p.1 

OAR Box 1131 

Prepped by Ollie Stewart 

Document Number: 

118)11-1-396 

Docket Number: 

A-83-22 

Printed 4/21/2008 2:34:12 PM Sheet 118 of 162 
K, 

Environmental Health Perspectives 

Vol. 78, pp. 139-155, 1988 

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Summary of Discussion Sessions: 

Symposium on Lead-Blood Pressure 

Relationships 

by W. Victery,* H. A. Tyroler,* R. Volpe,* and L. D. Grant* 

The International Symposium on Lead-Blood Pressure Relationships was held in Chapel Hill, NC, April 

27-29, 1987, with sponsorship from the Councils on 

Hypertension and Epidemiology of the American 

Heart Association; the Department of Epidemiology, 

University of North Carolina; the International Lead 

Zinc Research Organization; and the U.S. Environmental Protection Agency. The program was structured so as to first present an overview of theories and 

findings in the general area of human hypertension 

and then to have speakers review the extant literature 

on lead and blood pressure relationships, including 

papers on the human observational studies of lead and 

hypertension; related studies of lead and human 

hypertension; occupational studies of lead and hypertension; experimental studies of lead and hypertension; and papers presenting related information 

from work in progress. Invited discussants, invited 

speakers, and other workshop participants were 

encouraged to ask questions and to discuss needs for 

future research. This report summarizes key exchanges of information during discussions after 

individual papers were presented or during separate 

discussion sessions. It also summarizes presentations 

by several speakers who declined to publish in these 

proceedings full-length papers on ongoing work. 

In the first plenary session, the three speakers (H. A. 

Tyroler, A. Chobanian, and C. Hennekens) gave overview presentations on the epidemiology of hyperten-. 

sion as a public health problem, mechanisms of hypertension, and the impact of reducing high blood 

pressure on more serious cardiovascular sequelae. 

These talks oriented the audience and participants to 

•Environmental Criteria and Assessment Office, U.S. Environmental 

Protection Agency, MD 52, Research Triangle Park, NC 27711. 

fDepartment of Epidemiology, School of Public Health, University of 

North Carolina, Chapel Hill, NC 27599. 

^International Lead Zinc Research Organization, Inc., P.O. Box 

12036, Research Triangle Park, NC 27709. 

the types of studies and methods of analysis necessary 

to consider the possible influence of lead on blood pressure and other cardiovascular effects and reviewed the 

multiplicity of mechanisms that may influence the 

measured outcome of a change in blood pressure. Only 

limited discussion followed these introductory papers, 

with resulting clarification of certain key points concerning the relative role of various known or suspected 

risk factors for hypertension and associated sequelae. 

The next plenary session included a series of papers 

that discussed human observational studies of lead 

and hypertension, with special emphasis on additional analyses of National Health and Nutrition 

Survey II (NHANES II) data and further analyses of 

data from the British Regional Heart Survey. During 

discussions following these presentations, aspects of the 

NHANES analyses were clarified. 

J. Schwartz (U.S. EPA) commented that he used 

P. Gartside's (University of Cincinnati) regression 

models with interaction terms for age and found none 

of the interaction terms to be statistically significant. 

Using somewhat larger age groups than Gartside did, 

he found that lead was statistically significantly 

associated with both systolic and diastolic pressure in 

all 30 age groups. He questioned whether or not the 

failure of Gartside to observe statistically significant 

effects was due to small sample size subgroups. Gartside 

doubted that the difference between the 20- and 30-year 

age groupings was meaningful. He noted that it was 

not infrequent for two individuals analyzing the 

same data set to come up with totally different results. 

Schwartz, although agreeing with this and noting its 

relevance to Fort's findings (Schwartz obtained statistically significant coefficients on regression analyses 

for both systolic and diastolic pressure including all 64 

geographic sites in his regression), pointed out that an 

Expert Peer Review Panel convened by EPA, as well as 

a review committee of the EPA Science Advisory Board 

studying both his and the other NHANES analyses, 

accepted the Schwartz version. Schwartz added that 
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140 VICTERYETAL. 

inclusion of the 64 sites in his regression analyses 

reduced the magnitude of the regression coefficients by 

about 30%, not by the stated factor of three. 

0. Carter (NCHS) questioned whether the HispanicNHANES analysis was restricted to MexicanAmericans. B. F. Fort (Ethyl Corporation) answered 

in the affirmative, but pointed out that the analyses 

presented to date were preliminary and that a corrected 

data set was to be analyzed in the future. Carter pointed 

out that the revisions involved only three persons and 

that should, not change the analyses. Carter emphasized that others using the Hispanic-NHANES data 

should distinguish among Mexican-Americans, 

Puerto Ricans, and Cuban-Americans. Carter noted 

that acculturation, which may affect blood pressure 

levels, and birth place should be explored for their relationships to lead and blood pressure. K. Mahaffey 

(NIOSH) questioned whether there was a continuation in the decline of blood lead levels in the Hispanic 

NHANES. Schwartz responded that, although the 

blood lead levels in Hispanic-NHANES were lower than 

in NHANES II, one must acknowledge that there are 

population differences. Any attempt to separate out the 

Hispanics in NHANES II would be subject to the difficulties of small sample sizes. S. J. Pocock (University of 

London, UK) noted that the regression coefficient 

which Fort obtained for the relationship of lead to 

diastolic blood pressure was 1.96, a value quite similar 

to the coefficient of 2.1 in the British data. He also noted 

that when adjusting for site, the British coefficient 

moved from zero to slightly positive. The NHANES 

coefficients, when adjusted for site, were reduced to 

values that were still positive but of smaller magnitude. 

There was a discussion regarding the reproducibility of results based on analysis of the same data set. 

Fort and Gartside reported that they were unable to 

reproduce Schwartz's results, whereas the University 

of North Carolina group obtained exactly the same 

results as Schwartz, using precisely the same subjects, 

variables, models, and analytic techniques. 

P. Boscolo (University of Chieti, Italy) stated that 

lead exposure is associated with cadmium and other 

pollutant exposures and that interaction effects have to 

be considered. 

L. Grant (U.S. EPA) opened the general question 

session by identifying several key issues: the significance of adjustment for site, for geographical location, 

analyses within different age groupings, and the 

implications of any blood lead-blood pressure associations for major morbidity and mortality cardiovascular outcomes, such as strokes or heart attacks. 

D. Roxe (Northwestern University) inquired about 

the measurement techniques used for lead and blood 

pressure, whether subsets of the populations had had 

recent acute exposure and what environmental sources 

are considered the major sources of lead. Schwartz 

reported that NHANES blood lead measurements were 

taken in specially loaded vacutainers that were treated 

to be trace element-free. Quality control indicated a 

coefficient of variation of blood-lead levels of approximately 15%, equivalent to a confidence interval of 

approximately ± 2 ug/dL on the blood-lead determination. W. R. Harlan (University of Michigan) commented that blood pressure in NHANES II was taken 

on three occasions, seated at the beginning, supine 

midway through, and a second seated blood pressure 

near the end of the examination. Systolic pressure was 

recorded as the initiation of Korotkoff sounds and 

diastolic pressure as cessation of sounds (K-5). There 

were a large number of observers, trained to record 

blood pressure in a standard manner. Regarding 

acute exposures to lead, the only historic information 

was the 24-hr dietary recall. Those people who have had 

a significant number of calories on the day prior to 

examination were also the people reporting the highest 

intakes of alcohol as their habitual consumption. 

Schwartz remarked that the half-life of lead in the 

blood was typically 30 days and that a single, higherthan-average exposure dose is not going to have major 

perturbing effects on adults' blood lead levels. Individuals who work for lead exposure industries, as classified by NIOSH, were excluded from the sample. Exclusion of these individuals resulted in a slightly higher 

regression coefficient, which was still significant. 

Pocock remarked that the methodology of blood lead 

was more important than the methodology of obtaining blood pressure in these studies. Blood lead was 

measured under strict quality control methods at the 

leading British laboratory. Blood pressure was 

recorded on the London School of Hygiene zero-muddler sphygmomanometer. There were three observers 

per town. In addition to training to correct for observer 

variation, observer differences were adjusted for in the 

analyses. Pocock doubted that single exposures to 

alcohol would have meaningful effects. It was his 

opinion that food and water sources would be important causes of blood lead levels in the general population, in addition to effects of heavy drinking and 

smoking. Lead is still in British gasoline and is being 

removed gradually and is lower than it was previously. This will influence the lead in dust, air, and 

food. He was not aware of any occupational or ambient 

environmental problems from lead smelters influencing his data. Schwartz commented that in the United 

States there was a larger amount of lead in the general 

population coming from gasoline than in England 

and lower amounts coming from water. He estimated 

that approximately half the lead in the general popu' 

lation in the 1970s was based on gasoline as the pr'" 

mary exposure, accounting for higher levels in urban 

areas. 

M. Galvin (NIEHS) questioned the differences H| 

sample size between the Schwartz and DuPo° 

analyses. Schwartz responded that DuPont did not us 

the same covariates that he did and that given soiJJ 

missing covariate values there were resulting sligfydifferent sample sizes. Grant added that there are a's 

some differences in the subjects included or excluded' 

R. Lilis (Mt. Sinai, NY) raised questions regardiTM 
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DISCUSSION SUMMARY 141 

.ug comparability of the British and American studies 

n the distribution of the blood lead levels in the two 

populations, the existence of a similar secular trend in 

jhe United Kingdom and the United States, and 

information regarding trends in blood pressure levels 

in the United Kingdom compared to the United States, 

jvlahaffey inquired about hypertensives receiving 

medication in the British'studies, were they excluded, 

at what level of blood pressure would medication be 

prescribed, and regarding the distribution of blood 

lead levels, what information is available regarding 

quality control and intake of lead? Pocock thought 

there might be a slight tendency to higher blood lead 

levels in NHANES II but that in general the 

distributions would be similar. Schwartz indicated 

that the mean'blood lead level in the NHANES 

population was approximately 17 ug/dL. Pocock 

indicated that it was 0.76 umole/L (equivalent to 13 or 

14 ug/dL) in the British studies. The proportion of 

individuals with values over 30 ug/dL was small, 

suggesting generally similar ranges of blood lead in 

the two studies. Pocock suggested that there are not 

good epidemiologic data at present on trends in blood 

lead levels in the British experience. Such data are 

being assembled now and for monitoring over time 

with the removal of lead from gasoline. 

P. Elwood, Medical Research Council (MRC, UK) 

has assembled several different approaches to this 

question and he reported consistency among them of a 

fall of about 4% per year over the last 10 years in blood 

lead levels prior to reduction of lead in gasoline. Pocock 

commented that there are not good data on trends in 

blood pressure, but he suspected that there have not 

been substantial trends. He added that hypertensive 

medication is not as intensive in the U.K. as in the U.S. 

Further, it was his opinion that treatment was not 

initiated until relatively high levels of diastolic blood 

pressure were observed. Elwood concurred that blood 

pressure changes over time have been minimal and 

that there is no good evidence either in trends in blood 

pressure or antihypertensive treatment in Great Britain. 

Lilis referred to data from Scotland relating levels of 

lead in drinking water to blood lead, kidney function, 

and hypertension, data which were not presented by 

Pocock in his formal paper. Pocock responded that he 

restricted his analyses to the blood lead-blood pressure 

relationship. Lilis remarked that Pocock's data suggested that the localities which had higher blood lead 

levels were the areas of soft water and that the source of 

lead, whether it comes from water, air, gasoline, or 

other sources, is actually of secondary importance in 

this discussion of the effect of lead on blood pressure. 

Pocock concurred and justified his discussion of the 

association of higher blood pressure with water softness in his presentation as of background descriptive 

interest only. Pocock added that he included individuals on hypertensive medication in his analyses since 

their exclusion could lead to a bias due to their higher 

than average blood pressure values. Fort commented 

on studies of two towns in Massachusetts in which an 

association was detected between sodium chloride 

content of the water supply and blood pressure levels of 

school children, controlling for other relevant 

variables. He questioned whether there were other 

variables depending on location, water supply, and 

sodium chloride specifically, which could affect blood 

pressure, and had not been controlled for in the data 

sets under consideration. 

D.-L. Zhu (University of North Carolina) inquired 

about the relationship between erythrocyte protoporphyrin, body burden of lead, and blood pressure in the 

NHANES cohort. Schwartz noted that erythrocyte protoporphyrin did not correlate with blood pressure 

levels in the NHANES studies. He indicated that in the 

general adult population, erythrocyte protoporphyrin 

is dominated by iron status and is a poor predictor of 

lead status; this is in contrast to a child eating lead 

paint chips who has marked elevation of blood lead and 

marked elevation of protoporphyrin. 

S. T. Weiss (Harvard Medical School) commented 

on the implications of adjusting for site by pointing 

out that site may in fact be a link in the causal chain of 

the blood lead-blood pressure association, because site is 

associated with water or air sources of lead and, 

consequently, is the major determinant of blood lead. It 

was his opinion that this distinction between whether 

site is a confounder or a link in the causal chain could 

not be resolved with cross-sectional data and that a 

longitudinal study of changes in blood lead and blood 

pressure was one potential way of resolving the issue. 

A. J. Vander (University of Michigan Medical 

School) questioned the relationship between decreases 

in lead and the time necessary for an associated decline 

in blood pressure, assuming that lead had contributed 

to a rise in blood pressure. In particular, he inquired 

about the effect on statistical associations if over a 4-year 

period when lead was decreasing, blood pressure did 

not decrease. Schwartz responded that the question did 

not relate to the observations, since controlling for all 

other factors, blood pressure did change over time with 

changes in blood lead. Vander was skeptical about the 

time changes in blood pressure, but, assuming that 

blood pressure actually did decline, did it do so for 

reasons other than lead? Schwartz responded that 

elaborate, detailed models, including control for many 

potential confounders, failed to eliminate the blood 

lead-blood pressure association. This included siteand time-related variables. 

W. Kannel (Boston University School of Medicine) 

commented on blood pressure trends. It was his 

opinion that there was no way to know whether blood 

pressure actually changed in the general population. 

There has been a massive amount of treatment introduced over time, the indications for treatment have 

changed over time as well, and currently, physicians 

in the United States are treating people with lower 

blood pressure. Under these circumstances, it is difficult to determine whether the prevalence of hypertension has changed over time. Harlan noted that com-
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142 V1CTERYETAL. 

parison of the distributions of blood pressure in 

NHANES I and NHANES II, i.e., between the early and 

the late 1970s, and suggested that the differences were 

primarily at the upper end of the blood pressure distribution and suggested that treatment is one of the 

major reasons for the decline and that there are only 

small changes in mean values. Schwartz indicated 

that this is one reason his group did analyses excluding people on hypertensive medication, although he 

acknowledged that this approach results in truncating 

the sample. 

D. G. Beevers (University of Birmingham, Scotland) attempted to reconcile the apparent disparities 

between the U.S. NHANES and the British Regional 

Heart Studies. He suggested that participant selection 

may have been partially responsible in that there was 

oversampling of disadvantaged persons of relatively 

lower social class in NHANES and unintentional selection of higher social class individuals in the Regional Heart Study. Pocock indicated that an attempt 

was made to select a general practice that was representative of its community in each town in the British 

Regional Survey. However, there was only a 78% 

response rate of individuals coming in for screening. 

He noted that the distribution of manual to nonmanual workers in the sample was generally similar to that 

in Great Britain; however, there was a slight underrepresentation of unskilled manual workers and a 

slight overrepresentation of the professional classes. 

Schwartz indicated that there was in fact an 

oversampling of lower social status individuals in 

NHANES, but this was done by design in advance and 

sample weights were created, so that by weighing these 

people less than others it was possible in a weighted 

analysis to get back to a sample representative of the U.S. 

population. Weights also were assigned to adjust for 

nonparticipation in examinations, based on the fact 

that 97% of the persons selected had demographic and 

medical history information obtained from a home 

interview. 

Grant opened the question and discussion period of 

the panelists. H. Smith (Statistical Consultant) queried 

Pocock and Schwartz as to whether each had carried 

out regression analyses within each site, which would 

permit site-specific estimation of the blood lead-blood 

pressure association controlling for the other major 

covariates. Pocock indicated that his final model contained adjustments for body mass, age, alcohol consumption, social class, and smoking categories in 

addition to 23 dummy variables to adjust for differences between towns. The number of individuals 

within each site, approximately 300, were too few to 

permit site-specific detailed analyses with multi-covariables. Schwartz responded that he could not do sitespecific regression analyses because for the 40 to 59 year 

olds there were 543 people in 64 sites, and the information available per site would be markedly limited. 

Smith inquired about separate analysis at each site 

and then a meta-analysis of the derived coefficient 

across all sites. Smith suggested this (which had not 

been done) would be similar to the Landis approach, 

which was a pooling using the Mantel-Haenszel 

statistic across subgroups. Smith reiterated that what 

he was interested in was the magnitude of the regression coefficient across the groups and not the significance level. The magnitude of the estimated change in 

blood pressure per unit change of blood lead was of 

primary interest to see if any association detected was of 

importance. He stated that inference was the issue, not 

the test of hypothesis. Further, he argued that the 

selection criterion for admitting variables in a stepwise procedure, which mandates establishing a significance level to admit or discard a variable, is 

something that ought to be avoided or used only with 

caution. Schwartz responded by indicating that he 

had adopted a model with variables generally agreed to 

be associated with blood pressure, i.e., sex, age, body 

mass, and race, and then, since blood pressure has been 

hypothesized to be a multifactorial outcome, to have 

included a large number of dietary, serum micronutrient, demographic, and other factors which have 

been found associated with blood pressure in some 

studies. His approach was to see how stable the blood 

lead coefficient was, including or excluding these 

variables and under that circumstance using the stepwise regression analysis approach. Schwartz emphasized that this approach was not used to establish a 

model for blood pressure, but rather to test for the 

stability of the blood lead-blood pressure relationship as 

he expanded from the biologic model that included 

universally accepted variables to models that included 

variables that others have speculated about. 

Smith queried R. Landis (University of Michigan) 

regarding the rationale for adopting the procedures he 

had used and which are discussed in detail in his 

formal paper. His response was that the expected value 

and variance in each subtable is computed conservatively under a fixed margin assumption. It can be 

viewed as a randomization model in which the beta 

coefficient at each site can be estimated. Given the expected value and the variance for that component based 

on the fixed margins of a conservative Fisher exact 

kind of hypergeometric framework, you can see 

whether or not the observed cross-product tends to 

exceed its expected value on average across very small 

subgroups of individuals. In the extreme, this would 

be the matched pair design adjusting for all the covariates; although not done yet, it could be done and to 

determine whether on average, the matched pair tends 

to favor the elevated level of pressure being associated 

with elevated level of lead. Landis prefers this to a 

multiple-regression model with 63 site parameters' 

Additionally, the procedure permits adjustment for tn 

role of 64 sites without incorporating the site effec 

into the estimation of the partial beta coefficient. All tn 

statistical power is focused on estimating one beta c°e 

ficient adjusted for all the other covariates. That be 

coefficient has a test statistic that is nearly identical 

the Mantel-Haenszel. In response to a question fr° 

Grant, Smith responded that he had never seen 
DISCUSSION SUMMARY 143 

Mantel-Haenszel procedure applied this way before and 

ue was not certain whether the application was appropriate. 

Kannel commented that it was necessary to return to 

basic epidemiologic principles and to evaluate whether 

0r not a causal association is present. He set out the 

following criteria: to determine whether the observed 

relationship was found consistently, whether the association is strong, whether it is dose related, if it is biologically plausible, whether it can be reproduced experimentally, and finally, if it is present when taking 

confounding variables into account. Based on the 

information presented, he believed the effect of lead on 

blood pressure appears to be modest; however, within a 

population context, given ubiquitous exposure, the 

population attributable risk can be large, and this has 

public health implications. However, he believes that 

more information is needed. The shape of the doseresponse relationship of lead to blood pressure is not 

clear. Is there an effect on blood pressure at toxic 

exposures over the limit of 30 or 40 ug/dL? More information is required regarding mechanisms. Is the 

effect short term or long term and cumulative? Kannel 

noted that for hypertension in general, even for the 

strongest of known population risk factors such as 

obesity, mechanisms are unclear and so the absence of 

this knowledge is not unique to lead. In assessing the 

role of potential confounders, Kannel felt that, in place 

of "mindless statistical numerology," it would be preferable to have and test specific hypotheses as to how lead 

might affect blood pressure in a population. Finally, he 

noted that lack of knowledge is no excuse for inaction, if 

we know that there is a possible relationship and a 

modifiable population environmental exposure. However, Kannel did feel that there is a need to establish the 

nature of the association more precisely. 

H. Dustan (University of Alabama) summarized 

her reaction to the materials presented by stating that 

she regarded the evidence as quite unclear whether 

lead has an effect on blood pressure in large populations. She agreed with Kannel that it was difficult to 

know which of the multitude of analyses with different results was correct. 

The next plenary session was devoted to four related 

studies of lead and hypertension. Following D. Kromhout's (State University of Lieden) presentation on the 

Zutphen Community Study of elderly men, Boscolo 

commented that the effects of lead exposure are very 

different in young and old persons. He suggested that 

the effects of lead exposure in younger individuals 

would be mediated via mechanisms regulating blood 

pressure through the brain and kidneys. Pocock 

questioned whether Kromhout would have published 

his findings had they not been statistically significant 

(referring to the issue of publication bias). Kromhout 

answered that he would have published the findings 

regardless of the outcome, but would not have published the blood lead-blood pressure results separately. 

Lilis.commented that removal of one outlier observation of an individual with high blood lead and 

very high blood pressure resulted in the absence of a 

significant relationship between blood lead and blood 

pressure in Kromhout's presentation. Kromhout 

responded that removal of the one outlier resulted on 

univariate analysis in a borderline statistically significant relationship between blood lead and systolic 

blood pressure and absence of an association of blood 

lead and diastolic pressure, but that the association no 

longer was statistically significant upon adjustment 

for body mass index and age. 

Lilis further discussed the appropriateness of including or excluding the outlier in the final analysis. 

Smith commented that the decision rests upon the 

range of inference to be made. If, in fact, the outlier is in 

the range of inference, then obviously it has to remain 

in the study. Alternatively, if the range of inference is 

restricted to lower values, then it would be inappropriate to include it. Schwartz questioned the effect on 

the magnitude of the regression coefficient including 

and excluding the outlier. Kromhout responded that 

there was only a small change in the magnitude of the 

regression coefficient, but the p value became 0.06, i.e., 

no longer conventionally statistically significant. 

W. Lee (University of Manchester, UK) raised the possibility of a threshold response of blood pressure to 

blood lead levels. He interpreted the data presented as 

showing very little effect of low blood levels on blood 

pressure, suggesting a horizontal dose-response relationship with an upturn in blood pressure response at 

some threshold value. Recognizing the limitations in 

one observation, he suggested that perhaps the outlier 

might indicate where the dose-response curve for the 

blood lead-blood pressure relationship is beginning to 

turn up. 

Landis disagreed with Lee's interpretation of the 

dose-response relationship. He interpreted the 

NHANES data as showing an association of blood 

pressure with blood lead down to levels of 5 ug/dL. He 

suggested that, if anything, there is evidence that the 

response of blood pressure may taper off at the higher 

levels of lead. Landis commented that if there is a 

threshold, it is for higher levels than those observed in 

the NHANES data. Schwartz reported that he had tried 

fitting a threshold model in the NHANES data and 

had failed to find evidence of a threshold. He disagreed 

with the characterization of an outlier in the Kromhout data, arguing that the single value does not 

change the slope of the relationship much while being 

influential with respect to the significance level, and 

therefore it was not an outlier in the sense that there is 

a different relationship at the observed level and at 

lower levels. 

After T. Moreau's (INSERM) presentation, H. Gonick 

(Cedars Sinai, CA) requested some clarification of the 

conclusions regarding lead's effect on red cell membrane lead content and cation transport systems. If lead 

binding to red blood cells affects Na+/K+ ATPase, one 

would expect to see a positive correlation between the 

two. Since that did not occur, one could reverse the 

question and ask if the total blood lead or membrane-
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144 V1CTERYETAL. 

bound lead is a reflection of an active transport abnor-, 

mality characteristic of hypertension. Dustan also 

queried Moreau concerning the lack of correlation 

between membrane-bound lead and cotransport systems, in particular, how calcium may interact with 

lead. Moreau indicated that his group was disappointed in this particular finding, but there may be a 

positive relation of membrane lead and K+ channels. 

He suggested that the sulfhydryl groups of the Na/K 

ATPase enzyme are probably reacting with lead, even 

though the enzyme activity was not affected. 

A. Johns (University of Miami) asked if inhibition 

of this cotransport system could be responsible for the 

increased contractility in smooth muscle cells of blood 

vessels. Moreau replied in the affirmative. Johns said a 

similar pump exists in uterine smooth muscles that 

appears to be furosemide insensitive but it is still 

responsive to agonists causing contraction. 

Following the presentation of the paper by Weiss, 

Schwartz questioned the findings over time and 

whether or not a single measurement of blood lead lost 

power as a predictor of blood lead levels in successive 

years. Weiss responded that in the context of this 

model, it was necessary to treat blood lead as a fixed 

covariate, i.e., the assumption had to be made that blood 

lead does not change over time. Landis asked whether 

lead was analyzed as a continuous variable, rather 

than categorically as intermediate and high. This was 

of importance, since there was a large representation in 

the upper levels, i.e., 22% of the men. Weiss indicated 

that this had not been done; the data were simply 

categorized at the start of the analysis. 

Landis indicated that the Weiss study included a 

large proportion who would be in the upper end of the 

distribution of the general population, i.e., in NHANES 

II. Kannel questioned the associations of alcohol intake 

with blood pressure in the study and asked whether or 

not Weiss was implying that the alcohol-blood pressure association is entirely due to lead. Weiss responded that the distribution of reported alcohol consumption in his sample was similar to that reported by 

the average American. He suggested his findings may 

reflect reporting bias. Regarding the association with 

blood pressure, he pointed out that all men in the study 

were normotensive and that the findings might result 

from a relatively small study of limited power. He did 

not believe any of his results vitiated any of the earlier 

studies regarding the relationship of alcohol to 

hypertension or alcohol to blood lead levels. It was just 

that the alcohol association with blood pressure was not 

demonstrable in his (small) cohort. 

Gonick asked the first question about R. Wedeen's 

(V. A. Medical Center, E. Orange, NJ) presentation; it 

concerned whether the EDTA lead mobilization test or 

the X-ray fluorescence bone lead measures of lead 

burden had been correlated with any blood pressure 

measurements. Wedeen responded that the limited 

number of subjects did not make such analysis suitable. A follow-up question from Gonick asked the relationship of these two measures of lead to that in the 

postulated target tissue for hypertensive effects, e.g., 

vascular tissue. Wedeen did not feel this was likely to be 

the target tissue. He plans to examine platelets and their 

calcium metabolism further, as well as endothelial 

repair. Moreover, lead concentrations may not be perceptibly higher in any target tissue. Gonick asked 

Wedeen to consider as toxic, the lead in the ionized 

form circulating in extracellular fluid, platelets or 

vascular tissue. Wedeen agreed that lead in bone 

(while being the best measure of past exposures) was 

unlikely to be indicative of damage to the bones; 

however, it is available for exchange with extracellular 

fluid and consequently to other tissues. 

P. Grandjean (Odense University, Denmark) 

brought up various concerns about the use of X-ray 

fluorescence for lead burden measurements; the technique involves use of X-rays, it is expensive, and the 

measurement obtained varies with bone type. In 

addition, in renal failure dialysis patients, the serum 

level of aluminum is elevated. Aluminum binds to 

and affects bone hydroxyapatite, especially its ability to 

respond to homeostasis of serum calcium by parathyroid hormone. Therefore, bone metabolism of lead 

may be considerably altered in those patients with 

concomitant bone disease. Wedeen (in collaboration 

with scientists in the Netherlands) has histomorphometric evidence that the amount of lead in bones of 

renal disease is not altered. 

Dustan queried if there is a difference between races 

with regard to renal disease. According to Wedeen, 

blacks are overrepresented in dialysis units; in spite of 

small numbers, he found these blacks had higher lead 

levels. Unfortunately, in clinical research, the number 

of patients studied is necessarily limited. 

Vander asked for clarification on the ability of the 

X-ray fluorescence method to detect low level lead exposure. Dr. Wedeen indicated at present that detection 

limits are approximately 10 ppm with an error of 10 to 

20%. Values in the general population are expected to be 

6 ppm; therefore, the technique may be useful in 

selecting high risk groups. Vander was actually more 

concerned about the lack of correlation in the bone lead 

content with respect to the constant amount of lead 

measured in the EDTA mobilization test. Wedeen 

stated that the total number of patients has been rather 

limited when compared to the numbers in epidemiologic studies. 

The next plenary session consisted of three presentations on persons who were occupationally exposed to 

lead. 

Following the presentation of W. C. Cooper (physician-consultant) on his. lead mortality study, there 

was a question from P. Pontzer (Federated Fry Metals 

Company) as to whether Cooper had attempted to 

correct for incompleteness of data on the death certificates used in the study. Cooper responded in the negative because he felt that the same correction could not be 

done for the comparis'on groups. Kannel then questioned why lead battery workers were separated from 

smelter workers, since he felt that if you combined the 

I 
w 

DISCUSSION SUMMARY 145 

P.8 

Hata of lead-exposed workers and compared these data to 

i e general population, a level of statistical significance 

would be achieved for some of the outcomes. Cooper 

ndicated that he, had carried out such an analysis, but 

't did not alter the results enough to be justified. 

Furthermore, these two groups of workers are in different plant operations and thus have different possibilities for confounding exposures which are 

important ^or assessing relationships with various 

types of cancer, specifically lung cancer and stomach 

cancer. Cooper suggested that if the age distributions 

and different hire distributions of these populations 

were examined, one would feel more comfortable seeing these two groups separated. 

j . Bosch (George Washington University) asked 

whether there was any knowledge of workers that 

developed chronic renal failure and then died, to 

which Cooper indicated that he did not know about 

such cases. Lilis suggested to Cooper that since higher 

exposure levels were found in the smelters as compared 

to the battery plants and higher mortality rates for 

chronic renal disease were seen in the smelters, this 

would indicate that there is a dose-response relationship. Cooper responded that the data appeared consistent with that hypothesis. 

Smith then asked what the total population of 

workers available to exposure was in the smelter and 

battery plants and their person-years experience. 

Cooper stated that battery plants had roughly 100,000 

person-years and the smelters had 50,000 person-years. 

After S. Selevan's (U.S. EPA) paper, Gonick asked a 

question concerning Selevan's designation of high 

lead vs. high lead/low other for exposure levels in her 

study. Gonick felt that the high lead/low other 

designation might be different for chronic nephritis, 

than for cancer. For example, arsenic does not have an 

adverse effect on kidney function, but is presumably 

carcinogenic. On the other hand, silicon, copper, 

cadmium, and perhaps gold and silver do have an 

adverse affect on the kidney. Gonick suggested that a 

regrouping of the high lead/low other classification 

looking specifically for the silicon and cadmium effects 

on chronic nephritis might give a somewhat different 

insight to the current groupings in the study. Selevan 

responded that there would only be fairly minor 

differences, since the expected and observed were so low. 

Selevan suggested that NIOSH take a look at Gonick's 

suggestion. 

R. Goyer (University of W. Ontario, Canada) then 

questioned whether the use of autopsy material, as well 

as information from death certificates, might give a 

better view of the nature of the renal disease and 

possibly the incidence of renal tumors in the study 

population. Selevan agreed and indicated that NIOSH 

had recently collected some pathology reports for such a 

purpose. Dustan then noted that there was no increase 

in hypertension-related deaths, but wondered whether 

there was an increase in hypertension in the overall 

cohort. Selevan indicated that there was no information on this because the mortality study only included 

those things which find their way to the death certificate. Dustan suggested that this information might 

be found through annual physical examination 

records. Selevan stated that this was not necessarily so 

since there was not a lot of information on blood leads 

in the older medical records and since annual physical 

exams were not carried out at the plant. 

H. A. Tyroler (University of North Carolina) then 

asked whether Selevan examined multiple cause 

coding and whether or not in proportionate mortality 

terms or in relationship to high exposures, there were 

more instances of hypertension and hypertensionrelated conditions as secondary causes of death. Selevan 

indicated that a secondary analysis was not done except 

for silicosis. Tyroler suggested it might be informative 

to do a secondary analysis. 

Boscolo noted that Selevan's cohort consisted of a 

peculiar population of workers exposed not only to lead, 

but also to cadmium, arsenic, copper, and other 

elements, not only at work, but at home. He felt it would 

be difficult, therefore, to compare the data of this study 

to other data on people exposed only to lead. Selevan 

agreed with this observation, remarking that it was 

difficult to know what type of interactive effects may be 

occurring and what effects may be caused by other 

kinds of exposures. It is extremely hard to determine 

definite conclusions from this type of work. 

Following W. L. A. M. de Kort's (Ministry of Social 

Affairs and Employment, the Netherlands) paper, 

Dustan noted that an increase in the average arterial 

pressures for both systolic and diastolic blood pressures 

was observed. Also, among the lead workers as opposed 

to "the controls, there was a bit of an age difference 

between the two groups with the workers being a little 

older than the controls. Dustan noted that this age 

difference becomes very important in regard to blood 

pressures. Dustan then asked whether there "were people 

with real hypertension; people with diastolic pressures 

greater than 105, or was this just part of the aging 

process, de Kort--responded that mixed pair analyses 

had beenjlone and consistently a difference in systolic 

blood pressure was found. The diastolic blood pressure 

was not statistically significant in the mixed pairs 

analyses. 

de Kort noted that there were problems in obtaining 

exposure levels at the plant. There was an indication 

that the time-weighted averages appeared lower than 

the threshold limit value, which was 105 ug/m3 at the 

time, but peak values often exceeded 10-fold this 

threshold limit value. 

Lilis stated that she thought that not adjusting for 

body mass in a hypertension study was such a drawback that one could not possibly draw any conclusions, 

de Kort disagreed with this, stating that he had not 

seen studies where body mass index and blood leads 

were highly correlated, and, furthermore, if body mass 

index had been included, there would have been a risk 

of overmatching in such a small group which would 

be very serious, de Kort then noted in response to 

another question by Smith that the time frame of his 
P.9 

146 VICTERYETAL. 

data collection was one month. 

Lee noted from listening to all papers presented so far 

at the conference that there appeared to be a very slight 

rise of blood pressure over a range of blood leads, 

something like a 2-mm Hg/10 ug Pb/dL blood. Yet, in 

the first two mortality papers, there were observations 

of people dying from renal disease and perhaps hypertensive disease, from some rather ill-defined but 

generally accepted very high blood lead levels. Lee suggested that perhaps something was occurring at 

higher levels of exposure or that lead was having an 

effect in higher doses and producing renal disease 

without producing marked hypertension, de Kort 

responded that when people are exposed to high lead 

levels, effects will show up that will not necessarily 

show up at lower levels. Also, de Kort stated that he 

disagreed with the theory put forth by Wedeen that the 

kidney is of importance in the hypertension relationship. He believes it is the vascular wall that is 

important. However, if one is exposed to insoluble lead 

components, most of the material remains in the 

lungs. So, perhaps the lung is the target organ where 

the angiotensin converting enzyme plays a role in 

generating vasoactive agents. 

Schwartz remarked that he was disturbed by 

hearing people talking about very small effects and 

called the audience's attention back to the original 

comments made at the beginning of Monday's session 

on attributable versus relative risk. He stated that he 

did not believe that anybody who has done work on 

lead and blood pressure thinks that lead is the principal 

determinant of blood pressure. Furthermore, everyone 

agrees that the slope of the relationship with body mass 

is much bigger and more stable than blood lead. The 

problem is that it is very difficult to change people's 

body mass index. It is even more difficult to change 

their age, and that goes in one direction as far as we 

can tell. In terms,of a slope of 2 mm for a 10 ug/dL 

change in blood lead, Schwartz felt that that was 

roughly in the ballpark of the results that he found in 

his study and that Pocock found in his study. To put 

that into perspective, Schwartz noted that there had 

been almost a 10 ug/dL change in the average blood 

lead level of American adult males since the mid-1970s. 

If, in fact, 10 ug lowered the average systolic blood 

pressure in the United States by 2 mm Hg, then 

everything we have seen from prospective cardiovascular disease studies suggests that while it would not 

produce dramatic changes in the relative risk of the 

largest cause of death in the United States, it might 

have some important public health consequences, 

which is the real issue here. 

Tyroler then expanded on Schwartz's point by 

stating that there had been a mean difference of only 

about 5 mm of diastolic Hg between the treated and the 

control group in the Hypertension and Detection Follow-up Program (HDFP). That was attended by almost 

a 20% reduction in all-cause mortality among middleaged adults and so a seemingly small mean difference, 

2 mm Hg, at the population level would be associated 

with as much as an 8 to 10% decrease in all-cause mortality. It is not trivial in terms of its public health impact. Schwartz then remarked that a relative risk of 

1.08, while important for public health consequences, is 

rather hard to find in studies looking at specific mortality ratios. 

Vander noted that there appeared to be some 

unanimity. He agreed with Lee that there may very 

well be a difference in the dose response for renal disease 

and for hypertension in experimental animals. Most 

of the published work on experimental animals shows 

certain doses of lead will produce high blood pressure 

and as one goes higher, the high blood pressure 

vanishes. Given the difficulty of doing epidemiology 

studies, Vander felt that what he had heard so far was 

in pretty good agreement. In fact, Vander felt that there 

was a remarkable agreement in terms of the expected 

rise in blood pressure that would occur for a given rise 

in blood lead. If one uses those doubling doses, the 

value that one comes up with from lowering blood lead 

from 16 down to 4, and 4 is still quite a high number 

for preindustrialized societies, is in the ballpark of 5 

mm Hg. That is a very large reduction in blood pressure for the general population. In terms of what was 

heard on Monday, Vander noted that approximately 

40% of people would go from being labeled hypertensive 

to being labeled normotensive. He felt that these very 

small changes in blood pressure are extraordinarily 

important. 

J. Rosen (Albert Einstein Medical School. NY) then 

clarified some statements concerning the K X-ray 

fluorescence instrumentation that Wedeen spoke 

about. He noted that his instrumentation at Brookhaven, at Einstein, and at Montefiore Medical Center 

was completely different from the instrumentation 

used by Wedeen in East Orange, NJ. Rosen's instrumentation, which is based upon soft L X-rays of lead, 

has a minimum detection limit of 2 ppm. It also has 

the capability of exposing children as well as pregnant 

women to virtually no radiation other than what one 

would anticipate on a trip to Denver, CO. Rosen 

believes his instrumentation is widely applicable to the 

general U.S. population and noted that he would be 

presenting his data on 66 children using L X-ray 

fluorescence at an open meeting following the conference. 

The panel of invited discussants then gave their 

views on the session. Kannel made some general 

comments on the occupational epidemiology studiesHe felt the studies seemed to rely heavily on death 

certificate evidence of outcome and that these can be 

imprecise, particularly in respect to the hypertension 

end point depending upon whether one uses multip1*-

cause certification, underlying cause of death, or state 

causes of death. Kannel also felt that the studies relied 

upon external controls, or comparisons; that is, standardized mortality ratios which he felt rather uneas. 

about. He also noted that the healthy worker effect can 

often appear in epidemiologic studies becauinvestigators often use the general population exp 
DISCUSSION SUMMARY 147 

P.10 

rience as an external control. There is also a lack of 

djustment or information on major confounding 

variables such as relative weight, alcohol intake, 

cigarette smoking, and factors related either to lead or 

to hyPertens'

o n

- Kannel felt there was an imprecise 

measurement of the actual exposure to lead in these 

studies. There are arbitrary decisions as to where cut 

noints are made when the exact dose-response relationship is poorly defined. There also seems to be low 

power to detect some of the excess mortality for some of 

the uncommon causes which are being sought after 

making it very difficult to draw conclusions about the 

relationships. When one finds an excess of perhaps 30 

to 40% which is significant, the significance test 

merely tells you that you cannot place much confidence in your estimate. It is always troublesome to find 

a major excess that would be significant from a public 

health standpoint, but not be able to say whether your 

estimate is precise enough to judge whether it is true. 

Smith felt that one should be careful about saying 

that the papers presented were moving in the same 

direction. He noted C. Henneken's (Harvard Medical 

School) paper on the combination of clinical trials that 

pointed out very clearly the difficulty of combining 

information from across a wide variety of experiments. Henneken threw out half of the trials and ended 

up with a very small set because the investigators did 

not adhere to strict protocol and strict collection of 

information. One must, therefore, be very careful with 

a combinational type of inference when comparing 

groups of studies. 

Dustan then gave her comments. She stated that the 

evidence presented so far suggested that there is a 

relationship between blood lead or lead exposure and 

blood pressure. She noted that there was no information about the mechanism of this relationship; the 

relationship seemed to be of relatively low power, but 

could be significant. Dustan asked whether there is an 

experimental model for the effect of chronic lead 

intoxication on blood pressure, and if such a model 

exists, whether that model is different than acute 

intoxication. If it is not different in terms of its 

determinant, then Dustan suggested using acute 

intoxication for a further study. Dustan remarked 

that this is one of the major issues that needs to be 

addressed because it is the influence of lead on the blood 

pressure of the population that seems to be so subtle and 

that is very difficult to determine. Dustan noted 

another confounding factor. As we reduce the lead in 

the environment through the reduction of lead in 

gasoline, are we then going to see an important 

decrease in the mean blood pressure of the population. 

Dustan felt that if it does happen, it would be nice to 

know what the decrease is due to and questioned 

whether we would ever know what it is due to. Dustan 

suggested that in the discussions that followed later in 

the morning and afternoon perhaps one would get 

some idea as to whether there are experimental models 

of chronic lead intoxication that suggest lead having a 

role in producing hypertension. 

Investigators who have performed research in experimental settings on the effects of lead on the cardiovascular system spoke at the subsequent session. 

W. Victery (U.S. EPA) presented a short overview of 

chronic exposure protocols, using both high and low 

exposure levels, which were evaluated for blood pressure effects. Vander reviewed findings of a lead effect on 

the renin angiotensin system, and R. Webb (University of Michigan) discussed the effects of lead exposure on vascular reactivity. These talks were followed 

by S. Kopp's (Chicago College of Osteopathic Medicine) 

findings on cardiotoxic effects of lead; the final presentation by Boscolo was on neurohumoral effects of 

lead exposure. 

Following the presentation of Kopp on cardiotoxic 

effects of lead, there was a question from de Kort on the 

effect of anesthetics on the blood pressure and cardiac 

effects observed in the experimental animals. Kopp 

indicated that they no longer use pentobarbital because 

it tends to blunt the measured effects of lead or 

cadmium on the cardiovascular system but have 

found that a mixture of Ketamine and Xylozine are 

effective. In addition, pentobarbital depresses the cardiovascular system responses of lead-exposed animals 

more than those of control animals so that the differences seen between the groups is an underestimate 

rather than an overestimate. 

There was a question directed to the speakers regarding any evidence that the high renin levels observed 

in the lead-exposed animals were related to sodium or 

fluid imbalance. Vander responded by indicating that 

in other published reports from the Michigan group, 

animals with similar lead exposure had a subtle defect 

in sodium reabsorption by the kidney. The animals 

initially responded to a sodium-restricted diet by 

excreting more sodium than control animals. There 

were no differences in steady-state sodium balance. 

Whether this finding was correlated to the renin level 

was not determined, e.g., by using blocking drugs for 

the renin angiotensin system to determine the causal 

role of renin. 

Lilis asked for clarification regarding Boscolo's 

remarks about a possible genetic component to 

susceptibility to blood pressure changes related to lead 

exposure. The two agreed that this hypothesis would 

require further study. Wedeen indicated that humans 

with essential hypertension may have excess body 

burdens of lead that are not remedied by chelation 

therapy. On the other hand, patients with elevated 

blood pressure during an acute lead poisoning 

respond to chelation therapy by reduction in blood 

pressure. Vander pointed out that there is no experimental evidence that removal of lead from the animals 

will lower blood pressure. There were additional comments by the speakers who indicated that we should 

recognize that the data are quite different when 

animals are exposed to chronic low levels of lead compared to acute effects of higher level lead exposure. This 

appears to be the case in animal experiments but is 

probably also the case in the two types of human expo-
• ¥ 

148 VICTERYETAL. 

sure. Kopp explained that the cardiac effects seen with 

acute versus chronic exposure are clearly different 

(with acute or high-level chronic exposure being cardiodepressive while low level exposure produces 

enhanced contractility). 

The two invited discussants, Goyer and Johns, 

wrapped up the session. Goyer, a pathologist well 

known for his studies of ultrastructural and chemical 

changes in metal nephrotoxicity, indicated that from 

his viewpoint, blood lead levels resulting from lower 

doses of lead will not be reflected in renal lead concentration in rats of more than 2 to 3 ug/g. Pathological changes in the kidney are usually not 

observable until the renal concentration exceeds 10 to 

15 ug/g. At the high levels of exposure, there are 

measurable changes in intracellular calcium that are 

so severe that the cells are unable to perform their 

functions. At this point, he would not expect to see any 

physiological response to pressor amines, changes in 

renin levels, or other regulatory systems. These levels of 

lead exposure are quite different from the exposure 

levels seen in the general population. For experimental 

studies, documentation of the range of blood lead 

associated with the range of observed blood pressures is 

needed. Finally, Goyer urged that researchers consider 

the essential metal content of the dietary regimen 

administered with the lead dose because the toxicity of 

a specific lead dose can vary 20-fold by reducing 

calcium content in the diet. Similar effects can be 

obtained by altering iron or zinc levels. Several other 

scientists indicated that the relative inconsistency 

between administered dose and blood lead level 

achieved should be considered when considering the 

effect or lack thereof on blood pressure. In addition, 

because the rat kidney accumulates much more lead 

for a particular blood level than do human kidneys, we 

need to determine lead concentration of other critical 

target organs (including vascular smooth and cardiac 

muscle, and juxtaglomerular cells) in order to determine which responds in parallel with blood lead. 

Johns proposed a number of critical experiments to 

understand how lead may be affecting blood pressure 

and whether blood pressure changes can be reversed by 

removing lead from the diet. Inhibitors of angiotensin converting enzyme should be tried to determine if this prevents the pressure increase during lead 

exposure. Levels of intracellular calcium should be 

measured and calcium or potassium channel blockers 

might reduce the effects of lead. 

The discussion of the last few minutes of this session 

delved into why some experimental differences in 

blood pressure were so much greater than seen by other 

investigators (for example, the 50 mm Hg increase seen 

by the Italian scientists). Are we actually dealing with a 

model that is analogous to the human situation, or do 

we need to determine an animal model that demonstrates only a few millimeters of mercury increase in 

blood pressure which is attributable to lead exposure? 

There were two sessions devoted to mostly unpublished studies. Some of these are to be found elsewhere 

in this volume; the main findings coming from the 

other studies will be summarized here for sake of 

completeness. 

H. Perry (Washington University School of Medicine, St. Louis) presented new findings on low-level 

lead exposure in experimental animals. He noted that 

in a pilot experiment they found that if lead exposure 

was terminated for 2 months after a 6-month exposure, 

the 0.1 ppm lead-exposed rats became normotensive 

while the 5 ppm did not, and 1 ppm were between the 

two. In response to a question from Goyer, Perry gave 

the specific trace mineral components of the rat chow 

used. Several audience members tried to evaluate these 

lead doses with respect to that seen in the human 

population. A calculation made by Wedeen illustrated 

the total amount the rat ingests is of the same order as 

the human body burden over a lifetime. Vander 

pointed out that the true lead burden in the rat is 

much lower because of the lower gastrointestinal 

absorption rate of lead in rats compared to humans, 

de Kort pointed out that when anesthetics are used to 

obtain blood pressures in animals, there may be an 

effect of lead on the effect of the anesthetic on blood 

pressure. Perry agreed and indicated that animals are 

currently studied without anesthetic (which results 

in higher control blood pressure measurements), but 

the levels seen in the metal-exposed animals are unchanged. In addition, there is more consistency in the 

readings and lower standard deviations. 

In the discussion following Gonick's talk, it was 

noted that accurate and sensitive methods for measuring plasma lead as theV important biological 

indicator of lead exposure are not available as yet. 

C. Morris (Oregon Health Sciences Center) informed the audience about the findings in a clinical 

trial with calcium supplementation in patients who 

had their blood lead and erythrocyte protoporphyrin 

(EPP) measured and blood pressure monitored. They 

found that, in spite of modest blood lead levels, there 

was a positive correlation between blood lead, EPP, and 

diastolic blood pressure. In addition, they believe that 

the blood pressure response that occurs with calcium 

supplementation is probably independent of changes 

in blood lead concentration. 

F. Hodgson (University of Pittsburgh) presented the 

paper originally expected to be given by Parkinson. 

Cross-sectional data from approximately 250 occupationally exposed U.S. workers and 170 controls were 

reanalyzed to examine the contribution of current, 

recent, and cumulative indicators of lead exposure to 

systolic and diastolic pressure. Only TWA 01Ilie' 

weighted average) lead exposure (which was collinea 

with age) was statistically significantly correlate^ 

with both systolic and diastolic blood pressure. None 

the indices of lead exposure accounted for more tn 

2% of the variance. This regression coefficient is fal • 

similar to that derived in the NHANES data. J 

Schwartz queried Elwood regarding the bI 

pressure data from the Caerphilly Study in that ^ 

values were higher than those obtained in the res 
DISCUSSION SUMMARY 149 

Wales. Elwood noted that the data from the Welsh 

Heart Program are standardized to age 40, while the 

Caerphi^y men had a mean age of 54. Their blood 

oressure values are appropriate for the age differences. 

Grandjean reported on a study of blood lead-blood 

pressure relationships with alcohol consumption and 

hemoglobin values as confounders. The population 

studied was approximately iOOO men and women born 

in 1936 in 3.5 municipalities west of Copenhagen, 

Denmark, who were presumed to be representative of 

the entire country of Denmark. Blood lead was 

significantly associated with both systolic and 

diastolic pressures with a doubling of blood lead 

associated with an increase in blood pressure of 2 to 3 

mm Hg. Among several predictors, only blood hemoglobin and alcohol intake were true confounders. 

When taken into consideration in the regression 

analysis, all statistical significance was lost. There was 

also an association of blood lead with smoking; 

smoking is also an important risk factor for increased 

blood pressure. 

Kannel questioned the finding of a positive relationship between blood pressure and cigarette smoking, whereas most epidemiologic studies show an inverse relationship, i.e., those who smoke have somewhat lower blood pressures which may be attributable 

to lower relative weights among smokers. 

Grandjean responded to Kannel's question by indicating that smoking was treated as a discrete variable, 

categorized into five different groups and that smokers 

who smoke between 15 and 24 cigarettes per day actually had a lower blood pressure than did nonsmokers. 

Dustan questioned Grandjean's interpretation of the 

hemoglobin, blood lead-blood pressure association and 

questioned whether or not it was not possible that the 

causal chain was in the opposite direction, i.e., hypertensives tend to have lower blood plasma volumes and 

subsequently can have increased hematocrits. In that 

circumstance, the hemoglobin and hematocrit would 

be the explanation for the increased blood lead. 

Grandjean accepted that interpretation. 

Schwartz confirmed Kannel's observation and 

noted that there was a negative association between 

smoking and blood pressure in the NHANES II and 

that was present controlling for both body mass index 

and body fat. Smith questioned the nature of the univariate association between smoking and blood 

pressure prior to adjusting. Schwartz could not recall 

the association in the NHANES data. Kannel noted that 

it was negative in Framingham, i.e., that the negative 

univariate association was changed to a positive one 

after addition of the control variables. Schwartz also 

reported that in NHANES the hemoglobin did not 

seem to be responsible for the blood lead-blood pressure 

association, as stratifying by hemoglobin levels did 

not change the regression coefficient of blood pressure 

on blood- lead. Grandjean indicated that the association 

with smoking was complex in his study and blood 

pressure was higher among those who smoke between 

1 and 14 g of tobacco/day, whereas it was lower in those 

who smoke 15 to 24 g. 

Kromhout inquired about the association between 

change in blood lead and change in blood pressure. 

Grandjean did not have those data in a form available 

for presentation. Pocock requested information regarding regression coefficients rather than significance levels. Grandjean responded that the coefficients 

which approached statistical significance were positive 

and those that were not statistically significant were 

both positive and negative but very close to zero. 

Pocock questioned the evidence regarding alcohol 

consumption having an acute metabolic effect. 

Grandjean responded that this is based on an experimental study performed in Yugoslavia wherein a few 

"shots of ethanol" resulted in an increased blood lead 

level after a few hours. Thus, even if participants had 

had a 13-hr fast, there could be a residual metabolic 

effect of alcohol. Pocock questioned the statement that 

there is no lead in cigarettes and pointed out that he 

found relationships that persisted even after adjustment for alcohol consumption. Grandjean reported 

that studies of liver enzymes suggested underreporting of alcohol consumption, particularly in 

women in whom the correlation of smoking with 

blood lead persists after adjusting for alcohol intake, i.e., 

that there probably was underreporting of alcohol 

intake. Pocock continued questioning regarding the 

change in lead content of cigarettes in recent years. 

Grandjean reported that there was definitely a very 

high lead content 30 or 40 years ago; at the time, lead 

arsenate was used for spraying tobacco fields, a practice 

not followed any longer. Recent analyses have indicated there is much less lead in tobacco at present. Lilis 

commented on the exquisite control for age in 

Grandjean's study, which might be too narrow to be 

able to comprehensively assess any relationship between blood lead and hypertension. She requested more 

detail regarding the distribution of blood lead levels 

and systolic and diastolic blood pressure in Grandjean's study to permit comparison with other cohorts. 

Following the presentation by L. Neri (University of 

Ottawa, Canada), there was some discussion about the 

fact that the values for some blood lead measurements 

were so low that no parameter value was obtained. The 

authors tried several different methods to correct for 

these in the overall regression analysis. 

Beevers described studies performed in the city of 

Birmingham, an industrial city with workers occupationally exposed to lead. In 1976, Beevers published a 

report on these workers in which only a weak 

association between blood lead and blood pressure was 

found. In a new study, additional analyses and clinical measures have been obtained on approximately 

700 lead workers. No excess prevalence of hypertension 

was found in the lead workers. Workers with mean 

blood lead values of 33.6 ug/dL show a weak (r = 0.09), 

but statistically significant (p < 0.01), association 

between blood lead and blood pressure; this trend 
DISCUSSION SUMMARY 149 

. s Elwood noted that the data from the Welsh 

u rt Program are standardized to age 40, while the 

-philly men had a mean age of 54. Their blood 

ssure. values are appropriate for the age differences. 

'"Vrandjean reported on a study of blood lead-blood 

eSsure relationships with alcohol consumption and 

• jfmoglobin values as confounders. The population 

died wa s approximately 1000 men and women born 

? 1936 in 3.5 municipalities west of Copenhagen, 

Denmark, who were presumed to be representative of 

me entire country of Denmark. Blood lead was 

significantly associated with both systolic and 

diastolic pressures with a doubling of blood lead 

associated with an increase in blood pressure of 2 to 3 

mm Hg. Among several predictors, only blood hemoglobin and alcohol intake were true confounders. 

When taken into consideration in the regression 

analysis, all statistical significance was lost. There was 

a]so an association of blood lead with smoking; 

smoking is also an important risk factor for increased 

blood pressure. 

Kannel questioned the finding of a positive relationship between blood pressure and cigarette smoking, whereas most epidemiologic studies show an inverse relationship, i.e., those who smoke have somewhat lower blood pressures which may be attributable 

to lower relative weights among smokers. 

Grandjean responded to Kannel's question by indicating that smoking was treated as a discrete variable, 

categorized into five different groups and that smokers 

who smoke between 15 and 24 cigarettes per day actually had a lower blood pressure than did nonsmokers. 

Dustan questioned Grandjean's interpretation of the 

hemoglobin, blood lead-blood pressure association and 

questioned whether or not it was not possible that the 

causal chain was in the opposite direction, i.e., hypertensives tend to have lower blood plasma volumes and 

subsequently can have increased hematocrits. In that 

circumstance, the hemoglobin and hematocrit would 

be the explanation for the increased blood lead. 

Grandjean accepted that interpretation. 

Schwartz confirmed Kannel's observation and 

noted that there was a negative association between 

smoking and blood pressure in the NHANES II and 

that was present controlling for both body mass index 

and body fat. Smith questioned the nature of the univariate association between smoking and blood 

pressure prior to adjusting. Schwartz could not recall 

the association in the NHANES data. Kannel noted that 

it was negative in Framingham, i.e., that the negative 

univariate association was changed to a positive one 

after addition of the control variables. Schwartz also 

reported that in NHANES the hemoglobin did not 

seem to be responsible for the blood lead-blood pressure 

association, as stratifying by hemoglobin levels did 

not change the regression coefficient of blood pressure 

on blood lead. Grandjean indicated that the association 

with smoking was complex in his study and blood 

pressure was higher among those who smoke between 

1 and 14 g of tobacco/day, whereas it was lower in those 

who smoke 15 to 24 g. 

Kromhout inquired about the association between 

change in blood lead and change in blood pressure. 

Grandjean did not have those data in a form available 

for presentation. Pocock requested information regarding regression coefficients rather than significance levels. Grandjean responded that the coefficients 

which approached statistical significance were positive 

and those that were not statistically significant were 

both positive and negative but very close to zero. 

Pocock questioned the evidence regarding alcohol 

consumption having an acute metabolic effect. 

Grandjean responded that this is based on an experimental study performed in Yugoslavia wherein a few 

"shots of ethanol" resulted in an increased blood lead 

level after a few hours. Thus, even if participants had 

had a 13-hr fast, there could be a residual metabolic 

effect of alcohol. Pocock questioned the statement that 

there is no lead in cigarettes and pointed out that he 

found relationships that persisted even after adjustment for alcohol consumption. Grandjean reported 

that studies of liver enzymes suggested underreporting of alcohol consumption, particularly in 

women in whom the correlation of smoking with 

blood lead persists after adjusting for alcohol intake, i.e., 

that there probably was underreporting of alcohol 

intake. Pocock continued questioning regarding the 

change in lead content of cigarettes in recent years. 

Grandjean reported that there was definitely a very 

high lead content 30 or 40 years ago; at the time, lead 

arsenate was used for spraying tobacco fields, a practice 

not followed any longer. Recent analyses have indicated there is much less lead in tobacco at present. Lilis 

commented on the exquisite control for age in 

Grandjean's study, which might be too narrow to be 

able to comprehensively assess any relationship between blood lead and hypertension. She requested more 

detail regarding the distribution of blood lead levels 

and systolic and diastolic blood pressure in Grandjean's study to permit comparison with other cohorts. 

Following the presentation by L. Neri (University of 

Ottawa, Canada), there was some discussion about the 

fact that the values for some blood lead measurements 

were so low that no parameter value was obtained. The 

authors tried several different methods to correct for 

these in the overall regression analysis. 

Beevers described studies performed in the city of 

Birmingham, an industrial city with workers occupationally exposed to lead. In 1976, Beevers published a 

report on these workers in which only a weak 

association between blood lead and blood pressure was 

found. In a new study, additional analyses and clinical measures have been obtained on approximately 

700 lead workers. No excess prevalence of hypertension 

was found in the lead workers. Workers with mean 

blood lead values of 33.6 ug/dL show a weak (r = 0.09), 

but statistically significant [p < 0.01), association 

between blood lead and blood pressure; this trend 
150 VICTERYETAL. 

remained significant after analysis of covariance 

which took into account age, body mass index, and 

duration of lead exposure. No convincing relationship 

was found between blood lead and alcohol intake, but 

cigarette smokers did have higher blood lead levels 

than nonsmokers. There was no correlation between 

systolic or diastolic blood pressure and zinc protoporphyrin levels. In the comment period after this 

presentation, Boscolo indicated that it was very important to recognize that these workers were carefully 

monitored by their employer and that this was not 

always the case in factory settings. Hodgson reminded 

Beevers that in his original publication it appeared 

there might be a different (even negative) correlation 

between blood lead at high levels and blood pressure. 

Regression coefficients determined by dividing the 

blood lead range into four segments appeared to be 

different. Beevers had not done this in the present 

study but thought it would be helpful in additional 

analysis. Rosen asked if there appeared to be a relationship between blood pressure and length of exposure but 

Beevers said that they had not found this to be the case. 

The following discussion took place after D. Sharp's 

(University of California at Berkeley) presentation. 

Sharp questioned the inclusion of cigarette smoking 

in regression analyses if it is not related to blood pressure. Smoking can act as a vehicle for lead exposure. 

Similarly, even though there is some evidence that 

alcohol intake is related to increased blood pressure, 

there is even better evidence that alcohol can act as a 

vehicle for lead exposure. This may bias the blood leadblood pressure relationship toward zero by overcontrolling for lead exposure. Pocock responded that this 

has been an area of controversy and had it been 

excluded, he might have been accused of missing an 

important factor. Weiss indicated that, for a variable to 

be a confounder, it has to be associated both with the 

exposure and causally with the outcome variable. 

Pocock felt that the definition of a confounder and 

criteria of an appropriate covariate for inclusion in the 

model were two different things. He noted that among 

most of the studies presented there was a weak association between both smoking and alcohol and blood 

pressure. Since the blood lead-blood pressure association is weak and because the association of the covariates and the outcome variables vary among different 

data sets and are themselves weak, this might be one of 

the reasons why different results were being seen in 

different studies. 

Kannel noted that causal inference is the issue. He 

cited the analogy of overweight in relation to coronary 

disease, which disappeared as a risk factor when one 

took into account variables such as blood pressure, 

glucose, cholesterol, and uric acid. This, however, 

merely indicated links in the causal chain; as weight 

increased, the intervening variables left no variation 

to be explained by weight. He pointed out the necessity 

to keep the processes in mind when drawing causal 

inferences. 

Smith pointed out that the difficulty in interpretation relates to the research design. In the ideal 

model, one could determine the causal effects independent of each other. The difficulties with the experimental research relate to two factors; one, absence of 

hypotheses regarding the causal models and, second, 

in demographic survey research there is no unique 

model. 

Carter reported experiments in rats that indicated 

that rats with very high blood lead levels were the ones 

that ingested more alcohol and cautioned against the 

interpretation of cross-sectional associations of blood 

lead and alcohol consumption in terms of the causal 

direction. 

Schwartz declined to comment on whether people 

with higher blood lead values drink more or not. He 

commented that studies in humans show variability 

in the association of alcohol consumption with blood 

pressure. Similarly, there was variation among the 

studies between the relationship of blood lead and blood 

pressure. If alcohol is a source of lead, then the observational studies will be unable to distinguish the 

independent causal contribution of lead and alcohol to 

blood pressure. Pocock said that he did not see this as a 

major problem because alcohol remains a relatively 

minor source of lead. He noted that there are numerous individuals who are either nondrinkers or 

fairly light drinkers who still have measurable lead 

levels and that it was possible to treat these two as 

separable statistically and etiologically. 

Grandjean indicated that in his population a 

reported intake of two "shots" of alcohol per day was 

associated with an increase of blood leacLby about 1 

ug/dL, which was not insignificant. In the presence of 

a weak association, adjustment for alcohol may 

eliminate a blood lead-blood pressure association. He 

suggested, in prospective studies, that the cohorts be 

restricted to individuals who ingest just a certain 

amount of alcohol per day and can then be followed 

over time, i.e., for example, being measured when 

hired and then later as exposed lead workers. Ware 

pointed out that the animal experimental work 

indicated no influence of alcohol on absorption of lead 

and that, in his opinion, the question was how much 

lead there is in the alcoholic beverage. He suggested 

that this varies among studies performed in differen 

countries and that he did not believe that this was a 

significant question in this country. 

M. Velasquez (George Washington University; 

Washington, DC) questioned whether anyone ha 

studied the blood lead levels among a population °^ 

essential hypertensives and whether these wer 

different from the normal population. Further, 

questioned Kannel about the association of body ma -

index to blood pressure in the hypertensive

 ran ° j 

Kannel responded that the regression between bio 

pressure and weight appeared fairly linear, that 

regression between weight gain and change in bip 

pressure also appears to be quite linear and extends 

J 
r DISCUSSION SUMMARY 151 

P.15 

•he hypertensive range. Kannel disagreed with 

Velasquez's interpretation of a flattening of the blood 

oressure, body mass index relationship for blood 

nressures above 150 systolic or 90 diastolic mm Hg. 

Smith cited the use of standardized regression 

coefficients in the social science literature and questioned whether or not conversion of the NHANES data 

to that form might be a way of comparing association 

across studies and also within studies when controlling f°r

 °t n e r variables. There was no response to this 

suggestion. Gonick advanced an additional possible 

mechanism regarding alcohol. The diuresis associated 

with alcohol consumption could lead to hemoconcentration, increase the hemoglobin and therefore 

secondarily increase the measured total blood lead. He 

suggested that analyses should control for hemoglobin 

levels. 

Tyroler introduced the final session of the 

symposium and stated that it was planned to provide a 

synthesis and overview of the material presented at the 

symposium. The objectives of the symposium were to 

have the principal investigators review their published research and to have open discussions among 

them and the audience, and to present all identified 

ongoing relevant research that had not yet been 

published. An assembled panel of discussants were to 

synthesize the observational epidemiologic, clinical, 

and animal experimental materials. Questions that 

were to be considered included the following: What do 

we think the assembled information means? Is there 

an association between blood pressure and blood lead 

levels in epidemiologic studies? If there is, what is its 

strength and does it vary among subpopulations? 

Combined with the clinical and experimental observations, do we believe that there is an association 

which persists after controlling for potential confounders? Do we believe that it is causal? Insofar as 

those questions can not be answered definitively, additional research needs are to be identified. 

The summary that follows highlights the discussions in the order of their presentation. Considerable 

editing has been introduced; however, every effort was 

made to preserve the sense of the comments made and 

to convey the information presented without either an 

exhaustive or a literal recording of all comments. 

Although not listed as a discussant in the program, 

Pocock was called on to present a quantitative overview 

he had prepared of the effect measures derived from the 

different epidemiologic studies presented. The key 

elements of Pocock's overview analysis and his interpretation of them were incorporated into his manuscript, which has been included in these proceedings. 

In his summarization remarks presented during the 

overview discussion, Pocock suggested that the point 

estimate of the regression coefficient of blood pressure 

associated with blood lead and the confidence interval 

around- that estimate for each study indicated overlap 

among the various general population epidemiologic 

studies, with evidence of compatibility of estimates. It 

was his opinion that a zero increase in systolic blood 

pressure with a doubling of blood lead was not 

compatible with the overall data, nor was an increase of 

3 mm Hg in systolic blood pressure compatible. His 

impression was that a doubling of blood lead seemed 

associated with an increase of about 1 mm Hg in 

systolic blood pressure. Further, he felt that the understanding of and the control of confounding factors 

were quite different among studies and incomplete in 

some. He cited the example of alcohol and suggested 

that other confounding factors remained to be 

discovered and, obviously, adjustments for uniden-. 

tified factors can not have taken place in the observational studies reported to date. Although the 

overview was consistent with an association between 

blood lead and blood pressure, it was his impression 

that it was small in magnitude, weak in strength, and 

that the overall evidence did not permit an inference 

regarding a causal relationship between blood lead and 

blood pressure values. Following Pocock's remarks, the 

session heard from the planned panel discussants. 

Smith stated that he would play the role of devil's 

advocate and, despite his being impressed by the 

amount and quality of work reported, that his 

comments generally would be of a critical nature. In 

particular, he pointed out that the quantitative overview, which suggested a general trend of positive 

coefficients of the relationship of blood pressure to blood 

lead levels, was fraught with difficulties. The models 

used among the studies were for the most part 

different. The number and type of covariants included 

were not the same among the models used and the 

mathematical treatment of the variables included 

across models often varied; for example, the square of 

age was used in some studies and not in others. He 

suggested that although the use of these covariants 

might not make much difference in terms of the 

estimator, it could make a major difference in terms of 

confidence intervals. 

Smith called attention to the point of the implications of a policy decision to eliminate lead from gasoline focusing on new health outcomes based on 

alternative products. He emphasized the importance of 

this in the case of the relatively small effect associated 

with lead which the overview analysis had indicated. 

Smith pointed out some fundamental differences 

between the research designs used in experimental 

biologic research and the multivariate type measurements and analyses performed in the epidemiologic 

studies. He focused particularly on the need for more 

detailed analysis of the relationship of blood lead to 

blood pressure across the multiple NHANES study sites 

and inquired about the consistency of a positive 

association when this was done. He also raised the 

point of differences in the blood lead-blood pressure 

relationship among demographic subgroups, with the 

possibility of a negative association for women. 

Goyer presented an overview of a general nature 

regarding what he regarded as the two major objectives 

of experimental work: one was to confirm human 

observations and another to define mechanisms and 

i 

j 

! 
DISCUSSION SUMMARY 153 

data available, she was impressed with the striking 

finding that people who have died of lead nephropathy 

or

 have died of renal failure have not had secondary 

hypertension. For future research, she called for 

detailed analysis of the black examinees in the 

NHANES sample, noting the somewhat higher blood 

lead levels and well-known excess of hypertension in 

blacks. In these analyses/studies of serum creatinine 

might provide insight into whether or not hypertension in the black is kidney-related in either of two 

ways: one, the kidney as a victim of elevated pressure, 

and the other, the kidney as the culprit. 

Kannel presented a synthesis of the studies and a 

community perspective. He reviewed the rules of 

evidence in determining whether an observed 

association reflects a causal relationship. He noted 

consistency of results with a similarity of trends 

among population surveys, although in some 

instances the results were not statistically significant 

and other times when risk factors other than lead were 

not taken into account. He called for prospective studies 

on the predictive value of lead for subsequent 

hypertension and the need to study its effect on age 

trends in blood pressure over time. The strength of the 

blood lead-blood pressure relationship is rather weak 

and does not fulfill the usual criterion for causality. 

The weak association does not lead to a clear doseresponse relationship and the shape of the doseresponse curve is not known with certainty. There 

seems to be some loss of effect at higher or toxic doses of 

lead. If the relationship does hold at ambient levels of 

lead, this is of great public health importance owing to 

the large attributable risk and the modifiable nature of 

lead as a potential risk factor for hypertension. 

Although the effect seems to be independent, more data 

are needed concerning the associated cadmium and 

calcium intake and exploration for possible 

interactions should be carried out. The final criterion, 

biologic plausibility, is partially met. Although a 

number of possible mechanisms have been postulated, 

it is not clear from the evidence reviewed which are 

operative. In summary, Kannel suggested that the 

available information suggested a possible, but by no 

means certain, causal relationship; however, the public 

health implications are large in view of the current 

ubiquitous exposure, the effects of low-lead exposure on 

blood pressure, and the possibility of modification. 

Kannel felt that in terms of population research, 

there was a need for ongoing prospective studies to 

include blood lead in their next round of exams and 

then study prospectively the relationship to the trends 

in blood pressure over time. There will also be the 

opportunity to take advantage of areas with declining 

lead exposure and measure blood pressure before, 

during, and after change. Two particular deficiencies 

in the data available as identified by Kannel were those 

regarding information.on the association in women, 

where the effect seems to be less pronounced than for 

men, and the need for more information on the 

contribution of blood lead differences to the well-known 

black/white differences in blood pressure. 

In opening the general discussion, there were 

comments from Goyer, Smith, and Vander regarding 

the interpretation of epidemiologic findings compared 

with those derived from experimental work. Smith 

emphasized the point that the independent effect of one 

factor was not what was relevant to the human 

circumstance, but rather the potential for interaction of 

lead with other factors. This was agreed to by the 

experimentalists who had demonstrated positive 

interactive effects with cadmium and negative 

interactive effects with calcium. Schwartz elaborated 

on the point and suggested that this might explain 

why in Perry's experiments elevation in blood pressure was seen at lower doses of lead in contrast to 

Vander's experiments; one possibility is Perry may 

have had less calcium in the diet of his rats than was 

present in the experiments performed by Vander. 

Pocock indicated that he had blood cadmium measures on 7000 of the men in his studies and that 

cadmium did not seem related to blood pressure; however, he added he had not yet tested for interaction 

effects. Further, he pointed out that cigarette smoking 

is a major source of cadmium and that if cadmium 

were affecting blood pressure, one would expect a 

positive blood pressure smoking relationship which 

was not observed in his study, de Kort added that he 

too observed the absence of an association between 

cadmium and blood pressure in a small study of lead 

workers in the Netherlands. 

Kannel emphasized the desirability of performing 

animal experiments which have relevance to hypertension in humans, and this led to discussion of the 

desirability of study of exposures early in life. Vander 

advanced the idea of beginning animal experiments of 

this type based on lead exposure in utero. Wedeen 

returned to the question of the absence of hypertension 

in association with lead exposure in the presence of 

renal disease. He suspected that this follows from the 

epidemiologic ascertainment of the general population 

with normal pressure and blood-lead levels, and 

exclusion of diseased persons. He advanced the hypothesis that the massive overrepresentation of black 

males in dialysis units could be related to lead exposure 

in childhood combined with lower calcium intakes 

and the association with alcohol. 

Webb returned to the association of calcium with 

hypertension and pointed out that the evidence suggested that the problem was not so much one of concentration but regulation of the way calcium moves 

(flux) or activates contractile responses. He suggested 

that studies should be directed to regulation in terms 

of calcium interactions with lead. 

In response to a question that returned to the issue of 

the association of blood lead and blood pressure in 

blacks, Schwartz indicated that in some of his analyses, 

blood lead explains some of the black- excess in high 

blood pressure, but not all of it. Schwartz returned to 
P.17 

154 "V VICTERYETAL. 

the question raised by Smith regarding the issue of 

what replaced lead when it was to be removed from 

gasoline and he cited cost benefit analyses prepared for 

regulatory hearings. The possibility of some increase 

in emission of carcinogens, secondary to increases in 

the aromatic content and branching paraffins of 

gasoline, were estimated to result in markedly lower 

effects on health than those putatively associated with 

lead. J. Cole (ILZRO) asked the panel to discuss a comment that Schwartz made that a 1 mm Hg rise in blood 

pressure could be associated with a 1% increase in 

ischemic heart disease. Pocock stated that a 1% heart 

disease rate change was roughly that estimated to be 

associated with a 1 mm Hg change in blood pressure; 

•however, he argued that it was necessary to recognize 

two links in the chain of the argument, the lead blood 

pressure link and the blood pressure ischemic heart 

disease link. He suggested that the blood pressure 

ischemic heart disease link relates to the long-term 

pattern of blood pressure and its association with the 

risk of ischemic heart disease in late middle age, 

whereas the lead blood pressure association may be of a 

much more short-term nature and whether or not it 

reflects a chronic association is unknown. Tyroler and 

Kannel each advanced the idea that the human 

experimental data, i.e., the clinical trials evidence, 

clearly showed that lowering blood pressure decreases 

direct pressure related phenomena such as renal, 

cerebral, and congestive heart failure sequelae; however, clear evidence of efficacy of blood pressure 

reduction in prevention of atherosclerotic complications, such as ischemic heart disease, was not available. 

Mahaffey raised the question of the body burden of 

lead and asked what recommendations would be made 

to this end. Wedeen suggested that the measurement of 

bone stores of lead by in vivo X-ray fluorescence was an 

approach. Grandjean stated that his group has 

developed a method of analyzing lead in teeth using 

the lead level in circumpulpal dentine. There was some 

debate as to whether pulpal dentine or X-ray fluorescence was a more valid index of lead accumulated 

over a lifetime. Vander repeated a suggestion he had 

made regarding the possibility of estimating ultrafiltrable lead in plasma. Although theoretically ideal, 

he emphasized that it had been impossible in the past 

because of contamination, but that rigorous methodologic techniques, including absolutely ultraclean 

laboratory settings for determination, would make 

this feasible. He suggested also that isotopic equilibration of plasma with an isotope of lead, followed by 

ultrafiltration, might provide a technique applicable to 

large surveys. Grandjean pointed out that an additional reason for not using plasma lead other than the 

difficulty of its measurement is its marked variability 

with time and Bernard indicated that the half-life of 

plasma lead is only hours to perhaps a few days. \ 

S. Snedeker (NIEHS) expanded upon the implications of dealing with interactive effects of minerals\ 

She pointed out that this covers different levels o' 

research: the effect of calcium and other minerals on 

lead bioavailability and the lead body burden. These 

might be substantially different than the interactive 

effects of lead and calcium on tissue levels, such as 

vascular tissue or the kidney. Snedeker also pointed out 

that there are some subgroups that have not been discussed at length, in particular, women at the menopause. The release of calcium and the effects of hormone 

treatment were worthy of investigation since some 

preliminary data indicated a slightly higher blood 

lead-blood pressure slope in the 40- to 55-year age range 

with subsequent leveling off. Schwartz indicated that 

his group has a paper in manuscript suggesting that 

blood lead levels increase immediately after menopause 

and that a statistical interaction term for age suggests 

that they then decline and that this is similar to the 

pattern of calcium release after menopause following 

calcium mobilization from bone. 

A presentation and review of the design and plans 

for the National Health and Nutrition Examination 

Survey (NHANES) III were considered and served as a 

basis for discussion regarding studies that could be 

added to this survey to further elucidate the blood leadblood pressure relationship. 

S. Haynes (NCHS) described the plans for NHANES 

III. She indicated that with a sample size of 16,000 it 

would be larger than the previous two surveys. The 

plan is to start the survey in 1988 and to complete it by 

1994; however, estimates from the field will be available 

by 1991 for blacks and whites and at the end of the 6 

years for Mexican Americans and Puerto Ricans. 

Planning is moving forward to do a mortality followup of the population using the national death index. 

There also are plans to have a reexamination or 

reinterview of the NHANES III population, probably in 

1996. Among the elements of the examination, she 

mentioned a special kidney exam which will be more 

extensive than others previously done in the NHANES 

surveys to follow up persons at risk of kidney disease 

with special reexaminations for glomerular filtration 

rate in clinical centers. Wedeen pointed out that information could be derived from detailed analysis of 

serum creatinine and Haynes indicated that a manuscript was in preparation based on analyses of the 

serum creatinine values of NHANES II and that 

additional studies of their relationships to blood lead 

would be feasible by secondary analysis of these extant 

data. 

Haynes added that a home examination is to be 

added to the mobile unit survey. In this home surveylimited examinations will include blood pressures so 

that it will be "possible to iiave home blood pressures 

measures as well as clinic measures for the entir 

population. This will permit better definitions -

hypertension. In response to a question by Sffl"t • 

Haynes pointed out that detailed plans for analys^ 

have been developed in advance to identify the bas 

questions that need to he addressed following comp 

tion of this survey. Haynes also indicated that there 
P.18 

DISCUSSION SUMMARY 155 

a new philosophy at the National Center for Health 

Statistics in disseminating results. The first target is 

early publication in medical journals and following 

that, publication of the material in Center reports. In 

summary of the overall scope of the exam, excluding 

the environmental components, Haynes indicated that 

there will be an electrocardiogram, kidney exam, oral 

glucose tolerance test, hearing exam, visual and dental 

exams, a 24-hr diet recall, and a series of neurologic 

tests, measurement of height, weight, anthropometrics, 

body impedance, and bone densitometry to determine 

osteoporosis. 

G. Provenzano (U.S. EPA) summarized the EPA 

plans for measurement of environmental aspects 

within NHANES III. The exposure measurements will 

be based on estimation of exposure primarily in the 

home. These were ascertained by expanding the 

household interview to provide information on 

factors that affect indoor air quality, such as types of 

heating equipment, cooking equipment, size of indoor 

spaces, number of rooms, etc. The questionnaire 

information was to be supplemented by some indoor 

air monitoring, e.g., radon measurement. Tap water is 

to be analyzed for toxic and essential metals. In 

addition to environmental measurements, measurements of individuals are to be performed both to assess 

exposure and for effects estimation. Among the effects 

measurement, in addition to blood pressure, there will 

be a neurobehavioral test battery. The body measurements will include those determined from serum, 

whole blood, and urine and include a larger number 

of toxic metals and essential metals that were not 

measured in NHANES II. The final list of metals to be 

analyzed in addition to lead has not been determined, 

but will include cadmium, and most probably serum 

selenium, manganese, and aluminum, and urinary 

arsenic. Serum cotinine will be assessed to provide 

sensitive and objective evidence of exposure to tobacco 

smoke. Provenzano concluded with the posing of three 

types of questions relevant to the blood lead-blood 

pressure question. First, what laboratory analysis 

protocol should be used for measuring lead in blood in 

the NHANES III? Do we need increased sensitivity in 

view of the anticipated markedly lower blood lead levels 

in the early 1990s? Will we be able to detect low levels 

with appropriate precision and accuracy? Will it be 

possible to detect the shape of the dose response function 

at very low blood lead levels? Second, which covariates 

should be included in NHANES III? Despite the very 

long list available and analyzed in NHANES II, what 

other potential confounders were missing from 

NHANES II and should be added to the NHANES III? 

Finally, what are the recommendations for the techniques for blood pressure measurement in NHANES 

III. 

Schwartz reinforced Provenzano's comments 

regarding the anticipated much lower levels of blood 

lead in NHANES III and emphasized the need for more 

accurate and precise measurements of blood lead levels. 

Schwartz questioned whether there were going to be 

home dust samples analyzed for routes of exposure to 

metals other than drinking water. Provenzano 

indicated that the difficulties in sampling for metals 

made it unlikely that this would be attempted. 

Mahaffey emphasized the need to develop indices of 

integrated exposure to lead. Wedeen suggested that the 

estimation of bone density might provide techniques 

close to those used to measure bone lead. V. Bonar 

pointed out that there is considerable evidence that 

social variables are related both to blood pressure and 

blood lead and inquired regarding the measures of 

potential, social confounders in NHANES III. Lilis 

emphasized the importance of estimation of alcohol 

and smoking and added that these two plus water were 

major sources of lead exposure. 

Cole pointed out the limitations in the observational 

epidemiologic data available in the past and urged a 

systematic planned approach to NHANES III to 

contributeto the question of whether or not any 

observed association was causal. 

Tyroler notecKthat the morning's session began 

with an overview by^Rocock and asked Schwartz if he 

would conclude the session with his perspective On the 

overview of the blood pressut^jloj3d_Jea.d-relationship. 

Schwartz indicated that he generally agreed with 

Pocock's summarization, that is, that there is a broad 

consistency in the results across studies, that the 

coefficient relating blood lead to blood pressure on the 

log scale indicated that doubling of blood lead was 

associated with a 1 to 2 mm change in mercury. Thus, 

based on the epidemiologic data, he concluded that 

there is an association, it is not large in respect of the 

millimeters mercury explained, and the studies are 

consistently positively around that range. He 

disagreed with Pocock regarding the causal interpretation and suggested that although causal inferences could not readily be drawn from the epidemiologic data per se, that they were consistent with the 

animal data and that for the animal data it was not 

difficult to draw a causal inference. Information was 

emerging within the animal studies regarding 

mechanisms such as exaggerated alpha adrenergic 

responses, and disturbance of calcium metabolism and 

that similar mechanisms have been postulated for 

mild hypertension in humans. Based on these observations, Schwartz concluded that there is probably, 

although not definitively established, a causal relationship. Schwartz emphasized that lead is a controllable element in the environment and that removal of 

exposure early in life could prevent the emergence of 

elevated blood pressure, an approach much safer than 

that of treating elevated blood pressure after it had 

emerged.