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Cumulative community-level lead exposure and pulse pressure: the normative aging study.
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PMID:  18087585     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Pulse pressure increases with age in industrialized societies as a manifestation of arterial stiffening. Lead accumulates in the vasculature and is associated with vascular oxidative stress, which can promote functional and structural vascular disease.
OBJECTIVES: We tested the hypothesis that cumulative community-level lead exposure, measured with K-X-ray fluorescence, is associated with pulse pressure in a cohort of adult men.
METHODS AND RESULTS: In a cross-sectional analysis of 593 men not treated with antihypertensive medication, tibia lead was positively associated with pulse pressure (p < 0.001). Adjusting for age, race, diabetes, family history of hypertension, education, waist circumference, alcohol intake, smoking history, height, heart rate, fasting glucose, and total cholesterol-to-HDL ratio, increasing quintiles of tibia lead remained associated with increased pulse pressure (ptrend = 0.02). Men with tibia lead above the median (19.0 microg/g) had, on average, a 4.2-mmHg (95% confidence interval, 1.9-6.5) higher pulse pressure than men with tibia lead level below the median. In contrast, blood lead level was not associated with pulse pressure.
CONCLUSIONS: These data indicate that lead exposure may contribute to the observed increase in pulse pressure that occurs with aging in industrialized societies. Lead accumulation may contribute to arterial aging, perhaps providing mechanistic insight into the observed association of low-level lead exposure with cardiovascular mortality.
Todd Perlstein; Jennifer Weuve; Joel Schwartz; David Sparrow; Robert Wright; Augusto Litonjua; Huiling Nie; Howard Hu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Environmental health perspectives     Volume:  115     ISSN:  0091-6765     ISO Abbreviation:  Environ. Health Perspect.     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2007-12-18     Completed Date:  2008-02-01     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  0330411     Medline TA:  Environ Health Perspect     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1696-700     Citation Subset:  IM    
Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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MeSH Terms
Age Distribution
Aged, 80 and over
Aging / drug effects,  physiology*
Blood Pressure / drug effects*
Cohort Studies
Environmental Exposure*
Lead / blood
Lead Poisoning*
Middle Aged
Residence Characteristics*
Statistics, Nonparametric
Tibia / chemistry
Grant Support
Reg. No./Substance:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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Journal Information
Journal ID (nlm-ta): Environ Health Perspect
ISSN: 0091-6765
Publisher: National Institute of Environmental Health Sciences
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This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
Received Day: 11 Month: 4 Year: 2007
Accepted Day: 6 Month: 9 Year: 2007
Print publication date: Month: 12 Year: 2007
Electronic publication date: Day: 6 Month: 9 Year: 2007
Volume: 115 Issue: 12
First Page: 1696 Last Page: 1700
ID: 2137129
PubMed Id: 18087585
DOI: 10.1289/ehp.10350
Publisher Id: ehp0115-001696

Cumulative Community-Level Lead Exposure and Pulse Pressure: The Normative Aging Study
Todd Perlstein1
Jennifer Weuve2
Joel Schwartz2
David Sparrow34
Robert Wright256
Augusto Litonjua5
Huiling Nie25
Howard Hu257
1 Division of Cardiology, Department of Medicine, Brigham and Women?s Hospital, Harvard Medical School, Boston, Massachusetts, USA
2 Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA
3 Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA
4 Boston University Schools of Public Health and Medicine, Boston, Massachusetts, USA
5 Channing Laboratory, Department of Medicine, Brigham and Women?s Hospital, Harvard Medical School, Boston, Massachusetts, USA
6 Department of Emergency Medicine, Children?s Hospital, Harvard Medical School, Boston, Massachusetts, USA
7 Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA
Correspondence: Address correspondence to T.S. Perlstein, Cardiovascular Division, Brigham and Women?s Hospital, 75 Francis St., A Building, 3rd Floor, Boston, MA 02115 USA. Telephone: (617) 525-7168. Fax: (617) 264-5265. E-mail:
The authors declare they have no competing financial interests.

In industrialized societies, pulse pressure (systolic minus diastolic blood pressure) increases with age, a trend that accelerates in the sixth decade when the diastolic blood pressure begins to decrease (Franklin et al. 1997). The increase in pulse pressure reflects arterial aging and progressive vascular stiffening (Lakatta and Levy 2003), with the predominant contribution from increased aortic stiffness (Mitchell et al. 2004). Vascular oxidative stress contributes to arterial aging (Lakatta 2003). Accordingly, known contributors to vascular oxidative stress including obesity (Kwagyan et al. 2005), smoking (Mahmud and Feely 2003), hyperglycemia (van Dijk et al. 2002), and dyslipidemia (Miyagi et al. 2002) are associated with increased pulse pressure.

Lead exposure is also associated with vascular oxidative stress (Vaziri 2002). In vivo (Vaziri et al. 1999) and in vitro (Vaziri and Ding 2001) studies of lead demonstrate increased vascular reactive oxygen species generation. Lead accumulates in the vasculature of the lead-exposed rat and remains after the exposure has ended (Malvezzi et al. 2001). The lead-exposed rat develops hypertension ameliorable by antioxidant therapy (Vaziri et al. 1997). These findings suggest that accumulation of lead in the arterial tree may contribute to arterial stiffness by inducing oxidative stress.

In industrialized societies, accumulation of bone lead is many times greater than that observed in cultures that do not use lead (Drasch 1982). Therefore, bone lead may serve as a proxy marker of lead accumulated in the arterial tree. In fact, human autopsy studies demonstrate age- and dose-dependent aortic lead deposition and suggest that the aorta is the next most lead-avid tissue after bone (Barry and Mossman 1970; Schroeder and Tipton 1968). Although public health initiatives have been successful at lessening environmental lead exposures in the United States (Muntner et al. 2005), low-level lead exposure remains an important contributor to all-cause and cardiovascular mortality (Menke et al. 2006).

The effect of low-level environmental exposure to lead on blood pressure is an area of ongoing scientific debate. Some investigators have found the relationship between low-level lead exposure and blood pressure to be inconsistent and weak (Nawrot et al. 2002; Staessen et al. 1994), but several toxicologic studies by have found that lead elevates blood pressure (Khalil-Manesh et al. 1993; Vaziri et al. 1997; Victery et al. 1982). Other investigators have noted the consistency of the effect size of the blood lead?blood pressure association, and its significance in meta-analyses (Navas-Acien et al. 2007; Schwartz 1991, 1995). A limitation of this body of work is the use of lead in blood as a metric of exposure, where the median residence time of lead is measured in days. Yet autopsy studies indicate that around 95% of lead in the adult human body is deposited in the skeleton, and to the extent that the lead?s effect on blood pressure can be attributed to chronic exposures, a longer averaging time for exposure would be more relevant for evaluating these effects. For example, using K-X-ray fluorescence (KXRF) to directly measure levels of lead retained in bone, we have found that bone lead, compared with blood lead, more accurately reflects cumulative lead exposure (Hu et al. 1996b). We have also found bone lead level to be more strongly associated than blood lead level with blood pressure and hypertension in adult men (Cheng et al. 2001; Hu et al. 1996a).

We examined the cross-sectional association of community-level lead exposure with pulse pressure in the Normative Aging Study, a longitudinal cohort of men. We analyzed this association using both bone and blood lead levels, anticipating that the former, a more accurate indicator of cumulative lead exposure, would be more strongly associated with pulse pressure.


The Human Subjects Committees of the Boston VA Medical Center, the Brigham and Women?s Hospital, and the Harvard School of Public Health approved this research.

Study population

Participants were from the Normative Aging Study (NAS), a longitudinal study of aging established by the Veterans Administration in 1961. Male volunteers from the Greater Boston, Massachusetts, area were screened at entry and enrolled in the study if they had no history of heart disease, hypertension, diabetes, cancer, peptic ulcer, gout, recurrent asthma, bronchitis, or sinusitis. Those with either a systolic blood pressure > 140 mmHg or a diastolic blood pressure > 90 mmHg were disqualified. Between 1963 and 1968, 2,280 men were enrolled; their ages at entry ranged from 21 to 80 years. Participants were asked to return for follow-up examinations every 3?5 years, and the attrition rate was roughly 1% per year over the life of the study. Beginning in 1991, we invited the men still being monitored by the NAS to take part in a study of lead exposure, as assessed by KXRF measurements. The study was approved by the human subjects committees of both the Boston Veterans Administration Medical Center and the Brigham and Women?s Hospital.

Bone and blood lead measurements

NAS participants who gave their informed consent reported to the outpatient General Clinical Research Center of the Brigham and Women?s Hospital in Boston, where we measured their bone lead levels at two sites (the midtibial shaft and the patella) with a KXRF instrument (ABIOMED, Inc., Danvers, MA). The physical principles, technical specifications, and validation of this instrument have been described in detail elsewhere (Burger et al. 1990; Hu et al. 1990a, 1990b). Because the instrument provides a continuous unbiased point estimate (micrograms of lead per gram of bone mineral) that oscillates around the true bone lead value, it sometimes produces negative point estimates when the true bone lead value is close to zero. The instrument also provides an estimate of the uncertainty associated with each measurement that is derived from a goodness-of-fit calculation of the spectrum curves and is equivalent to a standard deviation (SD) if multiple measurements were taken. Although a minimally detectable limit calculation of twice this SD has been proposed for interpreting an individual?s bone lead estimate (Gordon et al. 1993), retention of all point estimates has been shown to make better use of the data in epidemiologic studies (Kim et al. 1995). The technicians measuring bone lead were blinded to the participants? health status. Thirty-minute measurements were taken at the midshaft of the left tibia and at the left patella. A priori we chose to examine tibia lead as a marker of cumulative lead exposure because tibia bone is mostly cortical bone, whereas the patella is mostly trabecular bone and has a greater turnover rate (Hu et al. 1996b).

Blood samples were obtained and analyzed by graphite furnace atomic absorption spectroscopy (GF-AAS; ESA Laboratories, Chelmsford, MA); this instrument was calibrated after every 21 samples with National Bureau of Standards? blood lead standards materials (Gaithersburg, MD). The limit of detection for the GF-AAS method is < 1 ?g/dL; thus, values are expressed as integers going down to 0 ?g/dL. Ten percent of the samples were run in duplicate; at least 10% of the analyses were controls, and 10% were blanks. In tests on reference samples from the Centers for Disease Control and Prevention (Atlanta, GA), the precision (the coefficient of variation) ranged from 8% for concentrations between 10 and 30 ?g/dL to 1% for higher concentrations. In comparison with a National Bureau of Standards? target of 5.7 ?g/dL, 24 measurements by this method gave a mean of 5.3 ?g/dL with an SD of 1.23 ?g/dL.

Blood pressure measurements

During each clinical visit, a physician using a standard mercury sphygmomanometer with a 14-cm cuff measured the participant?s blood pressure. With the participant seated, the systolic blood pressure and fifth-phase diastolic blood pressure were measured once in each arm to the nearest 2 mmHg. For this study, the mean of the right and left arm measurements was used as each participant?s systolic and diastolic blood pressures. Pulse pressure was calculated as the mean systolic minus the mean diastolic blood pressure. Heart rate was recorded as beats per minute.

Physical parameters and medical history

For each clinical visit, the NAS participant reported to the study center in the morning after an overnight fast and abstinence from smoking. At the start of the visit, height and weight were measured. Thereafter, a physician took a complete medical history and confirmed the identity and purpose of medications taken daily. Medications were considered anti-hypertensive if they included a beta-blocker, calcium channel blocker, diuretic, or other vascular agent prescribed by the participant?s physician. The participant also indicated whether his mother or father had hypertension that was diagnosed by a physician. Alcohol and dietary intake were assessed with a standardized semiquantitative food frequency questionnaire (Willett et al. 1988), in which participants reported the average frequency of each listed food item consumed in the previous year. In the present study, we examined sodium and calcium intakes, which we calculated by multiplying the frequency of intake by the nutrient content of the food items. We solicited information on current and past history of smoking using questions developed for the American Thoracic Society (Ferris 1978).

Statistical analysis

The present analysis is a cross-sectional examination of the association of blood and bone lead levels with pulse pressure in subjects with these measurement made in the years 1991?1997. The participants for the present study were a subgroup of the NAS cohort who underwent at least one KXRF bone lead measurement and were not on antihypertensive therapy at the time of this measurement. Of the 1,262 men who were seen for their regularly scheduled visits between August 1991 and December 1997, 840 (66.6%) underwent KXRF measurement. The most common reason given for not having a measurement was the inconvenience involved in making another visit to the bone lead laboratory on a separate day. As a standard quality-control procedure, we excluded seven men who had high uncertainty estimates (> 10 ?g/g) for bone lead measurement (Hu et al. 1996b). A comparison of the group of men who had KXRF examinations with the group of men who either did not have KXRF examinations or whose bone lead measurements had a high degree of uncertainty revealed no significant differences with respect to age, race, body mass index (BMI), smoking, alcohol consumption, systolic or diastolic blood pressure, family history of hypertension, dietary sodium or calcium intake, and blood lead level (Cheng et al. 2001; Hu et al. 1996a). Among the 833 participants in the bone lead study, 233 were on antihypertensive therapy at the time of their study visit, and seven men did not have blood pressure data to calculate pulse pressure. We therefore included 593 men in this analysis. The blood pressure measurement typically preceded the lead determinations, and the median (interquartile range) number of days between these measurements was 18 (8?39).

For each of the two lead biomarkers (blood lead and tibia lead), we used multiple linear regression to compare the mean pulse pressure across quintiles of the lead biomarker. We used quintiles of lead level to limit the influence of outliers and to not assume a linear relationship between lead level and pulse pressure. We determined covariates for our core models based on known determinants of bone and blood lead level, blood pressure, risk factors for arterial aging, and physiologic determinants of pulse pressure. Our regression analyses were all adjusted for the following variables, all of which were assessed at the time of bone lead measurement: age (years), age squared, height (meters), race (white vs. nonwhite), heart rate (beats/minute), waist circumference (centimeters), diabetes, family history of hypertension (yes/no), education level achieved, smoking (pack-years), alcohol intake (grams per day), fasting plasma glucose (mmol), and ratio of total cholesterol to HDL (high-density lipoprotein) cholesterol (Hu et al. 1996a, 1996b; Kwagyan et al. 2005; Mahmud and Feely 2003; Miyagi et al. 2002; van Dijk et al. 2002). We did not adjust our analyses for systolic and diastolic blood pressure, from which the pulse pressure is mathematically derived. We used an F-test (with p = Pr[F5-1,593-5> F ]) to evaluate the overall association between level of lead biomarker and pulse pressure, and we computed tests of linear trend by fitting models with an ordinal term, which took on the values of each biomarker quintile (i.e., 1, 2, 3, 4, 5). We fit additional models that further adjusted for dietary sodium and calcium as well as total caloric intake.

All analyses were conducted with the SAS software program (version 8.2; SAS Institute Inc., Cary, NC) with p < 0.05 as the level of statistical significance. All authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.


The blood lead levels of the study population ranged from < 1 to 35 ?g/dL, with a mean (? SD) of 6.12 ? 4.03 ?g/dL. These values are representative of community-level (i.e., nonoccupational) exposure in the U.S. general population in this age range (Pirkle et al. 1994). The mean levels (? SD) of blood lead among the first through fifth quintiles were 2.3 ? 0.8, 3.9 ? 0.3, 5.4 ? 0.5, 7.4 ? 0.6, and 12.4 ? 4.4 ?g/dL, respectively. The mean levels of tibia lead among the first through the fifth quintiles were 7.4 ? 3.2, 14.1 ? 1.4, 18.9 ? 1.4, 24.9 ? 2.2, and 40.9 ? 14.0 ?g/g bone, respectively.

We examined participants? characteristics in relation to quintile of tibia lead level to provide insight into potential confounders of the association between lead and pulse pressure (Table 1). Of particular note, higher tibia lead level was associated with age, smoking, lower education level, and shorter height. None of these characteristics varied across quintile of blood lead level (data not shown) [see Hu et al. (1996b) for more details on determinants of bone and blood lead levels].

We examined the progression of systolic and diastolic blood pressure and pulse pressure with age, categorized in 5-year increments (Figure 1). As demonstrated in other industrialized populations, the systolic blood pressure and pulse pressure increased with age, whereas the diastolic blood pressure decreased after the sixth decade (Franklin et al. 1997; Lakatta and Levy 2003).

We evaluated unadjusted, age-adjusted, and multivariable-adjusted correlations of blood and bone lead levels with systolic and diastolic blood pressure (Table 2). Blood lead level tended to be directly associated with systolic and diastolic blood pressure. Tibia lead level tended to be directly associated with systolic blood pressure and tended to be inversely associated diastolic blood pressure. After multivariable adjustment, the direct association of blood lead with diastolic blood pressure remained significant.

We observed significant differences in pulse pressure across quintiles of bone lead but not blood lead after multivariable adjustment. Tibia lead?level quintile was significantly associated with pulse pressure (overall F-test, p < 0.01), with pulse pressure increasing with tibia lead?level quintile (ptrend = 0.02; Table 3). Men with tibia lead level above the median (19.0 ?g/gm) had, on average, a mean pulse pressure that was 4.2 mmHg greater [95% confidence interval (CI), 1.9?6.5] than men with tibia lead levels below the median. Blood lead was not associated with pulse pressure (overall F-test, p = 0.20). Dietary intake of sodium, dietary intake of calcium, and hematocrit were all added individually to our models but did not substantially change these results. In addition, we did not find a significant interaction between dietary calcium intake and tibia lead quintile in determining the pulse pressure. The association of patella lead with pulse pressure was of borderline statistical significance (data not shown).

Analyses were repeated excluding the 14 nonwhite participants; the association of tibia lead with pulse pressure was not changed. We performed additional analysis including men treated with antihypertensive therapy (total n = 826), and adjusting for antihypertensive therapy (using vs. not using). In this analysis, tibia lead level remained associated with pulse pressure (Overall F-test p = 0.02, ptrend = 0.04), though the effect of tibia lead quintile on pulse pressure was somewhat attenuated [highest vs. lowest quintile, difference in pulse pressure = 1.9 mmHg (95% CI, 1.4?5.1)].


In this study of 593 older men, cumulative community-level lead exposure was independently associated with increased pulse pressure. Specifically, we observed this association with respect to bone lead level, but not blood lead level. These results are consistent with the concept that bone lead level is a better indicator of cumulative lead exposure. These data may provide some mechanistic insight into the association of low-level lead exposure with cardiovascular mortality (Menke et al. 2006).

The pulse pressure?the difference between the systolic and the diastolic blood pressures?is receiving increasing attention as both an indicator of and a risk factor for cardiovascular disease (Safar et al. 2003). Our data support the well-described progression of pulse pressure with age, with progressively higher systolic pressures throughout adulthood, and the diastolic pressure leveling off among men in the sixth decade and declining in older men (Franklin et al. 1997).

The progression of pulse pressure with age is largely attributed to progressive aortic stiffening (Mitchell et al. 2004). Age-related arterial stiffening is attributable to structural and functional changes in the vasculature (Lakatta and Levy 2003). Structurally, vascular aging is associated with increased collagen content, increased elastin fractures, increased calcification, and reduced elastin content. Functionally, vascular aging is associated with impaired endothelial function and endothelium-dependent vasodilation (Gerhard et al. 1996). A fundamental and shared mechanism for vascular structural and functional changes is vascular oxidative stress (Lakatta 2003; Touyz 2004). Observations in lead-exposed animals strongly suggest that vascular oxidative stress plays a key role in the pathophysiology of lead-induced hypertension and vascular disease (Farmand et al. 2005; Malvezzi et al. 2001; Ni et al. 2004; Vaziri 2002; Vaziri and Ding 2001; Vaziri and Sica 2004; Vaziri et al. 1997, 1999a, 1999b, 2001, 2003). Human studies indicate that lead accumulates in the aorta (Barry and Mossman 1970; Schroeder and Tipton 1968) and that lead exposure is associated with oxidative stress in humans (Gurer-Orhan et al. 2004; Ye et al. 1999), although to our knowledge the association of lead exposure with vascular oxidative stress in humans has not been specifically examined.

In this study, tibia bone lead was more strongly associated with pulse pressure than was patella bone lead (data not shown). The tibia bone is mostly cortical bone, whereas the patella is mostly trabecular bone and has a greater turnover rate (Hu et al. 1996b). Tibia lead has a longer half-life and is considered a better marker of cumulative lead exposure than patella lead. The stronger association of tibia lead with pulse pressure is consistent with an effect of long-term lead exposure on vascular structure and function. Interestingly, blood lead level was positively associated with diastolic blood pressure, causing us to speculate that circulating lead may have more of an influence on vascular tone than vascular structure, though this requires further exploration.

We found that men with bone lead levels above the median had pulse pressures that were on average 4.2 mmHg higher compared with men with lower bone lead levels. The magnitude of this association is numerically small but potentially clinically significant. In the Conduit Artery Function Evaluation (CAFE) study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) comparing amlodipine ? perindopril versus atenolol ? thiazide in the treatment of hypertension, a 3-mmHg decrement in central pulse pressure conferred a cardiorenal advantage to the amlodipine ? perindopril strategy (Williams et al. 2006). Pulse pressure is an important indicator of cardiovascular risk becasue pulse pressure is associated with inflammation (Abramson et al. 2002), coronary heart disease (Franklin et al. 1999), and cardiovascular death (Domanski et al. 2001). The association we have demonstrated between lead exposure and pulse pressure may provide mechanistic insight into the association of lead exposure with cardiovascular death (Menke et al. 2006).

Because this is a cross-sectional study, we cannot explicitly examine the temporal association between lead exposure and subsequent pulse pressure or individual changes in pulse pressure. Nonetheless, our bone lead measures, particularly tibia lead, do reflect exposures that occurred over the past years to decades, suggesting a temporal ordering of the association that we observed between bone lead and pulse pressure. Moreover, reverse causation?the situation in which pulse pressure affects lead exposure?is highly unlikely. Blood pressure was measured once in each arm; averaging these values increases the precision of our measurement. It is possible, however, that differences in the blood pressure between the arms due to subclavian stenosis or other processes may introduce error into our blood pressure determination and limit the precision of our lead effect estimates. Although our results were adjusted for numerous important potential confounders, we cannot rule out the possibility that the association we found derives from confounding by unmeasured factors or that categorical tibia lead level may not entirely account for the association of bone lead with aging. The data suggest that there may be a threshold to the effect of lead exposure on pulse pressure, because only the top two quintiles of tibia lead were associated with a mean pulse pressure greater than that of the first quintile. It is possible that selective survival biased our findings in this older cohort of men, in that survival may be related to lower lead exposures and lower pulse pressure; even so, such bias would tend to make our results a conservative estimate of the adverse association between bone lead and pulse pressure.

Although lead exposure has been associated with elevated blood pressure in women (Nash et al. 2003) and blacks (Vupputuri et al. 2003), our findings are limited to Caucasian men. This cohort of men had exposures to lead before major public health reforms that removed lead from paint and gasoline, and they may have been further exposed in their military careers, making their typical historical exposures higher than current exposure levels. A sufficient threshold of arterial aging needs to be achieved before brachial pulse pressure begins to widen; therefore, the association of lead and pulse pressure may not be present in younger populations (O?Rourke and Hashimoto 2007). Also, in older populations, the association of lead exposure with pulse pressure may be attenuated by selective survival, because both lead exposure and pulse pressure are strong predictors of mortality (Domanski et al. 2001; Schober et al. 2006). Finally, studies directly examining the association of lead exposure with vascular function and pulse hemodynamics are necessary to better define the relationship between lead exposure and arterial aging.

In conclusion, we found that cumulative lead exposure, as reflected by bone lead level, was independently associated with increased pulse pressure in a cohort of middle-aged and older men with community-level lead exposure. These findings implicate vascular accumulation of lead in the pathogenesis of vascular stiffening, a mechanism consistent with the findings of aortic lead deposition in humans and increased vascular oxidative stress in the lead-exposed animal. Future work will determine the effect of lead exposure on the progression of pulse pressure with aging. We suggest that further examinations of the association of lead exposure on arterial pressure should use bone lead level as an indicator of cumulative lead exposure.


This research was supported by National Institutes of Health (NIH) grants T32 HL007609, R01-ES05257, P20-MD000501, P42-ES05947, and GCRC M01-RR02635. The Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center, U.S. Department of Veterans Affairs. The KXRF instrument used was developed by ABIOMED, Inc. (Danvers, MA) with NIH grant support (ES03918-02).

Abramson JL,Weintraub WS,Vaccarino V. 2002;Association between pulse pressure and C-reactive protein among apparently healthy US adultsHypertension 39:197–202. [pmid: 11847183]
Barry PS,Mossman DB. 1970;Lead concentrations in human tissuesBr J Ind Med 27:339–351. [pmid: 5488693]
Burger DE,Milder FL,Morsillo PR,Adams BB,Hu H. 1990;Automated bone lead analysis by K-x-ray fluorescence for the clinical environmentBasic Life Sci 55:287–292. [pmid: 2088281]
Cheng Y,Schwartz J,Sparrow D,Aro A,Weiss ST,Hu H. 2001;Bone lead and blood lead levels in relation to baseline blood pressure and the prospective development of hypertension: the Normative Aging StudyAm J Epidemiol 153:164–171. [pmid: 11159162]
Domanski M,Norman J,Wolz M,Mitchell G,Pfeffer M. 2001;Cardiovascular risk assessment using pulse pressure in the first National Health and Nutrition Examination Survey (NHANES I)Hypertension 38:793–797. [pmid: 11641288]
Drasch GA. 1982;Lead burden in prehistorical, historical and modern human bonesSci Total Environ 24:199–231. [pmid: 7123205]
Farmand F,Ehdaie A,Roberts CK,Sindhu RK. 2005;Lead-induced dysregulation of superoxide dismutases, catalase, glutathione peroxidase, and guanylate cyclaseEnviron Res 98:33–39. [pmid: 15721881]
Ferris BG. 1978;Epidemiology Standardization Project (American Thoracic Society)Am Rev Respir Dis 118:1–120. [pmid: 742764]
Franklin SS,Gustin W,Wong ND,Larson MG,Weber MA,Kannel WB,et al. 1997;Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart StudyCirculation 96:308–315. [pmid: 9236450]
Franklin SS,Khan SA,Wong ND,Larson MG,Levy D. 1999;Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham Heart StudyCirculation 100:354–360. [pmid: 10421594]
Gerhard M,Roddy MA,Creager SJ,Creager MA. 1996;Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humansHypertension 27:849–853. [pmid: 8613259]
Gordon CL,Chettle DR,Webber CE. 1993;An improved instrument for the in vivo detection of lead in boneBr J Ind Med 50:637–641. [pmid: 8343425]
Gurer-Orhan H,Sabir HU,Ozgunes H. 2004;Correlation between clinical indicators of lead poisoning and oxidative stress parameters in controls and lead-exposed workersToxicology 195:147–154. [pmid: 14751670]
Hu H,Aro A,Payton M,Korrick S,Sparrow D,Weiss ST,et al. 1996a;The relationship of bone and blood lead to hypertension. The Normative Aging StudyJAMA 275:1171–1176. [pmid: 8609684]
Hu H,Milder FL,Burger DE. 1990a;X-ray fluorescence measurements of lead burden in subjects with low-level community lead exposureArch Environ Health 45:335–341. [pmid: 2270952]
Hu H,Payton M,Korrick S,Aro A,Sparrow D,Weiss ST,et al. 1996b;Determinants of bone and blood lead levels among community-exposed middle-aged to elderly men. The Normative Aging StudyAm J Epidemiol 144:749–759. [pmid: 8857824]
Hu H,Tosteson T,Aufderheide AC,Wittmers L,Burger DE,Milder FL,et al. 1990b;Distribution of lead in human bone: I. Atomic absorption measurementsBasic Life Sci 55:267–274. [pmid: 2088278]
Khalil-Manesh F,Gonick HC,Weiler EW,Prins B,Weber MA,Purdy RE. 1993;Lead-induced hypertension: possible role of endothelial factorsAm J Hypertens 6:723–729. [pmid: 8110424]
Kim R,Aro A,Rotnitzky A,Amarasiriwardena C,Hu H. 1995;K x-ray fluorescence measurements of bone lead concentration: the analysis of low-level dataPhys Med Biol 40:1475–1485. [pmid: 8532760]
Kwagyan J,Tabe CE,Xu S,Maqbool AR,Gordeuk VR,Randall OS. 2005;The impact of body mass index on pulse pressure in obesityJ Hypertens 23:619–624. [pmid: 15716705]
Lakatta EG. 2003;Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part III: cellular and molecular clues to heart and arterial agingCirculation 107:490–497. [pmid: 12551876]
Lakatta EG,Levy D. 2003;Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a ?set up? for vascular diseaseCirculation 107:139–146. [pmid: 12515756]
Mahmud A,Feely J. 2003;Effect of smoking on arterial stiffness and pulse pressure amplificationHypertension 41:183–187. [pmid: 12511550]
Malvezzi CK,Moreira EG,Vassilieff I,Vassilieff VS,Cordellini S. 2001;Effect of l-arginine, dimercaptosuccinic acid (DMSA) and the association of l-arginine and DMSA on tissue lead mobilization and blood pressure level in plumbismBraz J Med Biol Res 34:1341–1346. [pmid: 11593311]
Menke A,Muntner P,Batuman V,Silbergeld EK,Guallar E. 2006;Blood lead below 0.48 {micro}mol/L (10 {micro}g/dL) and mortality among US adultsCirculation 114:1388–1394. [pmid: 16982939]
Mitchell GF,Parise H,Benjamin EJ,Larson MG,Keyes MJ,Vita JA,et al. 2004;Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart StudyHypertension 43:1239–1245. [pmid: 15123572]
Miyagi T,Muratani H,Kimura Y,Fukiyama K,Kawano Y,Fujii J,et al. 2002;Increase in pulse pressure relates to diabetes mellitus and low HDL cholesterol, but not to hyperlipidemia in hypertensive patients aged 50 years or olderHypertens Res 25:335–341. [pmid: 12135310]
Muntner P,Menke A,DeSalvo KB,Rabito FA,Batuman V. 2005;Continued decline in blood lead levels among adults in the United States: the National Health and Nutrition Examination SurveysArch Intern Med 165:2155–2161. [pmid: 16217007]
Nash D,Magder L,Lustberg M,Sherwin RW,Rubin RJ,Kaufmann RB,et al. 2003;Blood lead, blood pressure, and hypertension in perimenopausal and postmenopausal womenJAMA 289:1523–1532. [pmid: 12672769]
Navas-Acien A,Silbergeld EK,Guallar E,Rothenberg SJ. 2007;Lead exposure and cardiovascular disease?a systematic reviewEnviron Health Perspect 115:472–482. [pmid: 17431501]
Nawrot TS,Thijs L,Den Hond EM,Roels HA,Staessen JA. 2002;An epidemiological re-appraisal of the association between blood pressure and blood lead: a meta-analysisJ Hum Hypertens 16:123–131. [pmid: 11850770]
Ni Z,Hou S,Barton CH,Vaziri ND. 2004;Lead exposure raises superoxide and hydrogen peroxide in human endothelial and vascular smooth muscle cellsKidney Int 66:2329–2336. [pmid: 15569323]
O?Rourke MF,Hashimoto J. 2007;Mechanical factors in arterial agingJ Am Coll Cardiol 50:1–13. [pmid: 17601538]
Pirkle JL,Brody DJ,Gunter EW,Kramer RA,Paschal DC,Flegal KM,et al. 1994;The decline in blood lead levels in the United States. The National Health and Nutrition Examination Surveys (NHANES)JAMA 272:284–291. [pmid: 8028141]
Safar ME,Levy BI,Struijker-Boudier H. 2003;Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseasesCirculation 107:2864–2869. [pmid: 12796414]
Schober SE,Mirel LB,Graubard BI,Brody DJ,Flegal KM. 2006;Blood lead levels and death from all causes, cardiovascular disease, and cancer: results from the NHANES III mortality studyEnviron Health Perspect 114:1538–1541. [pmid: 17035139]
Schroeder HA,Tipton IH. 1968;The human body burden of leadArch Environ Health 17:965–978. [pmid: 4177349]
Schwartz J. 1991;Lead, blood pressure, and cardiovascular disease in men and womenEnviron Health Perspect 91:71–75. [pmid: 1828226]
Schwartz J. 1995;Lead, blood pressure, and cardiovascular disease in menArch Environ Health 50:31–37. [pmid: 7717767]
Staessen JA,Bulpitt CJ,Fagard R,Lauwerys RR,Roels H,Thijs L,et al. 1994;Hypertension caused by low-level lead exposure: myth or fact?J Cardiovasc Risk 1:87–97. [pmid: 7614423]
Touyz RM. 2004;Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance?Hypertension 44:248–252. [pmid: 15262903]
van Dijk RA,van Ittersum FJ,Westerhof N,van Dongen EM,Kamp O,Stehouwer CD. 2002;Determinants of brachial artery mean 24 h pulse pressure in individuals with Type II diabetes mellitus and untreated mild hypertensionClin Sci (Lond) 102:177–186. [pmid: 11834137]
Vaziri ND. 2002;Pathogenesis of lead-induced hypertension: role of oxidative stressJ Hypertens 20(suppl 3):S15–S20.
Vaziri ND,Ding Y. 2001;Effect of lead on nitric oxide synthase expression in coronary endothelial cells: role of superoxideHypertension 37:223–226. [pmid: 11230275]
Vaziri ND,Ding Y,Ni Z. 1999a;Nitric oxide synthase expression in the course of lead-induced hypertensionHypertension 34:558–562. [pmid: 10523326]
Vaziri ND,Ding Y,Ni Z. 2001;Compensatory up-regulation of nitricoxide synthase isoforms in lead-induced hypertension; reversal by a superoxide dismutase-mimetic drugJ Pharmacol Exp Ther 298:679–685. [pmid: 11454931]
Vaziri ND,Ding Y,Ni Z,Gonick HC. 1997;Altered nitric oxide metabolism and increased oxygen free radical activity in lead-induced hypertension: effect of lazaroid therapyKidney Int 52:1042–1046. [pmid: 9328943]
Vaziri ND,Liang K,Ding Y. 1999b;Increased nitric oxide inactivation by reactive oxygen species in lead-induced hypertensionKidney Int 56:1492–1498. [pmid: 10504500]
Vaziri ND,Lin CY,Farmand F,Sindhu RK. 2003;Superoxide dismutase, catalase, glutathione peroxidase and NADPH oxidase in lead-induced hypertensionKidney Int 63:186–194. [pmid: 12472782]
Vaziri ND,Sica DA. 2004;Lead-induced hypertension: role of oxidative stressCurr Hypertens Rep 6:314–320. [pmid: 15257867]
Victery W,Vander AJ,Shulak JM,Schoeps P,Julius S. 1982;Lead, hypertension, and the reninangiotensin system in ratsJ Lab Clin Med 99:354–362. [pmid: 7057062]
Vupputuri S,He J,Muntner P,Bazzano LA,Whelton PK,Batuman V. 2003;Blood lead level is associated with elevated blood pressure in blacksHypertension 41:463–468. [pmid: 12623944]
Willett WC,Sampson L,Browne ML,Stampfer MJ,Rosner B,Hennekens CH,et al. 1988;The use of a self-administered questionnaire to assess diet four years in the pastAm J Epidemiol 127:188–199. [pmid: 3337073]
Williams B,Lacy PS,Thom SM,Cruickshank K,Stanton A,Collier D,et al. 2006;Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) studyCirculation 113:1213–1225. [pmid: 16476843]
Ye XB,Fu H,Zhu JL,Ni WM,Lu YW,Kuang XY,et al. 1999;A study on oxidative stress in lead-exposed workersJ Toxicol Environ Health A 57:161–172. [pmid: 10376883]

Article Categories:
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Keywords: aging, epidemiology, human, lead exposure, pulse pressure.

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