P.1 

OAR Box 1126 

Prepped by Ollie Stewart 

Document Number: 

78) 11-1-292 

Docket Number: 

A-83-22 

Printed 4/18/2008 9:58:24 AM Sheet 78 of 182 
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Environmental Health Perspectives 

Vol. 78, pp. 23-30, 1988 

P.2 

The Relationship Between Blood Lead, 

Blood Pressure, Stroke, and Heart Attacks 

in Middle-Aged British Men 

by S. J- Pocock,* A. G. Shaper,* D. Ashby/ H. T. Delves,* 

and B. E. Clayton* 

The relationship between blood lead concentration and blood pressure is examined in a survey of 

7371 men aged 40 to 59 Irom 24 British towns. After allowance for relevant confounding variables, 

including town of residence and alcohol consumption, there exists a very weak but statistically 

significant positive association between blood lead and both systolic and diastolic blood pressure. 

These cross-sectional data indicate that an estimated mean increase of 1.45 mm Hg in systolic blood 

pressure occurs for every doubling of blood lead concentration with a 95% confidence interval of 

0.47 to 2.43 mm Hg. 

After 6 years of follow-up, 316 of these men had major ischemic heart disease, and 66 had a 

stroke. After allowance for the confounding effects of cigarette smoking and town of residence there is 

no evidence that blood lead is a risk factor for these cardiovascular events. However, as the blood 

lead-blood pressure association is so weak, it is unlikely that any consequent association between 

lead and cardiovascular disease could be demonstrated from prospective epidemiological studies. 

An overview of data from this and other large epidemiological surveys provides reasonably 

consistent evidence on lead and blood pressure. While NHANES II data on 2254 U.S. men indicate 

a slightly stronger association between blood lead and systolic blood pressure, data from two Welsh 

studies on over 2000 men did not show a statistically significant association. However, the 

overlapping confidence limits for all these studies suggest that there may be a weak positive 

statistical association whereby systolic blood pressure is increased by about 1 mm Hg for.every 

doubling of blood lead concentration. Nevertheless, such statistical association cannot be taken as 

establishing a causal effect of low-level lead exposure on blood pressure, particularly since there are 

important confounders, e.g., alcohol consumption, which are much more strongly related to blood 

pressure. 

Introduction 

The hypothesis that moderate elevations in blood 

lead concentration are associated with increased blood 

pressure in humans is supported by considerable 

experimental evidence in laboratory animals (1,2). 

Since direct experimental evidence in humans cannot 

be obtained, the principal investigational approach in 

lmmans has been with observational studies in representative samples of either the general adult population 

or occupationaliy exposed groups. 

'Department of Clinical Epidemiology and General Practice, Royal 

i-n* Hospital School of Medicine, London NW3 2PF, UK. 

iii93Bvai

rtment

 °f Community Health, The University, Liverpool, 

department of Chemical Pathology and Human Metabolism, 

niverSlty of Southampton, Southampton, UK 

This paper describes cross-sectional results from one 

large survey, the British Regional Heart Study 

(BRHS). Since our original publication on this topic 

claiming a lack of association between blood lead and 

blood pressure (3), studies of data from the United 

States National Health and Nutrition Examination 

Survey (NHANES II) have concluded that there is an 

important association (4,5). Hence, it is opportune to reexamine our data, paying careful attention to the role 

of confounding factors such as town of residence and 

alcohol consumption. 

In addition, the BRHS is a prospective study, and the 

men are being followed for fatal or nonfatal cardiovascular events since initial screening. Hence, new 

results are presented concerning whether moderate 

elevations in blood lead are related to risk of ischemic 

heart disease (IHD) or stroke. 
v^ 

P.3 

24 POCOCK ETAL. 

It is unrealistic to expect any single epidemiological 

study to provide definitive answers concerning blood 

lead-blood pressure relationships. Therefore, this paper 

also presents an overview of the collective evidence 

from all the major surveys in this field and demonstrates a greater consistency of evidence than might be 

achieved from separate perusal of the findings and 

conclusions from each individual study. 

Methods 

The BRHS examined 7735 men aged 40 to 59 who 

were randomly selected from the age-sex registers of 

representative general practices in 24 British towns. 

Details of the selection of towns and general practices 

and the methods of screening and data collection have 

previously been reported (6). Each man's blood pressure was measured twice in succession with the London School of Hygiene sphygmomanometer, with the 

subject seated and his arm supported on a cushion. 

Diastolic blood pressure was recorded at disappearance 

of sounds (phase V). The mean of two readings of blood 

pressure was adjusted for observer variation within 

each town to allow for any inconsistencies among the 

three observers (7). 

Blood samples for lead analysis were obtained from 

7379 men (95%). Blood lead concentrations were analyzed at the University of Southampton with flame 

microsampling atomic absorption spectroscopy. A strict 

quality control protocol was maintained, and the 

performance of the laboratory was continually monitored by participation in national and international 

quality assessment schemes for analysis of blood lead 

concentration. 

Alcohol consumption was recorded using questions 

of frequency and quantity. A drink was defined as half 

a pint of beer, one glass of wine, or a single shot of 

spirits. For data analysis, eight drinking categories 

were used: nondrinker, occasional drinker, weekend 

drinker (1-2, 3-6, or > 6 drinks a day), and daily 

drinker (1-2, 3-6, or > 6 drinks a day). For 

illustration, in Figures 1 and 2 these are combined to 

160 

O) 

I 

E 

E 

150 

140 

CD 

-o 

O O 

.Q 

C 

ro 

0) 

Systolic 

901 

80 

70 

No. 

cn 

I 

E 

E 

:.6 .6- .9- 1.2- 1.5- 1.8-

Blood lead (/imol/l) 

otmen: 1984 3381 1420 386 126 74 

160" 

Sys'.olic 

150-

140-

Q) 

Q. 

-a 

o 

o 

J D 

c 

ro 

CD 

90 

8 0 -

Diastolic 

None or Light Moderate Heavy 

Occasional 

Alcohol intake 

160 

150" 

140 

90 

80 

Systolic 

Diastclic 

160n 

150 

140" 

<22.5 22.5- 24.5- 26.5- 28.5-

Body Mass Index (kg/m2). 

1256 1764 2043 1419 1243 

Systolic 

90-

80-

D'sstolic 

40-44 45-49 50-54 

Age 

55-59 

No. otmen: 3033 2911 947 830 1636 1896 1974 2021 

FIGURE 1. Mean systolic and diastolic blood pressures for men categorized by blood lead concentration, body mass index, alcohol consumption, $ 

age. 

I' 
(rr r BZ.OOD L£4D AWD BLOOD PRESSURE IN BRITISH MEN 25 

P.4 

four drinking categories: nondrinker or 

f°r m. ona l drinker, ligh^ drinker (1-2 daily or on 

°

cCtS

'nds) moderate (3-6 daily or on weekends), and 

drinker ( > 6 daily or on weekends), 

^r^arette smoking habits derived from a standardA questionnaire were as follows: never smoked 

ttes ex-cigarette smoker, and current cigarette 

Cignker at'four levels (1-19, 20, 21-39, > 40 per day). Ex-

• ette smokers who currently smoked a pipe/cigars 

""'^luded j n ex-cigarette smokers. Those men who 

hVonly ever smoked pipe/cigars are included in 

r smoked cigarettes. For both current and exneve

. ers the number of years a man had smoked cigs m° e s

 ^ a s also recorded, this variable (smoking years) 

rT'ne. a strong smoking-related predictor of IHD risk 

(8) All of the 7735 men who were initially examined 

from 1978 to 1980 were scheduled to be followed up for 

both morbidity and mortality for 8 years. So far, 99% of 

the original cohort still alive and living in Great 

Britain are being followed up. Details of the follow-up 

procedures have been published (9). All cases of major 

IHD and stroke occurring between screening and 

August 1985 are included in this paper. 

~ 1.01 

- 0.9 

X) 

0.7 

y 0.6 

0.5 

Results 

Personal Factors Related to Blood 

Pressure and Blood Lead 

Figure 1 shows a simple display of the univariate 

association between blood lead and blood pressure in 

the 7371 men for whom both were measured. There is 

some suggestion of a rise in mean systolic pressure as 

blood lead increases, but the correlation coefficient is 

only 0.03. However, there are several personal characteristics in middle-aged men that are known to be 

associated with blood pressure. For example, Figure 1 

also shows the trends in mean systolic and diastolic 

pressure for these same men grouped according to 

body mass index, age, and alcohol consumption. 

Clearly, body mass index and age are important 

determinants of individual blood pressure, but alcohol 

consumption is also an important confounding variable in view of its substantial association with blood 

lead concentration (10,11) (Fig. 2), as well as with blood 

pressure (6,12). Two other relevant personal factors are 

cigarette smoking and social class. The former is 

clearly associated with blood lead concentration (10,11) 

(Fig. 2); the latter has weak associations with both 

blood pressure and blood lead. 

Geographic Difference 

There are major geographic differences in both 

mean systolic blood pressure and mean blood lead 

concentration (Fig. 3). Although there is no evidence 

of a statistical association for the between-town differences in blood pressure and blood lead, it is still 

relevant that town of residence should be taken into 

account when studying this potential lead-blood pressure relationship in individuals. 

None or 

Occasional 

Light Moderate 

Alcohol intake 

Heavy 

and 

No. of men 2887 

aa? LO I 

2759 922 805 

-a 

o 

"D 

O 

O 

a 

0.9" 

0.8 

0.7 

0.6-

0.5 

Never Ex 1-19 20 21-39 >40 

•r 

Current per day 

Cigarette smoking 

Wo. ot men 1741 2597 1132 790 803 300 

<•'

 RK 2. Mean blood lead concentration for men categorized by their 

("ported alcohol consumption and cigarette smoking. 

160 

Q . 

CQ 

•2 150 

o 

ti5 

>. 

U) 

c 

•to 

<D 

E 

c 

3 

o 

140 

130 

0.5 

—t— 

0.8 

-T 

0.6 0.7 0.9 

Town mean blood lead (/tmol/l) 

—1 

1.0 

FIGURE 3. The town mean systolic blood pressure plotted against the 

town mean blood lead concentration for the men resident in each of 

24 British towns. 
P.5 

26' POCOCK ETAL. 

Blood Pressure and Blood Lead 

(Unadjusted) 

Figure 4 provides a more detailed display of mean 

systolic and diastolic blood pressure according to blood 

lead concentration. For blood lead between 0.4 and 1.1 

|imole/L, mean pressures are shown for each 0.1 

umole/L interval of blood lead. Above 1.1 umole/L, 

men are grouped into two categories, 1.2 to 1.3 (xmole/L 

and 1.4 jimole/L or more, so as to preserve approximately 300 men in each category. All the displayed 95% 

confidence intervals overlap with one another, and 

also the mean systolic and diastolic blood pressures in 

the highest blood lead category show no elevation 

above the average. Thus, detailed univariate analyses 

show no encouragement for the hypothesis that blood 

lead and blood pressure are positively associated. 

Blood Pressure and Blood Lead 

(Adjusted for Otiier Factors) 

The situation appears to change once relevant personal factors are taken into account. An analysis of 

covariance technique has been used to obtain adjusted 

mean systolic and diastolic blood pressure for each 

blood lead category, adjustment being for body mass 

index, age, alcohol consumption (8 categories), cigarette smoking (6 categories), social class (6 categories), 

and town of residence (24 categories). The consequent 

plots of adjusted mean systolic and diastolic blood pressure by blood lead in Figure 5 show signs of a weak 

positive association. Particularly, for the diastolic 

pressure there is a steady increase in adjusted mean 

from around 81 mm Hg for blood lead below 0.6 

umole/L to around 83.5 mm Hg for blood lead over 1.0 

umole/L. 

I 

E 

E, 

CD 

t_ 

</> O) 

a> 

a. 

-o 

o 

o 

o 

~o 

To 

>. 

w 

152 

148 

144 

140 —I 1 1 1 1 1 1 1 1 1 

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 

Wo 

I 

</> 

tal 

a) 

Q. 

T3 

o 

o 

-Q 

U 

~o 

m 

Blood lead (ftmol/l) 

of men: 255 1084 1204 682 295 

644 1209 967 443 298 

86 -| 

289 

84 

82 

80 

78 I 1 1 1 1 1 1 1 1 1 

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 

Wo 

Blood lead (^mol/l) 

of men: 255 1084 1204 682 295 

644 1209 967 443 298 

289 

Multiple Regression Analysis 

This association can be further explored by multiple 

regressions of systolic and diastolic blood pressure on 

log (blood lead) and the covariates just mentioned. Table 

0-

C0 

o 

03 >, 

tn 

c 

CD 

<D 

E 

D 

< 

150 

148 

146 

144 

142 

140 

Qm 

TO 

73 

c 

(0 

0) 

E 

"D B to 

< 

85 

84 

83 

8 2 -

80 

-i 1 1 

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 

Blood lead (/^mol/l) 

-i 1 1 r -i 1 r 

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1. 

2." 

FIGURK 4. Mean systolic and diastolic blood pressures (and their 95% 

confidence limits) for men categorized in intervals of 0.1 umole/L of 

blood lead concentration. (The two highest blood lead groupings 

are 1.2 to 1.3 pmole/L and 1.4 vimole/L.) 

Blood lead (/imol/l) 

FIGURK 5. Mean systolic and diastolic blood pressures by blood le* 

concentration after adjustment for body mass index, alcoh 

consumption, cigarette smoking, social class, and town of resident -
P.6 

BLOOD LEAD AND BLOOD PRESSURE IN BRITISH MEN 27 

hows the regression coefficients for log (blood lead) 

) r three different models: a) unadjusted for other 

fetors; b) adjusted for age, body mass index, alcohol, 

rnoking, and social class; and c) adjusted also for town 

f residence. The log transform is used because blood 

° J ^35 a lognormal distribution, the regression fit is 

liirhtly improved, and. also the findings are then 

S

 ore directly comparable with other studies. In the 

"nadjusted regression, systolic (but not diastolic) blood 

"ressure is significantly associated with log (blood 

P J\ Adjustment for personal characteristics, but not 

town of residence, renders both the systolic and diastolic regressions on log (blood lead) insignificant. This 

s chiefly because alcohol consumption is an important 

confounder, being positively related to both blood pressure and blood lead. Introducing an extra adjustment 

for town of residence makes both the systolic and diastolic regressions highly statistically significant (p = 

0 003 and 0.001, respectively). However, it should be 

noted that these adjusted statistical associations are still 

very weak, partial correlation coefficients being 0.04 

and 0.05 for the systolic-blood lead and diastolic-blood 

lead associations, respectively, so that statistical significance is achieved only because of the large number 

of subjects in the survey. 

As a means of quantifying the magnitude of these 

adjusted relationships, one can use the regression coefficient and its standard error for log(blood lead) to 

obtain the estimated increase in blood pressure for each 

doubling of blood lead concentration. This is 1.45 mm 

Hg for systolic pressure (95% confidence interval, 0.47-

2.43 mm Hg) and 1.25 mm Hg for diastolic pressure 

(95% confidence interval, 0.65-1.85 mm Hg). 

Separate Analyses Within Each Town 

It is important to remember the geographic basis of 

the BRHS whereby the sample of 7371 men analyzed 

here come from 24 towns, approximately 300 men per 

town. Table 2 shows the results of separate univariate 

regression analyses of blood pressure on log (blood lead) 

for the men in each town. These findings demonstrate 

that the weakness of the blood lead-blood pressure 

Table 2. Separate univariate regression analyses for the men in 

each town. 

Regression coefficient (SE) 

Town 

Newcastle 

Burnley 

Dewsbury 

Wigan 

Southport 

Harrogate 

Merthyr Tydfil 

Darlington 

Mansfield 

Falkirk 

Shrewsbury 

Grimsby 

Guildford 

Ipswich 

Scunthorpe 

Ayr 

Exeter 

Carlisle 

Lowestoft 

Maidstone 

Dunfermline 

Hartlepool 

Bedford 

Gloucester 

Systolic blood 

pressure on ln(Pb) 

11.4 

10.6 

5.8 

5.6 

5.6 

5.5 

5.5 

5.0 

5.0 

4.2 

3.8 

2.8 

2.5 

2.0 

1.9 

1.6 

1.5 

1.3 

1.0 

0.9 

0.6 

-1.4 

-1.7 

-3.1 

(4.3) 

(3.4) 

(3.5) 

(3.1) 

(4.3) 

(4.1) 

(4.2) 

(3.5) 

(4.4) 

(4.0) 

(4.3) 

(2.9) 

(3.8) 

(2.9) 

(2.8) 

(2.8) 

(3.0) 

(3.0) 

(3.9) 

(2.9) 

(3.5) 

(3.4) 

(4.5) 

(4.4) 

Diastolic blood 

pressure on ln(Pb) 

4.4 

7.2 

2.7 

2.6 

3.8 

4.8 

3.2 

-3.0 

6.1 

-0.4 

1.9 

1.6 

2.5 

-0.5 

3.0 

0.7 

-0.4 

1.8 

-2.2 

1.2 

-0.2 

0.8 

5.1 

2.4 

(2.9) 

(2.2) 

(2.4) 

(1.8) 

(2.3) 

(2.5) 

(2.3) 

(2.2) 

(2.6) 

(2.8) 

(2.6) 

(1.7) 

(2.3) 

(1.9) 

(1.7) 

(1.8) 

(2.2) 

(1.8) 

(2.4) 

(1.9) 

(2.2) 

(2.0) 

(2.8) 

(2.8) 

association is such that studies based on a few hundred 

men contain too much random variation and cannot 

be expected to produce consistent, precise findings. For 

instance, the within-town regressions of systolic blood 

pressure on log (blood lead) produced large significant 

coefficients in Newcastle and Burnley, while at the 

other extreme, there were three towns, Hartlepool, Bedford, and Gloucester, with small negative coefficients. 

In fact, from inspection of the standard errors of each 

such coefficient, one can see that such differences are 

largely attributable to random variation, and they are 

all in broad agreement with a true average regression 

coefficient of 3.0. Adjustment for alcohol consumption 

as a confounder reduces this coefficient to 2.0, which is 

the overall pooled estimate already derived in the 

multiple regression in Table 1. 

Table 1. Regressions of systolic and diastolic blood pressure on 

ln(blood lead) with and without adjustments for other personal 

factors and town of residence. 

Systolic blood pressure 

Unadjusted 

Adjusted for body mass 

""iex, age, alcohol, smoking, 

-and social class 

Adjusted also for town 

J'astolic blood pressure 

Unadjusted 

justed for body mass 

'"dex. age, alcohol, smoking, 

wd social class 

-^iH!!siakofortown 

Regression coefficient 

for ln (blood lead) Rvalue 

1.684 

0.675 

2.089 

0.302 

-0.063 

1.809 

0.009 

0.28 

0.003 

0.46 

0.87 

0.001 

Blood Lead and Cardiovascular Events 

Table 3 shows the mean blood lead concentration for 

316 men who have experienced major ischemic heart 

disease since initial screening compared with the 7063 

other men. The mean blood level concentration is 

significantly higher in these IHD cases (p = 0.01), but 

this is without taking account of important confounding variables. In particular, cigarette smoking is 

an established risk factor for IHD, which also elevates 

blood lead concentrations (Fig. 2). The towns with 

higher IHD mortality tend to have slightly higher 

blood lead concentrations, perhaps because blood lead 

levels are higher in soft water areas (13), which are 

known to have higher IHD mortality (14,15). Therefore, analysis of covariance has been used to obtain an 
P.7 

28 POCOCK ETAL. 

Table 3. Mean blood lead concentrations for men with 

subsequent ischemic heart disease and stroke compared 

with other men, with and without adjustment for age, 

smoking years, and town of residence. 

No. of men 

Mean blood lead, pmole/L 

Difference in means ± SE 

Difference in means ± SE 

after adjustment for age, 

smoking years, and town 

IHD 

cases 

316 

0.786 

0.051 

0.014 

Other 

men 

7063 

0.735 

±0.019 

±0.015 

Stroke 

cases 

66 

0.808 

0.071 

0.033 

Other 

men 

7313 

0.737 

±0.049 

±0.033 

adjusted difference in mean blood lead between IHD 

cases and other men adjustment being for age, number 

of years smoking cigarettes, and town of residence (24 

categories). This adjustment has reduced the mean 

excess in blood lead among IHD cases from 0.051 

umole/L to 0.014 umole/L, which is no longer significantly different from zero. Table 3 also shows similar results for the 66 cases of stroke compared with 

other men. 

An alternative method of studying blood lead as a 

possible IHD risk factor is to estimate the relative odds 

of becoming an IHD case for different intervals of blood 

lead. Using the 1986 men with blood lead concentration under 0.6 umole/L as a reference group, Figure 6 

shows that the odds (or risk) of IHD is somewhat 

greater at higher blood lead concentrations, particularly at 1.2 umole/L or more. However, use of logistic 

regression analysis to obtain relative odds adjusted for 

age, smoking years, and town of residence shows no 

evidence of an excess risk of IHD at these higher blood 

lead concentrations. 

Overview of Other Large Studies of 

Blood Lead-Blood Pressure 

Relationships 

In any specific field of epidemiological research, no 

single observational study can be relied upon to 

provide a definitive answer, particularly when the 

relationship under study is quite weak and in the 

presence of strong potential confounders. In this preliminary attempt to present the collective evidence 

from ours and other studies of the lead-blood pressure 

relationship, attention is confined to the larger studies 

for which appropriate regressions of systolic blood 

pressure on blood lead are available. As already illustrated in Table 2, studies on a few hundred subjects can 

produce highly variable estimates of the lead-blood 

pressure association. Also, the available data in such 

smaller studies are liable to suffer from publication 

bias, whereby the more positive small studies are more 

likely to be published. Studies of under 500 subjects will 

therefore not be mentioned further. All results presented refer to males only. 

For each study we present the estimated change in 

mean systolic blood pressure for a doubling of blood 

lead. This is obtained from the principal regression 

analysis that the authors selected. These findings are 

displayed in Figure 7 with the 95% confidence limits. 

For the BRHS these results are directly obtained from 

the regression coefficient for log (blood lead) after 

adjustment for town of residence and other covariates 

(Table 1). For NHANES II, the results are similarly 

determined from data on 2254 males aged 20 to 74 after 

adjustment for site and several other biochemical, 

dietary, and personal factors (16). For the two Welsh 

studies on 1164 and 865 men, respectively, linear 

regression was used, adjusting for age only, and hence 

we have plotted the mean change in systolic blood 

pressure for one specific doubling of blood lead concentration (8 to 16 ng/dL) in the middle of their blood 

lead distributions. 

The two Welsh studies show no significant association, whereas NHANES II data show an estimated 

increase of 2.24 mm Hg in systolic blood pressure for a 

doubling of blood lead concentration, which is larger 

than in the BRHS. However, the overlapping confidence intervals indicate that these findings are not 

consistent, and all studies are compatible with a possible increase in systolic blood pressure of approxi2.01 

D 

^ 1.5-1 

1.0-

0.5" 

0.0 

No. of Men 

No. of IHD cases 

<0.6 

1986 

68 

0.6-0.8 

3385 

152 

0.9-1.1 >1.2 /imol/l 

1421 

64 

587 

32 

FIGURE 6. Relative odds of major IHD for men categorized by blood lead 

concentration: (•) base group (< 0.6 umole/L); (•) unadjusted for 

other factors; ( x ) adjusted for age, smoking years, and town of 

residence, together with 95 % confidence limits. 

BRHS(N=7371) 

NHANE S II (N-=2254) 

Caerphilly (N= 1164) 

Wales (N=865) 

•2 -1 0 , . 1 2 3 4 

Estimated change in mean systolic blood pressure 

(mm Hg) tor a doubling ot blood lead 

FIGURE 7. An overview of four large studies relating systolic blo°, 

pressure to blood lead concentration. The graph shows each studyestimated change in mean systolic blood pressure for each doubli"* 

of blood lead (e.g., from 8-16 pg/dL) together with 95% confident 

limits. (Two other large studies in Canada and Denmark showed " 

significant association, but estimates.are not known to us.) 
P.8 

BLOOD LEAD AND BLOOD PRESSURE IN BRITISH MEN 29 

od 

y's 

ng 

ice 

no 

t iv 1 to 2 mm Hg for a doubling of blood lead 

1113

 ntration. j t should also be noted that two other 

conce dies in Canada (18) and Denmark (19) on 2193 and 

Q^O subjects, respectively, have found no significant 

ociation, but we do not have their regression results 

aSS

., jjie a s yet. This would imply that the lower figure 

3

f 1 mm Hg systolic increase per doubling of blood lead 

°s more plausible. 

Discussion 

Blood Lead and Blood Pressur e in BRHS 

^ d NHANES II 

Earlier publications on lead and blood pressure from 

the BRHS (3) and NHANES II (5) have appeared to 

reach widely divergent conclusions; this journal issue 

provides an opportunity for reassessment of these two 

studies using comparable statistical approaches. While 

NHANES II continues to show a markedly stronger 

relationship in the selected subgroup of white males 

aged 40 to 59, this discrepancy is largely removed once 

one compares regression results for all adult males in 

the two studies. 

Alcohol Consumption 

The choice of other covariates as potential confounders has had an important effect on the two 

studies' results. In the BRHS, alcohol consumption is 

of particular importance, being positively related to 

blood pressure and blood lead. It should be noted that 

the alcohol-blood pressure relation in the BRHS is 

virtually unaffected by adjustment for blood lead levels, 

indicating that alcohol's effect on blood pressure is not 

produced by any lead-related mechanism, such as the 

lead content of alcoholic drinks. This supports the view 

that alcohol is a genuine confounder. It is impossible to 

obtain a fully comprehensive measure of alcohol consumption by simple questionnaire (e.g., in the BRHS, 

all men drinking over six units per day are grouped 

together, and this may mean that the alcohol-related 

component in the univariate lead-blood pressure relationship is not completely allowed for in the multiple 

regression. This same point relates to NHANES II, as 

their information on alcohol was not very detailed. 

Allowance for Geographic Differences 

Both NHANES II and the BRHS are cross-sectional 

surveys among individuals from many geographical 

areas. They have a two-stage design, the first being 

nonrandom selection of geographic locations and the 

second being random selection of individuals from a 

defined sampling frame in each location. It has now 

become recognized that particularly when studying a 

w

eak statistical association such as lead and blood 

pressure it is important to take account of this 

geographical component to the study. In the BRHS, 

failure to adjust for town of residence actually underplayed the significance of the statistical association. 

However, in NHANES II, the strength of association 

was reduced after adjustment for site, perhaps because 

sites with higher mean blood pressure tended to have 

higher mean blood lead levels, possibly as a consequence of the time trends in both blood lead and percent 

urban dwellers at the sampling sites. 

Overview of Major Studies 

In our overview of the major studies in this field 

(Fig. 7) we have aimed for an objective quantification 

of the magnitudes of association between blood lead 

and systolic blood pressure. Subjective assessment of 

such data tend to classify studies as either significant 

or nonsignificant, but this dichotomous attitude 

toward assessment of scientific hypotheses is oversimplistic and counter-productive. It fails to take 

account of the limited power that individual studies 

have to detect weak relationships. We have been able to 

demonstrate some consistency between the larger 

studies suggestive of a very weak positive association, 

but it is also important to realize the limitations of this 

approach. Specifically, the different studies have 

adopted very different strategies toward the selection of 

other covariates to be used in the regression models. 

For instance, the BRHS selected a limited set of personal 

covariates related to blood pressure and blood lead, 

whereas NHANES II did an extensive selection process 

across a wide range of personal, biochemical, and 

dietary data. The Welsh analyses undertaken thus far 

have only adjusted for age. Greater consistency in the 

handling of confounders would provide more reassurance as to the validity of our overview approach. 

However, a previous NHANES II report (5) has 

claimed a stability of blood lead-blood pressure association for several different approaches to selecting 

covariates in their data. Therefore, it seems plausible to 

argue that the overall assessment of the data on all 

available studies is not likely to be changed substantially by further statistical analysis. 

Interpretation of the Statistical 

Association 

The crucial issue is whether this evidence of a weak 

statistical association is evidence of a causal effect of lowlevel lead exposure. Here we need to accept the limitations of observational epidemiology, which cannot 

provide definitive evidence of a causal link. Furthermore, the strength of statistical evidence here is not 

substantial. The difficulty of completely allowing for 

important confounders, e.g., alcohol consumption and 

the fact that only two of the six largest studies have 

achieved statistical significance, would suggest that 

this is one area where the epidemiological approach 

cannot provide a clear answer. It would be premature to 

conclude that these statistical findings are of practical 

relevance to public health. 
P.9 

30 POCOCK ETAL. 

Blood Lead, Heart Attacks, and Strokes 

We are not aware of any previous prospective 

epidemiological studies of coronary heart disease and 

stroke that have included blood lead as a potential risk 

factor. However, it has been hypothesized that trace 

metals such as lead may explain the relationship between soft water and cardiovascular disease and also 

that clinical lead poisoning includes signs suggestive 

of a toxic effect on the heart (20). Also, Pirkle et al. (5) 

have extrapolated from their blood lead-blood pressure 

relationship in NHANES II data to argue that there 

could be substantial reductions in the numbers of 

strokes and heart attacks as a result of the decline in 

blood lead levels in the United States since the mid1970s. 

In this paper we have shown that mean blood lead 

levels are somewhat higher in individuals who subsequently have a heart attack or stroke. However, after 

allowance for cigarette smoking and town of residence, 

this association is no longer statistically significant. 

One cannot automatically infer that low-level lead 

exposure has no effect on risk of stroke and heart attack, 

but the evidence clearly indicates that lead is not a 

major contributor to risk of cardiovascular disease. It is 

still worth considering whether a possible blood leadblood pressure relationship could have implications 

for risk of major cardiovascular events, but the 

estimates provided by earlier research (5) would seem 

extravagant, as the collective evidence suggests a much 

weaker blood lead-blood pressure relationship than 

they have previously claimed. Thus, there remains the 

possibility that an extremely small proportion (less 

than 1%) of strokes and heart attacks could be prevented 

by substantial reductions in mean blood lead concentration in the general population. This inference 

depends on a causal interpretation of statistical associations, but we have no direct evidence that changes 

in population lead levels would actually affect the 

population's blood pressure, and there even remains 

controversy over whether lowering of blood pressure 

reduces the risk of heart attacks (21). In conclusion, we 

see no convincing epidemiological evidence at present 

to support the claim that moderate elevations in body 

lead burden are of relevance to the risk of cardiovascular disease. 

The British Regional Heart Study is a British Heart Foundation 

Research Group and is also supported by the Medical Research 

Council, Department of Health and Social Security, the Scottish 

Endowment Research Trust and the Chest Heart and Stroke 

Association. Estimation of blood lead concentrations was supported by 

the Department of Health and Social Security. 

REFERENCES 

1. Kopp, S. J., Glonek, T., Erlanger, M., Perry, E. F., Perry, H. M., and 

2. 

3. 

4. 

5. 

Barany, M. Cadmium and lead effects on myocardial function and 

metaboUsm. J. Environ. Pathol. Toxicol. 4:205-227 (1980). 

Victery, W., Vander, A. J., Shulak, J. M., Schoeps, P., and Julius, S. 

Lead, hypertension and the renin-angiotensin system in rats. J. 

Lab. Clin. Med. 99: 354-362 (1982). 

Pocock, S. J., Shaper, A G., Ashby, D., Delves, T., and Whitehead, 

T P. Blood lead concentration, blood pressure and renal function. 

Br. Med. J. 289: 872-874 (1984). 

Harlan, W. R., Landis, J. R., Schmouder, B. L., Goldstein, N. G., and 

Harlan, L. C. Blood lead and blood pressure: Relationship in the 

adolescent and adult US population. JAMA 253: 530-534 (1985). 

Pirkle, J. L., Schwartz, J., Landis, J. R., and Harlan, W. R. The 

relationship between blood lead levels and blood pressure and its 

cardiovascular risk implications. Am. J. Epidemiol. 121: 246-258 

(1985). 

Shaper, A. G. Pocock, S. J., Walker, M., Cohen, N. M., Wale, C. J., 

and Thompson, A. G. British Regional Heart Study: Cardiovascular 

risk factors in middle-aged men in 24 towns. Br. Med. J. 283: 

179-186 (1981). 

Bruce, N. G., Shaper, A. G., Walker, M., and Wannamathee, G. 

Observer bias in blood pressure studies. J. Hypertension, in press. 

Shaper, A G., Pocock, S. J., Walker, M., Phillips, A. N., Whitehead, 

T P., and Macfarlane, P. W. Risk factors for ischaemic heart 

disease: The prospective phase of the British Regional Heart 

Study. J. Epidemiol. Community Health 39:197-209 (1985). 

Cook, D. G., Shaper, A. G., Pocock, S. J., and Kussick, S. J. Giving 

up smoking and the risk of heart attack. Lancet ii: 1376-80 (1986). 

Grandjean, P., Olsen, N. B., and Hollnagel, H. Influence of 

smoking and alcohol consumption on blood lead levels. Int. Arch. 

Occup. Environ. Health 48: 391-397 (1981). 

Shaper, A. G., Pocock, S. J., Walker, M., Wale, C. J., Clayton, B., 

Delves, H. T.,,and Hinks, L. Effects of alcohol and smoking on 

blood lead in middle-aged British men. Br. Med. J. 284: 299-302 

(1982). 

Shaper, A. G„ Ashby, D., and Pocock, S. J. Blood pressure and 

hypertension in middle-aged British men. J. Hypertension, in 

press. 

13. Pocock, S. J., Shaper, A. G., Walker, M., Wale, C. J., Clayton, B., 

Delves, T, Lacey, R. F., Packham, R. F., and Powell, P. Effects of 

tap water lead, water hardness, alcohol, and cigarettes on blood 

lead concentrations. J. Epidemiol. Community Health 37: 1-7 

(1983). 

14. National Academy of Sciences. Geochemistry of water in relation 

to cardiovascular disease. NAS, Washington, DC, 1979. 

Pocock, S. J., Shaper, A G., Cook, D. G., Packham, R. F., Lacey, 

R. F., Powell, P., and Russell, P. F. British Regional Heart Study: 

Geographic variations in cardiovascular mortality, and the role of 

water quality. Br. Med. J. 280:1243-1249 (1980). 

Schwartz, J. Evidence for a Blood Lead-Blood Pressure Relationship (memorandum to the Clean Air Science Advisory 

Committee). Environmental Protection Agency, Washington, DC, 

1985. 

Elwood, P. C, Davey-Smith, G., Oldham, P. D., and Toothill, C 

Two Welsh surveys of blood lead and blood pressure. Environ, 

Health Perspect. 78:119-121 (1988). 

Neri, L. C, Hewitt, D., and Orser, B. Blood lead and blood 

pressure: Analysis of cross-sectional and longitudinal data from 

Canada. Environ. Health Perspect. 78:123-126 (1988). 

Victery, W., Tyroler, H. A., Volpe, R., and Grant, L. D. Summary °f 

Discussion Sessions: Symposium on Lead-Blood Pressure 

Relationships. Environ. Health Perspect. 78:139-155 (1988). 

Shaper, A. G. Cardiovascular disease and trace metals. Proc. Roy* 

Soc. London B 205:135-143 (1979),. 

21. Medical Research Council Working Party. MRC trial of treatment 

of mild hypertension: Principal results. Br. Med. J. 291: 97-104 

(1985). 

8. 

10. 

11 

12 

15. 

16 

17 

18 

19 

20