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: [phone]. Fax: [phone]. E-mail: [e-mail]

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).