American Journal of Epidemiology

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American Journal of Epidemiology Vol. 153, No. 2 : 164-171
Copyright © 2001 by The Johns Hopkins University School of Hygiene and Public Health

ORIGINAL CONTRIBUTION

Bone Lead and Blood Lead Levels in Relation to Baseline Blood Pressure and the Prospective Development of Hypertension The Normative Aging Study

Yawen Cheng¹, Joel Schwartz², David Sparrow³, Antonio Aro^1,2, Scott T. Weiss^1,2 and Howard Hu^1,2

¹ Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
² Department of Environmental Health, Harvard School of Public Health, Boston, MA.
³ The Normative Aging Study, Department of Veterans Affairs Outpatient Clinic, Boston, MA.

	ABSTRACT

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Between 1991 and 1997, the authors studied 833 participants of the Normative Aging Study in a substudy of bone lead levels (measured by K-shell x-ray fluorescence), blood lead levels, and hypertension. Among these subjects, 337 were classified as normotensive, and 182 and 314 were classified as having borderline and definite hypertension, respectively, at baseline. These bone and blood lead levels were typical of those of community-exposed men. Among the 519 subjects with no history of definite hypertension at baseline, cross-sectional analyses revealed positive associations between systolic blood pressure and bone lead levels. Of the 474 subjects who were free from definite hypertension at baseline and had follow-up data, 74 new cases of definite hypertension were reported. Baseline bone lead levels were positively associated with incidence of hypertension. In proportional hazards models that controlled for age, age squared, body mass index, and family history of hypertension, an increase in patella (trabecular) lead from the midpoint of the lowest quintile to that of the highest quintile was associated with a rate ratio of definite hypertension of 1.71 (95% confidence interval: 1.08, 2.70). No association was found with blood lead level. These results support the hypothesis that cumulative exposure to lead, even at low levels sustained by the general population, may increase the risk of hypertension.

bone and bones; hypertension; lead; proportional hazards models

Abbreviations: CI, confidence interval; KXRF, K-shell x-ray fluorescence.

	INTRODUCTION

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The last two decades have seen a number of studies examining the possible relation between low-level lead exposure and blood pressure. This topic has been intensively reviewed (1–5). Recent epidemiologic studies in population settings and occupational cohorts have produced mixed results but overall suggest a small elevation of blood pressure in association with increased blood lead level. The causal nature of this relation and the direct impact of low-level lead exposure on cardiovascular outcomes remain controversial, however (6, 7). A major criticism of the existing epidemiologic data concerns the limitations of inferring causality from predominantly cross-sectional data. It has been argued that the observed association could be related to parallel declines in blood pressure and blood lead level, which have been seen in the United States as well as in many other industrialized countries over the past few decades. Since most of the epidemiologic studies were cross-sectional, inferring causality from this association may be premature.

One possible explanation for the weak and inconsistent association found in previous studies is that the level of lead in blood, which reflects very recent exposure, may not provide the most relevant estimate of overall exposure. Up to 95 percent of the total body lead burden in adults is known to accumulate in the skeleton (8). Bone lead undergoes constant interchange with lead circulating in the blood and soft tissues. During times of increased bone turnover, more lead can be released from these bone stores (9, 10). Thus, the issue arises of whether the bone lead level better represents the total body lead burden that is most biologically relevant to chronic lead toxicity. The reliance of most epidemiologic studies primarily on the concurrent blood lead concentration as the measure of lead exposure has hindered efforts to elucidate the cumulative effects of low-level lead exposure.

Even a small elevation of blood pressure in association with low-level lead exposure has significant public health consequences, given the ubiquity of such exposure in the general population and the predominance of cardiovascular disease as a cause of disability and death in all industrialized countries. With recently developed in vivo K-shell x-ray fluorescence (KXRF) instruments, we measured lead concentrations in the patella and tibia in a cohort of middle-aged to elderly men with community levels of lead exposure. A cross-sectional study we published earlier revealed significant associations of bone lead levels and the risk of hypertension in subjects of this cohort (11). Some criticisms of this study have arisen, however (12): the cutoff points for hypertension may be arbitrarily defined; analyses were done on the prevalence instead of the incidence of hypertension; and the temporal inference was difficult to establish because of the cross-sectional nature of the study design. In the present study, we addressed these concerns using a larger number of study subjects from an extended period of recruitment. We again examined the cross-sectional associations between lead exposure and hypertension, but we used continuous measures of blood pressure among subjects who were free from definite hypertension. In addition, we further examined the prospective relation of the baseline lead exposure level to the incidence of hypertension. The measurement of lead levels in the blood and at both bone sites helped us to clarify the role of long-term versus short-term lead exposure, and a longitudinal study design allowed us to address the issue of a temporal relation.

	MATERIALS AND METHODS

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Study population
Participants were from the Normative Aging Study, a longitudinal study of aging established by the Veterans Administration in 1963 (13). Male volunteers from the Greater Boston 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 of >140 mmHg or a diastolic blood pressure of >90 mmHg at screening were disqualified. Between 1963 and 1968, a total of 2,280 men who met the entry criteria were enrolled; their ages at entry ranged from 21 to 80 years, with a mean of 42 years. Participants were asked to return for follow-up examinations every 3–5 years. At each visit, an extensive physical examination was conducted, and laboratory, anthropometric, and questionnaire data were collected. Beginning in 1991, during each continuing participant's regularly scheduled evaluation at the Veterans Administration Outpatient Clinic in Boston, a fresh blood specimen was obtained for measurement of lead, and permission was sought for KXRF bone lead measurements. Consenting individuals reported to the outpatient Clinical Research Center of the Brigham and Women's Hospital in Boston.

Bone and blood lead measurements
Bone lead was measured at two sites (the midtibial shaft and the patella) with a KXRF instrument (ABIOMED, Inc., Danvers, Massachusetts). The tibia and patella have been targeted for bone lead research because these two bones consist mainly of pure cortical and pure trabecular bone, respectively, and therefore reflect the two main bone compartments. The physical principles, technical specifications, and validation of this instrument have been described in detail elsewhere (14, 15). Since the instrument provides a continuous unbiased point estimate (as micrograms of lead per gram of bone mineral) that oscillates around the true bone lead value, negative point estimates are sometimes produced 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 single standard deviation if multiple measurements were taken. Although a minimally detectable limit calculation of twice this value has been proposed for interpreting an individual's bone lead estimate (16), retention of all point estimates has been shown to make better use of the data in epidemiologic studies (17). For our study, 30-minute measurements were taken at the midshaft of the left tibia and at the left patella. The technicians measuring bone lead were blinded to the participants' health status.

Blood samples were obtained and analyzed by graphite furnace atomic absorption spectroscopy; this instrument (GF-AAS; ESA Laboratories, Chelmsford, Massachusetts) was calibrated after every 21 samples with National Bureau of Standards' blood lead standards materials. Ten percent of the samples were run in duplicate; at least 10 percent of the analyses were controls, and 10 percent were blanks. In tests on reference samples from the Centers for Disease Control and Prevention, the precision (the coefficient of variation) ranged from 8 percent for concentrations between 10 and 30 µg/dl to 1 percent for higher concentrations. In comparison with a National Bureau of Standards' target of 5.7 µg/dl, 24 measurements by this method gave a mean of 5.3 µg/dl with a standard deviation of 1.23 µg/dl.

History and physical parameters
Each Normative Aging Study 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 complete medical history was taken by a physician. The identity and purpose of medications taken daily were confirmed. Medications were considered antihypertensive if they include a ß-blocker, calcium channel blocker, diuretic, or other vascular agent prescribed by the subject's physician for hypertension. The participant was also asked if his mother or father had hypertension diagnosed by a physician. Dietary intake was assessed with a standardized semiquantitative food frequency questionnaire (18). Participants provided information on the average frequency of each listed food item consumed in the previous year. Nutrient intakes were calculated by multiplying the frequency of intake by the nutrient content of the food items. In the present study, the nutrients examined were sodium and calcium, which were adjusted for total energy intake. Information on educational level and on current and past smoking and alcohol consumption was also obtained by questionnaire.

Blood pressure was measured by a physician using a standard mercury sphygmomanometer with a 14-cm cuff. With the subject seated, the systolic blood pressure and fifth-phase diastolic blood pressure were measured in each arm to the nearest 2 mmHg. The means of the right- and left-arm measurements were used as each participant's systolic and diastolic blood pressures. For this study, definite hypertension was defined as an average systolic blood pressure higher than 160 mmHg or diastolic blood pressure higher than 95 mmHg or taking daily medication for the treatment of hypertension. Borderline hypertension encompassed a systolic blood pressure of 141–160 mmHg or a diastolic blood pressure of 91–95 mmHg. Normotension was a blood pressure not higher than 140 mmHg and a diastolic blood pressure not higher than 90 mmHg during the time of examination.

Statistical analysis
The subjects for the present study were a subgroup of the Normative Aging Study population who underwent at least one KXRF bone lead measurement. As a standard quality-control procedure (11), we excluded subjects who had uncertainty estimates for tibia or patella lead measurements of 10 or 15 µg/g, respectively. Subjects with a history of hypertension at baseline, i.e., at the time of initial bone lead measurement, were excluded from the follow-up analysis.

Multivariate linear regression models were used to assess the association of bone lead and blood lead levels with baseline blood pressure, and the effect of lead exposure on the incidence of hypertension was analyzed by a Cox proportional hazards model. The follow-up period started at the time of the first bone lead measurement and lasted until the time of hypertension diagnosis, censoring (last Veterans Administration clinic visit or death), or December 31, 1997, whichever came first. Possible confounding factors considered were age and age squared, body mass index (weight (kg)/height (m)²), family history of hypertension, race, educational level, pack-years of smoking, alcohol consumption (g/day), and dietary intakes of sodium and calcium (mg/day). These variables were measured at the time of bone lead measurement. For both cross-sectional and longitudinal analyses, baseline models were first constructed in which the outcome variables (blood pressure in the linear regression models and incidence of hypertension in the Cox proportional hazards models) were regressed on age, age squared, body mass index, and family history of hypertension. These variables were selected on the basis of their biologic significance and information from previous studies (3, 11). Each of the three lead biologic markers (blood lead, tibia lead, and patella lead) was then added separately to the baseline models to examine its relation to the outcome variables. The effects of other covariates were examined in bivariate models that adjusted for age, and their potential confounding effects on the association of lead exposure and outcome variables were assessed by their individual inclusion into the models. Covariates that met the 0.05 significance level in bivariate models or that changed the beta coefficients of lead exposure to up to 20 percent were included in the final models. All analyses were conducted with the Statistical Analysis System software program (SAS Institute, Inc., Cary, North Carolina).

	RESULTS

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Of the 1,262 subjects who were seen for their regularly scheduled visits between August 1991 and December 1997, 840 (66.6 percent) participated in the KXRF bone lead substudy and had data available on all variables of interest. The most common reason given for nonparticipation was the inconvenience involved in making another visit to the bone lead laboratory on a separate day. We excluded seven subjects who had uncertainty estimates for tibia or patella lead measurements of 10 or 15 µg/g, respectively. A comparison of participants (n = 833) with nonparticipants or participants with high uncertainty levels in bone lead measurement (n = 429) revealed no significant differences with respect to age, race, body mass index, pack-years of smoking, average alcohol consumption, systolic or diastolic blood pressure, family history of hypertension, dietary sodium or calcium intake, and blood lead level. The blood lead levels of the study population were low, ranging from <1 to 35 µg/dl, with a mean of 6.09 (standard deviation, 4.03) µg/dl, values representative of the US general population in this age range (19).

Among the 833 participants in the bone lead study, 337 were free from hypertension, 182 were classified as having borderline hypertension, and 314 were classified as having definite hypertension at baseline. As shown in table 1, subjects with borderline or definite hypertension were older, having a higher body mass index and a higher alcohol consumption level, and more likely to have a family history of hypertension when compared with the normotensive group. However, there are no apparent differences across groups in race, educational level, occupation level, and cumulative smoking level. The mean levels of blood lead, tibia lead, and patella lead appeared to be higher in the two hypertensive groups when compared with the normotensive group.

View this table: [in this window] [in a new window]   TABLE 1. Characteristics and lead exposure levels of subjects by hypertension status at the time of the first bone lead measurement, Normative Aging Study, from August 1, 1991, to December 31, 1997

 
The cross-sectional distributions of baseline blood pressures and lead exposure levels were examined among the 519 subjects who were free from definite hypertension at baseline. As shown in table 2, age, body mass index, and family history of hypertension were important predictors of baseline systolic blood pressure. Increased alcohol consumption and lower dietary calcium intakes were also found to be associated with increased systolic blood pressure. In addition, a significant positive association of systolic blood pressure was observed with the tibia lead level. A positive association was noticed with patella lead, although it was not statistically significant.

View this table: [in this window] [in a new window]   TABLE 2. Regression coefficients and 95% confidence intervals (CIs) from the multiple regression models of systolic blood pressure among participants in the Normative Aging Study who were free from definite hypertension at baseline (n = 519), from August 1, 1991, to December 31, 1997

 
Among the 519 subjects with no history of definite hypertension at baseline, 474 had returned for their next visits before December 31, 1997, and therefore had follow-up data (from one subsequent visit) available for the follow-up analyses. Of the 474 subjects who had follow-up data, 74 new cases of definite hypertension were observed during a follow-up period of 1,417.7 person-years. Table 3 shows the results of the Cox proportional hazards models' predictions of the incidence of definite hypertension. After adjustment for age, age squared, body mass index, and family history of hypertension, increases in tibia lead and patella lead for a standard deviation (13.65 µg/g for tibia lead and 19.55 µg/g for patella lead) were associated with a rate ratio of 1.22 (95 percent confidence interval (CI): 0.95, 1.57) and a rate ratio of 1.29 (95 percent CI: 1.04, 1.61), respectively. Increases in tibia lead and patella lead levels from the midpoint of the lowest quintile (8.5 µg/g for tibia lead and 12.0 µg/g for patella lead) to the midpoint of the highest quintile (36.0 µg/g for tibia lead and 53.0 µg/g for patella lead) were associated with rate ratios of 1.49 (95 percent CI: 0.89, 1.49) and 1.71 (95 percent CI: 1.08, 2.70), respectively. No association was found with the blood lead level, however. Increases in age and body mass index and having a family history of hypertension were associated with a slightly increased rate of definite hypertension, although these associations did not achieve statistical significance. None of the other variables (race, pack-years of smoking, alcohol consumption, educational level, and dietary intake of sodium and calcium) predicted the incidence of hypertension nor did their inclusion in the models change the regression coefficients of bone or blood lead levels to a notable extent. The associations changed little when age squared alone or both the age and age squared terms were dropped from the models.

View this table: [in this window] [in a new window]   TABLE 3. Results of Cox's proportional hazards models of incident definite hypertension in relation to lead biomarkers in subjects with no history of definite hypertension at baseline (n = 474), Normative Aging Study, from August 1, 1991, to December 31, 1997

 
Since higher bone lead levels were associated with increased baseline systolic blood pressure in this population, one might be concerned that the observed longitudinal association was secondary to a cross-sectional association between lead exposure level and baseline blood pressure. We examined this possibility by including baseline systolic blood pressure in the multivariate models. As expected, baseline systolic blood pressure was a strong predictor of the future occurrence of hypertension in this population. The rate ratio of definite hypertension associated with every 10-mmHg increase in baseline systolic blood pressure was 1.25 (95 percent CI: 1.04, 1.52). Nevertheless, rate ratios associated with bone lead remained elevated when baseline systolic blood pressure was included in the models: increases in tibia lead and patella lead for a standard deviation corresponded with rate ratios of definite hypertension of 1.21 (95 percent CI: 0.92, 1.58) and 1.28 (95 percent CI: 1.02, 1.61), respectively.

Analyses were also repeated after further excluding subjects who were classified as borderline hypertensive at baseline. A total of 62 new cases of hypertension (borderline and definite combined) were observed of 306 subjects during a follow-up period of 922.4 person-years. Table 4 summarizes the results of the Cox proportional hazards models. Although the sample size is smaller, the magnitude of effect of bone lead on the hypertension rate appears even stronger.

View this table: [in this window] [in a new window]   TABLE 4. Results of Cox's proportional hazards models of incident hypertension (borderline and definite combined) in relation to lead biomarkers in subjects who were classified as normotensive at baseline (n = 306), Normative Aging Study, from August 1, 1991, to December 31, 1997

 

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this prospective cohort study of men with community lead exposure, we examined the cross-sectional association of bone lead and blood lead levels with blood pressure at baseline, as well as the prospective incidence rate of hypertension in relation to baseline bone lead and blood lead levels. The results of our cross-sectional analyses suggested a positive association between bone lead levels and systolic blood pressure, even when the effects of age along with other possible confounding factors were controlled in the regression models. The longitudinal analyses also suggested that the baseline bone lead level predicted future development of hypertension, after adjustment of age, body mass index, and family history of hypertension. Consistent with our previous cross-sectional study (11), our data support the hypothesis that long-term lead accumulation may increase blood pressure and the risk of hypertension, and bone lead appears to be a better predictor in the associations.

Compared with the subjects who did not participate in the bone lead substudy, the study participants had relatively comparable levels of blood pressures and blood lead that are direct indicators for lead exposure and hypertension risk. Thus, the selection of study subjects from this cohort is unlikely to have been influenced by either exposure or the risk of hypertension.

Many determinants of bone and blood lead levels have also been shown to influence blood pressure and the risk of cardiovascular disease. These include age, body mass index, cigarette smoking status, alcohol consumption level, heredity, race, socioeconomic factors, and some nutritional factors (e.g., sodium and calcium intakes) (1, 3). In a previous study in the same population, we found that higher levels of bone lead were associated with older age, higher levels of cumulative smoking and alcohol consumption, lower levels of education, and lower levels of dietary calcium and vitamin D intakes (20, 21). The potential effects of these factors were evaluated in this study. The results of this study showed that, in multivariate regression models, age, body mass index, family history of hypertension, and intake levels of alcohol and calcium were important predictors of blood pressure in cross-sectional analyses; however, they were not so in longitudinal analyses of hypertension incidence. The inconsistencies might be due to a poorer study power in the longitudinal analysis because of a much smaller study size. In addition, by converting a continuous feature (blood pressure) into a dichotomized measure (hypertension), the power of the longitudinal study might have been further reduced. No association was found among several important predictors of hypertension, such as cigarette smoking, educational level, and race, in the multivariate regression models. The significance of these variables might have been masked because of a strong colinearity with lead exposure.

Tibia bone lead was found to be more consistently associated with systolic blood pressure in the cross-sectional analysis, whereas patella bone lead was found to be more significantly associated with the development of hypertension in the longitudinal analysis. Unlike the tibia bone, which is made up mostly of cortical bone, the patella bone is made up mostly of trabecular bone and is known to have a much greater turnover rate with consequent mobilization of bone lead (22). Thus, one could interpret the findings of our study to suggest that the current blood pressure was more dependent on long-term lead stores than mobilizable lead stores, whereas future development of hypertension was dependent more on mobilizable lead stores than on long-term lead stores. On the other hand, this may risk overinterpretation of our findings, since patella lead measurements are also known to have higher uncertainties than tibia lead measurements (23).

Most experimental studies have shown that moderate exposure to lead increases blood pressure in animals (24–27). The particular target tissue for an effect of lead on blood pressure has not yet been established, but several biologic mechanisms have been suggested. The two major modes of action identified are direct effects on end-arterial smooth muscle mediated through disturbed calcium metabolism and effects on the renin-angiotensin axis (1). In addition, both in vivo and in vitro studies have revealed that lead may interact with vasoactive agents. For instance, increased reactivity to -adrenergic stimulation has been observed in lead-exposed animals (28). In the present study, bone lead, but not blood lead, was associated with an increased incidence of hypertension, suggesting that the hypertensive effect of lead is more likely to be a chronic than an acute phenomenon. On the other hand, recent research has suggested that plasma lead (which is difficult to measure, constitutes less than 1 percent of circulating lead, but is the fraction of circulating lead that was unbound and most biologically available) may vary considerably in relation to whole blood lead levels, which mostly reflect lead bound to red blood cells (29, 30). Moreover, bone lead levels appear to independently influence plasma lead levels (22, 29, 30). Thus, the effect of bone lead levels in this study may be a function of an ongoing and direct effect of plasma lead on vascular smooth muscle.

The longitudinal nature of this study has enabled us to minimize the potential for biases that are often encountered in cross-sectional or case-control studies and to establish more clearly the temporal nature of the association. Our cross-sectional examination of baseline blood pressure by lead exposure categories suggested that the inverse association between bone lead level and systolic blood pressure seemed to be more apparent in younger men. However, our sample size is too small to assess for the possible modifying effect of age on the association of lead exposure and hypertension. Such an effect was documented in a study based on cross-sectional data from the Second National Health and Nutrition Examination Survey, in which the blood lead-blood pressure association was most notable in younger age groups (31).

In conclusion, this prospective study suggests that the cumulative lead exposure in the general population, as reflected by bone lead levels, may increase the incidence of hypertension. As hypertension is a leading risk factor for morbidity and mortality due to cardiovascular disease in all developed countries, this effect, if causal, may have a great public health impact. Moreover, rapid industrialization and the continued use of leaded gasoline appear to be increasing lead exposure throughout the developing world, such as Latin America (32). Further research will be needed to confirm our findings and to study their direct impact on cardiovascular outcomes.

	ACKNOWLEDGMENTS

 
Support for this research was provided by grants ES 05257-06A1 and P42-ES05947 project 4 and Occupational and Environmental Health Center grant 2 P30 ES 00002 from the National Institute of Environmental Health Sciences and by the Health Services Research and Development Service of the Department of Veterans Affairs. Dr. Sparrow is an Associate Research Career Scientist of the Medical Research Service of the Department of Veterans Affairs. Subjects were evaluated in the outpatient Clinical Research Center of the Brigham and Women's Hospital with support from National Institutes of Health grant NCRR GCRC M01RR02635. The KXRF instrument used in this work was developed by ABIOMED, Inc., Danvers, Massachusetts, with support from National Institutes of Health grant SBIR 2R44 ES03918-02.

The authors gratefully acknowledge the research assistance of Sybil Harcourt, Randi Heldman, Gayann Barbella, Steve Oliveira, Trinh Luu, Gail Fleischaker, Marisa Barr, and Laura Hennessey. Soma Datta assisted with database and analytical programming related to this study. Drs. Doug Burger and Fred Milder provided technical assistance in the initial phase of the KXRF measurements. Julie McCoy provided editorial assistance. Finally, the authors are indebted, as always, to the continued enthusiastic cooperation of the participants in the Normative Aging Study.

	NOTES

 
Reprint requests to Dr. Howard Hu, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115 (e-mail: rehhu{at}gauss.bwh.harvard.edu).

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Received for publication March 19, 1999. Accepted for publication June 1, 2000.

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