiner was blinded with Y N U
 respect to the participant
 exposure status
Authors controlled for Y N N
 relevant confounding factors
 in addition to age, sex

 Other cardiac abnormalities
 Shcherbak Sroczynski Gatagonova
 1988 et al. 1990 1995 a,b,d

Association estimates based on N N N
 lead assessed at the
 individual level
Association estimates based on N N N
 blood or bone lead measures
Cardiovascular tests were U Y N
 based on a standardized
 protocol
Authors indicate that N N N
 examiners received training
 to conduct cardiovascular
 tests
Inclusion and exclusion Y U U
 criteria were similar for
 all participants
Recruitment procedures were Y U U
 similar for all participants
Response rate was at least 70% U U U
Examiner was blinded with U U U
 respect to the participant
 exposure status
Authors controlled for N N N
 relevant confounding factors
 in addition to age, sex

 Other cardiac
 abnormalities Other vasc.
 Gatagonova Cheng Aiba et al.
 1995 c et al. 1998 1999

Association estimates based on N Y Y
 lead assessed at the
 individual level
Association estimates based on N Y Y
 blood or bone lead measures
Cardiovascular tests were N Y N
 based on a standardized
 protocol
Authors indicate that N Y U
 examiners received training
 to conduct cardiovascular
 tests
Inclusion and exclusion U Y U
 criteria were similar for
 all participants
Recruitment procedures were U Y U
 similar for all participants
Response rate was at least 70% U Y U
Examiner was blinded with U Y U
 respect to the participant
 exposure status
Authors controlled for N Y N
 relevant confounding factors
 in addition to age, sex

Abbreviations: N, no; U, unclear; vasc., vascular; Y, yes;.
(a) Criteria modified from Appel et al. (2002).
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Title Annotation:Mini-Monograph
Author:Rothenberg, Stephen J.
Publication:Environmental Health Perspectives
Date:Mar 1, 2007
Words:15871
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