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Lead, Blood Pressure, and Cardiovascular Disease 

in Men and Women 

Joel Schwartz 

U.S. Environmental Protection Agency PM221 

Office of Policy Analysis 

Washington, D.C. 20460 

'« P"-*z £H£ 
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ABSTRACT 

Lead, Blood Pressure, and Cardiovascular Disease 

in Men and Women 

Joel Schwartz, U.S. Environmental Protection Agency 

Lead has been shown to be associated with elevated blood pressure in males in the 

NHANES II survey, and in numerous other studies. This study confirms the association 

in males aged 20-74, and documents a significant, although weaker association, in 

females as well. Prospective cardiovascular disease studies such as the Framingham 

study indicate that increases in blood pressure should be associated with increased risk 

of cardiovascular disease. Using electrocardiogram data from NHANES II, this study 

confirms the expected association of lead with left ventricular hypertrophy (p < 0.01). 

Such an association with permanent cardiovascular changes adds weight to the blood 

pressure findings. The logistic risk coefficients from the Framingham study can be 

combined with this study's association between lead and blood pressure to examine its 

implication for more serious outcomes. The results suggest that a halving of the 

population mean blood lead level would reduce myocardial infarctions by approximately 

24,000 events per year, and incidence of all cardiovascular disease by over one hundred 

thousand. These numbers suggest a small attributable risk, compared to the vast 

incidence of cardiovascular disease in the U.S., but a large attributable risk compared to 

most environmental toxins. Several biological mechanisms have been identified, with 

different implications for the use of bone lead as an exposure measure. 
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INTRODUCTION 

While numerous studies in animals and humans have implicated lead exposure as 

a factor in increasing blood pressure, they have often focused only on males and on 

restricted age ranges. Studies of direct cardiovascular outcomes have been hampered by 

the low relative risks implied by the blood pressure relationships that have been found. 

To address these issues, data from the Second National Health and Nutrition 

Examination Survey (NHANES II) were examined for males and females aged 20 years 

and older. The NHANES II included electrocardiograms as well as blood pressure 

measurements, and the association of lead with both outcomes was examined. This 

allowed a direct examination of the assumption that increased blood pressure due to 

lead will have cardiovascular implications. 

DATA AND METHODS 

The second National Health and Nutrition Examination Survey was conducted 

between February 1976 and February 1980. The sample was chosen to be 

representative of the civilian non-institutionalized U.S. population, aged 6 months to 74 

years. Medical histories, serum biochemistries, and dietary questionnaires were obtained 

(1). Blood lead levels were obtained on a sub-sample of 9,932. Extensive analyses of 

the relationship between blood lead and blood pressure in males have been presented 

previously (2,3,4), and they provide details of the medical history questionnaire, blood 

biochemistry methods, dietary information, and physical examinations. 

Electrocardiograms were performed on all subjects aged 25-74 years, using a 

standard 12 lead ECG. Results were digitally encoded, and then classified according to 

the Minnesota Codes of Electrocardiographic Findings (5) using the Novacoder program 
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of Dalhousie University (6,7). 

Using variables identified as important in those earlier studies, the relationship 

between blood lead and blood pressure was examined in both males and females, aged 

20 -74 years. Table 1 shows the covariates considered in the analysis. 

The blood pressure data were analyzed in stages. First, separate regressions 

were performed for males and females. Diastolic blood pressure was regressed on age, 

age2, race, Quetelet's body mass index (weight/height2), and the natural logarithm of 

blood lead. If lead was significant in this first step, then a stepwise regression was 

performed, using the variables shown on Table 1. An interaction term was used to 

assess the possibility of a racial difference in the effect of lead. Final models were 

estimated using SURREGR, a program that incorporates the design effects in the study 

(8). 

The probability of left ventricular hypertrophy was modeled using logistic 

regression. Since the definition of left ventricular hypertrophy incorporates body 

habitus, body mass index and tricep skinfold were not included in these regressions. 

Stepwise logistic regression of the remaining covariates on Table 1 was used to identify 

a model. The design effects were incorporated using RTILOGIT (9). Because of the 

limited number of cases, sex differences in any lead effect were investigated using an 

interaction term. An interaction term was also used to test for racial differences. 

RESULTS 

Blood lead was a significant predictor of blood pressure in both males, (p < 0.01) 

and females (p < 0.01) in the first stage regressions, controlUng for age, race, and body 

mass index. In separate stepwise regressions for males and females, lead continued to 

be significantly related to diastolic blood pressure. The final models for blood pressure, 
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incorporating the design effects of the survey are shown on Table 2. While the 

coefficient of blood lead was lower in females than in males, the difference in 

magnitudes is not significant. This was confirmed in a regression with both sexes, 

using an interaction term to test for a different slope. The interaction was insignificant 

(p > 0.30). An interaction term for race was similarly insignificant. Race was not 

significant in the regression for males, presumably because racial differences in the 

biological risk factors explained the racial difference in blood pressure. Since blacks 

have higher blood lead levels than whites, the race term was forced into the regression 

to give a conservative estimate of the effect of lead. 

Blood lead was also a significant predictor of left ventricular hypertrophy. Table 

3 shows the logistic regression model, incorporating the design effects. The interaction 

terms for sex or race differences in the cardiovascular effects of lead were also 

insignificant (p > 0.20). 

As in previous analyses (2,3), the natural logarithm of blood lead was more 

significant than blood lead in predicting blood pressure. This implies a relationship 

with a larger marginal impact of blood lead changes at low blood lead levels than at 

high blood lead levels. In contrast, the linear form of blood lead was more significant 

as a predictor of left ventricular hypertrophy. 

DISCUSSION 

The existence of a strong association between blood lead and blood pressure 

across the entire adult age range has already been noted in males in this survey. This 

analysis demonstrates that a significant association is present in females as well. The 

association appears somewhat weaker in magnitude and in significance level than that 

for males. While most other epidemiology studies have focused on males, Rabinowitz et 
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al. (10) have reported an association of lead with both blood pressure and pregnancy 

hypertension in females. Victery et al. (11) have reported a sex difference in the effect 

of lead on blood pressure in rats, with insignificant effects in females. However, Perry 

and Erlander (12) have reported a significant association in female rats, in a diet lower 

in calcium. 

A large body of experimental data, both in vivo and in vitro, shows that lead 

increases blood pressure in several species of rats, pigeons, and dogs (13-18). These 

studies have also documented increased reactivity to alpha adrenergic stimulation 

(14,16), and an interaction with calcium metabolism (15). Many of these studies 

examined several dose levels, and Victery (19) has summarized them as indicating a 

biphasic response, with a strong effect of low level exposure that disappears at high 

levels. A similar pattern has been seen in the pressor effects of cadmium (20). These 

findings in the experimental Uterature are consistent with the logarithmic dose response 

relationship found in this study. 

Prospective studies of cardiovascular disease, such as Framingham (21) clearly 

demonstrate that the risk of cardiovascular disease varies continuously with blood 

pressure. No plausible reason exists to assume that increases in blood pressure due to 

lead exposure would not have the same impact. Studies of the use of drug therapy to 

reduce blood pressure have been more mixed, with the Hypertension Detection and 

FoUowup Study (22) finding significant reductions in risk, but not the MRFIT study 

(23). However, hypertensive medication has adverse side effects, including disturbances 

of potassium metaboUsm, that may counteract, in whole or part, the beneficial impacts 

of blood pressure reduction. Reducing lead exposure has no similar counter-risk, since 

lead has only harmful effects in the body. It therefore seems prudent to assume that 

reducing body lead burdens will reduce blood pressure and cardiovascular disease in 

both the new generation of adults, who wiU not become exposed, as weU as the current 
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one, whose exposure will be reduced. 

Nevertheless, direct evidence for a cardiovascular effect of lead would clearly 

strengthen these conclusions. The regression coefficients in Table 2 indicate that a 

halving of blood lead levels in the United States would reduce the mean male blood 

pressure by over 2 mmHg, and the mean female blood pressure by over 1 mmHg. The 

logistic risk coefficients from the Framingham study predict that these changes would 

result in about 24,000 fewer myocardial infarctions per year, and over 100,000 fewer 

cases of cardiovascular disease. While these are large numbers compared to most risk 

assessments for environmental toxins, they represent relative risks of about 1.05, due to 

the high background rate of these outcomes. Such relative risks are unlikely to be 

detected in any prospective study. Electrocardiogram abnormaUties indicative of left 

ventricular hypertrophy represent an early indicator of cardiovascular disease that is 

more common than myocardial infarctions. Left ventricular hypertrophy is also a 

prevalence, rather than incidence measure. This increases the power to detect a direct 

cardiovascular impact of lead. The finding of a significant association between blood 

lead levels and left ventricular hypertrophy in both men and women, leaves Uttle doubt 

that lead exposure is not merely raising blood pressure, but producing the expected 

cardiovascular impacts. 

While cardiovascular effects of lead intoxication have long been noted, ECG 

outcomes have been studied infrequently at the exposure levels of current concern. 

Kirkby and Gyntelberg (24) noted a 20% increase (p < 0.01) in ischemic changes, as 

coded on the Minnesota Codes, in lead workers compared to controls matched on age, 

race, sex, height, weight, alcohol consumption, and smoking. Kopp (25) in an ECG 

study of rats, found prolonged PR intervals, and depressed contractility, protein 

phosphorylation, and high energy phosphate levels. Hejtmancik and Williams (26) have 

reported increased susceptibiUty to arrhythmias in lead exposed rats. While not directly 
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parallel, Khera (27) did note increased blood and urine lead levels in cardiovascular 

patients compared to hospital controls. 

Potential Mechanisms and Bone Lead 

The experimental studies provide more than simple biological support for the 

epidemiological findings. They also provide insight into several possible biological 

mechanisms for the effect of lead on blood pressure. The two major modes of action 

identified are in the calcium metaboUsm of the vascular smooth muscle, and renal 

effects mediated through the renin-angiotensin system. In addition, direct 

cardiovascular effects may also occur. 

Piccinini and coworkers (18) found that lead induced contraction and hyperreactivity in perfused rat tail arteries. Tissue analysis indicated the lead exposed 

vascular smooth muscle ceUs had increased free cytosoUc calcium, and increased total 

calcium stores. This is consistent with the finding that lead increases ceUular calcium 

concentration in brain capiUaries (28), neurons (29), hepatocytes (30), and other tissues. 

Hyper-reactivity has also been noted by lannaconne and coworkers (131), Carmignani et 

al. (14), Boscolo and Carmignani (31) and Webb and associates (16). These findings 

suggest a mechanism with increased intracellular calcium stores, leading to increased 

release of calcium in response to stimulation, and hence increased contractiUty via 

calcium's role in mediating muscle contraction. Supporting this hypothesis is the 

observation of Chai and Webb (32) that methoxamine induced contractions in the tail 

arteries of lead exposed rats were less sensitive to calcium channel blockers, and relaxed 

at a slower rate than unexposed arteries. 

A second mode of action for lead in disturbing the calcium mediated control of 

vascular reactivity and tension may be via disturbance of protein kinase C metaboUsm. 
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Machovac and Goldstein (33) have shown that lead activates protein kinase C in rat 

brain microvessels. Protein kinase C is involved in the phosphorylation of proteins 

involved in contraction (34). Recent studies by Chai and Webb (32) have shown that 

isolated strips of rabbit tail artery contracted in response to lead. This contractile 

response was enhanced by protein kinase C activators, but attenuated by a selective 

inhibitor of protein kinase C. 

Both of the above mechanisms seem dependent on the current concentration of 

lead at the membrane or in the cytosol of the smooth muscle ceU. This suggests that 

the appropriate measure of exposure is one that is relatively contemporaneous. Blood 

lead is such a measure. The entire effect cannot be considered instantaneous, since 

both Victery and coUeagues (11) and Perry and Erlanger (12) found that rat blood 

pressure did not reach its equiUbrium elevation until several months after blood lead 

levels equiUbrated. Bone lead measurements that are targeted to shorter residence 

compartments, possibly including trabecular bone, may be a superior measure of 

exposure, but this remains to be seen. 

A mechanism more consistent with cumulative exposure measures postulates 

permanent kidney changes resulting in effects on the renin-angiotensin system. The 

animal and human data on the effect of lead on this system is confusing, with findings 

of both increased and decreased plasma renin activity foUowing lead exposure. Vander 

and associates (35) have postulated an elevation of plasma renin activity upon initial 

exposure, foUowed by an eventual reduction after chronic exposure. This hypothesis 

comes closest to making sense out of the conflicting data, and accords with the finding 

of Boscolo and Carmignani (14) of a similar pattern in human exposure. 

AU or some of the above mechanisms may be important in lead induced 

hypertension, but they are consistent with different averaging times for the best 

measure of exposure. It seems most likely that short term exposure, and altered 
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calcium metaboUsm are the most important pathways for blood pressure elevation. 

Cardiovascular outcomes seem Ukely to vary with duration as weU as level of blood 

pressure change, suggesting a more cumulative exposure measure would be appropriate 

for them. FinaUy, it should be noted that Revis et al.(15) found lead associated with 

atherosclerosis in pigeons. These findings, plus some of the direct cardiovascular effects 

noted by Kopp (25), also suggest that cumulative measures of lead may be important for 

assessing cardiovascular disease. Final resolution of the appropriate exposure measure 

wiU await studies use aU of them. 
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REFERENCE 

1. National Center for Health Statistics. Plan and Operation of the Second National 

Health and Nutrition Examination Survey 1976-1980. Washington, D.C. Vital and health 

Statistics, Series 1, No. 15. 

2. Pirkle, JL Schwartz J, Landis JR, Harlan WR. The relationship between blood lead 

levels and blood pressure and its cardiovascular risk impUcations. Am. J. Epidemiol. 

1985 121:246-258. 

3. Schwartz J. The relationship between blood lead and blood pressure in the NHANES 

II survey. Environ Hlth Persp 78:15-22 1988. 

4. Harlan WR, Landis JR, Schmouder RL, Goldstein NG, Harlan LC. Blood lead and 

blood pressure relationship in the adolescent and adult U.S. population. JAMA 253:530-

534 1985. 

5. Blackburn H, Keys A, Simonson E, Rautaharju PM, Punsar S. The Electrocardiogram 

in population studies: a classification system. Circulation, 21:1160-1175, 1960. 

6. Wolf HK, Maclnnis PJ, Stock S, Helppi RK, Rautaharju PM. The Dalhousie Program: 

A comprehensive analysis program for rest and exercise electrocardiograms. In: Zyweitz 

c and Schneider B Eds. Computer Applications on ECG and VCG analysis. North 

HoUand. Amsterdam-London 1973: pp231-40. 

7.Rautaharju PM, Broste SK, Prineas RJ, Eifler WF, Crow RS, Furberg CD. QuaUty 

control procedures for the resting electrocardiogram in the Multiple Risk Factor 

Intervention Trial. J. Controlled Clinical Trials 7:465-655, 1986. 

8. Shah BV. SURREGR: Research Triangle Institute, Research Triangle Park, N.C. 1982. 

9. Shah BV. RTILOGIT:Research Triangle Institute, Research Triangle Park, N.C. 1987. 

10. Rabinowitz M, Bellinger D, Leviton A, Needleman H, Schoenbaum S. Pregnancy 

hypertension, blood pressure during pregnancy, and blood lead levels. Hypertension 
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10:447-451 1987. 

11. Victery W, Vander AJ, Shulak JM, Schoeps P, JuUus S. Lead, hypertension, and 

the renin-angiotensin system in rats. J Lab Clin Med 99:354-362 1982. 

12. Perry HM Erlanger EJ. Pressor effects of chronicaUy feeding cadmium and lead 

together. In:Trace Substances in Environmental Health, Vol 12 (DD Hemphill Ed) 

University of Columbia, Columbia MO 268-275 1978. 

13. Iannaccone, A, Carmignani M, Boscolo P. Cardiovascular reactivity in the rat 

foUowing chronic exposure to cadmium and lead. Ann. 1st Super Sanita, vol 17 

655-660 1981. 

14. Carmignani M, Boscolo P, Ripanti G, FinelU GN. Effects of chronic exposure to 

cadmium and lead on some neurohumoral mechanisms regulating cardiovascular 

function in the rat. 1983 Proceedings of the fourth International Conference on Heavy 

Metals in the Environment. I 557-560. 

15. Revis NW, Zinsmeister AR, Bull R. Atherosclerosis and hypertension induced by lead 

and cadmium ions: an effect prevented by calcium ion. Proc Natl Acad Sci (US) 8:6494-

6498 (1981). 

16. Webb RC, Winquist RJ, Victery W, Vander AJ. In vivo and in vitro effects of lead on 

vascular reactivity in rats. Am J Physiol 214:H211-216 1981. 

17. Skoczynska A, Juzwa W, Smolok R, Szechinski J, Behal FJ. Response of the 

cardiovascular system to catecholamines in rats given small doses of lead. Toxicol. 39: 

275-289 1986. 

18. Piccinini, F, FavaUi L, Chiari MC. Experimental investigations on the contraction 

induced by lead in arterial smooth muscle. Toxicol. 8:43-51 1977. 

19. Victery W. Evidence for effects of chronic lead exposure on blood pressure in 

experimental animals: An Overview. Environ Hlth Persp 78:71-76. 1988. 

20. Perry HM Jr, Erlanger MW, Perry EF. Hypertension following chronic very low dose 
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cadmium feeding. Proc Soc Exp Biol Med 156:173-176. 1977. 

21. Shurtleff D. Some characteristics related to the incidence of cardiovascular disease 

and death: Framingham study, 18-year foUow up. Section 30, DHEW Pub No (NIH) 74-

599 1974. 

22. Hypertension Detection and FoUowup Program Cooperative Group. The effect of 

treatment on mortaUty in mild hypertension. New Eng J Med 307:976-80 1983. 

23. Multiple Risk Factor Intervention Trial: Risk factor changes and mortaUty results. 

Multiple Risk Factor Intervention Trial Research Group. JAMA 248:1465-77 1982. 

24. Kirkby H, Gyntelberg F. Blood Pressure and other cardiovascular risk factors of 

long-term exposure to lead. Scand J Work Environ health 11:15-19 1985. 

25. Kopp SJ, Baker JC, D'Agrosa LS, Hawley PL. Simulataneous recording of His 

bundle electrogram, electrocardiogram, and systoUc tension from intact modified 

Langendorff rat heart preparations I: effect of perfusion time, cadmium, and lead. 

Toxicol Appl Pharmacol 46:475-487 1978. 

26. Hejtmancik MR, WilUams BJ. Effect of chronic lead exposure on the direct and 

indirect components of the cardiac response to norepinephrine. Toxicol Appl Pharmacol 

51:239-245 1979. 

27. Khera AK, Wibberley DG, Edwards KW, Waldron HA. Cadmium and lead levels in 

blood and urine in a series of cardiovascular and normotensive patients. Int J Eviron 

Stud 14:309:312 1980. 

28. Goldstein GW. Lead encephalopathy: the significance of lead inhibition of calcium 

uptake by brain mitochondria. Brain Res. 136:185-188 1977. 

29. Kim CS, O'Tuama LA, Cookson SL, Mann JD. The effects of lead poisoning on 

calcium transport by brain in 30-day-old albino rabbits. Toxicol App Pharmacol 52:491-

496 1980. 

30. Pounds JG Effect of lead intoxication calcium homeostasis and calcium-mediated cell 
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function: A review. Neurotoxicology 5: 295-332 (1984). 

31. Boscolo P, Carmignani M. Neurohumoral Blood Pressure Regulation in Lead 

Exposure. Environ Hlth Persp 78:101-106 1988. 

32. Chai S, Webb RC. Effects of Lead on Vascular Reactivity. Environ Hlth Persp 78:85-

89 1988. 

33. Machovac J, Goldstein GW. Lead induced activation of protein kinase C in rat brain 

microvessels. J CeU Biochem (suppl) 10c:L53 1986. 

34. Rasmussen H, Takuwa Y, Park S. Protein kinase C in the regulation of smooth 

muscle contraction. FASEB J 1:177-185 1987. 

35. Vander AJ. Chronic Effects of Lead on the Renin-Angiotensin system. Environ Hlth 

Persp 78:77-83 1988. 
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TABLE 1 

VARIABLES CONSIDERED IN THE REGRESSIONS 

Age (years) 

Race+ 

Sex* 

Body Mass Index (kg/m2) 

Cigarettes/day 

Tricep Skinfold (mm) 

Family history of Hypertension 

Recreational Exercise* 

ln(Serum Zinc) 

ln(Blood Lead) 

Dietary Potassium 

Dietary Sodium 

Serum Cholesterol 

Height (m) 

ln(Dietary Vitamin C) 

+ 2=black, 1=white 

* Left Ventricular Hypertrophy regression: 2=females, 1=males 

# 1 = Uttle, 2=moderate, 3=substantial 
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TABLE 2 

REGRESSION RESULTS FOR DIASTOLIC BLOOD PRESSURE 

MALES 

Variable 

Intercept 

Age 

Age2 

Body Mass Index 

Race 

Family History 

Cholesterol 

Blood Lead* 

Height 

Cigarettes 

Zinc 

Tricep 

Coefficient 

29.86 

.6073 

-0.0057 

.7312 

1.549 

2.543 

.0247 

2.928 

12.89 

-.057 

-4.37 

.0110 

Intercept 

age 

age-5 

Body Mass Index 

Race 

Zinc* 

Family History 

Blood Lead* 

Tricep 

Cholesterol 

57.64 

.6135 

-.005 

.6857 

2.408 

-5.54 

1.145 

1.640 

.0084 

.0113 

SE p -value 

10.90 

.0887 

.0010 

.0932 

.8955 

.4210 

.0071 

1.002 

3.251 

0.023 

1.491 

0.005 

FEMALES 

7.578 

.1105 

.0012 

.0582 

.7920 

1.646 

.3688 

.6963 

.0035 

.0055 

-

< 0.0001 

< 0.0001 

< 0.0001 

0.0934 

< 0.0001 

0.0016 

0.0063 

0.0004 

0.0183 

0.0062 

0.0490 

. 

< 0.0001 

0.0001 

< 0.0001 

0.0047 

0.0020 

0.0040 

0.0247 

0.0203 

0.0477 

•natural logarithm 
TABLE 3 

LOGISTIC REGRESSION RESULTS: LEFT VENTRICULAR HYPERTROPHY 

Variable 

Intercept 

Age 

Race 

Sex 

lead 

Coefficient 

-3.94 

.0140 

1.357 

-1.01 

.0283 

S.E. 

.5081 

.0052 

.2017 

.1649 

.0100 

p -value 

. 

.0117 

<0.0001 

< 0.0001 

0.0087